A novel class of ectomycorrhiza-regulated cell wall polypeptides in Pisolithus tinctorius.
Development of the ectomycorrhizal symbiosis leads to the aggregation of fungal hyphae to form the mantle. To identify cell surface proteins involved in this developmental step, changes in the biosynthesis of fungal cell wall proteins were examined in Eucalyptus globulus-Pisolithus tinctorius ectomycorrhizas by two-dimensional polyacrylamide gel electrophoresis. Enhanced synthesis of several immunologically related fungal 31- and 32-kDa polypeptides, so-called symbiosis-regulated acidic polypeptides (SRAPs), was observed. Peptide sequences of SRAP32d were obtained after trypsin digestion. These peptides were found in the predicted sequence of six closely related fungal cDNAs coding for ectomycorrhiza up-regulated transcripts. The PtSRAP32 cDNAs represented about 10% of the differentially expressed cDNAs in ectomycorrhiza and are predicted to encode alanine-rich proteins of 28.2 kDa. There are no sequence homologies between SRAPs and previously identified proteins, but they contain the Arg-Gly-Asp (RGD) motif found in cell-adhesion proteins. SRAPs were observed on the hyphal surface by immunoelectron microscopy. They were also found in the host cell wall when P. tinctorius attached to the root surface. RNA blot analysis showed that the steady-state level of PtSRAP32 transcripts exhibited a drastic up-regulation when fungal hyphae form the mantle. These results suggest that SRAPs may form part of a cell-cell adhesion system needed for aggregation of hyphae in ectomycorrhizas.


Factors associated with outcome in unaided smoking cessation, and a comparison of those who have never tried to stop with those who have.
This survey set out to determine the factors associated with outcome of unaided smoking cessation attempts and to compare the characteristics of smokers who had tried to stop with those who had never tried. A postal questionnaire was sent to a random sample of 2000 adults in Aberdeen, Scotland. Those respondents who smoked or who were ex-smokers were sent a second questionnaire. The outcome measure for success in trying to stop smoking was abstinence for more than four months. Light and heavy smokers were more successful at smoking cessation than moderate smokers. Those who succeeded perceived that they had more social support than failures, and were more likely to have 'simply just stopped'. They were less likely to have used nicotine gum or to believe that smoking was harmful. Those who failed experienced more withdrawal symptoms, and were more likely to be tempted by the presence of others smoking. Eleven per cent of smokers had never tried to stop. These smokers were older and more dependent than those who had tried to stop. They were less likely to acknowledge the health risks of smoking or to conform to social pressures, but were more likely to consider stopping for financial reasons alone. Heavily dependent smokers may fare better in unaided cessation than the results of clinic-based research suggest. For those who have tried to stop, increasing motivation and social support, and minimizing withdrawal symptoms, may be more productive than further emphasis on health risks. Motivating smokers who have not previously tried to stop may involve more emphasis on the health risks of smoking and the health benefits of stopping, as well as on other non-financial benefits of stopping such as social acceptability. Fiscal measures may be particularly effective in motivating this group of smokers to try to stop.


MEF2D and MEF2C pathways disruption in sporadic and familial ALS patients.
Amyotrophic lateral sclerosis (ALS) is a progressive neuro-muscular disease characterized by motor neuron loss. MEF2D and MEF2C are members of the myocyte enhancer factor 2 family (MEF2), a group of transcription factors playing crucial roles both in muscle and in neural development and maintenance; for this reason, a possible involvement of MEF2 in ALS context has been investigated. Since the transcriptional activity of each tissue specific MEF2 isoform is conserved in different cell types, we chose to assess our parameters in an easily accessible and widely used experimental tool such as peripheral blood mononuclear cells (PBMCs) obtained from 30 sporadic ALS patients (sALS), 9 ALS patients with mutations in SOD1 gene (SOD1+) and 30 healthy controls. Gene expression analysis showed a significant up-regulation of MEF2D and MEF2C mRNA levels in both sporadic and SOD1+ ALS patients. Although protein levels were unchanged, a different pattern of distribution for MEF2D and MEF2C proteins was evidenced by immunohistochemistry in patients. A significant down-regulation of MEF2 downstream targets BDNF, KLF6 and RUFY3 was reported in both sALS and SOD1+ ALS patients, consistent with an altered MEF2 transcriptional activity. Furthermore, the potential regulatory effect of histone deacetylase 4 and 5 (HDAC4 and HDAC5) on MEF2D and MEF2C activity was also investigated. We found that MEF2D and HDAC4 colocalize in PBMC nuclei, while HDAC5 was localized in the cytoplasm. However, the unchanged HDACs localization and protein levels between sALS and controls seem to exclude their involvement in MEF2 altered function. In conclusion, our results show a systemic alteration of MEF2D and MEF2C pathways in both sporadic and SOD1+ ALS patients, underlying a possible common feature between the sporadic and the familial form of disease. Although further analyses in other neuromuscular diseases are needed to determine the specificity of changes in these pathways to ALS, measuring MEF2 alterations in accessible biofluids may be useful as biomarkers for disease diagnosis and progression.


Fluorescent mimetics of CMP-Neu5Ac are highly potent, cell-permeable polarization probes of eukaryotic and bacterial sialyltransferases and inhibit cellular sialylation.
Oligosaccharides of the glycolipids and glycoproteins at the outer membranes of human cells carry terminal neuraminic acids, which are responsible for recognition events and adhesion of cells, bacteria, and virus particles. The synthesis of neuraminic acid containing glycosides is accomplished by intracellular sialyl transferases. Therefore, the chemical manipulation of cellular sialylation could be very important to interfere with cancer development, inflammations, and infections. The development and applications of the first nanomolar fluorescent inhibitors of sialyl transferases are described herein. The obtained carbohydrate-nucleotide mimetics were found to bind all four commercially available and tested eukaryotic and bacterial sialyl transferases in a fluorescence polarization assay. Moreover, it was observed that the anionic mimetics intruded rapidly and efficiently into cells in vesicles and translocated to cellular organelles surrounding the nucleus of CHO cells. The new compounds inhibit cellular sialylation in two cell lines and open new perspectives for investigations of cellular sialylation.


The effect of hepatic regeneration on the expression of the glutathione S-transferases.
The effect of hepatic regeneration on expression of four glutathione S-transferase (GST) subunits (Ya, Yc, Yb1, Yb2) was examined in rats following partial hepatectomy (PH). mRNA levels of the Ya and Yc subunits (Alpha class) decreased and were 13% and 42% of levels in sham-operated animals respectively 12 h after surgery. mRNA levels for the Yb1 subunit (Mu class) also decreased but were not maximally reduced until 24 h after PH (22% of sham-treated level). mRNA levels of the Yb2 subunit were affected little by PH. Changes in levels of mRNA appeared to reflect a decrease in both transcriptional activity and mRNA stability. The decrease in mRNA levels was associated with a fall in enzymic activity and in protein levels of Alpha-class GSTs. Within 48 h of surgery, levels of mRNA, protein enzymic activity and transcriptional activity had all fully recovered. GSH levels also decreased in the first 6 h after PH. However, 24 h after surgery GSH levels in animals having undergone PH exceeded those in sham-treated animals by 2-fold and this difference persisted for 72 h. These findings suggest that during the early phases of hepatic regeneration, because of decreased GST and GSH levels, the liver may be unusually susceptible to injury by toxic compounds. However, by the first round of cell division (36-48 h post-surgery) the liver has fully recovered its ability to metabolize toxic electrophiles.


Value of chemotherapy post immunotherapy in stage IV non-small cell lung cancer (NSCLC).
Lung cancer is the number one cause of mortality among all types of cancer worldwide. Its treatment landscape has shifted from the classic chemotherapy alone to newer regimens based on the discovery of new immunotherapy and targeted therapy drugs. However, chemotherapy is still an option for treatment of advanced non-small cell lung cancer (NSCLC) after progression on immunotherapy alone or in combination with first-line chemotherapy. This is a retrospective study based on chart review of patients diagnosed with advanced NSCLC cases who received Docetaxel as second or third line after being treated by immunotherapy and/or chemotherapy in previous lines. The data was collected from the medical records of physicians' clinics in three different hospital centers in Lebanon over the period of 5 years from July 2015 until December 2020. February 2021 was data analysis cut off time. The main aim was to assess the role of Docetaxel post-chemoimmunotherapy for patients with diagnosed NSCLC. A total of 21 patients were included in this study. The majority of our patients were males (81%). As for histologic type, most patients had non-squamous lung cancer (67%) as compared to 33% who had squamous lung cancer. Overall, our study reported a 24% response rate to Docetaxel including stable disease and partial response and a median progression free survival (PFS) of 3 months. The mean time interval elapsed from diagnosis to the initiation of Docetaxel was 11.5 months. New therapeutic options should be validated for the treatment of NSCLC in the second and subsequent lines of therapy considering the poor prognosis of this disease. The chemotherapy in second and third line may keep an important role in the treatment after progression on newer agents, but it needs more evidence in prospective studies including a larger number of patients.


'I thought I was the only one': the misrecognition of LGBT youth in contemporary Vietnam.
While recent LGBT rights demonstrations and discussions about same-sex marriage have thrust the issue of homosexuality into the spotlight, it was not long ago that the issue of homosexuality was notable by its absence in Vietnam. Drawing on semi-structured interviews with young gay, lesbian and bisexual people in Vietnam's capital city Hanoi, this paper considers the increasing visibility of homosexuality through the theoretical lens of recognition, and illustrates the heterosexist misrecognition that LGBT young people have been subjected to in legislation, the media, their families, and through the education system. Drawing on the narratives of LGBT young people, the paper highlights the potentially negative impact such misrecognition may have on psychological and social wellbeing.


Advances in adjuvant chemotherapy for breast cancer: the role of taxanes.
The role of adjuvant chemotherapy in breast cancer is an area of intense clinical research. New agents are being evaluated with the hope that they will eradicate microscopic metastatic disease that may evolve into macroscopic systemic disease. The data emerging from clinical trials incorporating the taxanes before or after anthracycline-based chemotherapy (AC or FAC) are not yet mature to make a definite statement regarding their effect on the clinical endpoints. Numerous clinical trials have been completed that address the taxane issue and are awaiting analysis. Numerous other clinical trials in the United States and internationally are actively accruing patients. As the data from large clinical trials become available and the existing data from reported trials mature, a unifying understanding of the contribution that taxanes provide in the treatment of breast cancer will emerge.


Lyst mutation in mice recapitulates iris defects of human exfoliation syndrome.
Human eyes with exfoliation syndrome (XFS) exhibit a distinctive pattern of iris transillumination defects that are recapitulated in Lyst mutant mice carrying the beige allele. The purpose of this study was to determine the anatomic basis for Lyst-mediated transillumination defects, test whether Lyst mutant mice develop other features of XFS, and describe the molecular basis of the beige mutation. Lyst mutant mice and strain-matched controls were compared by clinical, histologic, immunohistochemical, and molecular genetic analyses. Slit-lamp examination showed that Lyst mutant mice uniformly exhibit XFS-like transillumination defects. Histologic analysis showed that these defects correlate with a sawtooth morphology of the iris pigment epithelium. Lyst mutant mice also produce an exfoliative-like material and exhibit pronounced pigment dispersion. Despite these insults, Lyst mutation does not cause increased intraocular pressure or optic nerve damage in the C57BL/6J genetic background. Sequence analysis identified that the beige mutation is predicted to delete a single isoleucine from the WD40 domain of the LYST protein, suggesting that this mutation is likely to disrupt a protein-protein interaction. Lyst mutant eyes exhibit multiple features of XFS. Recent human genetic association studies have identified changes occurring in the LOXL1 gene as an important risk factor for XFS but also indicated that other factors contributing to risk likely exist. These results demonstrated that mutation of the Lyst gene can produce ocular features of human XFS and suggested that LYST or LYST-interacting genes may contribute to XFS.


Small RNA and its application in andrology and urology.
Small non-coding RNAs such as small interfering RNA (siRNA), microRNA (miRNA) and piwi-interacting RNA (piRNA) exist in almost all kingdoms of organisms and have recently emerged as master regulators of gene expression to affect a diverse range of important biological processes. They exert their functions largely through two related but opposing mechanisms: RNA interference (RNAi) mediated by siRNA, miRNA and piRNA, and RNA activation (RNAa) mediated by small activating RNA (saRNA) and miRNA, leading to silencing and overexpression of target genes respectively. Dysregulation of these mechanisms have been implicated in a variety of human diseases including urological and andrological diseases. Importantly, both mechanisms can be readily harnessed for therapeutic purposes for a variety of diseases by using small RNA molecules as the "ribodrug". In this review, we highlight recent advances in the applications of small RNA as therapeutics for urological cancer, male infertile and erectile dysfunction.


Educating executive function.
Executive functions are thinking skills that assist with reasoning, planning, problem solving, and managing one's life. The brain areas that underlie these skills are interconnected with and influenced by activity in many different brain areas, some of which are associated with emotion and stress. One consequence of the stress-specific connections is that executive functions, which help us to organize our thinking, tend to be disrupted when stimulation is too high and we are stressed out, or too low when we are bored and lethargic. Given their central role in reasoning and also in managing stress and emotion, scientists have conducted studies, primarily with adults, to determine whether executive functions can be improved by training. By and large, results have shown that they can be, in part through computer-based videogame-like activities. Evidence of wider, more general benefits from such computer-based training, however, is mixed. Accordingly, scientists have reasoned that training will have wider benefits if it is implemented early, with very young children as the neural circuitry of executive functions is developing, and that it will be most effective if embedded in children's everyday activities. Evidence produced by this research, however, is also mixed. In sum, much remains to be learned about executive function training. Without question, however, continued research on this important topic will yield valuable information about cognitive development. WIREs Cogn Sci 2017, 8:e1403. doi: 10.1002/wcs.1403 For further resources related to this article, please visit the WIREs website.


Enhanced prokaryotic expression of dengue virus envelope protein.
To highlight the expression and purification of the recombinant dengue virus type-1 antigen exploiting the codon optimized full length envelope for increased yield in E. coli. A 6x His tag was inserted at the C terminus to facilitate purification. The purified protein was recognized in Western blot by Monoclonal antibody specific for the tag. The in vitro refolded recombinant protein was used to immunize mice for the development of hybridomas and also analyzed for its biological functionality with heparan sulfate binding assay. The polyclonal anti-sera from the immunized mice were found to recognize the envelope protein thereby establishing the immunogenicity of the protein. The purified envelope protein could potentially be used towards dengue diagnostics and vaccine development efforts. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Does the self-similar species distribution model lead to unrealistic predictions?
J. Harte et al. demonstrated that the power law form of the species-area relationship may be derived from a bisected, self-similar landscape and a community-level probability rule. Harte's self-similarity model has been widely applied in modeling species distributions. However, R. D. Maddux showed that this self-similarity model generates biologically unrealistic predictions. We resolve the Harte-Maddux debate by demonstrating that the problems identified by Maddux result from an assumption that the probability of occurrence of a species at one scale is independent of its probability of occurrence at the next. We refer to this as a "non-heritage assumption." By altering this assumption to one in which each species in the community has an occupancy status that is partially inherited across scales (a scale-heritage assumption), the predictions of the self-similarity model are neither mathematically inconsistent nor biologically unrealistic. Harte's self-similarity model remains an important framework for modeling species distributions. Our results illustrate the importance of considering patterns of species co-occurrence, and the way in which species occupancy patterns change with scale, when modeling species distributions.


Induction of apoptosis by fenretinide in tumor cell lines correlates with DLX2, DLX3 and DLX4 gene expression.
We investigated a possible relationship between apoptosis induction by fenretinide (4HPR) and the expression of a group of genes thought to be essential in morphogenesis and development, the DLX genes. We analyzed their expression under normal conditions or upon 4HPR stimulation in several tumor cell lines. We show that DLX2, DLX3 and DLX4 were expressed at higher levels in cell lines which where more sensitive to apoptotic induction, whereas DLX 5 and 6 appeared to segregate in a distinct functional compartment. Our data support the notion that DLX2, 3, 4 genes could participate in the control of 4HPR-mediated apoptosis, making them important molecules for the monitoring of therapy efficacy in cancer patients.


Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease.
The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.


Inhibition of Pythium spp. and Suppression of Pythium Blight of Turfgrasses with Phosphonate Fungicides.
Pythium aphanidermatum and other Pythium spp. cause Pythium blight of turfgrasses in the United States. Phosphonate fungicides suppress Pythium blight when applied preventatively, but efficacy may vary with product, rate and timing of application, and host species. The objectives of this study were to assess the inhibitory effects of phosphorous acid on Pythium spp. in vitro, and determine if active ingredient and formulation of phosphonate fungicides provide similar levels of Pythium blight suppression on perennial ryegrass and creeping bentgrass when applied at equivalent rates of phosphorous acid. Phosphorous acid EC50 values (effective concentration that reduces mycelial growth by 50%) for P. aphanidermatum isolates ranged from 35.6 to 171.8 μg/ml. EC50 values for isolates of six other Pythium spp. were between 38.7 and 220.8 μg/ml. In 2004 and 2005, all phosphonate treatments provided significant suppression of Pythium blight symptoms on creeping bentgrass and perennial ryegrass relative to the untreated control. No differences in percentage of blighted turf occurred among phosphonate treatments when applied at equivalent rates of phosphorous acid in either year of the study, regardless of active ingredient, formulation, or turfgrass species.


What if? The farther shores of neuroethics: commentary on "Neuroscience may supersede ethics and law".
Neuroscience is clearly making enormous progress toward understanding how human brains work. The implications of this progress for ethics, law, society, and culture are much less clear. Some have argued that neuroscience will lead to vast changes, superseding much of law and ethics. The likely limits to the explanatory power of neuroscience argue against that position, as do the limits to the social relevance of what neuroscience will be able to explain. At the same time neuroscience is likely to change societies through increasing their abilities to predict future behavior, to infer subjective mental states by observing physical brain states ("read minds"), to provide evidence in some cases relevant to criminal responsibility, to provide new ways to intervene to "treat antisocial brains," and to enhance healthy brains. Neuroscience should make important cultural changes in our special, and specially negative, views of "mental" versus "physical" illness by showing that mental illness is a dysfunction of a physical organ. It will not likely change our beliefs, implicit or explicit, in free will, or spark a new conflict between science and religion akin to the creationism controversy.


The Amazon River: A Major Source of Organic Plastic Additives to the Tropical North Atlantic?
The release of emerging organic contaminants is identified among the most critical hazards to the marine environment, and plastic additives have received growing attention due to their worldwide distribution and potential deleterious effects. Here, we report dissolved surface water concentrations of two important families of plastic additives (organophosphate esters (OPEs) and bisphenols) and other related organic compounds (perfluorinated chemicals) measured in the North Atlantic from Cape Verde to the West Indies. We found that OPEs were the most abundant contaminants, reaching remarkably high concentrations in open ocean waters (1200 km offshore of the American Coast, at the location of the Amazon river plume during the sampling period), with up to 1.3 μg L-1 (Σ9OPEs). A Lagrangian analysis confirmed that these high concentrations of contaminants originated from the Amazon River plume and were transported more than 3000 km by the North Brazil Current and its retroflection. We thus consider the Amazon River as a major source of organic contaminants of emerging concern to the tropical North Atlantic Ocean and suggest that medium-/long-range contaminant transport occurs, most certainly facilitated by the highly stratified conditions offered by the river plume.


The age of three Middle Palaeolithic sites: Single-grain optically stimulated luminescence chronologies for Pech de l'Azé I, II and IV in France.
Optically stimulated luminescence (OSL) measurements were made on individual, sand-sized grains of quartz from Middle Palaeolithic deposits at three sites (Pech de l'Azé I, II and IV) located close to one another in the Dordogne region of southwest France. We were able to calculate OSL ages for 69 samples collected from these three sites. These ages reveal periods of occupation between about 180 and 50 thousand years ago. Our single-grain OSL chronologies largely support previous age estimates obtained by thermoluminescence dating of burnt flints at Pech IV, electron spin resonance dating of tooth enamel at Pech I, II and IV and radiocarbon dating of bone at Pech I and IV, but provide a more complete picture due to the ubiquitous presence of sand-sized quartz grains used in OSL dating. These complete chronologies for the three sites have allowed us to compare the single-grain ages for similar lithic assemblages among the three sites, to test the correlations among them previously proposed by Bordes in the 1970s, and to construct our own correlative chronological framework for the three sites. This shows that similar lithic assemblages occur at around the same time, and that where a lithic assemblage is unique to one or found at two of the Pech sites, there are no deposits of chronologically equivalent age at the other Pech site(s). We interpret this to mean that, at least for these Pech de l'Azé sites, the Mousterian variants show temporal ordering. Whether or not this conclusion applies to the wider region and beyond, the hypothesis that Mousterian industrial variation is temporally ordered cannot be refuted at this time.


Developmental assays using invasive cane toads, Rhinella marina, reveal safety concerns of a common formulation of the rice herbicide, butachlor.
Identifying the adverse impacts of pesticide exposure is essential to guide regulations that are protective of wildlife and human health. Within rice ecosystems, amphibians are valuable indicators because pesticide applications coincide with sensitive reproductive and developmental life stages. We conducted two experiments using wild cane toads (Rhinella marina) to test 1) whether environmentally relevant exposure to a commercial formulation of butachlor, an acetanilide herbicide used extensively in rice, affects amphibian development and 2) whether cane toad tadpoles are capable of acclimatizing to sub-lethal exposure. First, we exposed wild cane toads to 0.002, 0.02, or 0.2 mg/L of butachlor (Machete EC), during distinct development stages (as eggs and hatchlings, as tadpoles, or continuously) for 12 days. Next, we exposed a subset of animals from the first experiment to a second, lethal concentration and examined survivorship. We found that cane toads exposed to butachlor developed slower and weighed less than controls, and that development of the thyroid gland was affected: exposed individuals had smaller thyroid glands and thyrocyte cells, and more individual follicles. Analyses of the transcriptome revealed that butachlor exposure resulted in downregulation of transcripts related to metabolic processes, anatomic structure development, immune system function, and response to stress. Last, we observed evidence of acclimatization, where animals exposed to butachlor early in life performed better than naïve animals during a second exposure. Our findings indicate that the commercial formulation of butachlor, Machete EC, causes thyroid endocrine disruption in vertebrates, and suggest that exposure in lowland irrigated rice fields presents a concern for wildlife and human health. Furthermore, we establish that developmental assays with cane toads can be used to screen for adverse effects of pesticides in rice fields.


The effect of aided language modeling on symbol comprehension and production in 2 preschoolers with autism.
The purpose of the present study was to examine the effectiveness of an instructional procedure called aided language modeling (ALM) on symbol comprehension and expression in 2 preschool children with autism who used few words functionally. ALM consists of engaging the child in interactive play activities and providing models of use of augmentative and alternative communication symbols during play. A multiple-baseline design across sets of symbol vocabulary was used with 2 children who had autism. Four vocabulary items were taught in each of 3 legs of the design, for each child. Both participants demonstrated increased symbol comprehension and elicited symbol production. In addition, both participants demonstrated that symbol comprehension and symbol production could be maintained. For both children, performance on symbol production lagged behind rate of responses on symbol comprehension. The current research presents preliminary evidence that a modeling intervention may be effective in increasing symbol comprehension and production, and may be an appropriate intervention strategy for some preschoolers with autism. Future research should continue to investigate this strategy and its effects on functional communication.


Cost-effective bandwidth-reduced Brillouin optical time domain reflectometry using a reference Brillouin scattering beam.
We propose a simple and cost-effective technique that can reduce the electrical bandwidth for Brillouin frequency-shift sensors with heterodyne detection without the need for expensive instruments or a complicated system. With this technique we use only a reference fiber. The reference Brillouin scattering light in the reference fiber is used as a local light for heterodyne detection. We confirm that this method can be used for measuring the Brillouin scattering spectrum distribution with a much lower frequency bandwidth (0.2 GHz) than that employed for conventional heterodyne detection (11 GHz). The method operates in a way similar to conventional Brillouin optical time domain reflectometry with comparable accuracy. Moreover, we successfully demonstrate temperature distribution sensing and show that we can compensate for temperature variation in the reference fiber.


Changes in the fish community of the Kpong Headpond, lower Volta River, Ghana after 25 years of impoundment.
The Kpong Headpond was the second created on the Volta River after Akosombo Dam, primarily as a source of hydroelectric power generation and potable water supply, and additionally, it has supported some fish production in Ghana since impoundment. The changes in fish community of the Kpong Headpond were studied to provide baseline information for strategies formulation to support the socio-economic development of the reservoir. The study identified changes in the fish community of the reservoir by comparing occurrence, composition, relative abundance and relative importance estimates of fish species, families and trophic groups, from available previous studies in the reservoir. From the collated information all fishes identified in the reservoir were categorised based on occurrence and importance as disappeared, appeared, permanent, declined or important, to show current status. The results indicated that the fish community has experienced a shift in the composition and relative abundance of important species, families and trophic groups in terms of number and weight, while remaining ecologically balanced. Representatives of the families Osteoglossidae, Centropomidae and Characidae have declined while representatives of the families Claroteidae, Cyprinidae and Cichlidae have increased. The aufwuch-detritus and herbivores declined while semi-pelagic omnivores increased resulting in a shift in dominance to benthic and semi pelagic omnivores. The appearance of five species and the disappearance of 25 others indicated a dynamic restructuring of the fish community in the reservoir, as expected. Enforcement of fishing regulations including the use of appropriate gear and fishing methods, fishery access control, promotion of culture-based fisheries and improvement in fisher education are recommended topics for sustainable fisheries in the reservoir.


Coelom formation: binary decision of the lateral plate mesoderm is controlled by the ectoderm.
Most triploblastic animals including vertebrates have a coelomic cavity that separates the outer and inner components of the body. The coelom is lined by two different tissue components, somatopleure and splanchnopleure, which are derived from the lateral plate region. Thus, the coelom is constructed as a result of a binary decision during early specification of the lateral plate. In this report we studied the molecular mechanisms of this binary decision. We first demonstrate that the splitting of the lateral plate into the two cell sheets progresses in an anteroposterior order and this progression is not coordinated with that of the somitic segmentation. By a series of embryological manipulations we found that young splanchnic mesoderm is still competent to be respecified as somatic mesoderm, and the ectoderm overlying the lateral plate is sufficient for this redirection. The lateral ectoderm is also required for maintenance of the somatic character of the mesoderm. Thus, the ectoderm plays at least two roles in the early subdivision of the lateral plate: specification and maintenance of the somatic mesoderm. We also show that the latter interactions are mediated by BMP molecules that are localized in the lateral ectoderm. Evolutionary aspects of the coelom formation are also considered.


Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus.
The large majority of patients with the autoimmune disease myasthenia gravis characteristically have detectable antibodies against the acetylcholine receptor (AChR). We used synthetic peptides to identify antibodies in sera of myasthenia gravis patients reactive with the human acetylcholine receptor (HuAChR) alpha-subunit, residues 160-167. Affinity purification of these antibodies, using the HuAChR alpha-subunit 157-170 peptide immobilized on thiopropyl-Sepharose, yielded IgG antibodies that bound to the native AChR and inhibited the binding of alpha-bungarotoxin to the receptor. The HuAChR alpha-subunit 160-167 peptide demonstrated specific immunological cross-reactivity with a shared homologous domain on herpes simplex virus glycoprotein D, residues 286-293, by both binding and inhibition studies. Thus, HuAChR alpha-subunit, residues 160-167, elicits antibodies in myasthenic patients that binds to the native AChR protein and is capable of eliciting a biologic effect. Immunologic cross-reactivity of this "self" epitope with herpes simplex virus suggest that this virus may be associated with the initiation of some cases of myasthenia.


Starvation and emotion regulation in anorexia nervosa.
Self-starvation, with concomitant weight loss, may serve as a dysfunctional behavior to attenuate negative affective states in anorexia nervosa (AN). A total of 91 participants composed of patients with acute AN, women recovered from AN, clinical controls with either depression or anxiety disorder, and healthy controls were tested on a measure of emotion regulation. Patients with acute AN as well as recovered patients with AN and clinical controls showed increased emotion regulation difficulties as compared with healthy controls. In patients with acute AN, a specific association between body weight and emotion regulation was found: the lower the body mass index in patients with acute AN, the lesser were their difficulties in emotion regulation. This association could only be found in the subsample of patients with acute AN but not in the control groups. Moreover, there were no confounding effects of depression or duration of illness. The findings are consistent with the hypothesis that self-starvation with accompanying low body weight serves as a dysfunctional behavior to regulate aversive emotions in AN.


Phenotypic clines, plasticity, and morphological trade-offs in an intertidal snail.
Understanding the genetic and environmental bases of phenotypic variation and how they covary on local and broad geographic scales is an important goal of evolutionary ecology. Such information can shed light on how organisms adapt to different and changing environments and how life-history trade-offs arise. Surveys of phenotypic variation in 25 Littorina obtusata populations across an approximately 400-km latitudinal gradient in the Gulf of Maine revealed pronounced clines. The shells of snails from northern habitats weighed less and were thinner and weaker in compression than those of conspecifics from southern habitats. In contrast, body size (as measured by soft tissue mass) followed an opposite pattern; northern snails weighed more than southern snails. A reciprocal transplant between a northern and southern habitat revealed substantial plasticity in shell form and body mass and their respective measures of growth. Southern snails transplanted to the northern habitat produced lighter, thinner shells and more body mass than controls raised in their native habitat. In contrast, northern snails transplanted to the southern site produced heavier, thicker shells and less body mass than controls raised in their native habitat. Patterns of final phenotypic variation for all traits were consistent with cogradient variation (i.e., a positive covariance between genetic and environmental influences). However, growth in shell traits followed a countergradient pattern (i.e., a negative covariance between genetic and environmental influences). Interestingly, body growth followed a cogradient pattern, which may reflect constraints imposed by cogradient variation in final shell size and thickness. This result suggests the existence of potential life-history trade-offs associated with increased shell production. Differences in L. obtusata shell form, body mass, and their respective measures of growth are likely induced by geographic differences in both water temperature and the abundance of an invading crab predator (Carcinus maenas). Water temperatures averaged 6.8 degrees C warmer during the transplant experiment and C. maenas abundance is greater in the southern Gulf of Maine. Because both increased water temperature and crab effluent affect shell form in the same way, future experiments are needed to determine the relative importance of each. Nevertheless, it is clear that phenotypic plasticity has an important role in producing geographic variation in L. obtusata shell form. Moreover, the evolution of phenotypic plasticity in L. obtusata and other marine gastropods may be driven by architectural constraints imposed by shell form on body mass and growth.


Nerve-induced remodeling of muscle basal lamina during synaptogenesis.
To identify mechanisms that regulate the deposition of the junctional basal lamina during synaptogenesis, immunocytochemical experiments were carried out on cultured nerve and muscle cells derived from Xenopus laevis embryos. In some experiments successive observations were made on individual muscle cells after pulse-labeling with a fluorescent monoclonal antibody specific for a basal lamina proteoglycan. In others, old and new proteoglycan molecules were differentially labeled with antibody conjugated to contrasting fluorochromes. These observations revealed that surface deposits of antibody-labeled proteoglycan remain morphologically stable for several days on developing muscle cells. Over the same period, however, new sites of proteoglycan accumulation formed that contained primarily those antigenic sites recently exposed at the cell surface. When muscle cells became innervated by cholinergic neurites, new proteoglycan accumulations were induced at the developing neuromuscular junctions, and these too were composed almost exclusively of recently deposited antigen. In older muscle cultures, where many cells possessed relatively high background concentrations of antigen over their surfaces, developing neuromuscular junctions initially showed a markedly reduced proteoglycan site-density compared with the adjacent, extrajunctional muscle surface. Much of this perineural region eventually became filled with dense, nerve induced proteoglycan plaques at later stages of synapse development. Motoneurons thus appear to have two, superficially paradoxical effects on muscle basal lamina organization. They first cause the removal of any existing, extrajunctional proteoglycan from the path of cell contact, and then induce the deposition of dense plaques of recently synthesized proteoglycan within the developing junctional basal lamina. This observation suggests that the proteolytic enzyme systems that have already been implicated in tissue remodeling may also contribute to the inductive interaction between nerve and muscle cells during synaptogenesis.


Long-term morbidity and mortality in patients without early complications after stroke or transient ischemic attack.
Secondary prevention after stroke and transient ischemic attack (TIA) has focused on high early risk of recurrence, but survivors of stroke can have substantial long-term morbidity and mortality. We quantified long-term morbidity and mortality for patients who had no early complications after stroke or TIA and community-based controls. This longitudinal case-control study included all ambulatory or hospitalized patients with stroke or TIA (discharged from regional stroke centres in Ontario from 2003 to 2013) who survived for 90 days without recurrent stroke, myocardial infarction, all-cause admission to hospital, admission to an institution or death. Cases and controls were matched on age, sex and geographic location. The primary composite outcome was death, stroke, myocardial infarction, or admission to long-term or continuing care. We calculated 1-, 3- and 5-year rates of composite and individual outcomes and used cause-specific Cox regression to estimate long-term hazards for cases versus controls and for patients with stroke versus those with TIA. Among patients who were initially stable after stroke or TIA (n = 26 366), the hazard of the primary outcome was more than double at 1 year (hazard ratio [HR] 2.4, 95% confidence interval [CI] 2.3-2.5), 3 years (HR 2.2, 95% CI 2.1-2.3) and 5 years (HR 2.1, 95% CI 2.1-2.2). Hazard was highest for recurrent stroke at 1 year (HR 6.8, 95% CI 6.1-7.5), continuing to 5 years (HR 5.1, 95% CI 4.8-5.5), and for admission to an institution (HR 2.1, 95% CI 1.9-2.2). Survivors of stroke had higher mortality and morbidity, but 31.5% (1789/5677) of patients with TIA experienced an adverse event within 5 years. Patients who survive stroke or TIA without early complications are typically discharged from secondary stroke prevention services. However, these patients remain at substantial long-term risk, particularly for recurrent stroke and admission to an institution. Novel approaches to prevention, potentially embedded in community or primary care, are required for long-term management of these initially stable but high-risk patients.


Teaching medical students about disability and rehabilitation: methods and student feedback.
The predicted increase in the prevalence of chronic and disabling diseases in the population over the next 30 years calls for a more effective approach to educating medical students about the assessment and management of disability. The introduction of a new postgraduate medical course at Flinders University of South Australia in 1996 allowed the development of a new topic on disability and rehabilitation. Over a 4-week period, students undertake four activities. First, they follow a particular patient in an inpatient rehabilitation setting and learn about the multidisciplinary approach to rehabilitation. Secondly, they each visit two people with a disability living in the community and assess their physical, mental, functional and social status. Thirdly, they each visit a service which supports those people in the community. Finally, they simulate having a disability which is randomly allocated to them. During these 4 weeks, students also participate in problem-based learning (PBL) and have 27 h of associated sessions or lectures. The PBL cases and associated sessions have a 'chronic disease' theme. We developed a questionnaire to obtain student feedback on this new topic in the first 2 years of its delivery. A 69% response rate has been obtained. Overall, the topic was well-received, and as a result most students felt more comfortable in dealing with disabled people. They were enthusiastic about ward work, and enjoyed learning about aspects of multidisciplinary team care. Exercises involving simulation of disability were largely acceptable. We believe that this topic helps our students to deal better with the problems of disabled people.


Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals.
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2 During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.


Insomnia and circadian misalignment: an underexplored interaction towards cardiometabolic risk.
Insomnia remains the most prevalent sleep disorder worldwide, and its pathophysiology suggests an interface with circadian rhythm sleep-wake disorders (CRSWDs). Some epidemiological studies have linked insomnia and circadian misalignment with adverse cardiometabolic outcomes, but the mechanisms underlying this relationship are still unclear. The autonomic nervous system (ANS) has been pointed out as a crucial/key mediator that triggers cardiometabolic risk. Therefore, a critical review of the literature focused on the past ten years was conducted to highlight the relationship between insomnia, circadian misalignment and cardiometabolic risk, with particular emphasis on the influence of the ANS. Shift work, as a model of circadian misalignment, was shown to increase both cardiovascular and metabolic risk and so may integrate a proof of concept on this link. Furthermore, there is good evidence from previous studies supporting that cardiac autonomic dysfunction is indeed a possible mechanism that potentiates cardiometabolic risk in insomniacs and individuals with a misalignment of the circadian timing system (e.g., shift workers), via changes in autonomic variables. Further research is however required in order to definitively establish this interactive relationship.


Local structural effects and related dynamics in supercritical ethanol. 2. Hydrogen-bonding network and its effect on single reorientational dynamics.
The local hydrogen-bonding (HB) network and its possible interconnection with the single reorientational dynamics in pure supercritical (sc) ethanol have been systematically investigated by employing molecular dynamics simulation techniques. The results obtained reveal a nonlinear density dependence of the calculated average number of hydrogen bonds n(HB), similar to that of the calculated coordination numbers N(c), signifying also the interrelation between the local HB network and the local density augmentation in sc ethanol. Additionally, the HB dynamics were investigated in terms of several appropriate time correlation functions. The results obtained reveal that the density dependence of HB dynamics has some similarities with local density and residence dynamics, corresponding to very short length scales. Moreover, the effect of mutual reorientation on HB dynamics seems to be more important than that of mutual diffusion. Finally, the reorientational dynamics of several intramolecular vectors of ethanol have been systematically studied. From the results obtained, we may observe that the dynamics of several reorientational modes in the molecule exhibit significant differences between them. Furthermore, the effect of the HB state of each molecule on these dynamics has also been studied, revealing significant differences, especially in the case of the dynamics of HB free molecules.


Assembly of the Caulobacter cell division machine.
Cytokinesis in Gram-negative bacteria is mediated by a multiprotein machine (the divisome) that invaginates and remodels the inner membrane, peptidoglycan and outer membrane. Understanding the order of divisome assembly would inform models of the interactions among its components and their respective functions. We leveraged the ability to isolate synchronous populations of Caulobacter crescentus cells to investigate assembly of the divisome and place the arrival of each component into functional context. Additionally, we investigated the genetic dependence of localization among divisome proteins and the cell cycle regulation of their transcript and protein levels to gain insight into the control mechanisms underlying their assembly. Our results revealed a picture of divisome assembly with unprecedented temporal resolution. Specifically, we observed (i) initial establishment of the division site, (ii) recruitment of early FtsZ-binding proteins, (iii) arrival of proteins involved in peptidoglycan remodelling, (iv) arrival of FtsA, (v) assembly of core divisome components, (vi) initiation of envelope invagination, (vii) recruitment of polar markers and cytoplasmic compartmentalization and (viii) cell separation. Our analysis revealed differences in divisome assembly among Caulobacter and other bacteria that establish a framework for identifying aspects of bacterial cytokinesis that are widely conserved from those that are more variable.


Temporal constraints of behavioral inhibition: relevance of inter-stimulus interval in a Go-Nogo task.
The capacity to inhibit prepotent and automatic responses is crucial for proper cognitive and social development, and inhibitory impairments have been considered to be key for some neuropsychiatric conditions. One of the most used paradigms to analyze inhibitory processes is the Go-Nogo task (GNG). This task has been widely used in psychophysical and cognitive EEG studies, and more recently in paradigms using fMRI. However, a technical limitation is that the time resolution of fMRI is poorer than that of the EEG technique. In order to compensate for these temporal constraints, it has become common practice in the fMRI field to use longer inter-stimulus intervals (ISI) than those used in EEG protocols. Despite the noticeable temporal differences between these two techniques, it is currently assumed that both approaches assess similar inhibitory processes. We performed an EEG study using a GNG task with both short ISI (fast-condition, FC, as in EEG protocols) and long ISI (slow-condition, SC, as in fMRI protocols). We found that in the FC there was a stronger Nogo-N2 effect than in the SC. Moreover, in the FC, but not in the SC, the number of preceding Go trials correlated positively with the Nogo-P3 amplitude and with the Go trial reaction time; and negatively with commission errors. In addition, we found significant topographical differences for the Go-P3 elicited in FC and SC, which is interpreted in terms of different neurotransmitter dynamics. Taken together, our results provide evidence that frequency of stimulus presentation in the GNG task strongly modulates the behavioral response and the evoked EEG activity. Therefore, it is likely that short-ISI EEG protocols and long-ISI fMRI protocols do not assess equivalent inhibitory processes.


Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies.
CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.


Magneto-vibratory separation of glass and bronze granular mixtures immersed in a paramagnetic liquid.
A fluid-immersed granular mixture may spontaneously separate when subjected to vertical vibration, separation occurring when the ratio of particle inertia to fluid drag is sufficiently different between the component species of the mixture. Here, we describe how fluid-driven separation is influenced by magneto-Archimedes buoyancy, the additional buoyancy force experienced by a body immersed in a paramagnetic fluid when a strong inhomogeneous magnetic field is applied. In our experiments glass and bronze mixtures immersed in paramagnetic aqueous solutions of MnCl2 have been subjected to sinusoidal vertical vibration. In the absence of a magnetic field the separation is similar to that observed when the interstitial fluid is water. However, at modest applied magnetic fields, magneto-Archimedes buoyancy may balance the inertia/fluid-drag separation mechanism, or it may dominate the separation process. We identify the vibratory and magnetic conditions for four granular configurations, each having distinctive granular convection. Abrupt transitions between these states occur at well-defined values of the magnetic and vibrational parameters. In order to gain insight into the dynamics of the separation process we use computer simulations based on solutions of the Navier-Stokes' equations. The simulations reproduce the experimental results revealing the important role of convection and gap formation in the stability of the different states.


MultiLog: a tool for the control and output merging of multiple logging applications.
MultiLog is a logging tool that controls, gathers, and combines the output, on-the-fly, from existing research and commercial logging applications or "loggers." Loggers record a specific set of user actions on a computing device, helping researchers to better understand environments or interactions, guiding the design of new or improved interfaces and applications. MultiLog reduces researchers' required implementation effort by simplifying the set-up of multiple loggers and seamlessly combining their output. This in turn increases the availability of logging systems to non-technical experimenters for both short-term and longitudinal observation studies. MultiLog supports two operating modes: "researcher mode" where experimenters configure multiple logging systems, and "deployment mode" where the system is deployed to user-study participants' systems. Researcher mode allows researchers to install, configure log filtering and obfuscation, observe near real-time event streams, and save configuration files ready for deployment. Deployment mode simplifies data collection from multiple loggers by running in the system tray at user log-in, starting loggers, combining their output, and securely uploading the data to a web-server. It also supports real-time browsing of log data, pausing of logging, and removal of log lines. Performance evaluations show that MultiLog does not adversely affect system performance, even when simultaneously running several logging systems. Initial studies show the system runs reliably over a period of 10 weeks.


MVApp-Multivariate Analysis Application for Streamlined Data Analysis and Curation.
Modern phenotyping techniques yield vast amounts of data that are challenging to manage and analyze. When thoroughly examined, this type of data can reveal genotype-to-phenotype relationships and meaningful connections among individual traits. However, efficient data mining is challenging for experimental biologists with limited training in curating, integrating, and exploring complex datasets. Additionally, data transparency, accessibility, and reproducibility are important considerations for scientific publication. The need for a streamlined, user-friendly pipeline for advanced phenotypic data analysis is pressing. In this article we present an open-source, online platform for multivariate analysis (MVApp), which serves as an interactive pipeline for data curation, in-depth analysis, and customized visualization. MVApp builds on the available R-packages and adds extra functionalities to enhance the interpretability of the results. The modular design of the MVApp allows for flexible analysis of various data structures and includes tools underexplored in phenotypic data analysis, such as clustering and quantile regression. MVApp aims to enhance findable, accessible, interoperable, and reproducible data transparency, streamline data curation and analysis, and increase statistical literacy among the scientific community.


Animal carcinogenicity studies: 1. Poor human predictivity.
The regulation of human exposure to potentially carcinogenic chemicals constitutes society's most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation's International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors.


Differential dynamic and structural behavior of lipid-cholesterol domains in model membranes.
Changes in the cholesterol (Chol) content of biological membranes are known to alter the physicochemical properties of the lipid lamella and consequently the function of membrane-associated enzymes. To characterize these changes, we used steady-state and time resolved fluorescence spectroscopy and two photon-excitation microscopy techniques. The membrane systems were chosen according to the techniques that were used: large unilamellar vesicles (LUVs) for cuvette and giant unilamellar vesicles (GUVs) for microscopy measurements; they were prepared from dipalmitoyl phosphatidylcholine (DPPC) and dioctadecyl phosphatidylcholine (DOPC) in mixtures that are well known to form lipid domains. Two fluorescent probes, which insert into different regions of the bilayer, were selected: 1,6-diphenyl-1,3,5-hexatriene (DPH) was located at the deep hydrophobic core of the acyl chain regions and 2-dimethylamino-6-lauroylnaphthalene (Laurdan) at the hydrophilic-hydrophobic membrane interface. Our spectroscopy results show that (i) the changes induced by cholesterol in the deep hydrophobic phospholipid acyl chain domain are different from the ones observed in the superficial region of the hydrophilic-hydrophobic interface, and these changes depend on the state of the lamella and (ii) the incorporation of cholesterol into the lamella induces an increase in the orientation dynamics in the deep region of the phospholipid acyl chains with a corresponding decrease in the orientation at the region close to the polar lipid headgroups. The microscopy data from DOPC/DPPC/Chol GUVs using Laurdan generalized polarization (Laurdan GP) suggest that a high cholesterol content in the bilayer weakens the stability of the water hydrogen bond network and hence the stability of the liquid-ordered phase (Lo).


Costs of the 'Hartslag Limburg' community heart health intervention.
Little is known about the costs of community programmes to prevent cardiovascular diseases. The present study calculated the economic costs of all interventions within a Dutch community programme called Hartslag Limburg, in such a way as to facilitate generalisation to other countries. It also calculated the difference between the economic costs and the costs incurred by the coordinating institution. Hartslag Limburg was a large-scale community programme that consisted of many interventions to prevent cardiovascular diseases. The target population consisted of all inhabitants of the region (n = 180.000). Special attention was paid to reach persons with a low socio-economic status. Costs were calculated using the guidelines for economic evaluation in health care. An overview of the material and staffing input involved was drawn up for every single intervention, and volume components were attached to each intervention component. These data were gathered during to the implementation of the intervention. Finally, the input was valued, using Dutch price levels for 2004. The economic costs of the interventions that were implemented within the five-year community programme (n = 180,000) were calculated to be about euro900,000. euro555,000 was spent on interventions to change people's exercise patterns, euro250,000 on improving nutrition, euro50,000 on smoking cessation, and euro45,000 on lifestyle in general. The coordinating agency contributed about 10% to the costs of the interventions. Other institutions that were part of the programme's network and external subsidy providers contributed the other 90% of the costs. The current study calculated the costs of a community programme in a detailed and systematic way, allowing the costs to be easily adapted to other countries and regions. The study further showed that the difference between economic costs and the costs incurred by the coordinating agency can be very large. Cost sharing was facilitated by the unique approach used in the Hartslag Limburg programme.


The Association between Prebiotic Fiber Supplement Use and Colorectal Cancer Risk and Mortality in the Women's Health Initiative.
Fiber-based prebiotic supplements are marketed for maintaining bowel health and promoting beneficial gut bacteria. However, the association between prebiotic supplement use and colorectal cancer risk and mortality is unknown. The association between prebiotic use and colorectal cancer risk and mortality was evaluated in postmenopausal women in the Women's Health Initiative study. Self-reported prebiotic use was documented at study enrollment. Adjudicated colorectal cancer cases and mortality were captured using medical and death records. Cox proportional hazards models were used to estimate the HR related to prebiotic use and colorectal cancer risk and mortality. In total, 3,032 colorectal cancer cases were diagnosed during an average 15.4 years of follow-up. Overall, 3.7% of women used a prebiotic with psyllium, the major fiber type. Use of any prebiotic supplement was not associated with colorectal cancer risk or mortality. The type of prebiotic supplement (none vs. insoluble or soluble) was not associated with colorectal cancer risk; however, use of insoluble fiber prebiotics compared with none was associated with higher colorectal cancer mortality [HR, 2.79; 95% confidence interval (CI), 1.32-5.90; P = 0.007]. Likelihood ratio tests indicated no significant interactions between prebiotic use and other colorectal cancer risk factors, including metabolic syndrome. Prebiotic fiber supplement use was not associated with colorectal cancer risk. Insoluble, but not soluble, prebiotic fiber use was associated with higher colorectal cancer mortality. These findings do not support the promotion of prebiotic fiber supplements to reduce colorectal cancer risk or colorectal cancer mortality. Further investigation is warranted for findings regarding insoluble prebiotic fiber and higher colorectal cancer mortality in postmenopausal women.


An entropy-based analysis of lane changing behavior: An interactive approach.
As a novelty, this article proposes the nonadditive entropy framework for the description of driver behaviors during lane changing. The authors also state that this entropy framework governs the lane changing behavior in traffic flow in accordance with the long-range vehicular interactions and traffic safety. The nonadditive entropy framework is the new generalized theory of thermostatistical mechanics. Vehicular interactions during lane changing are considered within this framework. The interactive approach for the lane changing behavior of the drivers is presented in the traffic flow scenarios presented in the article. According to the traffic flow scenarios, 4 categories of traffic flow and driver behaviors are obtained. Through the scenarios, comparative analyses of nonadditive and additive entropy domains are also provided. Two quadrants of the categories belong to the nonadditive entropy; the rest are involved in the additive entropy domain. Driving behaviors are extracted and the scenarios depict that nonadditivity matches safe driving well, whereas additivity corresponds to unsafe driving. Furthermore, the cooperative traffic system is considered in nonadditivity where the long-range interactions are present. However, the uncooperative traffic system falls into the additivity domain. The analyses also state that there would be possible traffic flow transitions among the quadrants. This article shows that lane changing behavior could be generalized as nonadditive, with additivity as a special case, based on the given traffic conditions. The nearest and close neighbor models are well within the conventional additive entropy framework. In this article, both the long-range vehicular interactions and safe driving behavior in traffic are handled in the nonadditive entropy domain. It is also inferred that the Tsallis entropy region would correspond to mandatory lane changing behavior, whereas additive and either the extensive or nonextensive entropy region would match discretionary lane changing behavior. This article states that driver behaviors would be in the nonadditive entropy domain to provide a safe traffic stream and hence with vehicle accident prevention in mind.


Pds1p is required for meiotic recombination and prophase I progression in Saccharomyces cerevisiae.
Sister-chromatid separation at the metaphase-anaphase transition is regulated by a proteolytic cascade. Destruction of the securin Pds1p liberates the Esp1p separase, which ultimately targets the mitotic cohesin Mcd1p/Scc1p for destruction. Pds1p stabilization by the spindle or DNA damage checkpoints prevents sister-chromatid separation while mutants lacking PDS1 (pds1Delta) are temperature sensitive for growth due to elevated chromosome loss. This report examined the role of the budding yeast Pds1p in meiotic progression using genetic, cytological, and biochemical assays. Similar to its mitotic function, Pds1p destruction is required for metaphase I-anaphase I transition. However, even at the permissive temperature for growth, pds1Delta mutants arrest with prophase I spindle and nuclear characteristics. This arrest was partially suppressed by preventing recombination initiation or by inactivating a subset of recombination checkpoint components. Further studies revealed that Pds1p is required for recombination in both double-strand-break formation and synaptonemal complex assembly. Although deleting PDS1 did not affect the degradation of the meiotic cohesin Rec8p, Mcd1p was precociously destroyed as cells entered the meiotic program. This role is meiosis specific as Mcd1p destruction is not altered in vegetative pds1Delta cultures. These results define a previously undescribed role for Pds1p in cohesin maintenance, recombination, and meiotic progression.


Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study.
Staging of non-small cell lung cancer (NSCLC) is important for determining choice of treatment and prognosis. The accuracy of FDG-PET scans for staging of lymph nodes is too low to replace invasive nodal staging. It is unknown whether the accuracy of integrated FDG-PET/CT scanning makes invasive staging redundant. In a prospective study, the mediastinal and/or hilar lymph nodes in patients with proven NSCLC were investigated with integrated FDG-PET/CT scanning. Pathological confirmation of all suspect lymph nodes was obtained to calculate the accuracy of the fusion images. In addition, the use of the standardised uptake value (SUV) in the staging of intrathoracic lymph nodes was analysed. 105 intrathoracic lymph node stations from 52 patients with NSCLC were characterised. The prevalence of malignancy in the lymph nodes was 36%. The sensitivity of the integrated FDG-PET/CT scan to detect malignant lymph nodes was 84% and its specificity was 85% (positive likelihood ratio 5.64, negative likelihood ratio 0.19). SUV(max), SUV(mean) and the SUV(max)/SUV(liver) ratio were all significantly higher in malignant than in benign lymph nodes. The area under the receiver operating curve did not differ between these three quantitative variables, but the highest accuracy was found with the SUV(max)/SUV(liver) ratio. At a cut-off value of 1.5 for the SUV(max)/SUV(liver )ratio, the sensitivity and specificity to detect malignant lymph node invasion were 82% and 93%, respectively. The accuracy of integrated FDG-PET/CT scanning is too low to replace invasive intrathoracic lymph node staging in patients with NSCLC. The visual interpretation of the fusion images of the integrated FDG-PET/CT scan can be replaced by the quantitative variable SUV(max)/SUV(liver) without loss of accuracy for intrathoracic lymph node staging.


Mapping the scope of occupational therapy practice in palliative care: A European Association for Palliative Care cross-sectional survey.
Occupational therapists play an integral role in the care of people with life-limiting illnesses. However, little is known about the scope of occupational therapy service provision in palliative care across Europe and factors influencing service delivery. This study aimed to map the scope of occupational therapy palliative care interventions across Europe and to explore occupational therapists' perceptions of opportunities and challenges when delivering and developing palliative care services. A 49-item online cross-sectional survey comprised of fixed and free text responses was securely hosted via the European Association for Palliative Care website. Survey design, content and recruitment processes were reviewed and formally approved by the European Association for Palliative Care Board of Directors. Descriptive statistics and thematic analysis were used to analyse data. Setting/respondents: Respondents were European occupational therapists whose caseload included palliative care recipients (full-time or part-time). In total, 237 valid responses were analysed. Findings demonstrated a consistency in occupational therapy practice in palliative care between European countries. Clinician time was prioritised towards indirect patient care, with limited involvement in service development, leadership and research. A need for undergraduate and postgraduate education was identified. Organisational expectations and understanding of the scope of the occupational therapy role constrain the delivery of services to support patients and carers. Further development of occupational therapy in palliative care, particularly capacity building in leadership and research activities, is warranted. There is a need for continuing education and awareness raising of the role of occupational therapy in palliative care.


On psychoanalytic writing.
Analytic writing constitutes a literary genre of its own. It involves the linking of an analytic idea (developed in a scholarly manner) with an analytic experience created in the medium of language. What makes this literary genre so demanding is that experience--including analytic experience--does not come to us in words. This fact generates a paradox that lies at the core of analytic writing: analytic experience (which cannot be said or written) must be transformed into 'fiction' (an imaginative rendering of experience in words) in order to convey to the reader something of what is true to the emotional experience that the analyst had with the patient. The author discusses a clinical passage from one of his recently published papers in an effort to demonstrate some of the conscious and unconscious thinking that goes into his writing. He then looks closely at the way the language works in a successful piece of theoretical analytic writing. The paper concludes with a discussion of a number of facets of the author s experience with analytic writing including the psychological 'state of writing', which is at once a meditation and a wrestling match with language; experimenting with the form (structure) of an analytic essay; and the question of originality in analytic writing.


Interventricular septum hematoma during cineventriculography.
Intraseptal hematoma and subsequent myocardial infarction due to accidental contrast agent deposition complicating diagnostic cineventriculography is a previously undescribed complication of angiography. A 61 year old man was admitted at intensive care unit because of unstable angina pectoris 1 hour after coronary angiography. Transthoracic contrast echocardiography showed a non-perfused area in the middle of interventricular septum with an increase of thickening up to 26 mm. Review of cineventriculography revealed contrast enhancement in the interventricular septum after contrast medium injection and a dislocation of the pigtail catheter tip. Follow up by echocardiography and MRI showed, that intramural hematoma has resolved after 6 weeks. After 8 weeks successful stent implantation in LAD was performed and after 6 month the patient had a normal LV-function without ischemic signs or septal thickening demonstrated by stressechocardiography. A safe and mobile position of the pigtail catheter during ventriculography in the middle of the LV cavity should be ensured to avoid this potentially life-threatening complication. For assessment and absolute measurement of intramural hematoma contrast-enhanced echocardiography is more feasible than MRI and makes interchangeable results.


Combined ECG, Echocardiographic, and Biomarker Criteria for Diagnosing Acute Myocardial Infarction in Out-of-Hospital Cardiac Arrest Patients.
Acute coronary lesions commonly trigger out-of-hospital cardiac arrest (OHCA). However, the prevalence of coronary artery disease (CAD) in Asian patients with OHCA and whether electrocardiogram (ECG) and other findings might predict acute myocardial infarction (AMI) have not been fully elucidated. Of 284 consecutive resuscitated OHCA patients seen between January 2006 and July 2013, we enrolled 135 patients who had undergone coronary evaluation. ECGs, echocardiography, and biomarkers were compared between patients with or without CAD. We included 135 consecutive patients aged 54 years (interquartile range 45-65) with sustained return of spontaneous circulation after OHCA between 2006 and 2012. Sixty six (45%) patients had CAD. The initial rhythm was shockable and non-shockable in 110 (81%) and 25 (19%) patients, respectively. ST-segment elevation predicted CAD with 42% sensitivity, 87% specificity, and 65% accuracy. ST elevation and/or regional wall motion abnormality (RWMA) showed 68% sensitivity, 52% specificity, and 70% accuracy in the prediction of CAD. Finally, a combination of ST elevation and/or RWMA and/or troponin T elevation predicted CAD with 94% sensitivity, 17% specificity, and 55% accuracy. In patients with OHCA without obvious non-cardiac causes, selection for coronary angiogram based on the combined criterion could detect 94% of CADs. However, compared with ECG only criteria, the combined criterion failed to improve diagnostic accuracy with a lower specificity.


Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1.
To examine the risk of anti-cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region. A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA-DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA-DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA-DRB1 alleles were evaluated using the likelihood ratio test. Significant associations were found for 9 SNPs (smallest P value being 2.4x10(-8)) and in 4 HLA-DRB1 alleles (smallest P value being 2.0x10(-10) in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9x10(-11)). Risks among SE and non-SE alleles were significantly heterogeneous (P=0.0095 and P=9.8x10(-9), respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44-2.79], P=2.6x10(-5)). Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA-DRB1 was confirmed.


Biochemical and Structural Characterization of a Schiff Base in the Radical-Mediated Biosynthesis of 4-Demethylwyosine by TYW1.
TYW1 is a radical S-adenosyl-l-methionine (SAM) enzyme that catalyzes the condensation of pyruvate and N-methylguanosine to form the posttranscriptional modification, 4-demethylwyosine, in situ on transfer RNA (tRNA). Two mechanisms have been proposed for this transformation, with one of the possible mechanisms invoking a Schiff base intermediate formed between a conserved lysine residue and pyruvate. Utilizing a combination of mass spectrometry and X-ray crystallography, we have obtained evidence to support the formation of a Schiff base lysine adduct in TYW1. When 13C labeled pyruvate is used, the mass shift of the adduct matches that of the labeled pyruvate, indicating that pyruvate is the source of the adduct. Furthermore, a crystal structure of TYW1 provides visualization of the Schiff base lysine-pyruvate adduct, which is positioned directly adjacent to the auxiliary [4Fe-4S] cluster. The adduct coordinates the unique iron of the auxiliary cluster through the lysine nitrogen and a carboxylate oxygen, reminiscent of how the radical SAM [4Fe-4S] cluster is coordinated by SAM. The structure provides insight into the binding site for tRNA and further suggests how radical SAM chemistry can be combined with Schiff base chemistry for RNA modification.


Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO).
While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke-lung cancer relationship by histological type based on pooled data from 18 case-control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 control who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack-years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17-1.45) for all histological types combined, 1.26 (95% CI: 1.10-1.44) for adenocarcinoma, 1.41 (95% CI: 0.99-1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89-2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62-5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for nonsmall cell lung cancers (OR=2.11, 95% CI: 1.11-4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention.


Garlic extract therapy in children with hypercholesterolemia.
To determine whether garlic extract therapy is efficacious and safe in children with hypercholesterolemia. Randomized, double-blind, placebo-controlled clinical trial. Specialized pediatric lipid disorders ambulatory clinic. Thirty pediatric patients, aged 8 to 18 years, who had familial hyperlipidemia and a minimum fasting total cholesterol level greater than 4.8 mmol/L (> 185 mg/dL). An 8-week course of a commercially available garlic extract (Kwai [Lichtwer Pharma, Berlin, Germany], 300 mg, 3 times a day) or an identical placebo. Absolute and relative changes in fasting lipid profile parameters. The groups were equivalent at baseline and compliance was similar in the 2 groups (P = .45). There was no significant relative attributable effect of garlic extract on fasting total cholesterol (+0.6% [95% confidence interval, -5.8% to +6.9%1) or low-density lipoprotein cholesterol (-0.5% [95% confidence interval, -8.7% to +7.6%]). The lower limits of the confidence intervals did not include -10%, the minimum relative attributable effect believed to be clinically important. Likewise, no significant effect was seen on the levels of high-density lipoprotein, triglycerides, apolipoprotein B-100, lipoprotein (a), fibrinogen, homocysteine, or blood pressure. There was a small effect on apolipoprotein A-I (+10.0% [95% confidence interval, +1.2% to +16.5%] P=.03). There were no differences in adverse effects between groups. Garlic extract therapy has no significant effect on cardiovascular risk factors in pediatric patients with familial hyperlipidemia.


Regulation of transforming growth factor-beta subtypes by members of the steroid hormone superfamily.
Transforming growth factor-beta s (TGF-beta s) are potent regulators of cell growth and differentiation. Expression of the closely related TGF-beta subtypes in vivo is differentially regulated both temporally and spatially. Members of the steroid hormone superfamily may play an important role in this gene- and tissue-specific regulation. We have shown that anti-estrogens induce the production of TGF-beta 1 in mammary carcinoma cells and fetal fibroblasts, whereas retinoic acid specifically induces TGF-beta 2 in primary epidermal keratinocytes. The induction of TGF-beta 2 by retinoids is accompanied by an increase in TGF-beta 2 mRNAs, but little change in transcription rates, suggesting an effect of retinoids on message stability or processing. In contrast, TGF-beta 1 mRNA levels are unchanged by anti-estrogen treatment, suggesting these compounds may regulate the translatability of the TGF-beta 1 message or some post-translational processing event. We have identified a stable stem-loop structure in the 5' untranslated region (UTR) of the TGF-beta 1 mRNA that inhibits translation of a heterologous reporter gene, and we are investigating the possibility that anti-estrogens may regulate the activity of this element, and hence the translatability of the TGF-beta 1 message. A significant fraction (25-90%) of the TGF-beta induced by retinoids and anti-estrogens is in the biologically active rather than the latent form. We have shown that active TGF-beta has a much shorter in vivo half-life than latent TGF-beta, suggesting that the TGF-beta induced by retinoids and steroids may act locally at the site of production. Since many tumor cells retain sensitivity to the growth inhibitory effects of active TGF-beta, the use of members of the steroid hormone superfamily for inducing this potent growth inhibitor locally at the tumor site may have therapeutic potential.


Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry.
Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications. In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results. The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients). The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations. The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.


Influence of long-term administration of serum albumin on the prognosis of liver cirrhosis in man.
To investigate the efficacy of long term administration of salt-poor albumin in the prognosis of cirrhotic patients with ascites, we administered albumin for more than six months at regular intervals to nine cirrhotic patients who had been confirmed to have ascites for the first time, and maintained their serum albumin levels above 3.0 g/dl. The other 11 cirrhotic patients who had also developed ascites for the first time were treated with diuretics only, as a control group. In the albumin treated group, one patient developed a hepatoma, and another had acute viral hepatitis after transfusion during splenectomy, and they were excluded. In the control group, one developed chronic liver failure after an operation for choledocholithiasis, and she was excluded from the study. All seven patients who had been administered albumin survived for more than two years, whereas three out of 10 in the control group died of chronic liver failure within two years. In the patients who showed a B.S.P. retention rate of more than 35% at the beginning of the study, all five treated with albumin survived for more than two years, whereas three out of four in the control group died within two years (P less than 0.025). In the albumin treated patients, the increase in serum albumin level was generally accompanied by an increase in the choline-esterase level. Long term administration of serum albumin to cirrhotic patients with ascites appears to lead to a better prognosis.


Cone photoreceptors develop normally in the absence of functional rod photoreceptors in a transgenic swine model of retinitis pigmentosa.
Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP. Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy. Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes. Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients.


Anti-receptor antibody-induced H-Y-specific delayed-type hypersensitivity responses in nonresponder mice.
The present study examines an antiserum prepared against antigen-reactive T cells that induces murine H-Y-specific delayed-type hypersensitivity (DTH) responses. This anti-H-Y receptor antibody (ARA) was raised in C57BL/6 male mice against splenic T lymphocytes from H-Y immune syngeneic females. Subcutaneous administration of ARA to cyclophosphamide-pretreated C57BL/6 females is able to induce H-Y-specific delayed-type footpad swelling responses. The DTH inducing capacity in ARA was selectively retained on rabbit anti-mouse immunoglobulin columns and was absorbed completely by H-Y immune lymphoid cells from C57BL/6 females. The induction of H-Y DTH reactivity was due at least in part to the activation of H-Y antigen-specific T lymphocytes that could adoptively transfer DTH-like responses to naive female mice. ARA induces DTH responses in strains with the same lgh regions, including selected strains of H-Y nonresponders. Therefore, MHC-linked lr genes do not appear to be as critical when responses are triggered by ARA instead of by antigen. Possible mechanisms for the induction of immune responses by ARA are discussed.