Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain.
In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, and oligodendrocyte-like cells). Novel cell type-specific EV protein markers were then identified for the excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), microglia-like cells (ITGAM, LCP1), and oligodendrocyte-like cells (LAMP2, FTH1), as well as 16 pan-EV marker candidates, including integrins and annexins. To further demonstrate how cell-type-specific EVs may be involved in Alzheimer's disease (AD), we performed protein co-expression network analysis and conducted cell type assessments for the proteomes of brain-derived EVs from the control, mild cognitive impairment, and AD cases. A protein module enriched in astrocyte-specific EV markers was most significantly associated with the AD pathology and cognitive impairment, suggesting an important role in AD progression. The hub protein from this module, integrin-β1 (ITGB1), was found to be significantly elevated in astrocyte-specific EVs enriched from the total brain-derived AD EVs and associated with the brain β-amyloid and tau load in independent cohorts. Thus, our study provides a featured framework and rich resource for the future analyses of EV functions in neurodegenerative diseases in a cell type-specific manner.


The harms of screening: a proposed taxonomy and application to lung cancer screening.
Making rational decisions about screening requires information about its harms, but high-quality evidence is often either not available or not used. One reason may be that we lack a coherent framework, a taxonomy, for conceptualizing and studying these harms. To create a taxonomy, we categorized harms from several sources: systematic reviews of screening, other published literature, and informal discussions with clinicians and patients. We used this information to develop an initial taxonomy and vetted it with local and national experts, making revisions as needed. We propose a taxonomy with 4 domains of harm from screening: physical effects, psychological effects, financial strain, and opportunity costs. Harms can occur at any step of the screening cascade. We provide definitions for each harm domain and illustrate the taxonomy using the example of screening for lung cancer. The taxonomy provides a systematic way to conceptualize harms as experienced by patients. As shown in the lung cancer screening example, the taxonomy also makes clear where (which domains of harms and which parts of the screening cascade) we have useful information and where there are gaps in our knowledge. The taxonomy needs further testing and validation across a broad range of screening programs. We hope that further development of this taxonomy can improve our thinking about the harms of screening, thus informing our research, policy making, and decision making with patients about the wisdom of screening.


[END-STAGE RENAL DISEASE, DIALYSIS TREATMENT AND MANAGEMENT OF COMORBIDITY].
Chronic kidney disease is clearly defined as a state of damaged kidney function lasting for more than three months. Changes manifest in serum and urine pathological findings with frequent morphological changes in the kidneys and reduction in glomerular filtration. The aim is to show the possibilities of renal replacement therapy and waste related disease during dialysis treatment. The methods are based on strong evidence and guidelines. Glomerular filtration is the basis in evaluating the stage of chronic kidney disease. Based on the measures of glomerular filtration reduction, chronic kidney disease is classified into five stages, thus facilitating approach to treatment of particular groups of patients depending on the level of glomerular filtration damage. Kidney function can be replaced by dialysis or transplantation and in certain cases symptomatically if the patient refuses dialysis treatment. Malnutrition, hypertension, kidney anemia and bone-mineral disease are often present in patients with higher stages of chronic kidney disease, particularly stage 5 and kidney function replacement by dialysis. In conclusion, timely treatment reduces morbidity and mortality in patients with chronic kidney disease.


[Dynamics of nucleic acid synthesis in the granulation tissue of skin wounds in the rat].
Dynamics of nucleic acid synthesis was studied in granulation tissue, harvested within 2-11 days after an injury of rats with full-layer skin wounds, simultaneously with evaluation of the morphometric patterns of the tissue. Synthesis of nuclear DNA exhibited a wave-shaped dynamics. The intervals between the maximal values of the DNA synthesis constituted 3 days. Within the early steps of wound healing the intensive incorporation of 3H-thymidine into mitochondrial DNA was found, which appears to occur due to active mitochondriogenesis. In dynamics of total and nuclear RNA contents two peaks were observed, which did not coincide in time, thus suggesting the wave-shaped increase in biosynthetic processes in cells.


Effects of substance P on the binding of ligands to nicotinic acetylcholine receptors.
The effect of substance P on the binding of many ligands that interact with the nicotinic acetylcholine receptor was examined in membrane preparations of Torpedo electroplaque and BC3H-1 cells and in solubilized membranes of rat, chick, and goldfish brain. In the absence of carbamylcholine, the affinity of [3H]phencyclidine for the high affinity local anesthetic binding site on Torpedo membranes was increased by substance P with an EC50 of approximately 5 microM. In the presence of carbamylcholine, which itself increases [3H]phencyclidine binding affinity, substance P caused a decrease in the affinity of [3H]phencyclidine. The concentration dependence of the inhibition, however, was inconsistent with a competitive interaction, since the apparent Hill coefficient was significantly less than one. We conclude from these results that substance P does not directly interact with the high affinity local anesthetic binding site on the nicotinic receptor of Torpedo membranes. Substance P also does not appear to interact directly with the agonist binding site since the peptide had no significant effect on [3H]acetylcholine binding to Torpedo membranes. Substance P inhibited [125I]alpha-bungarotoxin binding to both native and Triton X-100 solubilized Torpedo membranes, although the IC50 was 8-fold higher for the solubilized preparation (12 versus 93 microM). We interpret this inhibition in solubilized membranes as evidence that the peptide may interact directly with a binding site on the nicotinic acetylcholine receptor. Substance P also decreased the initial rate of [125I]alpha-bungarotoxin to membranes prepared from BC3H-1 cells (IC50 = 108 microM) and to solubilized membranes from rat, chick, and goldfish brain. In the brain membranes, however, the peptide did not completely inhibit binding; at the highest concentration examined (100 microM), the maximum inhibition observed was 60%. Consistent with the results for [3H]acetylcholine binding to Torpedo membranes, the peptide had no effect on the binding of the cholinergic agonist [3H](-)nicotine to these tissue preparations. These data suggest that substance P may have a general modulatory action on a subclass of nicotinic receptors that include muscle-type, ganglionic-type, and a putative subpopulation of central nervous system receptors.


Genetic analysis of life-history constraint and evolution in a wild ungulate population.
Trade-offs among life-history traits are central to evolutionary theory. In quantitative genetic terms, trade-offs may be manifested as negative genetic covariances relative to the direction of selection on phenotypic traits. Although the expression and selection of ecologically important phenotypic variation are fundamentally multivariate phenomena, the in situ quantification of genetic covariances is challenging. Even for life-history traits, where well-developed theory exists with which to relate phenotypic variation to fitness variation, little evidence exists from in situ studies that negative genetic covariances are an important aspect of the genetic architecture of life-history traits. In fact, the majority of reported estimates of genetic covariances among life-history traits are positive. Here we apply theory of the genetics and selection of life histories in organisms with complex life cycles to provide a framework for quantifying the contribution of multivariate genetically based relationships among traits to evolutionary constraint. We use a Bayesian framework to link pedigree-based inference of the genetic basis of variation in life-history traits to evolutionary demography theory regarding how life histories are selected. Our results suggest that genetic covariances may be acting to constrain the evolution of female life-history traits in a wild population of red deer Cervus elaphus: genetic covariances are estimated to reduce the rate of adaptation by about 40%, relative to predicted evolutionary change in the absence of genetic covariances. Furthermore, multivariate phenotypic (rather than genetic) relationships among female life-history traits do not reveal this constraint.


[Hidden motor dysfunctions in children with epilepsy].
At the National Center for Epilepsy, many years of clinical experience with children with difficult-to treat epilepsy has left the impression that many of these children may have motor difficulties in addition to their seizures. The aim of this prospective, uncontrolled study was to investigate if this impression could be confirmed. In 41 children with "epilepsy only", i.e. without mental retardation or cerebral palsy, their motor performance was evaluated by means of the ABC test (Movement Assessment Battery for Children). More than half of the children had test results consistent with motor difficulties. The motor problems were most pronounced among those with MRI-detectable brain lesions and symptomatic localisation-related epilepsy. Gender, type and number of antiepileptic drugs or seizure frequency did not influence the test results. Hidden motor dysfunctions, which may be caused by the aetiology of the epilepsy, the epilepsy itself, or the epilepsy treatment may easily be overlooked and may represent an extra burden for the children both at school and in their leisure time. We recommend that motor function should be tested in children with severe epilepsy as part of a comprehensive multiprofessional evaluation. Those with poor motor performance should be offered sensory motor stimulation.


Public health surveillance in the United States: evolution and challenges.
In its landmark 1988 report, a committee of the Institute of Medicine highlighted assessment as one of the three core functions of public health along with policy development and assurance. The committee recommended that every public health agency regularly and systematically collect, assemble, analyze, and make available information on the health of the community, including statistics on health status, community health needs, and epidemiologic and other studies of health problems. Public health surveillance, often called the cornerstone of public health practice, is an essential element of the assessment function.


[Surgical treatment of microbladder of tuberculous etiology].
In tuberculous microcysts two technics of plastic surgery are suggested depending on the state of the prostatic gland and urethra. In patients with microcysts without specific lesions of the prostatic gland and urethra vertical sigmocystoplasty was performed after subtotal resection of the urinary bladder. In microcysts associated with tuberculosis of the prostatic gland or urethra perineal sigmocystoplasty after the authors' technic was employed.


Bacterial succession on decomposing leaf litter exhibits a specific occurrence pattern of cellulolytic taxa and potential decomposers of fungal mycelia.
The decomposition of dead plant biomass contributes to the carbon cycle and is one of the key processes in temperate forests. While fungi in litter decomposition drive the chemical changes occurring in litter, the bacterial community appears to be important as well, especially later in the decomposition process when its abundance increases. In this paper, we describe the bacterial community composition in live Quercus petraea leaves and during the subsequent two years of litter decomposition. Members of the classes Alpha-, Beta- and Gammaproteobacteria and the phyla Actinobacteria, Bacteroidetes and Acidobacteria were dominant throughout the experiment. Bacteria present in the oak phyllosphere were rapidly replaced by other taxa after leaf senescence. There were dynamic successive changes in community composition, in which the early-stage (months 2-4), mid-stage (months 6-8) and late-stage (months 10-24) decomposer communities could be distinguished, and the diversity increased with time. Bacteria associated with dead fungal mycelium were important during initial decomposition, with sequence relative abundances of up to 40% of the total bacterial community in months 2 and 4 when the highest fungal biomass was observed. Cellulose-decomposing bacteria were less frequent, with abundance ranging from 4% to 15%. The bacterial community dynamics reflects changes in the availability of possible resources either of the plant or microbial origin.


Effect of inositol 1,4,5-trisphosphate receptor stimulation on mitochondrial [Ca2+] and secretion in chromaffin cells.
Ca(2+) uptake by mitochondria is a potentially important buffering system able to control cytosolic [Ca(2+)]. In chromaffin cells, we have shown previously that stimulation of either Ca(2+) entry or Ca(2+) release via ryanodine receptors triggers large increases in mitochondrial [Ca(2+)] ([Ca(2+)](M)) approaching the millimolar range, whose blockade dramatically enhances catecholamine secretion [Montero, Alonso, Carnicero, Cuchillo-Ibañez, Albillos, Garcia, Carcia-Sancho and Alvarez (2000) Nat. Cell Biol. 2, 57-61]. In the present study, we have studied the effect of stimulation of inositol 1,4,5-trisphosphate (InsP(3)) receptors using histamine. We find that histamine produces a heterogeneous increase in [Ca(2+)](M), reaching peak levels at approx. 1 microM in 70% of the mitochondrial space to several hundred micromolar in 2-3% of mitochondria. Intermediate levels were found in the rest of the mitochondrial space. Single-cell imaging experiments with aequorin showed that the heterogeneity had both an intercellular and a subcellular origin. Those mitochondria responding to histamine with increases in [Ca(2+)](M) much greater than 1 microM (30%) were the same as those that also responded with large increases in [Ca(2+)](M) following stimulation with either high-K(+) medium or caffeine. Blocking mitochondrial Ca(2+) uptake with protonophores or mitochondrial inhibitors also enhanced catecholamine secretion induced by histamine. These results suggest that some InsP(3) receptors tightly co-localize with ryanodine receptors and voltage-dependent Ca(2+) channels in defined subplasmalemmal functional units designed to control secretion induced by different stimuli.


A systematic process for content review in a problem-based learning curriculum.
The integrative nature of a problem-based curriculum provides unique challenges to the task of maintaining a current curriculum. This paper describes a systematic process for content review in a problem-based curriculum, which utilizes consultation among students, faculty and the clinical community, use of external reviewers and a faculty consensus process. Advantages of the process include increased communication and cooperation among faculty and development of a curriculum that balances the need for preparing students for new evidence-based practice with preparing them for clinical reality.


[Elucidation of structures and functions through Peyer's patches of responsible carbohydrate chains in intestinal immune system modulating polysaccharides from Japanese medicinal herbs].
Carbohydrate chains in glycoconjugates play important roles in various life phenomena, and there are numerous types of recognition system for carbohydrate chains due to carbohydrate-lectin interactions/carbohydrate-carbohydrate interactions in all higher life forms. It has been proposed that macromolecular polysaccharides isolated from plants, marine organisms, or fungi cross-interact with known and unknown recognition systems in mammals to express their pharmacological activities. Therefore the elucidation of carbohydrate structures related to the activities and functions of these polysaccharide molecules will lead us to utilize the related information in the development of novel carbohydrate-based drugs and functional foods for human health care. Peyer's patches present in the upper intestinal tract play important roles as inductive sites for both protective IgA production and immune tolerance induction in mucosal and systemic immune systems. Dysfunction of the immunocompetent cells of Peyer's patches is thought to induce allergic/autoimmune diseases and down-regulation of the protective system against infectious agents on mucosal sites. We have isolated several Peyer's patch cell-modulating polysaccharides from medicinal herbs used in traditional Japanese herbal remedies, and they have been assumed to comprise the responsible carbohydrate chains with oligosaccharide sizes for expression of modulating activity. Accumulation of knowledge on the structures and functions of these responsible carbohydrate chains in polysaccharide molecules is believed to be important for the development of methodology for logically factitious regulation of functions of immunocompetent cells in Peyer's patches. This review deals with recent results of our study on the structural clarification of responsible carbohydrate chains in modulating polysaccharides against functions of immunocompetent cells in Peyer's patches.


Enrichment of functional properties of ice cream with pomegranate by-products.
Pomegranate peel rich in phenolics, and pomegranate seed which contain a conjugated fatty acid namely punicic acid in lipid fraction remain as by-products after processing the fruit into juice. Ice cream is poor in polyunsaturated fatty acids and phenolics, therefore, this study was conducted to improve the functional properties of ice cream by incorporating pomegranate peel phenolics and pomegranate seed oil. Incorporation of the peel phenolics into ice cream at the levels of 0.1% and 0.4% (w/w) resulted in significant changes in the pH, total acidity, and color of the samples. The most prominent outcomes of phenolic incorporation were sharp improvements in antioxidant and antidiabetic activities as well as the phenolic content of ice creams. Replacement of pomegranate seed oil by milk fat at the levels of 2.0% and 4.0% (w/w) increased the conjugated fatty acid content. However, perception of oxidized flavor increased with the additional seed oil. When one considers the functional and nutritional improvements in the enrichment of the ice cream together with overall acceptability results of the sensory analysis, then it follows from this study that ice creams enriched with pomegranate peel phenolics up to 0.4% (w/w) and pomegranate seed oil up to 2.0% (w/w) could be introduced to markets as functional ice cream. Enrichment of ice creams with pomegranate by-products might provide consumers health benefits with striking functional properties of punicalagins in pomegranate peel, and punicic acid in pomegranate seed oil.


Neoadjuvant chemotherapy before definitive treatment for stage III carcinoma of the breast.
One hundred women with American Joint Committee (AJC) stage III (T2, N2; T3, N0/1/2; T4, N0/1/2) carcinoma of the breast were treated with combination chemotherapy following biopsy to confirm the diagnosis and determine hormone receptor status before any other treatment of the local disease (so-called neoadjuvant chemotherapy). Response was assessed after three cycles of treatment, and responders were treated until the tumor and/or axillary nodes failed to show further regression. Definitive surgery was then performed, usually radical mastectomy. Chemotherapy was resumed following surgery for a total of 12 cycles. Ninety patients are assessable, and 70% have responded to chemotherapy. Outcomes of both responders and nonresponders were analyzed. Radical mastectomy without postoperative radiotherapy seems to be the preferable surgical treatment for the responders. Median follow-up of the assessable patients was 27 months; projected five-year disease-free survival of the responders is greater than 65%, and projected overall five-year survival of this group is greater than 85%. Because the follow-up of these patients suggests a marked improvement in outcome compared with similar patients treated traditionally with mastectomy or radiotherapy followed by adjuvant chemotherapy, we advocate more widespread use of combination chemotherapy before definitive treatment for stage III carcinomas of the breast.


Microinjected antibodies interfere with protein nucleocytoplasmic shuttling by distinct molecular mechanisms.
The observation that some antibodies can enter the nucleus after their microinjection into the cytoplasm established the principle of protein nucleocytoplasmic shuttling. Here, we introduce the concept of stationary antibodies for studying nuclear transport, particularly of native proteins. Contrary to the aforementioned translocating immunoglobulins, stationary antibodies do not cross the nuclear envelope. They are distinguished by their ability to trigger the nucleocytoplasmic redistribution of their antigen. What determines these apparently contradictory outcomes has not been explored. We studied a stationary STAT1 antibody and a translocating importin-beta antibody. The stationary phenotype resulted from the inhibition of carrier-independent transport. This was not due to crosslinking or precipitation of antigen, because the antigen-antibody complex remained highly mobile. Rather, decoration with stationary antibody precluded actual nuclear pore passage of antigen. In addition, both antibodies inhibited the carrier-dependent translocation via importin-alpha, but by diverse mechanisms. The translocating antibody blocked the association with importin-alpha, whereas the stationary antibody prevented the phosphorylation of its antigen, and thus functioned upstream of the importin-alpha binding step. We identified a stationary antibody to green-fluorescent protein (GFP) and probed the translocation of GFP fusions of STAT1, thyroid hormone receptor and histones, demonstrating general application of this approach. Our results provide an experimental rationale for the use of antibodies as unique tools for dissecting protein nuclear translocation. As the microinjection of stationary antibodies extends to analyses of native proteins, this method can complement and validate results obtained with fluorescent-labeled derivatives.


Exceptional oxygen barrier performance of pullulan nanocomposites with ultra-low loading of graphene oxide.
Polymer nanocomposites are increasingly important in food packaging sectors. Biopolymer pullulan is promising in manufacturing packaging films or coatings due to its excellent optical clarity, mechanical strength, and high water-solubility as compared to other biopolymers. This work aims to enhance its oxygen barrier properties and overcome its intrinsic brittleness by utilizing two-dimensional planar graphene oxide (GO) nanoplatelets. It has been found that the addition of only 0.2 wt% of GO enhanced the tensile strength, Young's modulus, and elongation at break of pullulan films by about 40, 44 and 52%, respectively. The light transmittance at 550 nm of the pullulan/GO films was 92.3% and haze values were within 3.0% threshold, which meets the general requirement for food packaging materials. In particular, the oxygen permeability coefficient of pullulan was reduced from 6337 to 2614 mL μm m(-2) (24 h(-1)) atm(-1) with as low as 0.05 wt% of GO loading and further to 1357 mL μm m(-2) (24 h(-1)) atm(-1) when GO concentration reached 0.3 wt%. The simultaneous improvement of the mechanical and oxygen barrier properties of pullulan was ascribed to the homogeneous distribution and prevalent unidirectional alignment of GO nanosheets, as determined from the characterization and theoretical modelling results. The exceptional oxygen barrier properties of pullulan/GO nanocomposites with enhanced mechanical flexibility and good optical clarity will add new values to high performance food packaging materials.


Distinct linear and non-linear trajectories of reward and punishment reversal learning during development: relevance for dopamine's role in adolescent decision making.
Abnormalities in value-based decision making during adolescence have often been attributed to non-linear, inverted-U shaped development of reward-related processes. This hypothesis is strengthened by functional imaging work revealing an inverted-U shaped relationship between age and reward-related activity in the striatum. However, behavioural studies have mostly reported linear rather than non-linear increases in reward-related performance. In the present study, we investigated the mechanisms underlying the development of reward- and punishment-related processing across four age groups using a reversal learning task previously shown to depend on striatal dopamine. We demonstrate both linear and non-linear age effects on distinct components of reversal learning. Specifically, results revealed a linear shift with age in terms of valence-dependent reversal learning, with children exhibiting better punishment than reward reversal learning, adults exhibiting better reward than punishment reversal learning and adolescents exhibiting an intermediate performance pattern. In addition, we also observed a non-linear, inverted-U shaped relationship between age and valence-independent reversal learning, which was due to aberrant ability of adolescents to update behaviour in response to negative performance feedback. These findings indicate that the (linear or nonlinear) nature of the relationship between age and reward learning depends on the type of reward learning under study.


SARS-CoV spike proteins expressed by the vaccinia virus Tiantan strain: secreted sq protein induces robust neutralization antibody in mice.
The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target in the development of diagnostic assays and vaccines, but its antigenic and immunogenic properties remain unclear. Seven SARS-CoV spike proteins (S, SQ, S1, RBD, S2, S2Q, and CX) were generated using the modified vaccinia virus (Tiantan strain) as a vector, and their antigenicity and immunogenicity were evaluated. The secreted SQ protein in which the transmembrane domain was deleted, as well as the full-length spike protein, showed the most potential to induce the production of neutralizing antibody (nAb) in mice. S1 and RBD proteins initialized significantly lower levels of nAb production. In addition, the S proteins were recognized specifically by the sera of convalescent patients with SARS, and that of mice immunized with inactivated SARS-CoV, but did not react with anti-sera of HCoV-OC43 or HCoV-229E, or sera from healthy donors (although RBD showed a false-positive in 1 of 55 control samples of human sera). Our results demonstrate that SQ protein may be an effective vaccine candidate and a convenient and safe diagnostic antigen for SARS-CoV.


Protective effect of the natural flavonoid naringenin in mouse models of retinal injury.
Glaucoma is an eye disease with a high rate of blindness and a complex pathogenesis. Ocular hypertension (OHT) is a critical risk factor, and retinal ischemia/reperfusion (I/R) is an important pathophysiological basis. This study was designed to investigate the retinal neuroprotective effect of oral naringenin in an acute retinal I/R model and a chronic OHT model and the possible mechanism involved. After the I/R and OHT models were established, mice were given vehicle or naringenin (100 mg/kg or 300 mg/kg). Hematoxylin-eosin (HE) staining and immunostaining of RBPMS and glial fibrillary acidic protein (GFAP) were used to evaluate retinal injury. GFAP, CD38, Sirtuin1 (SIRT1), and NOD-like receptor protein 3 (NLRP3) expression levels were measured by Western blotting. In the OHT model, intraocular pressure (IOP) was dynamically maintained at approximately 20-25 mmHg after injury. The retinal structure was damaged, and retinal ganglion cells (RGCs) were lost in both models. Naringenin ameliorated the abovementioned indications but also demonstrated that high concentrations of naringenin significantly inhibited retinal astrocyte activation and inhibited damage-induced increases in the expression of GFAP, NLRP3, and CD38 proteins, while SIRT1 protein expression was upregulated. This study showed for the first time that naringenin can reduce microbead-induced IOP elevation in the OHT model, providing new evidence for the application of naringenin in glaucoma. Naringenin may mediate the CD38/SIRT1 signaling pathway, inhibit astrocyte activation, and ultimately exert an anti-inflammatory effect to achieve retinal neuroprotection.


Estimating the spatial autocorrelation function for ultrasound scatterers in isotropic media.
The autocorrelation function pertaining to spatial distributions of ultrasonic scatterers in soft tissue is believed to contain useful information related to tissue morphology. A simple processing method applied to radio-frequency echo signals estimates this function for a sample having isotropic scattering conditions. It utilizes backscattered echo signals from the sample and echo signals from a reference object having defined scattering properties. The ratio of the echo signal power spectrum from the sample to the echo signal power spectrum from the reference object is obtained, and corrected for attenuation differences between the two media. This yields a "form factor" for the sample, whose inverse Fourier transform is the autocorrelation function. The method was tested using tissue-mimicking samples for which spatial autocorrelation functions could be modeled from the dimensions of embedded scatterers. The shapes of the measured autocorrelation functions were in reasonable agreement with those estimated, although measured functions overestimated the function at small lag distances. Scatterer diameters estimated from the zeros of the autocorrelation function agreed to within 6% of expected values when the measurement system bandwidth satisfied minimal criteria.


Comments on the 2001 WHO proposal for the classification of haematopoietic neoplasms.
In the preface, the World Health Organization (WHO) classification vows to offer pathologists, oncologists and geneticists worldwide a system of classification for human neoplasms based on histopathological and genetic features. Standardization of nomenclature and agreed-upon criteria for definition of the various types of cancer are felt to be a prerequisite for progress in clinical oncology, multicentre therapy trials and comparative studies in different countries. In fact, the WHO effort represents the first worldwide comprehensive consensus classification of the haematological malignancies. Consensus was reached among a subgroup of investigators, carefully selected for their experience and contributions to existing classifications. In the present climate of daily new discoveries that yield a constant stream of fascinating insights into the biology of leukaemias and lymphomas and, above all, resulting in an explosion of potential therapeutic targets, the WHO system has taken the stand of compiling established classification approaches and providing order to known facts. This furnishes an essential skeleton upon which to build in the future. The WHO committee decided that sorting neoplasms according to prognosis was neither practical nor necessary and could be misleading. While justifiable at the present time, it is important to realize that the classifications of the haematological malignancies are a moving target and that the trend is to move away from currently accepted gold standards, such as morphological evaluations, in favour of genetic characterizations, especially those with therapeutic relevance. The goal of this chapter is to fill in some gaps that, as per the author's opinion, exist in the WHO classification, predominantly, where it concerns the role of immunophenotyping as a complementary discipline for genotyping through its potential to generate surrogate marker profiles for molecular lesions. By introducing some state-of-the-art classification modalities, some of which are still awaiting confirmation, this chapter also aims to spark excitement and provide a glimpse at the future.


Time, monetary and other costs of participation in family-based child weight management interventions: qualitative and systematic review evidence.
Childhood overweight and obesity have health and economic impacts on individuals and the wider society. Families participating in weight management programmes may foresee or experience monetary and other costs which deter them from signing up to or completing programmes. This is recognised in the health economics literature, though within this sparse body of work, costs to families are often narrowly defined and not fully accounted for. A societal perspective incorporating a broader array of costs may provide a more accurate picture. This paper brings together a review of the health economics literature on the costs to families attending child weight management programmes with qualitative data from families participating in a programme to manage child overweight and obesity. A search identified economic evaluation studies of lifestyle interventions in childhood obesity. The qualitative work drew on interviews with families who attended a weight management intervention in three UK regions. We identified four cost-effectiveness analyses that include information on costs to families. These were categorised as direct (e.g. monetary) and indirect (e.g. time) costs. Our analysis of qualitative data demonstrated that, for families who attended the programme, costs were associated both with participation on the scheme and with maintaining a healthy lifestyle afterwards. Respondents reported three kinds of cost: time-related, social/emotional and monetary. Societal approaches to measuring cost-effectiveness provide a framework for assessing the monetary and non-monetary costs borne by participants attending treatment programmes. From this perspective, all costs should be considered in any analysis of cost-effectiveness. Our data suggest that family costs are important, and may act as a barrier to the uptake, completion and maintenance of behaviours to reduce child obesity. These findings have implications for the development and implementation of child weight initiatives in particular, in relation to reducing inequalities in health.


The DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure as a Screening Tool.
The DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure was developed to aid clinicians with a dimensional assessment of psychopathology; however, this measure resembles a screening tool for several symptomatic domains. The objective of the current study was to examine the basic parameters of sensitivity, specificity, positive and negative predictive power of the measure as a screening tool. One hundred and fifty patients in a correctional community center filled out the measure prior to a psychiatric evaluation, including the Mini International Neuropsychiatric Interview screen. The above parameters were calculated for the domains of depression, mania, anxiety, and psychosis. The results showed that the sensitivity and positive predictive power of the studied domains was poor because of a high rate of false positive answers on the measure. However, when the lowest threshold on the Cross-Cutting Symptom Measure was used, the sensitivity of the anxiety and psychosis domains and the negative predictive values for mania, anxiety and psychosis were good. In conclusion, while it is foreseeable that some clinicians may use the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure as a screening tool, it should not be relied on to identify positive findings. It functioned well in the negative prediction of mania, anxiety and psychosis symptoms.


Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells.
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the CNS, which has long been used as an animal model for human multiple sclerosis. Development of autoimmune disease requires coordinated expression of a number of genes that are involved in the activation and effector functions of inflammatory cells. These include genes that encode costimulatory molecules, cytokines, chemokines, and adhesion molecules. Activation of these genes is regulated at the transcriptional level by several families of transcription factors. One of these is the NF-kappa B family, which is present in a variety of cell types and becomes highly activated at sites of inflammation. To test the roles of NF-kappa B in the development of autoimmune diseases, we studied EAE in mice deficient in one of the NF-kappa B isoforms, i.e., NF-kappa B1 (p50). We found that NF-kappa B1-deficient mice were significantly resistant to EAE induced by myelin oligodendrocyte glycoprotein. The resistance was primarily evidenced by a decrease in disease incidence, clinical score, and the degree of CNS inflammation. Furthermore, we established that the resistance to EAE in NF-kappa B1-deficient mice was associated with a deficiency of myelin oligodendrocyte glycoprotein-specific T cells to differentiate into either Th1- or Th2-type effector cells in vivo. These results strongly suggest that NF-kappa B1 plays crucial roles in the activation and differentiation of autoreactive T cells in vivo and that blocking NF-kappa B function can be an effective means to prevent autoimmune encephalomyelitis.


Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity.
Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.


Validation of the Duke Social Support and Stress Scale.
The Duke Social Support and Stress Scale (DUSOCS) was validated in 249 adult family practice patients using the Family Strengths, the Family Inventory of Life Events, and the Duke Health Profile (DUKE) as comparison instruments. Validity was supported in that the DUSOCS family support measure had the clinically expected positive associations with DUKE health measures (regression coefficients of +7.4 to +18.7) and negative associations with DUKE anxiety and depression measures (-2.0 to -17.2). DUSOCS family stress had negative associations with the health measures (-11.6 to -34.5) and positive associations with anxiety and depression (+18.9 to +32.1). Family and non-family stress contributed more than severity of illness to elevated levels of anxiety and depression and lowered levels of mental health, social health, and self-esteem, while these same stresses contributed only half as much as severity of illness to lowered physical health.


Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats.
Secoisolariciresinol diglucoside (SDG) is an important dietary lignan that is found at very high levels in flaxseed (1-4 %, w/w). Flaxseed lignans have received much research interest in recent years because of reported phyto-oestrogenic, anticarcinogenic, and anti-atherogenic effects. Previously, flaxseed feeding has been shown to decrease vitamin E concentrations in rats despite the antioxidant potential of SDG in vitro. Sesamin, a sesame lignan, on the other hand has been shown to increase vitamin E concentrations in rats. The aim of the present study was to investigate the effect of dietary SDG and its oligomers on vitamin E and cholesterol concentrations in rats. SDG was extracted from defatted flaxseed flour with a dioxane-ethanol mixture and purified by silica column chromatography. The major oligomers with 3-hydroxy-3-methyl glutaric acid, containing a high ratio of SDG to p-coumaric and ferulic acid glucosides, were purified from the extracts by reversed-phase liquid chromatography. When fed to rats at 0.1 % in the diet for 27 d, both SDG and its oligomers had no effect on animal performance but caused an increase in liver cholesterol and a 2-fold reduction in the levels of alpha- and gamma-tocopherols in rat plasma and liver. It is notable that a phenolic antioxidant, such as SDG, causes a vitamin E-lowering effect in rats. This cannot be explained at present, but warrants further investigations with respect to the magnitude, mechanism, and significance of the observed effect for human nutrition.


Modulation of the activity of acetyl-CoA carboxylase and other lipogenic enzymes by growth hormone, insulin and dexamethasone in sheep adipose tissue and relationship to adaptations to lactation.
The mechanisms whereby growth hormone and dexamethasone modulate the stimulation of fatty acid synthesis by insulin in adipose tissue from lactating and non-lactating sheep have been investigated. Maintenance of adipose tissue from wethers (castrated male sheep) in tissue culture for 24 or 48 h with insulin resulted in an increased proportion of acetyl-CoA carboxylase being present in the active state; this effect was enhanced by dexamethasone and was antagonized by growth hormone. Lactation results in a decrease in both the total acetyl-CoA carboxylase of sheep adipose tissue and the proportion of the enzyme in the active state. Maintenance of adipose tissue from lactating sheep in tissue culture for 48 h in the presence of insulin plus dexamethasone increased markedly the proportion of acetyl-CoA carboxylase in the active state and increased slightly the total activity of the enzyme. Both of these effects were prevented by actinomycin D, and the change in activation status was prevented by growth hormone. Tissue culture for 6 days showed that growth hormone could also prevent the ability of insulin plus dexamethasone to increase the total activity of the enzyme. Analogous studies showed that insulin, dexamethasone and growth hormone modulated the activities of other lipogenic enzymes, but the effects were proportionately smaller than for acetyl-CoA carboxylase. Insulin also increased total protein synthesis in adipose tissue, but this was not antagonized by growth hormone. The results suggest that the fall in fatty acid synthesis in sheep adipose tissue during lactation is due to a decrease in both the total acetyl-CoA carboxylase activity and the proportion of the enzyme in the active state; these changes are probably induced by known changes in the serum concentrations of insulin and growth hormone. Lactation appears to result in the loss of a protein that is required for activation of acetyl-CoA carboxylase by insulin; production of this component appears to be prevented by growth hormone.


Cystic dilatation as a radiographic sign of cholangiocarcinoma complicating sclerosing cholangitis.
A 40-year-old woman with ulcerative colitis and sclerosing cholangitis developed jaundice unresponsive to steroids. Endoscopic retrograde cholangiopancreatography showed multiple cystic dilatations similar in appearance to a previous report of a patient with sclerosing cholangitis who had an associated cholangiocarcinoma. Subsequent laparotomy led to the diagnosis of a cholangiocarcinoma. We conclude that the presence of cystic dilatation on cholangiography in patients with sclerosing cholangitis is highly suggestive of an associated cholangiocarcinoma.


The Coronavirus Anxiety Scale: Cross-national measurement invariance and convergent validity evidence.
Coronavirus Anxiety Scale (CAS) is a widely used measure that captures somatic symptoms of coronavirus-related anxiety. In a large-scale collaboration spanning 60 countries (Ntotal = 21,513), we examined the CAS's measurement invariance and assessed the convergent validity of CAS scores in relation to the fear of COVID-19 (FCV-19S) and the satisfaction with life (SWLS-3) scales. We utilized both conventional exact invariance tests and alignment procedures, with results revealing that the single-factor model fit the data well in almost all countries. Partial scalar invariance was supported in a subset of 56 countries. To ensure the robustness of results, given the unbalanced samples, we employed resampling techniques both with and without replacement and found the results were more stable in larger samples. The alignment procedure demonstrated a high degree of measurement invariance with 9% of the parameters exhibiting noninvariance. We also conducted simulations of alignment using the parameters estimated in the current model. Findings demonstrated reliability of the means but indicated challenges in estimating the latent variances. Strong positive correlations between CAS and FCV-19S estimated with all three different approaches were found in most countries. Correlations of CAS and SWLS-3 were weak and negative but significantly differed from zero in several countries. Overall, the study provided support for the measurement invariance of the CAS and offered evidence of its convergent validity while also highlighting issues with variance estimation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB.
The phenoxy alkyl benzimidazoles (PABs) have good antitubercular activity. We expanded our structure-activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc1 oxidase of the electron transport chain. QcrB mutant strains were resistant to all PAB compounds, whereas Rv1339 mutant strains were only resistant to a subset, suggesting that QcrB is the target. The discovery of the target for PAB compounds will allow for the improved design of novel compounds to target intracellular M. tuberculosis.


Neural Network Approach for a Rapid Prediction of Metal-Supported Borophene Properties.
We developed a high-dimensional neural network potential (NNP) to describe the structural and energetic properties of borophene deposited on silver. This NNP has the accuracy of density functional theory (DFT) calculations while achieving computational speedups of several orders of magnitude, allowing the study of extensive structures that may reveal intriguing moiré patterns or surface corrugations. We describe an efficient approach to constructing the training data set using an iterative technique known as the "adaptive learning approach". The developed NNP is able to produce, with excellent agreement, the structure, energy, and forces obtained at the DFT level. Finally, the calculated stability of various borophene polymorphs, including those not initially included in the training data set, shows better stabilization for ν ∼ 0.1 hole density, and in particular for the allotrope α (ν=1/9). The stability of borophene on the metal surface is shown to depend on its orientation, implying structural corrugation patterns that can be observed only from long-time simulations on extended systems. The NNP also demonstrates its ability to simulate vibrational densities of states and produce realistic structures with simulated STM images closely matching the experimental ones.


The development of the 'Cancer Home-Life Intervention': An occupational therapy-based intervention programme for people with advanced cancer living at home.
Occupational therapy-based interventions may help people with advanced cancer to live actively despite their illness. However, there is limited evidence concerning what kinds of content intervention should encompass, and how this should be done. To describe the development and content of an occupational therapy-based intervention programme for people with advanced cancer living at home. In the development of the intervention, an evidence synthesis was performed based on a systematic literature search, data from a cross-sectional study, and experiences from an expert panel. The programme contains six components: 1) An initial interview to select which of the other five components to address, based on the participants' individual needs. The interview addressed problems and needs of participants in relation to prioritized activities, in order to tailor the following components: 2) prioritisation of resources, energy and everyday activities; 3) adaptation of activities; 4) adaptation of posture and seating; 5) provision of assistive technology; and, 6) modification of the physical home environment. An occupational therapy-based intervention programme for people with advanced cancer living at home has been developed. The study generates knowledge and insights relevant to improving the treatment of this patient group.


Moving on from interpretivism: an argument for constructivist evaluation.
Moving on from interpretivism: an argument for constructivist evaluation This paper examines the research process in the context of an evaluation of work-based learning. The findings of the evaluation are used to illustrate issues around roles and relationships within interpretivist research where a separation is maintained between the researcher, as investigator, and the participants, as the subject of their investigation. The discussion focuses on: the threatening nature of evaluation and the way in which that affects the process of inquiry and learning; the ways in which people's perceptions of research can act as barriers to the implementation of change; and the consequences of this role separation for practice development. In exploring these issues the paper argues for an approach to evaluation research which (a) emphasizes collaboration, (b) is orientated to change and (c) treats the evaluation process as a learning opportunity through which professionals acquire the skills and knowledge to investigate and advance their own practice.


"Getting Everyone on the Same Page": Interprofessional Team Training to Develop Shared Mental Models on Interprofessional Rounds.
This study aimed to evaluate the effect of a team training program to support shared mental model (SMM) development in interprofessional rounds. A three-arm randomized controlled trial study was conducted for interprofessional teams of 207 health profession learners who were randomized into three groups. The full team training program included a didactic training part on cognitive tools and a virtual simulation to support clinical teamwork in interprofessional round. Group 1 was assigned to the full program, group 2 to the didactic part, and group 3 (control group) with no intervention. The main outcome measure was team performance in full scale simulation. Secondary outcome was interprofessional attitudes. Teamwork performance and interprofessional attitude scores of the full intervention group were significantly higher (P < 0.05) than those of the control group. The two intervention groups had significantly higher (P < 0.05) attitude scores on interprofessional teamwork compared with the control group. Our study indicates the need of both cognitive tools and experiential learning modalities to foster SMM development for the delivery of optimal clinical teamwork performances. Given its scalability and practicality, we anticipate a greater role for virtual simulations to support interprofessional team training.


Morphological plasticity of the coral skeleton under CO2-driven seawater acidification.
Ocean acidification causes corals to calcify at reduced rates, but current understanding of the underlying processes is limited. Here, we conduct a mechanistic study into how seawater acidification alters skeletal growth of the coral Stylophora pistillata. Reductions in colony calcification rates are manifested as increases in skeletal porosity at lower pH, while linear extension of skeletons remains unchanged. Inspection of the microstructure of skeletons and measurements of pH at the site of calcification indicate that dissolution is not responsible for changes in skeletal porosity. Instead, changes occur by enlargement of corallite-calyxes and thinning of associated skeletal elements, constituting a modification in skeleton architecture. We also detect increases in the organic matrix protein content of skeletons formed under lower pH. Overall, our study reveals that seawater acidification not only causes decreases in calcification, but can also cause morphological change of the coral skeleton to a more porous and potentially fragile phenotype.


Structures and bioactivities of monomeric and dimeric carvotacetones from Sphaeranthus africanus.
Four previously undescribed carvotacetones including one monomeric (1) and three dimeric (8, 9, 10) derivatives, together with six known compounds were isolated from the n-hexane extract of the aerial parts of Sphaeranthus africanus L. The structures of the previously undescribed compounds were elucidated as 3-angeloyloxy-5-isobutanoyloxy-7-hydroxycarvotacetone (1), 7,7'-oxybis{3-angeloyloxy-5-[(2R*,3R*)-2,3-dihydroxy-2-methylbutanoyloxy]carvotacetone} (8), (2″S*,3″R*)-7-{3-angeloyloxy-5-[(2R*,3R*)-2,3-dihydroxy-2-methylbuta-noyloxy]carvotaceton-7-yloxy}-3-angeloyloxy-5-(2,3-dihydroxy-2-methylbutanoyloxy)carvo-tacetone (9), and 7,7'-oxybis{3-angeloyloxy-5-[(2S*,3R*)-2,3-dihydroxy-2-methylbutanoyl-oxy]carvotacetone} (10). The three dimeric derivatives (8-10) showed potent anti-proliferative activity against human cancer cell lines (CCRF-CEM, MDA-MB-231, U-251, HCT-116) with IC50 values ranging from 0.2 to 2.0 μM. Caspases 3 and 7 were found to be activated by all compounds, indicating apoptosis induction activity. Monomers exhibited a specific inhibition of NO production in BV2 and RAW 264.7 cells with IC50 values ranging from 4.2 to 6.8 μM which were 2-3.5-fold lower than IC50 values causing cytotoxicity. In addition, the carvotacetones reduced NF-κB1 (p105) mRNA expression at concentrations of 10 and 2.5 μM. Altogether, the results indicate that carvotacetones may be interesting lead structures for the development of anti-cancer and anti-inflammatory drugs.


IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii.
T1/ST2 is an immunoregulatory protein of the IL-1 receptor family that has recently been reported as being a component of the IL-33 receptor. IL-33 is a newly described cytokine known to amplify the Th2 response and reduce production of Th1 cytokines. The function of T1/ST2 during Toxoplasma gondii infection is as yet undescribed. Given the requirement of a balanced type 1/type 2 response for effective control of parasite number and immunopathology, it is likely that T1/ST2 may play a part in aiding this process. Accordingly, we have shown that T1/ST2 mRNA transcripts are upregulated in the brains of mice infected with T. gondii and that mice deficient in T1/ST2 demonstrated increased susceptibility to infection with T. gondii that correlated with increased pathology and greater parasite burden in the brains. Real-time PCR analysis of cerebral cytokine levels revealed increased mRNA levels of iNOS, IFN-gamma and TNF-alpha in infected T1/ST2(-/-) mice. These effects were independent of changes in IL-10 production. This study provides the first evidence of a specific role for IL-33 receptor signalling in the brain as well as highlighting the requirement of this mechanism in limiting infection with an intracellular parasite.


Identification of an antimalarial synthetic trioxolane drug development candidate.
The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.


Report on the NCCN Third Annual Patient Safety Summit.
The issues of patient safety and preventing medical errors routinely make headlines, with reports of thousands of preventable deaths and costs in the billions of dollars per year. Far less noticeable, but potentially more important, is the work taking place on a daily basis to develop new systems and processes of safety and use of technology in the effort to reduce preventable adverse events. The NCCN Third Annual Patient Safety Summit examined 3 processes central to maintaining patient safety in the oncology setting: medication reconciliation, communication during patient hand-offs, and reporting of events, including "near-miss" events that do not reach a patient or result in harm. The NCCN Patient Safety Summit included a multidisciplinary audience of safety experts, clinicians, and hospital administrators from NCCN member institutions, with speakers from member institutions sharing clinical and practical experiences in implementing safety improvements. Common themes included transitions from paper to electronic systems, education and training for individuals and teams as new methods are put into place, and the need for all members of the multidisciplinary care team to recognize their impact on patient safety.


[Determination of the filtration characteristics of the fermentation broths of antibiotic producers].
Main filtration characteristics of the fermentation broths are necessary for estimation of the filtration equipment, rational choice of the filtering apparatus, determination of the optimal conditions for their exploitation. In this connection studies were carried out with a purpose of determining the specific resistance and the content of the solid phase in the fermentation broths of the main antibiotics. It was shown that the above characteristics were closely connected with the biosynthetic conditions and medium composition. It was noted that the specific resistance of the precipitates of the fermentation broths of various antibiotic-producing organisms significantly differed, sometimes by several orders. Preliminary treatment of the fermentation broths before filtration provided a marked decrease in the resistance of the precipitate.


The effect of prior task loading on mental workload: an example of hysteresis in driving.
This study examined how transitions in task demand during a driving and navigation task manifested themselves as delayed adaptation in driver mental workload. A delayed reaction to changes in demand levels, termed hysteresis, has been identified in a number of settings. However, little research has specifically examined the driving task for hysteresis effects. A total of 32 drivers completed drives while using a navigation system that would fail within the drive. Subjective mental workload was recorded prior to and following system failure as well as at the conclusion of the drive. Results indicated that a gradual reduction in overall mental workload across trials and a lagged recovery to reduction in task demand was present within trials. Analysis of the mental workload subscales within trials indicated that this effect was produced by the mental effort component of workload. A moderate hysteresis effect is present in mental workload transitions within the driving task. Although subjective mental workload decreases across trials, the magnitude of the lagged recovery within trials remains unchanged. Scaling of in-vehicle information is beneficial with respect to driver mental workload. Display and communication technologies designers should consider not only the immediate task demand but also the driver's task demand history when determining what and how to provide information.


Optimizing Case-based detection performance in a multiview CAD system for mammography.
When reading mammograms, radiologists combine information from multiple views to detect abnormalities. Most computer-aided detection (CAD) systems, however, use primitive methods for inclusion of multiview context or analyze each view independently. In previous research it was found that in mammography lesion-based detection performance of CAD systems can be improved when correspondences between MLO and CC views are taken into account. However, detection at case level detection did not improve. In this paper, we propose a new learning method for multiview CAD systems, which is aimed at optimizing case-based detection performance. The method builds on a single-view lesion detection system and a correspondence classifier. The latter provides class probabilities for the various types of region pairs and correspondence features. The correspondence classifier output is used to bias the selection of training patterns for a multiview CAD system. In this way training can be forced to focus on optimization of case-based detection performance. The method is applied to the problem of detecting malignant masses and architectural distortions. Experiments involve 454 mammograms consisting of four views with a malignant region visible in at least one of the views. To evaluate performance, five-fold cross validation and FROC analysis was performed. Bootstrapping was used for statistical analysis. A significant increase of case-based detection performance was found when the proposed method was used. Mean sensitivity increased by 4.7% in the range of 0.01-0.5 false positives per image.


Optimage central organised image quality control including statistics and reporting.
Quality control of medical imaging systems is performed using dedicated phantoms. As the imaging systems are more and more digital, adequate image processing methods might help to save evaluation time and to receive objective results. The developed software package OPTIMAGE is focusing on this with a central approach: On one hand, OPTIMAGE provides a framework, which includes functions like database integration, DICOM data sources, multilingual user interface and image processing functionality. On the other hand, the test methods are implemented using modules which are able to process the images automatically for the common imaging systems. The integration of statistics and reporting into this environment is paramount: This is the only way to provide these functions in an interactive, user-friendly way. These features enable the users to discover degradation in performance quickly and document performed measurements easily.


Osteoarthritis biomarker responses and cartilage adaptation to exercise: A review of animal and human models.
Regular physical activity has been suggested as having both preventive and therapeutic benefits for individuals with osteoarthritis (OA). However, evidence of whether exercise and which type of exercise constitutes a benefit or a risk in the development and progression of OA remains debatable. This may be due to the evaluation of the effect of physical activity or new disease-modifying OA drugs which is currently based on radiographic criteria (eg, joint space width) and the lack of correlation with clinical signs and symptoms (eg, pain and loss of function). Moreover, OA typically manifests itself as changes within the joint space and subchondral bone as well as the whole joint structure, including progressive degradation of cartilage, menisci, ligaments, and synovial inflammation. Biomarkers are being developed to quantify joint remodeling and disease progression notably involving the articular cartilage and synovial fluid. The primary purpose of this review was to evaluate the current literature and to provide further insight based on OA biomarkers and the role physical activity plays in the management of OA. Osteoarthritis biomarkers together with radiographic imaging evidence will ideally guide healthcare providers to incorporate exercise recommendations into clinical management and offer patients evidence-based and individually tailored exercise prescriptions.


Ethanol inhibition of NMDA receptor function in primary cultures of rat cerebellar granule cells and cerebral cortical cells.
Ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal systems, but the mechanism of the inhibition has not been elucidated. Previous work, using primary cultures of rat cerebellar granule cells, showed that both exposure to alcohol and activation of protein kinase C (PKC) by the phorbol ester PMA reduced the potency of the co-agonist, glycine, to enhance NMDA receptor function (measured as an increase in intracellular Ca2+), resulting in inhibition of the NMDA response at low glycine concentrations. Inhibition of NMDA receptor function by PMA and ethanol could also be overcome by PKC antagonists, implicating PKC in the inhibitory effect of ethanol. We have now compared the effects of ethanol and PKC activation of NMDA receptor function in primary cultures of rat cerebral cortical cells. The receptor in these cells was much less sensitive to ethanol inhibition, and the inhibition was not overcome by high concentrations of glycine. Furthermore, PMA treatment resulted in an increased response to NMDA at low glycine concentrations. The results indicate that PKC does not mediate ethanol inhibition of NMDA receptor function in cerebral cortical cells, and that the mechanism of ethanol inhibition can vary among brain regions and/or cell types. Possible determinants of the differing mechanisms of ethanol's actions include the subunit composition of the NMDA receptor and/or the isoforms of PKC present in the different cells.


The Indirect Effects of Parent Psychopathology on Offspring Affective Disorder Through Difficulty During the Leaving Home Transition.
The current study examined risk for young adult affective disorder in the children of parents with alcohol use disorders (AUDs), and tested whether negative experiences during the leaving home transition mediated this effect. Using multiple reporter data from a high-risk community sample, the current study included 346 emerging adults (M = 21.97 years old; 49% female, 72% non-Hispanic Caucasian, and 47% with at least one alcohol-disordered parent) from a large metropolitan area. We found that offspring of parents with AUDs were more likely to have negative experiences during the leaving home transition, which in turn predicted increased risk of affective disorders in adulthood. Parents with alcohol disorders may attempt to limit their children's independence from the family of origin or fail to appropriately scaffold their leaving home transition, which is an important developmental task, placing children of alcohol-disordered parents at greater risk of affective disorders in adulthood.


Diatom Assemblage Changes in Agricultural Alluvial Plain Streams and Application for Nutrient Management.
In large, alluvial floodplains dominated by agriculture, small streams have the potential to experience nutrient enrichment affecting algal assemblage structure and metabolism. Nutrient enrichment is largely driven by application of nutrients and altered hydrologic regimes. To inform stressor-response-based nutrient reduction goals for agricultural alluvial plain streams, diatom assemblages were sampled from 25 streams located within the Mississippi Alluvial Plain (MAP) with various land management practices and associated P and N inputs. From August through September 2015, epidendric diatom assemblage samples were collected from instream woody debris. Field nutrient gradients were skewed toward higher concentrations, and ranges of previously reported diatom assemblage response thresholds indicative of oligotrophic conditions were not well represented. Ordination analysis identified a gradient in species composition associated with increasing P and decreasing dissolved oxygen. A significant shift in diatom assemblage structure occurred when total P concentrations in the MAP streams exceeded 0.12 mg L-. Phosphorus-enriched systems were represented by a distinct set of indicator species, lower abundances of ubiquitous species, greater abundances of highly tolerant species, and greater abundances of high-P indicator species. No relationships were observed among diatom assemblage measures or traits with increasing N. Current results do not address potential criteria for identifying high-quality, oligotrophic streams. However, measures of diatom assemblage structure have potential for helping set benchmarks to reduce nutrient impacts and monitor effects of agricultural best management practices on MAP streams.


Computer evaluation of drug interactions with P-glycoprotein.
The (Q)SAR models for evaluating the structure-property relationships, fit for prediction of drug interactions with P-glycoprotein as inhibitors or substrates, were constructed using PASS and GUSAR software. The models were constructed and validated on the basis of information on the structure and characteristics of 256 and 94 compounds used as P-glycoprotein substrates and inhibitors, respectively. The initial samples were divided 80:20 into training and test samples. The best prediction accuracy for the test samples was 78% for P-glycoprotein substrate prediction (PASS) and 89% for inhibitor prediction (GUSAR).


Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI.
The risk of spontaneous first trimester abortion is estimated to be between 10 and 20%. Although it is common knowledge that the incidence of abortion decreases as pregnancy progresses, exact data in relation to the duration of pregnancy are scarce. We reviewed 1597 clinical IVF/ICSI pregnancies with known outcome and tabulated the number of miscarriages or fetal demise per intervals of 2 weeks. We furthermore compared the outcome in terms of fetal survival of 1200 singleton pregnancies with that of 397 twin pregnancies. The overall incidence of non-ongoing singleton pregnancies was 21.7%. Fetal death, after positive heart activity had been recorded, occurred in 12.2% of singleton pregnancies. The overall incidence of spontaneous abortion in twin pregnancies was 17.1% (12.1% vanishing twins and 5.0% complete miscarriages). The incidence of miscarriage in the twin pregnancies, expressed per gestational sac, was 11.1%. Once fetal heart activity was present, the risk of abortion (per gestational sac) was 7.3%, which is significantly lower than that in singleton pregnancies. Our data give an estimate of the probability of miscarriage or fetal demise at any given period of the first trimester both for singleton and twin pregnancies. Twin pregnancies after IVF have a better potential for survival than singleton pregnancies.


Coronary vascular injury due to ischemia-reperfusion is reduced by pentoxifylline.
Myocardial ischemia and reperfusion cause coronary vascular injury involving both the large epicardial arteries and the microcirculation. Although the mechanisms are unclear, leukocytes appear to play an important role. Since the methylxanthine derivative pentoxifylline (PTX) decreases neutrophil activity in vitro, we hypothesized that it might diminish coronary vascular injury due to ischemia and reperfusion. We investigated the effects of PTX on coronary microvascular and epicardial artery injury in open chest, anesthetized dogs undergoing moderate (60 min) or more prolonged (90 min) ischemia due to left anterior descending coronary artery occlusion followed by 60 min of reperfusion. As an index of microvascular injury, we assessed regional permeability with a dual radioisotope protein leak index (PLI) method. Both ischemic periods with reperfusion increased the PLI of severely ischemic (flow less than or equal to 20/ml/min/100 g) myocardium by 2.5- and 3-fold, respectively, compared to nonischemic (flow greater than or equal to 100 ml/min/100 g) myocardium. Treated dogs received PTX (20 mg/kg bolus plus 0.1 mg/kg/min infusion) before ischemia. PTX reduced the increase in the PLI by 40% after 60 min of ischemia (PLI = 5.87 +/- 0.48 vs. 4.10 +/- 0.52 untreated vs. PTX-treated; P less than .05), and by 25% after 90 min of ischemia (6.84 +/- 0.49 vs. 4.84 +/- 0.42; P less than .05). The amount of protein leak was inversely related to ischemic blood flow, and the magnitude of this relationship was significantly reduced in PTX-treated animals. In arterial rings from untreated dogs exposed to 90 min of ischemia followed by reperfusion, there was impaired relaxation to ADP and acetylcholine, but not to sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)


Lower levels of low-density lipoprotein cholesterol are associated with a lower prevalence of thin-cap fibroatheroma in statin-treated patients with coronary artery disease.
Reducing low-density lipoprotein cholesterol (LDL-C) levels with statins slows the progression of atherosclerotic plaques and reduces cardiovascular events. The 2019 European Society of Cardiology/European Atherosclerosis Society guidelines recommend absolute LDL-C treatment targets of <100 mg/dL, <70 mg/dL and <55 mg/dL according to coexisting patient risk factors. To clarify the difference in the plaque characteristics of coronary lesions associated with these LDL-C levels in statin-treated patients. A total of 685 consecutive statin-treated patients with coronary artery disease (CAD) who underwent optical coherence tomography (OCT) imaging of culprit lesions were enrolled. The characteristics of culprit plaques evaluated by OCT were compared among the high LDL-C group (≥100 mg/dL, n=247), the moderate LDL-C group (70-100 mg/dL, n=289), the low LDL-C group (55-70 mg/dL, n=106) and the very low LDL-C group (<55 mg/dL, n=43). A significant trend toward a lower prevalence of thin-cap fibroatheroma (TCFA) associated with the LDL-C groups was observed (23.1, 18.3, 9.4 and 11.6%, respectively, in each group; p=0.002). A trend toward a lower prevalence of TCFAs associated with the LDL-C groups was also observed among patients with lower hemoglobin A1c (<6.2%; p=0.003). LDL-C <70 mg/dL (the low/very low group) was independently associated with the lack of TCFAs (odds ratio, 0.50; 95% confidence interval, 0.27-0.87, p=0.014). Lower LDL-C levels were associated with a lower prevalence of TCFAs in culprit plaques among statin-treated patients with CAD.


Immunoglobulin formation in B lymphoid cells.
A considerable amount is known about Ig biosynthesis by mature plasma cells, which form large amounts of Ig for secretion from the cell. A brief summary is given of the formation of light (L) and heavy (H) chains by polyribosomes aligned on the endoplasmic reticulum and the rapid assembly of the chains into 7S molecules (H2L2) by disulphide bonding. There is a time-ordered secretion from the cell of 7S Ig molecules; the polymeric forms of Ig, ie, IgM and IgA, are formed from monomers by disulphide bond interchange and J chain incorporation at the time of secretion. Myeloma cells from mouse and man have proved very useful in this type of study but such malignant cells show many defects in regulatory mechanisms; therefore, no conclusions can be drawn about normal control mechanisms without analysis of lymphoid tissues from normal or immunized animals. The pattern of Ig synthesis by the mature cell contrasts with that by small B lymphocytes which form 1/50 to 1/100 the amount of Ig produced by mature cells. Most of the small lymphocyte Ig is associated with the cell surface, and in IgM-producing cells the surface receptors are 7S monomer subunits of IgM. Such receptors turn over slowly (24-48 hours); they may be gradually shed from the cell surface but the small lymphocyte does not actively secrete Ig. Antigen- and cell-cell interactions stimulate small B lymphocytes to divide and mature into Ig-secreting cells. Little is known about the associated intracellular events, but preliminary data on lipopolysaccaride-stimulated mouse spleen cells indicate that transcription of m-RNA for H-chain mirrors the kinetics of DNA synthesis. A translational block then occurs during cell maturation and there is a lag of at least 24 hours before Ig production rises sharply and reaches peak levels.


Characterization of monoclonal antibodies reactive with murine leukemia viruses: use in analysis of strains of friend MCF and Friend ecotropic murine leukemia virus.
Sixteen mouse and rat monoclonal antibodies reactive with gag or env proteins of Friend murine leukemia virus (F-MuLV) or recombinant MCF viruses related to F-MuLV were derived. Specificity of these was determined by immunofluorescence, immunoprecipitation, and reactivity with viral proteins blotted onto nitrocellulose paper. Seven antibodies reacted with envelope protein antigens of certain nonecotropic viruses only. Nine antibodies reacted with both ecotropic and nonecotropic viruses. Of this latter group, three were antienvelope, four were anti-p15, one was anti-p12, and one was anti-p30 in specificity. When tested as a panel against 10 strains of F-MuLV, these antibodies could distinguish seven different antigenic patterns. However, all 10 strains retained reactivity for three anti-gp70 antibodies uniquely specific for Friend and Rauscher MuLVs. Our antibody panel could also identify MCF viruses isolated from mice neonatally inoculated with F-MuLV as recombinants related to a particular F-MuLV strain based on identity of p15 gag antigenic profiles. However, recombinant viruses lacked several envelope antigens always associated with F-MuLV and instead had new envelope reactivities. These anti-MCF monoclonal antibodies detected no shared envelope antigens between MCF and xenotropic viruses isolated from mice inoculated with F-MuLV, however many of them did react with MCF viruses derived from AKR mice and NFS mice congenic for endogenous ecotropic virus loci.


T cell independence of bleomycin-induced pulmonary fibrosis.
The role of T cells and cytokines in bleomycin (BLM)-induced fibrosis was evaluated in susceptible and resistant strains of normal and SCID mice. Histology and hydroxyproline analysis showed that BLM induced pulmonary fibrosis in C57BL/6 and (C57BL/6 x BALB/c)F1 mice, whereas BALB/c mice were resistant to the disease. To test whether lymphocytes were required for the induction of BLM-induced pulmonary fibrosis, SCID mice were injected intratracheally with BLM and evaluated for the development of pulmonary inflammation and fibrosis. Similar morphological changes and increases in hydroxyproline were observed in both C57BL/6 SCID and (C57BL/6 x CB.17)F1 SCID animals compared to those seen in wild-type C57BL/6 and (C57BL/6 x BALB/c)F1 mice. In contrast, CB.17 SCID mice, which are genetically similar to BALB/c mice, were resistant to disease induction. Analysis of the cellular infiltrate in BLM-treated C57Bl/6 SCID mice confirmed a lack of T cells in the lungs of SCID mice and demonstrated a pronounced accumulation of eosinophils in areas of developing pulmonary fibrosis. NK cells were significantly elevated in untreated SCID mice and did not increase further after BLM treatment. Analysis of selected cytokines 1 day after initiation of BLM-induced pulmonary fibrosis indicated that the levels of TNF-alpha and IFN-gamma appeared to segregate with fibrosis in both the SCID and wild-type mice. The data demonstrate that T cells are not required for the induction of fibrosis by BLM and suggest that responses by non-lymphoid cells may be sufficient for the induction of fibrosis.


Identification of novel somatic fusions of ERG-VEGFA, TMPRSS2-ERG, and VEGFA-TMPRSS2 in prostate cancer treated with anlotinib and androgen deprivation therapy: A case report.
The TMPRSS2-ERG fusion gene has frequently been found in prostate cancer and is associated with malignancy. Identifying novel fusions will help to stratify patients and establish patient-tailored therapies. A 78-year-old man presented to our hospital with severe symptoms of urinary urgency and frequency for 2 years, as well as severe bone pain for 1 year. He was diagnosed with metastatic prostate cancer with a Gleason score of 5 + 5. Three gene fusions, ERG_VEGFA, TMPRSS2_ERG, and VEGFA_TMPRSS2, were identified in the patient's prostate cancer tissue. Notably, administration of the tyrosine kinase inhibitor, anlotinib, in combination with a gonadotropin-releasing hormone agonist (GnRHa) and abiraterone, reduced the patient's bone pain and also stabilized his prostate cancer for more than 2 years. This is the first report of somatic fusions among the VEGFA, ERG, and TMPRSS2 genes in cancer tissues from a patient with prostate cancer who responded well to antiangiogenic treatment combined with a GnRHa and abiraterone.


Standing in the gap: ref lections on translating the Jung-Neumann correspondence.
This paper considers the experience of translating the correspondence between C.G. Jung and Erich Neumann as part of the Philemon series. The translator explores the similarities between analytical work and the task of translation by means of the concepts of the dialectical third and the interactional field. The history and politics of the translation of analytic writing and their consequences for the lingua franca of analysis are discussed. Key themes within the correspondence are outlined, including Jung and Neumann's pre-war exploration of Judaism and the unconscious, the post-war difficulties around the publication of Neumann's Depth Psychology and a New Ethic set against the early years of the C.G. Jung Institute in Zurich, and the development of the correspondents' relationship over time.


Infant growth patterns in the slums of Dhaka in relation to birth weight, intrauterine growth retardation, and prematurity.
Relations between size and maturity at birth and infant growth have been studied inadequately in Bangladesh, where the incidence of low birth weight is high and most infants are breast-fed. This study was conducted to describe infant growth patterns and their relations to birth weight, intrauterine growth retardation, and prematurity. A total of 1654 infants born in selected low-socioeconomic areas of Dhaka, Bangladesh, were enrolled at birth. Weight and length were measured at birth and at 1, 3, 6, 9, and 12 mo of age. The infants' mean birth weight was 2516 g, with 46.4% weighing <2500 g; 70% were small for gestational age (SGA) and 17% were premature. Among the SGA infants, 63% had adequate ponderal indexes. The mean weight of the study infants closely tracked the -2 SD curve of the World Health Organization pooled breast-fed sample. Weight differences by birth weight, SGA, or preterm categories were retained throughout infancy. Mean z scores based on the pooled breast-fed sample were -2.38, -1. 72, and -2.34 at birth, 3 mo, and 12 mo. Correlation analysis showed greater plasticity of growth in the first 3 mo of life than later in the first year. Infant growth rates were similar to those observed among breast-fed infants in developed countries. Most study infants experienced chronic intrauterine undernourishment. Catch-up growth was limited and weight at 12 mo was largely a function of weight at birth. Improvement of birth weight is likely to lead to significant gains in infant nutritional status in this population, although interventions in the first 3 mo are also likely to be beneficial.


Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates.
The deposition of protein aggregates in various parts of our body gives rise to several devastating diseases, and the development of probes for the selective detection of aggregated proteins is crucial to advance our understanding of the pathogenesis underlying these diseases. LCPs (luminescent conjugated polythiophenes) are fluorescent probes that bind selectively to protein aggregates. The conjugated thiophene backbone is flexible and offers a connection between the conformation and the emission properties, hence binding of LCPs gives the molecule a spectral fingerprint. The present review covers the utilization of LCPs to study the heterogeneity of protein aggregates. It emphasizes specifically the introduction of well-defined probes called LCOs (luminescent conjugated oligothiophenes) and reports how these molecules can be used for real-time in vivo imaging of cerebral plaques as well as for spectral discrimination of protein aggregates and detection of early species in the fibrillation pathway of amyloid β-peptide.


STATE-SPACE SOLUTIONS TO THE DYNAMIC MAGNETOENCEPHALOGRAPHY INVERSE PROBLEM USING HIGH PERFORMANCE COMPUTING.
Determining the magnitude and location of neural sources within the brain that are responsible for generating magnetoencephalography (MEG) signals measured on the surface of the head is a challenging problem in functional neuroimaging. The number of potential sources within the brain exceeds by an order of magnitude the number of recording sites. As a consequence, the estimates for the magnitude and location of the neural sources will be ill-conditioned because of the underdetermined nature of the problem. One well-known technique designed to address this imbalance is the minimum norm estimator (MNE). This approach imposes an L(2) regularization constraint that serves to stabilize and condition the source parameter estimates. However, these classes of regularizer are static in time and do not consider the temporal constraints inherent to the biophysics of the MEG experiment. In this paper we propose a dynamic state-space model that accounts for both spatial and temporal correlations within and across candidate intra-cortical sources. In our model, the observation model is derived from the steady-state solution to Maxwell's equations while the latent model representing neural dynamics is given by a random walk process. We show that the Kalman filter (KF) and the Kalman smoother [also known as the fixed-interval smoother (FIS)] may be used to solve the ensuing high-dimensional state-estimation problem. Using a well-known relationship between Bayesian estimation and Kalman filtering, we show that the MNE estimates carry a significant zero bias. Calculating these high-dimensional state estimates is a computationally challenging task that requires High Performance Computing (HPC) resources. To this end, we employ the NSF Teragrid Supercomputing Network to compute the source estimates. We demonstrate improvement in performance of the state-space algorithm relative to MNE in analyses of simulated and actual somatosensory MEG experiments. Our findings establish the benefits of high-dimensional state-space modeling as an effective means to solve the MEG source localization problem.


3D MRI segmentation and 3D circumferential resection margin evaluation for a standard rectal cancer assessment.
Recent studies focused on rectal cancer suggested that a 3D imaging segmentation obtained from MRI data could contribute in the definition of the circumferential resection margin (CRM) and in the assessment of the tumor regression following neo-adjuvant treatments. Here, we propose a method for defining and visualizing the circumferential margins using 3D MRI segmentation; this methodology was tested in a clinical study comparing 3D CRM assessment vs standard MRI imaging. MRI scans performed before neo-adjuvant treatments were selected and reviewed. 3D mesorectal/tumor segmentations were obtained using Digital Imaging and COmmunications in Medicine (DICOM) data; CRMs were calculated using 3D volumes plus a color scale for the closest distances. 3D reconstructions were possible in all selected cases and 3D images implemented by the color scale were positive for immediate CRM visualization. Statistical analyses comparing standard radiology disclosed that the degree of consistency, the reliability of ratings, the correlation and precision were optimal considering the overall cases, but lower in the CRM>0 mm sub-group. This new method is not inferior comparing standard radiology; moreover, the imaging segmentation we obtained was highly promising and could be helpful in defining a standard CRM measurement, thus it could improve clinical practice.


A universal signature in the melting of metallic nanoparticles.
Predicting when phase changes occur in nanoparticles is fundamental for designing the next generation of devices suitable for catalysis, biomedicine, optics, chemical sensing and electronic circuits. The estimate of the temperature at which metallic nanoparticles become liquid is, however, a challenge and a standard definition is still missing. We discover a universal feature in the distribution of the atomic-pair distances that distinguishes the melting transition of monometallic nanoparticles. We analyse the solid-liquid change of several late-transition metals nanoparticles, i.e. Ni, Cu, Pd, Ag, Au and Pt, through classical molecular dynamics. We consider various initial shapes from 146 to 976 atoms, corresponding to the 1.5-4.1 nm size range, placing the nanoparticles in either a vacuum or embedded in a homogeneous environment, simulated by an implicit force-field. Regardless of the material, its initial shape, size and environment, the second peak in the pair-distance distribution function, expected at the bulk lattice distance, disappears when the nanoparticle melts. As the pair-distance distribution is a measurable quantity, the proposed criterion holds for both numerical and experimental investigations. For a more straightforward calculus of the melting temperature, we demonstrate that the cross-entropy between a reference solid pair-distance distribution function and the one of nanoparticles at increasing temperatures present a quasi-first order transition at the phase-change temperature.


Fundamental limits on inferring epidemic resurgence in real time using effective reproduction numbers.
We find that epidemic resurgence, defined as an upswing in the effective reproduction number (R) of the contagion from subcritical to supercritical values, is fundamentally difficult to detect in real time. Inherent latencies in pathogen transmission, coupled with smaller and intrinsically noisier case incidence across periods of subcritical spread, mean that resurgence cannot be reliably detected without significant delays of the order of the generation time of the disease, even when case reporting is perfect. In contrast, epidemic suppression (where R falls from supercritical to subcritical values) may be ascertained 5-10 times faster due to the naturally larger incidence at which control actions are generally applied. We prove that these innate limits on detecting resurgence only worsen when spatial or demographic heterogeneities are incorporated. Consequently, we argue that resurgence is more effectively handled proactively, potentially at the expense of false alarms. Timely responses to recrudescent infections or emerging variants of concern are more likely to be possible when policy is informed by a greater quality and diversity of surveillance data than by further optimisation of the statistical models used to process routine outbreak data.


Spinal cholinergic neurons and the expression of morphine withdrawal symptoms in the rat.
Behavioral and autonomic signs of the morphine withdrawal syndrome were measured in dependent rats injected with the opiate antagonist naloxone. The purpose of this study was to determine whether spinal cholinergic pathways play a role in the expression of spinally mediated withdrawal symptoms. Intrathecal (i.t.) administration of 1 microgram carbachol or 5 micrograms neostigmine resulted in increases in mean arterial pressure (MAP) of 32 and 45 mm Hg, respectively, in conscious, freely moving rats. The pressor response to carbachol began almost immediately after injection, but that to neostigmine was delayed in onset. Both responses were completely abolished following i.v. injection of 2 mg/kg atropine. However, in spinal-transected (C-1), ventilated rats, i.t. injection of carbachol or neostigmine resulted in only small, transient increases in MAP. Intraarterial (i.a.) injection of 0.5 mg/kg naloxone to morphine-dependent rats resulted in an immediate increase in MAP (to 33 mm Hg) that lasted at least 1 hr. This was accompanied by classical behavioral signs of withdrawal. Pretreatment of dependent rats with i.t. injection of atropine or hemicholinium-3 (HC-3) significantly reduced the pressor and several behavioral responses elicited by naloxone. In contrast, when morphine-dependent, spinal-transected rats were pretreated with i.t. injection of cholinergic antagonists, i.a. injection of naloxone resulted in an enhanced MAP response. Finally, in intact dependent rats, i.t. injection of naloxone (6 micrograms) produced a 14 mm Hg increase in MAP that was significantly augmented (21 mm Hg) following i.t. pretreatment with HC-3.(ABSTRACT TRUNCATED AT 250 WORDS)


Serological studies on the epidemiology of sandfly fever in the Old World.
Selected human sera from 59 different localities in Africa, the Mediterranean littoral, eastern Europe and Asia were examined by plaque reduction neutralization test against eight sandfly (Phlebotomus) fever virus serotypes (Sicilian, Naples, Arumowot, SudAn 754-61, Karimabad, Salehabad, Gordil and Saint Floris) known to occur in the Old World. Results of these studies provide new information on the geographic distribution and prevalence of human infection with each of the viruses. Specific neutralizing antibodies were detected against all of the agents except Salehabad. Naples and Sicilian antibodies were encountered most frequently and had the widest geographic range; moreover they were found only in areas where Phlebotomus papatasi occurs. Age-specific antibody rates for several of the viruses are presented. These data and the epidemiology of sandfly fever are discussed.


Myelin-associated oligodendrocytic basic protein mRNAs reside at different subcellular locations.
The mRNAs for two myelin proteins, myelin basic protein (MBP) and myelin-associated oligodendrocytic basic protein (MOBP)-81A, are uniquely located at sites where myelin sheaths are assembled. Here, we use subcellular fractionation to show that four MOBP mRNAs, like MBP mRNA, are located at sites of myelin sheath assembly, and that three other MOBP mRNAs are located in oligodendrocyte soma. The MOBP-81 protein is found in myelin and in another subcellular fraction, whereas other myelin proteins, including MBP, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and myelin-associated glycoprotein, are largely restricted to myelin. Different MBP mRNAs are generated by alternative splicing. All of them contain an RNA transport sequence (RTS) that directs them to sites in oligodendrocytes, where myelin sheaths are assembled. Consequently, all are enriched in myelin. After fractionation, four MOBP mRNAs, MOBP-71, MOBP-81A, MOBP-99, and MOBP-169 (identified in this study), are enriched in myelin. These mRNAs contain a common exon, exon 8b, which has a nucleotide sequence that is similar to MBP mRNA RTS. This sequence likely directs these mRNAs to sites of myelin sheath assembly. Three other MOBP mRNAs, MOBP-69, MOBP-81B, and MOBP-170, lack this exon. Their subcellular distribution indicates that they are largely retained in oligodendrocyte soma. We conclude that the distribution of MOBPs in oligodendrocytes is strongly influenced by alternative splicing of the corresponding mRNAs.


[Statin therapy: cost-effectiveness and evaluation of evidence as criterium for improving expenditure within the National Health Program].
The choice is difficult in medicine. But individual physicians and patients must make medical decisions rather than organizations or pharmaceutical companies. The choice concerns the transparency of the decision-making process (evidence based medicine), and mistrust of the methods used in cost-effectiveness analysis. Medicare's policy of paying for any medical advance that has positive benefits, regardless of its costs, is un-sustainable. Cost-effectiveness information may assume a more important role in future coverage decisions with regard to outpatient prescription drugs, but at the private level, rather than at the national one. Functional equivalence of drugs reflects a reference-pricing technique applied to a therapeutic category--reimbursement for compounds of similar efficacy within a therapeutic class set to the lowest-priced product in the class. Essentially, a standard of functional equivalence applies a cost-effectiveness principle: assuming that alternative interventions are equivalent, one should not pay more for one of them.