Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks?
Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.


The effect of chaperonin buffering on protein evolution.
Molecular chaperones are highly conserved and ubiquitous proteins that help other proteins in the cell to fold. Pioneering work by Rutherford and Lindquist suggested that the chaperone Hsp90 could buffer (i.e., suppress) phenotypic variation in its client proteins and that alternate periods of buffering and expression of these variants might be important in adaptive evolution. More recently, Tokuriki and Tawfik presented an explicit mechanism for chaperone-dependent evolution, in which the Escherichia coli chaperonin GroEL facilitated the folding of clients that had accumulated structurally destabilizing but neofunctionalizing mutations in the protein core. But how important an evolutionary force is chaperonin-mediated buffering in nature? Here, we address this question by modeling the per-residue evolutionary rate of the crystallized E. coli proteome, evaluating the relative contributions of chaperonin buffering, functional importance, and structural features such as residue contact density. Previous findings suggest an interaction between codon bias and GroEL in limiting the effects of misfolding errors. Our results suggest that the buffering of deleterious mutations by GroEL increases the evolutionary rate of client proteins. We then examine the evolutionary fate of GroEL clients in the Mycoplasmas, a group of bacteria containing the only known organisms that lack chaperonins. We show that GroEL was lost once in the common ancestor of a monophyletic subgroup of Mycoplasmas, and we evaluate the effect of this loss on the subsequent evolution of client proteins, providing evidence that client homologs in 11 Mycoplasma species have lost their obligate dependency on GroEL for folding. Our analyses indicate that individual molecules such as chaperonins can have significant effects on proteome evolution through their modulation of protein folding.


The impact of tutoring on early reading achievement for children with and without attention problems.
This study examined whether the benefits of reading tutoring in first grade were moderated by children's level of attention problems. Participants were 581 children from the intervention and control samples of Fast Track, a longitudinal multisite investigation of the development and prevention of conduct problems. Standardized reading achievement measures were administered after kindergarten and 1st grade, and teacher ratings of attention problems were obtained during 1st grade. During 1st grade, intervention participants received three 30-min tutoring sessions per week to promote the development of initial reading skills. Results replicated prior findings that attention problems predict reduced 1st grade reading achievement, even after controlling for IQ and earlier reading ability. Intervention was associated with modest reading achievement benefits for inattentive children without early reading difficulties, and substantial benefits for children with early reading difficulties who were not inattentive. It had no discernible impact, however, for children who were both inattentive and poor early readers. Results underscore the need to develop effective academic interventions for inattentive children, particularly for those with co-occurring reading difficulties.


Homeopathic medicinal products for preventing and treating acute respiratory tract infections in children.
Acute respiratory tract infections (ARTIs) are common and may lead to complications. Most children experience between three and six ARTIs each year. Although these infections are self limiting, the symptoms can be distressing. Many treatments are used to control symptoms and shorten the duration of illness. They often have minimal benefit and may lead to adverse effects. Oral homeopathic medicinal products could play a role in the treatment of ARTIs for children if evidence for effectiveness is established. To assess the effectiveness and safety of oral homeopathic medicinal products compared with placebo or conventional therapy to prevent and treat acute respiratory tract infections in children. We searched CENTRAL (2017, Issue 11), which contains the Cochrane Acute Respiratory Infections Specialised Register, MEDLINE (1946 to 27 November 2017), Embase (2010 to 27 November 2017), CINAHL (1981 to 27 November 2017), AMED (1985 to December 2014), CAMbase (searched 29 March 2018), British Homeopathic Library (searched 26 June 2013 - no longer operating). We also searched the WHO ICTRP and ClinicalTrials.gov trials registers (29 March 2018), checked references, and contacted study authors to identify additional studies. Double-blind, randomised controlled trials (RCTs) or double-blind cluster-RCTs comparing oral homeopathy medicinal products with identical placebo or self selected conventional treatments to prevent or treat ARTIs in children aged 0 to 16 years. We used standard methodological procedures expected by Cochrane. We included eight RCTs of 1562 children receiving oral homeopathic medicinal products or a control treatment (placebo or conventional treatment) for upper respiratory tract infections (URTIs). Four treatment studies examined the effect on recovery from URTIs, and four studies investigated the effect on preventing URTIs after one to three months of treatment and followed up for the remainder of the year. Two treatment and two prevention studies involved homeopaths individualising treatment for children. The other studies used predetermined, non-individualised treatments. All studies involved highly diluted homeopathic medicinal products.We found several key limitations to the included studies, in particular methodological inconsistencies and high attrition rates, failure to conduct intention-to-treat analysis, selective reporting, and apparent protocol deviations. We assessed three studies as at high risk of bias in at least one domain, and many had additional domains with unclear risk of bias. Three studies received funding from homeopathy manufacturers; one reported support from a non-government organisation; two received government support; one was cosponsored by a university; and one did not report funding support.Methodological inconsistencies and significant clinical and statistical heterogeneity precluded robust quantitative meta-analysis. Only four outcomes were common to more than one study and could be combined for analysis. Odds ratios (OR) were generally small with wide confidence intervals (CI), and the contributing studies found conflicting effects, so there was little certainty that the efficacy of the intervention could be ascertained. All studies assessed as at low risk of bias showed no benefit from oral homeopathic medicinal products; trials at uncertain and high risk of bias reported beneficial effects.We found low-quality evidence that non-individualised homeopathic medicinal products confer little preventive effect on ARTIs (OR 1.14, 95% CI 0.83 to 1.57). We found low-quality evidence from two individualised prevention studies that homeopathy has little impact on the need for antibiotic usage (N = 369) (OR 0.79, 95% CI 0.35 to 1.76). We also assessed adverse events, hospitalisation rates and length of stay, days off school (or work for parents), and quality of life, but were not able to pool data from any of these secondary outcomes.There is insufficient evidence from two pooled individualised treatment studies (N = 155) to determine the effect of homeopathy on short-term cure (OR 1.31, 95% CI 0.09 to 19.54; very low-quality evidence) and long-term cure rates (OR 1.01, 95% CI 0.10 to 9.96; very low-quality evidence). Adverse events were reported inconsistently; however, serious events were not reported. One study found an increase in the occurrence of non-severe adverse events in the treatment group. Pooling of two prevention and two treatment studies did not show any benefit of homeopathic medicinal products compared to placebo on recurrence of ARTI or cure rates in children. We found no evidence to support the efficacy of homeopathic medicinal products for ARTIs in children. Adverse events were poorly reported, so conclusions about safety could not be drawn.


Theoretical studies of energetics and binding isotope effects of binding a triazole-based inhibitor to HIV-1 reverse transcriptase.
Understanding of protein-ligand interactions is crucial for rational drug design. Binding isotope effects, BIEs, can provide intimate details of specific interactions between individual atoms of an inhibitor and the binding pocket. We have applied multi-scale QM/MM simulations to evaluate binding energetics of a novel triazole-based non-nucleoside inhibitor of HIV-1 reverse transcriptase and to calculate associated BIEs. The binding sites can be distinguished based on the (18)O-BIE.


The molecular characterization of fatal infectious mononucleosis.
We describe a retrospective study of 4 cases of sporadic fatal infectious mononucleosis (IM), 1 case of fatal IM, and 1 case of sporadic severe IM. Patients were 26 months to 17 years old; 3 were male. Five died of complications of IM. All 5 of these patients had the Epstein-Barr virus (EBV) present in examined tissue specimens; EBV was monoclonal in 3 patients and biclonal in 1. EBV clonality studies were not performed in the remaining patient. All 5 patients also had monoclonal gene rearrangements. The sixth patient survived despite a life-threatening clinical course; EBV was oligoclonal, and gene rearrangements were not detected. EBV clonality and gene rearrangement studies may be usefulfor predicting which patients with clinically aggressive IM are at highest risk for fatal outcome. Patients in whom IM has a fatal outcome are more likely to have monoclonal or biclonal EBV and immunoglobulin heavy chain or T-cell receptor gene rearrangements. In contrast, patients with nonfatal IM may lack monoclonal EBV and monoclonal rearrangements of the aforementioned genes. The reasons EBV induces a monoclonal proliferation only in some patients remain to be elucidated.


Asymmetric tetranuclear nickel chains with unidirectionally ordered 2-(α-(5-phenyl)pyridylamino)-1,8-naphthyridine ligands.
The new ligand, 2-(α-(5-phenyl)pyridylamino)-1,8-naphthyridine (Hphpyany), was synthesised by a palladium(0)-catalysed reaction of 2-chloro-1,8-naphthyridine with 2-amino-5-phenylpyridine in the presence of potassium tert-butoxide. Linear tetranickel metal complexes, [Ni4(phpyany)4Cl2](CF3SO3) 1, [Ni4(phpyany)4Cl2](BF4)22, [Ni4(phpyany)4(NCS)2](ClO4) 3 and [Ni4(phpyany)4(NCS)2](CF3SO3)24 were prepared and crystallographically characterised. Complexes 1-4 demonstrate that, for the first time, four asymmetric ligands align unidirectionally and thus configure (4,0)-form tetranickel strings, specifically, with the phenyl groups of the four phpyany- pointing to one side of the Ni4 chain and naphthyridyl to the other. The remarkably short Ni-Ni distances (ca. 2.33 Å) for 1 and 3 indicate partial metal-metal bonding, which can be viewed as both complexes containing one mixed-valence Ni23+ unit. The measurements of the magnetic susceptibility reveal that Ni47+ complexes 1 and 3 exhibit antiferromagnetic interactions (J = -42 cm-1 for 1 and -46 cm-1 for 3) between the terminal Ni2+ ion and the Ni23+ unit, while Ni48+ complexes 2 and 4 exhibit antiferromagnetic interactions (J = -33 cm-1 for 2 and -35 cm-1 for 4) between the two terminal Ni2+ ions. The results of the cyclic voltammetry indicate the presence of two reversible redox couples at E1/2(1) = 0.12 V, E1/2(2) = -0.65 V for 1, and at E1/2(1) = 0.12 V, E1/2(2) = -0.72 V for 3. The products of the first oxidation for 1 and 3 are the oxidised species 2 and 4, respectively. The values of single-molecule resistance (15.4 (±3.46) MΩ for 3 and 16.2 (±5.04) MΩ for 4) were determined by STM-based break-junction methods. The results represent the first conductance measurements of linear tetranickel chains.


Visualizing cellular phosphoinositide pools with GFP-fused protein-modules.
Inositol phospholipids are well known for their pivotal role in calcium signaling as precursors of important second messengers generated in response to various stimuli. However, over the last 10 years, inositides have also emerged as universal signaling components present in virtually every membrane of eukaryotic cells. These lipids are locally produced and degraded by the numerous inositide kinase and phosphatase enzymes, to control the recruitment and activity of protein signaling complexes in specific membrane compartments. The spatial and temporal constraints imposed on changes in cellular inositides pose new challenges in finding experimental techniques through which such changes can be examined. Taking advantage of the protein domains selected by evolution to recognize cellular phosphoinositides, we have created fluorescent molecules by fusing these domains to the improved version of green fluorescent protein (EGFP); the distribution of these fusion proteins can be followed within live cells, thereby reporting on changes in phosphoinositides. Although this technique is one of the few that provide information on phosphoinositide dynamics in live cells with subcellular resolution and has rapidly gained popularity, it also has limitations that need to be taken into account when interpreting the data. Here, we summarize our experience in designing and using these constructs and review our position concerning the interpretation of the data obtained by this technique.


Alternative splicing in multiple sclerosis and other autoimmune diseases.
Alternative splicing is a general mechanism for regulating gene expression that affects the RNA products of more than 90% of human genes. Not surprisingly, alternative splicing is observed among gene products of metazoan immune systems, which have evolved to efficiently recognize pathogens and discriminate between "self" and "non-self", and thus need to be both diverse and flexible. In this review we focus on the specific interface between alternative splicing and autoimmune diseases, which result from a malfunctioning of the immune system and are characterized by the inappropriate reaction to self-antigens. Despite the widespread recognition of alternative splicing as one of the major regulators of gene expression, the connections between alternative splicing and autoimmunity have not been apparent. We summarize recent findings connecting splicing and autoimmune disease, and attempt to find common patterns of splicing regulation that may advance our understanding of autoimmune diseases and open new avenues for therapy.


Problem-focussed interactive telephone therapy for cancer patients: a phase II feasibility trial.
The study aimed to evaluate Problem-Focussed Interactive Telephone Therapy, an individual psychological therapy based on cognitive-behavioural therapy adapted for telephone delivery to cancer patients with high psychological needs. A non-randomised, within-group prospective design was used. Outcome measures pre-therapy and post-therapy included were as follows: Hospital Anxiety and Depression Scale, Mental Adjustment to Cancer Scale: helpless/hopeless sub-scale only, Checklist of Cancer Concerns, Cancer Coping Questionnaire and EQ-5D quality of life. A study-specific Service Evaluation Questionnaire was included. Eligible patients were either (i) offered out-patient screening for anxiety/depression/helplessness (n=649) or (ii) referred for psychological care by oncology clinicians (n=160). Thirty two percent (36/114) of screen-identified cases and 22% (35/160) of referred patients participated, and 42 were available for analysis. There were significant post-therapy improvements in Hospital Anxiety and Depression Scale anxiety (p=0.002) and depression (p=0.003), Mental Adjustment to Cancer Scale helpless/hopeless (p=0.036), cancer concerns (p=0.005) and overall quality of life (p=0.048). Overall, 81% (34/42) of participants were defined as clinical cases at baseline and 32% were no longer cases post-therapy. There were significant improvements in coping consistent with the therapy method. A minority of symptomatic patients opt for telephone psychological therapy; however, where they do, there are significant improvements indicating that telephone-delivered therapy is feasible in patients with high needs. Findings are discussed in relation to current issues on the implementation of distress screening and psychological therapy provision within clinical settings.


Homology modeling and molecular dynamics simulation studies of an inward rectifier potassium channel.
A homology model has been generated for the pore-forming domain of Kir6.2, a component of an ATP-sensitive K channel, based on the x-ray structure of the bacterial channel KcsA. Analysis of the lipid-exposed and pore-lining surfaces of the model reveals them to be compatible with the known features of membrane proteins and Kir channels, respectively. The Kir6.2 homology model was used as the starting point for nanosecond-duration molecular dynamics simulations in a solvated phospholipid bilayer. The overall drift from the model structure was comparable to that seen for KcsA in previous similar simulations. Preliminary analysis of the interactions of the Kir6.2 channel model with K(+) ions and water molecules during these simulations suggests that concerted single-file motion of K(+) ions and water through the selectivity filter occurs. This is similar to such motion observed in simulations of KcsA. This suggests that a single-filing mechanism is conserved between different K channel structures and may be robust to changes in simulation details. Comparison of Kir6.2 and KcsA suggests some degree of flexibility in the filter, thus complicating models of ion selectivity based upon a rigid filter.


Population genomics of the Viking world.
The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.


Physiotherapists in Balint group training.
Balint group training (BGT) is a method widely used for enhancing understanding of the relationship and communication between health professionals and their patients. Participants meet in small groups, on a regular basis, with a tutor to discuss their experiences of problem cases. The method was originally developed in the 1950s for enhancing understanding of the doctor-patient relationship. Few studies have focused on BGT and physiotherapists. The aim of the present study was to describe and analyse physiotherapists' experiences of participation in BGT as a means of learning and understanding the physiotherapist-patient relationship. Semi-structured, in-depth interviews were conducted with three physiotherapists working in private practice, all participating in BGT. The interviews were transcribed and subjected to a qualitative analysis. The results are presented in a sequential model, featuring eight themes in which the physiotherapists' experiences of the training process are portrayed. The results suggest that BGT and sharing the experiences of others may be considered a way of enhancing understanding of the patient encounter in clinical practice, possibly to the benefit of physiotherapists and their patients.


Unveiling the formation pathway of single crystalline porous silicon nanowires.
Porous silicon nanowire is emerging as an interesting material system due to its unique combination of structural, chemical, electronic, and optical properties. To fully understand their formation mechanism is of great importance for controlling the fundamental physical properties and enabling potential applications. Here we present a systematic study to elucidate the mechanism responsible for the formation of porous silicon nanowires in a two-step silver-assisted electroless chemical etching method. It is shown that silicon nanowire arrays with various porosities can be prepared by varying multiple experimental parameters such as the resistivity of the starting silicon wafer, the concentration of oxidant (H(2)O(2)) and the amount of silver catalyst. Our study shows a consistent trend that the porosity increases with the increasing wafer conductivity (dopant concentration) and oxidant (H(2)O(2)) concentration. We further demonstrate that silver ions, formed by the oxidation of silver, can diffuse upwards and renucleate on the sidewalls of nanowires to initiate new etching pathways to produce a porous structure. The elucidation of this fundamental formation mechanism opens a rational pathway to the production of wafer-scale single crystalline porous silicon nanowires with tunable surface areas ranging from 370 to 30 m(2) g(-1) and can enable exciting opportunities in catalysis, energy harvesting, conversion, storage, as well as biomedical imaging and therapy.


Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial.
To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]-Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.


The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost-effectiveness modelling studies.
Cost-effectiveness studies inform resource allocation, strategy, and policy development. However, due to their complexity, dependence on assumptions made, and inherent uncertainty, synthesising, and generalising the results can be difficult. We assess cost-effectiveness models evaluating expected health gains and costs of HIV pre-exposure prophylaxis (PrEP) interventions. We conducted a systematic review comparing epidemiological and economic assumptions of cost-effectiveness studies using various modelling approaches. The following databases were searched (until January 2013): PubMed/Medline, ISI Web of Knowledge, Centre for Reviews and Dissemination databases, EconLIT, and region-specific databases. We included modelling studies reporting both cost and expected impact of a PrEP roll-out. We explored five issues: prioritisation strategies, adherence, behaviour change, toxicity, and resistance. Of 961 studies retrieved, 13 were included. Studies modelled populations (heterosexual couples, men who have sex with men, people who inject drugs) in generalised and concentrated epidemics from Southern Africa (including South Africa), Ukraine, USA, and Peru. PrEP was found to have the potential to be a cost-effective addition to HIV prevention programmes in specific settings. The extent of the impact of PrEP depended upon assumptions made concerning cost, epidemic context, programme coverage, prioritisation strategies, and individual-level adherence. Delivery of PrEP to key populations at highest risk of HIV exposure appears the most cost-effective strategy. Limitations of this review include the partial geographical coverage, our inability to perform a meta-analysis, and the paucity of information available exploring trade-offs between early treatment and PrEP. Our review identifies the main considerations to address in assessing cost-effectiveness analyses of a PrEP intervention--cost, epidemic context, individual adherence level, PrEP programme coverage, and prioritisation strategy. Cost-effectiveness studies indicating where resources can be applied for greatest impact are essential to guide resource allocation decisions; however, the results of such analyses must be considered within the context of the underlying assumptions made. Please see later in the article for the Editors' Summary.


Depressive Symptoms Affect Working Memory in Healthy Older Adult Hispanics.
Low and middle income nations will experience an unprecedented growth of the elderly population and subsequent increase in age-related neurological disorders. Worldwide prevalence and incidence of all-types of neurological disorders with serious mental health complications will increase with life expectancy across the globe. One-in- ten individuals over 75 has at least moderate cognitive impairment. Prevalence of cognitive impairment doubles every 5 years thereafter. Latin America's population of older adult's 65 years and older is growing rapidly, yet little is known about cognitive aging among healthy older Latinos. Clinically significant depressive symptomatology is common among community-dwelling older adults and is associated with deficits across multiple cognitive domains, however much of the literature has not modeled the unique effects of depression distinct from negative and low positive affect. Our objective was to understand how mental health affects cognitive health in healthy aging Latinos. The present study used confirmatory factor analysis (CFA) and structural equation modeling (SEM) to examine the relative effects of Negative Affect, Positive Affect and Geriatric Depression on Verbal Memory, Verbal Reasoning, Processing Speed, and Working Memory in healthy aging Latinos. Data was collected from a sample of healthy community dwelling older adults living in San Jose, Costa Rica. Modeling of latent variables attenuated error and improved measurement reliability of cognition, affect, and depression variables. Costa Ricans enjoy a notoriety for being much happier than US citizens and are renowned as one of the happiest nations in the world in global surveys. This was born out in these data. Costa Rican affective profiles differed substantively from US profiles. Levels of negative affect and depression were similar to US samples, but their levels of positive affect were much higher. Cognitive performance of these Costa Rican older adults was similar to US-age and education matched peers. CFA and SEM found that increased depressive symptomatology had deleterious effects on Working Memory made up of subtest scores sampling simple attention and vigilance for numbers. Verbal Memory, Verbal Reasoning, and Processing Speed were not affected by self-reported Positive Affect, Negative Affect or Depressive symptoms. Costa Rican older adults were happy, as evidenced by the high ratio of positive affect to relatively low negative affect. Thus, we were somewhat surprised to find that depressive symptoms were selectively correlated to decrements in working memory and that negative and positive affect contributed negligible amounts of variance to any of the cognitive factors. Because of the methodological rigor of latent variable analysis, these results are very specific. The Working Memory factor is not contaminated with Speed of Processing or other measured cognitive factors. Likewise, the measured Geriatric Depression represents symptoms that are richly cognitive, not overtly affective.


Enhanced absorption and electro-optic Pockels effect of electrostatically self-assembled CdSe quantum dots.
The spectrum and electro-optic properties of CdSe quantum dots are studied. Spectrum wavelength shifts that are due to the quantum size effect and to the electro-optic Stark effect are investigated. It is found that CdSe quantum dot-polymer composites formed by an electrostatic self-assembly (ESA) technique exhibit high internal electric fields. Using the second-order perturbation theory of the 1s-1s energy shift (Stark effect), we estimate the internal field of the ESA film to be as high as 2.6 x 10(8) V/m. This value results in a much higher absorption coefficient and electro-optic coefficients for ESA films than for their bulk crystal counterparts or for spin-coated film samples. The relationships among unusual spectra, film structure, and high electro-optic response are analyzed. These results are useful both for understanding the physical mechanisms of semiconductor quantum dots and for developing high-performance photonic devices.


Epidemic of salmonellosis in passerine birds in Switzerland with spillover to domestic cats.
A die-off of passerine birds, mostly Eurasian siskins (Carduelis spinus), occurred in multiple areas of Switzerland between February and March 2010. Several of the dead birds were submitted for full necropsy. Bacteriological examination was carried out on multiple tissues of each bird. At gross examination, common findings were light-tan nodules, 1 to 4 mm in diameter, scattered through the esophagus/crop. Histologically, a necroulcerative transmural esophagitis/ingluvitis was observed. Bacterial cultures yielded Salmonella enterica subsp. enterica serovar Typhimurium. At the same time, 2 pet clinics reported an unusual increase of domestic cats presented with fever, anorexia, occasionally dolent abdomen, and history of presumed consumption of passerine birds. Analysis of rectal swabs revealed the presence of S. Typhimurium in all tested cats. PFGE (pulsed field electrophoresis) analysis was performed to characterize and compare the bacterial isolates, and it revealed an indistinguishable pattern between all the avian and all but 1 of the feline isolates. Cloacal swabs collected from clinically healthy migrating Eurasian siskins (during autumn 2010) did not yield S. Typhimurium. The histological and bacteriological findings were consistent with a systemic infection caused by S. Typhimurium. Isolation of the same serovar from the dead birds and ill cats, along with the overlapping results of the PFGE analysis for all the animal species, confirmed a spillover from birds to cats through predation. The sudden increase of the number of siskins over the Swiss territory and their persistency during the whole winter of 2009-2010 is considered the most likely predisposing factor for the onset of the epidemic.


Comparison of Plant Morphology, Yield and Nutritional Quality of Fagopyrum esculentum and Fagopyrum tataricum Grown under Field Conditions in Belgium.
Buckwheat is a pseudocereal with high nutritional and nutraceutical properties. Although common buckwheat (Fagopyrum esculentum) is the main cultivated species, Tartary buckwheat (Fagopyrum tataricum) is gaining interest. In this paper, we compared plant growth, yield-related parameters and seed nutritional qualities of two varieties of F. esculentum and F. tataricum under field conditions in Belgium. Fagopyrum esculentum flowered earlier, produced less nodes, less branches, less inflorescences, but more flowers per inflorescence than F. tataricum. The yield was higher in F. tataricum, while the thousand-grain weight was higher in F. esculentum. Yield ranged between 2037 kg/ha and 3667 kg/ha depending on the species and year. Regarding nutritional qualities, seeds of F. esculentum contained more proteins (15.4% vs. 12.8%) than seeds of F. tataricum although their amino acid profile was similar. Seeds of F. esculentum contained also more Mg (1.36 vs. 1.15 mg/g dry weight (DW)) and less Fe (22.9 vs. 32.6 µg/g DW) and Zn (19.6 vs. 24.5 µg/g DW) than F. tataricum. The main difference between seed nutritional quality was the concentration of flavonoids that was 60 times higher in F. tataricum than in F. esculentum. Both species grow well under Belgian conditions and showed good seed quality.


Defining high-risk individuals in a population-based molecular-epidemiological study of lung cancer.
Within the framework of the Liverpool Lung Project (LLP), population-based case-control and prospective cohort studies are in progress to identify molecular and epidemiological risk factors and define populations and individuals most at risk of developing lung cancer. This report describes a strategy for selection of a high-risk population and further provides support for the inclusion of occupational and genetic risk factors in future models. Data from the case-control study (256 incident cases and 314 population controls) were analysed to define a high-risk population. Detailed lifestyle and occupational information were collected during structured interviews. Models were constructed using conditional logistic regression and included terms for age, tobacco consumption and previous respiratory disease. Smoking duration was chosen as the most important predictor of lung cancer risk [>50 years (OR 15.65, 95% CI 6.10-40.15)]. However, such a model would preclude younger individuals. Several combinations of previous respiratory disease were also considered, of which a history of bronchitis, emphysema or pneumonia (BEP) was the most significant (OR 1.86, 95% CI 1.28-2.69). A high-risk subset (based on combinations of smoking duration and BEP) was identified, which have a 4.5-fold greater risk of developing lung cancer (OR 4.5, 95% CI 2.33-8.68). Future refinement of the risk model to include individuals occupationally exposed to asbestos and with the p21 genotypes is discussed. There is real potential for environmental and genetic factors to improve on risk prediction and targeting of susceptible individuals beyond the traditional models based only on smoking and age. The development of a molecular-epidemiological model will inform the development of effective surveillance, early detection and chemoprevention strategies.


Linkage disequilibrium in MNSs blood group system in population of south Backa.
Linkage disequilibrium is a characteristic of MNSs blood group system which performs more frequent association of linked alleles than it is expected in comparison with their allelic frequencies. Measure of linkage disequilibrium is the difference between expected and actual genotypic frequencies which is stated in coefficient of linkage disequilibrium. The purpose of this study was to fortify existence of linkage disequilibrium phenomenon inside MNSs blood group system in population of South Backa in comparison with calculated allelic frequencies. Blood group typing in MNSs system included 1,000 healthy nonrelated persons where allelic frequencies, expected and actual genotype frequencies had been calculated, as well as the differences between them. Results of investigation showed that allele has the highest allelic frequency (0.672), S allele has the lowest frequency (0.33), the highest expected frequencies are calculated for Ms/Ns (Ms/NS) (0.218) and Ms/Ns (0.2235) genotypes, while the actual frequencies are highest for MS/NS (Ms/NS) (0.184), Ms/Ns (0.193) and Ns/Ns (0.153) genotypes. Statistically significant difference between expected and actual genotypic frequencies occurs for Ms/MS and Ns/Ns genotypes, which means that S and M and N and s alleles are more frequently associated and prove the existence of linkage disequilibrium phenomenon in population of South Backa.


Precursors for liver gluconeogenesis in periparturient dairy cows.
The review is based on a compiled data set from studies quantifying liver release of glucose concomitant with uptake of amino acids (AA) and other glucogenic precursors in periparturient dairy cows. It has become dogma that AAs are significant contributors to liver gluconeogenesis in early lactation, presumably accounting for the observed lack of glucogenic precursors to balance estimated glucose need. Until recently, there has been paucity in quantitative data on liver nutrient metabolism in the periparturient period. Propionate is the quantitatively most important glucogenic precursor throughout the periparturient period. However, the immediate post partum increment in liver release of glucose is not followed by an equivalent increment in propionate uptake, because of the lower rate of increment in feed intake compared with the rate of increment in requirements for milk synthesis. The quantitative data on liver metabolism of AA do not support the hypothesis that the rapid post partum increase in net liver release of glucose is supported by increased utilisation of AA for gluconeogenesis. Only alanine is likely to contribute to liver release of glucose through its role in the inter-organ transfer of nitrogen from catabolised AA. AAs seem to be prioritised for anabolic purposes, indicating the relevance of investigating effects of supplying additional protein to post partum dairy cows. Combining data from quantitative and qualitative experimental techniques on L-lactate metabolism point to the conclusion that the quantitatively most important adaptation of metabolism to support the increased glucose demand in the immediate post partum period is endogenous recycling of glucogenic carbon through lactate. This is mediated by a dual site of adaptation of metabolism in the liver and in the peripheral tissues, where the liver affinity for L-lactate is increased and glucose metabolism in peripheral tissues is shifted towards L-lactate formation over complete oxidation.


Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers.
To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan-Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III-IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I-II (74, 82, and 86%; P<0.0001) and stage III-IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.


Association of -1082 interleukin-10 gene polymorphism in Peruvian adults with chronic periodontitis.
The aim of this study was to assess association of the -1082 IL-10 gene polymorphism with chronic periodontitis CP in a Peruvian population. Samples of venous blood and DNA were obtained from 106 Peruvian subjects: a) 53 periodontally healthy; and b) 53 with CP. The association of the -1082 IL-10 promoter sequences was assessed by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Student's t test were used to assess the clinical parameters, as well as the χ2 test and the odds ratio (OR), with 95% confidence intervals (CI) used performed for estimates regarding genotype and allele frequencies. There were statistically significant differences between groups regarding the mean bleeding on probing, mean attachment level and mean probing depth (p < 0.00001) indicating that the matching based on the evaluated groups was adequate. The χ2 test found a statistically significant imbalance of genotypes between groups (p = 0.0172). The prevalence of CP was significantly higher in subjects harboring at least one A allele at position -1082 (AA and GA genotypes) in comparison to patients with the GG genotype (OR = 2.96; CI: 0.52; 5.41; p = 0.0099). Equally, subjects with the AA genotype were significantly associated to a diagnosis of CP (OR = 2.71; CI: 0.38; 5.04; p = 0.0231). On the other hand, subjects presenting a healthy periodontal status presented at least one G allele in comparison with the AA genotype (OR = 0.37; CI: 0.05, 0.69; p = 0.0231). For subjects with the GG genotype, the same positive association was observed (OR = 0.34; CI: 0.06, 0.62; p = 0.0099). There were no significant differences between groups amongst subjects with the GA genotype (OR = 1.19; CI: 0.22, 2.16; p = 0.6774). Within the limits of this study, IL-10 gene polymorphism at position -1082 does not appear to be associated to CP. Conversely, subjects with AA genotype seem to be at an increased risk of developing CP.


A New Methodology for Before-After Safety Assessment Using Survival Analysis and Longitudinal Data.
The widely used empirical Bayes (EB) and full Bayes (FB) methods for before-after safety assessment are sometimes limited because of the extensive data needs from additional reference sites. To address this issue, this study proposes a novel before-after safety evaluation methodology based on survival analysis and longitudinal data as an alternative to the EB/FB method. A Bayesian survival analysis (SARE) model with a random effect term to address the unobserved heterogeneity across sites is developed. The proposed survival analysis method is validated through a simulation study before its application. Subsequently, the SARE model is developed in a case study to evaluate the safety effectiveness of a recent red-light-running photo enforcement program in New Jersey. As demonstrated in the simulation and the case study, the survival analysis can provide valid estimates using only data from treated sites, and thus its results will not be affected by the selection of defective or insufficient reference sites. In addition, the proposed approach can take into account the censored data generated due to the transition from the before period to the after period, which has not been previously explored in the literature. Using individual crashes as units of analysis, survival analysis can incorporate longitudinal covariates such as the traffic volume and weather variation, and thus can explicitly account for the potential temporal heterogeneity.


Pre-pharyngeal Swallow Effects of Recurrent Laryngeal Nerve Lesion on Bolus Shape and Airway Protection in an Infant Pig Model.
Recurrent laryngeal nerve (RLN) damage in infants leads to increased dysphagia and aspiration pneumonia. Recent work has shown that intraoral transport and swallow kinematics change following RLN lesion, suggesting potential changes in bolus formation prior to the swallow. In this study, we used geometric morphometrics to understand the effect of bolus shape on penetration and aspiration in infants with and without RLN lesion. We hypothesized (1) that geometric bolus properties are related to airway protection outcomes and (2) that in infants with RLN lesion, the relationship between geometric bolus properties and dysphagia is changed. In five infant pigs, dysphagia in 188 swallows was assessed using the Infant Mammalian Penetration-Aspiration Scale (IMPAS). Using images from high-speed VFSS, bolus shape, bolus area, and tongue outline were quantified digitally. Bolus shape was analyzed using elliptical Fourier analysis, and tongue outline using polynomial curve fitting. Despite large inter-individual differences, significant within individual effects of bolus shape and bolus area on airway protection exist. The relationship between penetration-aspiration score and both bolus area and shape changed post lesion. Tongue shape differed between pre- and post-lesion swallows, and between swallows with different IMPAS scores. Bolus shape and area affect airway protection outcomes. RLN lesion changes that relationship, indicating that proper bolus formation and control by the tongue require intact laryngeal sensation. The impact of RLN lesion on dysphagia is pervasive.


Pesticide management and their residues in sediments and surface and drinking water in the Mekong Delta, Vietnam.
Public concern in Vietnam is increasing with respect to pesticide pollution of the environment and of drinking water resources. While established monitoring programs in the Mekong Delta (MD) focus on the analysis of organochlorines and some organophosphates, the environmental concentrations of more recently used pesticides such as carbamates, pyrethroides, and triazoles are not monitored. In the present study, household level pesticide use and management was therefore surveyed and combined with a one year environmental monitoring program of thirteen relevant pesticides (buprofezin, butachlor, cypermethrin, α-endosulfan, β-endosulfan, endosulfan-sulfate, fenobucarb, fipronil, isoprothiolane, pretilachlor, profenofos, propanil, and propiconazole) in surface water, soil, and sediment samples. The surveys showed that household level pesticide management remains suboptimal in the Mekong Delta. As a consequence, a wide range of pesticide residues were present in water, soil, and sediments throughout the monitoring period. Maximum concentrations recorded were up to 11.24 μg l(-1) in water for isoprothiolane and up to 521 μg kg(-1) dm in sediment for buprofezin. Annual average concentrations ranged up to 3.34 μg l(-1) in water and up to 135 μg kg(-1) dm in sediment, both for isoprothiolane. Occurrence of pesticides in the environment throughout the year and co-occurrence of several pesticides in the samples indicate a considerable chronic exposure of biota and humans to pesticides. This has a high relevance in the delta as water for drinking is often extracted from canals and rivers by rural households (GSO, 2005, and own surveys). The treatment used by the households for preparing surface water prior to consumption (flocculation followed by boiling) is insufficient for the removal of the studied pesticides and boiling can actually increase the concentration of non-volatile pollutants.


Efficacy of phenelzine and haloperidol in borderline personality disorder.
To compare the efficacy of a neuroleptic (haloperidol) to a monoamine oxidase inhibitor antidepressant (phenelzine sulfate) against the affective, cognitive, and impulsive-aggressive symptoms of criteria-defined borderline inpatients in an effort to dissect apart affective and schizotypal symptom patterns or subtypes using medication response. Randomized, double-blind, placebo-controlled trial. Inpatient unit of a tertiary care university psychiatric hospital serving a large public catchment area. One hundred eight consecutively admitted borderline inpatients defined by Gunderson's Diagnostic Interview for Borderline Patients and DSM-III-R criteria, randomly assigned to 38 phenelzine, 36 haloperidol, and 34 placebo trials. Following 1 week free of medication, haloperidol (average dose, 4 mg/d), phenelzine sulfate (average dose, 60 mg/d), or placebo were given for 5 weeks with weekly symptom ratings and plasma drug level determinations. Efficacy was measured on depression (Hamilton Rating Scale, Beck Depression Inventory), global severity (Global Assessment Scale, Symptom Checklist-90 items [SCL-90]), anxiety, anger-hostility (SCL-90, Inpatient Multidimensional Psychiatric Scale [IMPS], Buss-Durkee Hostility Inventory), psychoticism (Schizotypal Symptom Inventory, SCL-90, IMPS), impulsivity (Ward Scale, Barratt Impulsiveness Scale, Self-Report Test of Impulse Control), and borderline psychotherapy (Borderline Syndrome Index). Three-way comparisons between groups indicated superior efficacy for phenelzine, followed by placebo and haloperidol on measures of depression, borderline psychopathologic symptoms, and anxiety. Pairwise comparisons between medication and placebo revealed significant efficacy for phenelzine against anger and hostility but no efficacy against atypical depression or hysteroid dysphoria. We were unable to replicate prior reports of efficacy for the neuroleptic. Pharmacologic dissection of borderline personality disorder patients into affective and schizotypal subtypes could not be demonstrated.


Neonatal hypoxic encephalopathy: Correlation between post-cooling brain MRI findings and 2 years neurodevelopmental outcome.
This study aims to evaluate the magnetic resonance imaging (MRI) brain patterns among hypoxic-ischemic encephalopathy (HIE) babies who underwent post-cooling MRI brain as well as to correlate the post-cooling brain scoring with patient's neurodevelopmental outcome at 2 years. It was a retrospective cross sectional study carried out at a tertiary university hospital. Record of patients diagnosed with neonatal HIE from 2007 until 2016 who completed 72 h of cooling therapy and had MRI brain within 2 weeks of life were included in this study. A new scoring system by Trivedi et al. that emphasizes on subcortical deep gray matter and posterior limb internal capsule injury were utilized upon MRI assessment, using TW, T2W, and diffusion-weighted imaging (DWI) sequences. Cumulative MRI brain score was obtained and graded as none, mild, moderate, and severe brain injury. The MRI brain scoring was then correlated with patient's 2 years neurodevelopmental outcome using Fisher's Exact Test. A total of 23 patients were eligible of which 19 term neonates were included. 13% of these neonates (n = 3) had mild MRI brain injury grading with 52.2% (n = 12) moderate and 34.8% (n = 8) severe. There was no significant correlation seen between MRI brain grading and developmental outcome at 2 years old (P > 0.05). There was no significant correlation between neonatal MRI brain injury grading and 2 years neurodevelopmental outcome. Nevertheless, the new MRI brain scoring by Trivedi et al. is reproducible and comprehensive as it involves various important brain structures, assessed from different MRI sequences.


Synthesis and processing of simian virus 40-specific RNA in adenovirus-infected, simian virus 40-transformed human cells.
Human simian virus 80 (SV80) cells transformed by simian virus 40 (SV40) synthesize substantial quantities of the SV40 large T-antigen (Henderson & Livingston, 1974; Tjian, 1978) and cytoplasmic, poly(A)-containing RNA species that exhibit spliced structures characteristic of the SV40, early messenger RNA species that encode both large and small T-antigens (Flint & Beltz, 1979). When SV80 cells were infected with type C adenovirus, both the synthesis of SV40 large T-antigen and the appearance in the cytoplasm of newly synthesized, SV40-specific RNA sequences were inhibited during the late phase of infection. The results of hybridization to SV40 DNA of SV80 nuclear RNA, prepared from mock- or adenovirus-infected cells after labeling for short periods in vivo or in vitro, indicated that transcription of integrated SV40 was, by contrast, not disrupted during the late phase of adenovirus infection. Poly(A)-containing, nuclear RNA species that hybridized to SV40 DNA sequences and exhibited the sizes of spliced, large and small T-antigen mRNA species were also synthesized in infected cells at a time when the corresponding mRNA sequences did not leave the nucleus. These results suggest that the failure of non-adenoviral mRNA sequences to enter the cytoplasm of adenovirus-infected cells does not reflect inhibition of either their transcription or the normal enzymatic processing reactions to which pre-mRNA species are subject. Several lines of evidence do, however, establish that nuclear, SV40-specific RNA sequences are less stable in adenovirus-infected compared to mock-infected SV80 cells.


Feasibility of using global positioning systems (GPS) with diverse urban adults: before and after data on perceived acceptability, barriers, and ease of use.
Global positioning systems (GPS) have emerged as a research tool to better understand environmental influences on physical activity. This study examined the feasibility of using GPS in terms of perceived acceptability, barriers, and ease of use in a racially/ethnically diverse sample of lower socioeconomic position (SEP). Data were from 2 pilot studies involving a total of 170 African American, Hispanic, and White urban adults with a mean (standard deviation) age of 47.8 (±13.1) years. Participants wore a GPS for up to 7 days. They answered questions about GPS acceptability, barriers (wear-related concerns), and ease of use before and after wearing the GPS. We found high ratings of GPS acceptability and ease of use and low levels of wear-related concerns, which were maintained after data collection. While most were comfortable with their movements being tracked, older participants (P < .05) and African Americans (P < .05) reported lower comfort levels. Participants who were younger, with higher education, and low incomes were more likely to indicate that the GPS made the study more interesting (P < .05). Participants described technical and wear-related problems, but few concerns related to safety, loss, or appearance. Use of GPS was feasible in this racially/ethnically diverse, lower SEP sample.


Expression of Ki67 and P53 in primary squamous cell carcinoma of the larynx.
We studied a series of untreated laryngeal carcinomas in an attempt to determine the relationship between Ki67 and p53 expression and clinicopathological findings. The relationship between expression of these markers in non-tumoral tissue was also evaluated in order to investigate the possible role of immunohistochemistry as a diagnostic aid in evaluating laryngeal biopsies. Samples from 54 patients with laryngeal squamous cell carcinoma (SCC) were analyzed retrospectively. The uninvolved vocal cord was evaluated as a non-tumoral sample. Paraffin sections of tumors were immunohistochemically stained for p53 and Ki67 expression. Overall, p53 expression was found in 35 (64.8%) of the patients. There was a significant correlation among tumoral p53 expression and tumor location, tumor stage and lymph node involvement. Most grade I tumors had a Ki67 labeling index <50% and a labeling index ≥ 50 was found mainly in high-grade tumors. Tumoral Ki67 expression correlated significantly with tumor grade and mitotic count. There was no correlation between Ki67 labeling index and tumor region. In non-tumoral tissue, 95% of high-grade pre-neoplastic lesions revealed a high expression of Ki67. Non-tumoral p53 expression did not correlate with histological findings. p53 and Ki67 expression in tumoral tissue may be a prognostic marker in patients with laryngeal SCC. Evaluation of the proliferative index in biopsy samples of dysplastic laryngeal mucosa is potentially useful for predicting the progression toward carcinoma.


Probing hot spots on protein-protein interfaces with all-atom free-energy simulation.
Modulation of protein-protein interactions by competitive small-molecule binding emerges as a promising avenue for drug discovery. Hot spots, i.e., amino acids with important contributions to the overall interaction energy, provide useful targets within these interfaces. To avoid time-consuming mutagenesis experiments, computational alanine screening has been developed for the prediction of hot spots based on existing structural information. Here we use the all-atom free-energy force field PFF02 to identify important amino acid residues in the complexes of the chemokine interleukin-8 (CXCL8) and an N-terminal peptide of its cognate receptor CXCR1, and of ERBIN, a molecular marker of the basolateral membrane in epithelial cells, in complex with the ERBIN-binding domain of tyrosin kinase ERBB2. The results of our analysis agree with available experimental functional assays, indicating that this approach is suitable for computational alanine screening and may help to identify competitive peptides as starting points for the development of inhibitors of protein-protein interactions for pharmaceutically relevant targets.


Effect of Fungicide Seed Treatments, Cultivars, and Soils on Soybean Stand Establishment.
Seedling diseases are one of the major production problems for soybean. The primary control of soybean seedling diseases is by fungicide seed treatments but comparisons of seed treatments are difficult because stand responses are often erratic in the field. The objective of this study was to determine the efficacy of soybean fungicide seed treatments in naturally infested soils under controlled environments at three temperatures. Seed of three soybean cultivars were treated with six fungicide treatments or not treated and planted in two soil types collected from two fields in April, May, and June 2008 and 2009. Tests were conducted in growth chambers at 21°C (April planting), 25°C (May planting), or 28°C (June planting). Stands were determined when at least 25% of the seedlings reached the V4 growth stage. Seed treatments improved stands at all three temperatures, in both soils, and in both years. In general, the broad-spectrum fungicides trifloxystrobin + metalaxyl and mefenoxam + fludioxonil + azoxystrobin resulted in the highest stands. The selective fungicide treatments metalaxyl and pentachloronitrobenzene + carboxin were effective at all three temperatures, implying that Pythium spp. and Rhizoctonia solani, respectively, were involved in seedling disease and active over a range of temperatures. The efficacy of fungicides was not consistently associated with the cultivars used in this study.


Dispersion Characteristics and Aggregation in Titanate Nanowire Colloids.
Titanate nanowires (TiONWs) are synthesized through the hydrothermal method and characterized in acidic aqueous dispersions by using electrophoresis, dynamic light scattering, and atomic force microscopy. The TiONWs have a rodlike shape with an average length of about 600 nm and a thickness of 35 nm. They are positively charged under the conditions used. Their surface charge properties and aggregation are investigated in the presence of oppositely charged poly(styrene sulfonate) (PSS) polyelectrolyte. Charge neutralization followed by a subsequent charge reversal process is observed, which is attributed to the adsorption of PSS. The colloids are unstable near the charge neutralization point and stable at lower and higher PSS doses, in good qualitative agreement with the theory developed by Derjaguin, Landau, Verwey, and Overbeek (DLVO). The nanowires prefer to align along the walls, leading to "spaghetti-like" oriented aggregates. The aggregation processes of bare and PSS-coated TiONWs are monitored at different concentrations of an inert electrolyte; slow aggregation is found at low salt levels, whereas aggregation is rapid beyond the critical coagulation concentration, as predicted by the DLVO theory, which describes the colloid stability of the TiONWs adequately in all the systems investigated. Coating of the nanowires with the polyelectrolyte leads to a critical coagulation concentration 75 times higher than that of the bare titanates, indicating the enormous stabilizing effect of PSS.


Local cholinergic mechanisms mediate nitric oxide-dependent flow-induced vasorelaxation in vitro.
To determine whether local cholinergic mechanisms evoke nitric oxide (NO)-mediated flow-induced vasorelaxation, canine coronary artery rings without endothelium were suspended beneath an organ chamber that contained a stainless steel tube and a femoral artery segment with endothelium. The rings were superfused at a basal rate of 1 ml/min with physiological salt solution that was bubbled with 95% O2-5% CO2 and maintained at 37 degrees C. They were stretched to optimal length and contracted with prostaglandin F 2 alpha (2 x 10(-6) M). When flow through the stainless steel tube (direct superfusion) was increased from the basal rate of 1 to 4 ml/min, coronary force did not change. Superfusion of the rings (n = 8) with effluent from the femoral segment (endothelial superfusion) at 4 ml/min to study flow-induced vasodilation caused a 67.3 +/- 10.8% relaxation. Treatment of the segment with the NO synthase blocker NG-monomethyl-L-arginine (10(-4) M) eliminated the relaxation seen during endothelial superfusion (P < 0.05 vs. control). Application of atropine (10(-6) M) to additional femoral segments (n = 8) abolished the coronary relaxation observed during endothelial superfusion at 1 ml/ min, and the flow-induced relaxation observed at 4 ml/min was reduced from 64 +/- 8.3 to 27 +/- 5.6% (P < 0.05 vs. control). In studies on additional segments and rings (n = 6), the flow-induced relaxations at 4 ml/min of endothelial superfusion were blunted from 86 +/- 10 to 28 +/- 13% after the segments were treated with acetylcholinesterase (0.00028 U/min for 20 min). These data indicate that basal- and flow-induced release of NO from the vascular endothelium can be mediated by local cholinergic mechanisms. It is possible that flow causes acetylcholine release from certain endothelial cells, which stimulates NO release from these cells or from neighboring endothelial cells.


Management of full thickness burns to lactating breasts.
A 19-year-old female sustained 8 per cent full thickness petrol flame burns to the neck, chest, breasts, upper abdomen and portions of the right upper limb. The patient had been breast-feeding until the time of the injury. Following assessment of the risks of potential complications such as engorgement, hyperprolactinaemia, mastitis, milk fistulae, glandular loss, scarring and nipple distortion, surgical tangential excision was delayed until bromocriptine produced cessation of lactation and breast involution occurred. This case report demonstrates that consideration of the potential problems in burns to the lactating breasts and prophylactic management can lead to successful healing and probable restoration of function.


Identifying Optimal Overload and Taper in Elite Swimmers over Time.
The aim of this exploratory study was to identify the most influential training designs during the final six weeks of training (F6T) before a major swimming event, taking into account athletes' evolution over several seasons. Fifteen female and 17 male elite swimmers were followed for one to nine F6T periods. The F6T was divided into two sub-periods of a three-week overload period (OP) and a three-week taper period (TP). The final time trial performance was recorded for each swimmer in his or her specialty at the end of both OP and TP. The change in performances (ΔP) between OP and TP was recorded. Training variables were derived from the weekly training volume at several intensity levels as a percentage of the individual maximal volume measured at each intensity level, and the individual total training load (TTL) was considered to be the mean of the loads at these seven intensity levels. Also, training patterns were identified from TTL in the three weeks of both OP and TP by cluster analysis. Mixed-model was used to analyse the longitudinal data. The training pattern during OP that was associated with the greatest improvement in performance was a training load peak followed by a linear slow decay (84 ± 17, 81 ± 22, and 80 ± 19 % of the maximal training load measured throughout the F6T period for each subject, Mean ± SD) (p < 0.05). During TP, a training load peak in the 1(st) week associated with a slow decay design (57 ± 26, 45 ± 24 and 38 ± 14%) led to higher ΔP (p < 0.05). From the 1(st) to 3(rd) season, the best results were characterized by maintenance of a medium training load from OP to TP. Progressively from the 4(th) season, high training loads during OP followed by a sharp decrease during TP were associated with higher ΔP. Key PointsDuring the overload training period, a medium training load peak in the first week followed by an exponential slow decay training load design was linked to highest performance improvement.During the taper period, a training load peak in the first week associated with a slow decay design led to higher performances.Over the course of the swimmers' athletic careers, better performances were obtained with an increase in training load during the overload period followed by a sharper decrease in the taper period.Training loads schedules during the final six weeks of training before a major swimming event and changes over time could be prescribed on the basis of the model results.


Structure and dynamics of endogenous protein complexes in human heart tissue captured by native nanoproteomics.
Protein complexes are highly dynamic entities that display substantial diversity in their assembly, post-translational modifications, and non-covalent interactions, allowing them to play critical roles in various biological processes. The heterogeneity, dynamic nature, and low abundance of protein complexes in their native states present tremendous challenges to study using conventional structural biology techniques. Here we develop a "native nanoproteomics" strategy for the native enrichment and subsequent native top-down mass spectrometry (nTDMS) of low-abundance protein complexes. Specifically, we demonstrate the first comprehensive characterization of the structure and dynamics of cardiac troponin (cTn) complexes directly from human heart tissue. The endogenous cTn complex is effectively enriched and purified using peptide-functionalized superparamagnetic nanoparticles under non-denaturing conditions to enable the isotopic resolution of cTn complexes, revealing their complex structure and assembly. Moreover, nTDMS elucidates the stoichiometry and composition of the heterotrimeric cTn complex, localizes Ca2+ binding domains (II-IV), defines cTn-Ca2+ binding dynamics, and provides high-resolution mapping of the proteoform landscape. This native nanoproteomics strategy opens a new paradigm for structural characterization of low-abundance native protein complexes.


Assessment of health-related quality-of-life in males with Anderson Fabry Disease before therapeutic intervention.
Anderson Fabry Disease (AFD) is an extremely painful and debilitating multi-system X-linked disorder due to alpha-galactosidase enzyme deficiency. To date, no baseline data on health-related quality-of-life (HR-QoL) have been reported in males affected with this condition. In this study, 38 males with AFD completed Medical Outcomes Study Short Form, EuroQoL questionnaires and an AFD-specific questionnaire prior to the start of a trial involving replacement therapy with alpha-galactosidase. Results from these questionnaires were compared to the results from a similar HR-QoL study in males with severe haemophilia (factor VIII/IX deficiency) that used the same questionnaires and to the results of two large normative studies. The results on both questionnaires showed that in most instances males with AFD recorded significantly lower HR-QoL compared with males in the general population and individuals with severe haemophilia after adjusting for differences in age. These findings suggest therefore, that the scope for improvement in HR-QoL as a result of treatment with an appropriate agent is extremely large.


Theoretical study on CDK2 inhibitors using a global softness obtained from the density of states.
We report a theoretical study on a series of CDK2 inhibitors using a set of global reactivity indices defined in terms of the density of states. The statistical analysis was performed on the basis of two groups of 11 and 6 compounds, respectively, reported by Hardcastle et al. (J. Med. Chem. 2004, 47, 3710-3722). Both series were classified on the basis of the correlations obtained for the complete set of compounds and the sites targeted within the active site of CDK2. The comparison between the biological activity and the electronic chemical potential approached as the Fermi level yields poor results, thereby suggesting that the interaction between the hinge region (HR) of CDK2 and the ligands may have a marginal contribution from the charge transfer (CT) component. Comparison between the biological activity and global softness shows a better correlation, thereby suggesting that polarization effects outweigh the CT contribution in the HR-ligand interaction. We stress the importance to include in the evaluation of the reactivity indices all of the occupied energy states in order to assess the effects coming from the internal electronic structure involved in the HR-ligand interaction.


Adherence to the Mediterranean diet and IVF success rate among non-obese women attempting fertility.
Is adherence to the Mediterranean diet (MedDiet) associated with better IVF performance in women attempting fertility? Greater adherence to the MedDiet, defined using the validated Mediterranean diet score (MedDietScore), was associated with a higher likelihood of achieving clinical pregnancy and live birth among non-obese women <35 years of age. Diet impacts fertility and certain nutrients and food groups appear to have a greater effect on reproductive health, but there are relatively few published data on the role of dietary patterns, and the MedDiet in particular, on assisted reproductive performance. This prospective cohort study included 244 non-obese women (22-41 years of age; BMI < 30 kg/m2) who underwent a first IVF treatment in an Assisted Conception Unit in Athens, Greece, between November 2013 and September 2016. The study was designed to evaluate the influence of habitual dietary intake and lifestyle on fertility outcomes. Diet was assessed before the IVF treatment via a validated food-frequency questionnaire. Adherence to the MedDiet was assessed through the MedDietScore (range: 0-55), with higher scores indicating greater adherence. Intermediate outcomes (oocyte yield, fertilization rate and embryo quality measures) and clinical endpoints (implantation, clinical pregnancy and live birth) were abstracted from electronic medical records. Associations between MedDietScore and IVF outcomes were analysed using generalized linear models adjusting for age, ovarian stimulation protocol, BMI, physical activity, anxiety levels, infertility diagnosis, caloric intake and supplements use. No association of MedDietScore with any of the intermediate outcomes or with implantation was found. However, compared with women in the highest tertile of the MedDietScore (≥36, n = 86), women in the lowest tertile (≤30, n = 79) had significantly lower rates of clinical pregnancy (29.1 vs 50.0%, P = 0.01) and live birth (26.6 vs 48.8%, P = 0.01). The multivariable-adjusted relative risk (95% CI) for clinical pregnancy comparing women in the lowest with women in the highest tertile of the MedDietScore was 0.35 (0.16-0.78; P-trend=0.01), and for live birth it was 0.32 (0.14-0.71; P-trend = 0.01). These associations were significantly modified by women's age (P-interaction <0.01 for both outcomes). MedDietScore was positively related to clinical pregnancy and live birth among women <35 years old (P ≤ 0.01) but not among women ≥35 years. Among women <35 years, a beneficial 5-point increase in the MedDietScore was associated with ~2.7 times higher likelihood of achieving clinical pregnancy and live birth. Our finding cannot be generalized to the whole reproductive population nor to obese women nor to women attending infertility clinics around the world. In addition, due to the observational study design, causal inference is limited. The results suggest that diet modifications and greater compliance to the Mediterranean diet may help increase the chances of a successful pregnancy and delivering a live baby for women undergoing IVF treatment. This work was partially supported by a grand from Harokopio University (KE321). All authors declare no conflicts of interest. NCT03050944.


16S rDNA sequencing of Ruminococcus albus and Ruminococcus flavefaciens: design of a signature probe and its application in adult sheep.
The ruminococci are an important group of fibrolytic bacteria inhabiting the rumen. Seventeen strains of presumptively identified Ruminococcus were evaluated by a combination of nearly complete and partial 16S rDNA sequence that identified all strains as either Ruminococcus albus or Ruminococcus flavefaciens. All sequences fell into cluster IV of the clostridia, while other species of ruminococci (e.g. Ruminococcus obeum, Ruminococcus gnavus, Ruminococcus lactaris) fall into cluster XIVa of the clostridia. Ruminococcus cluster IV sequences were used to design a 16S rRNA oligonucleotide probe to assess the relative abundance of target populations in a stable ruminal environment. A stable population (animals fed eight times per day) was established in sheep so that statistically robust comparisons could be made in the absence of variation due to diurnal rumen fluctuations. The steady state populations were sampled six times over a 24 d period and direct microscopic counts (DC), total culturable counts (TCC), and total cellulolytic counts (CEL) were determined. DC and culturable data (TCC and CEL) were compared with relative abundance estimates of Ruminococcus IV and Fibrobacter succinogenes. A combination of the Ruminococcus and F. succinogenes probes accounted for 4.0% of the bacterial population and cellulolytic bacteria (measured by most-probable numbers) were 5.2% of the total culturable count. These data suggest that a major portion of the Ruminococcus and Fibrobacter diversity has been cultured and is represented by available sequences. Steady state populations were measured over several days in three sheep and an estimate of variation in DC, TCC, CEL and 16S-based data were obtained. These variance estimates could be used to determine the theoretical sample sizes required to obtain statistically significant differences under different experimental conditions.


LSD and genetic damage.
Of nine studies in vitro, six have indicated some degree of induced chromosomal breakage after exposure to LSD; three failed to confirm these results. The damage, when found, was generally of the chromatid type, arising during or after DNA synthesis. This damage, with one exception, was the result of concentrations of drug and durations of exposure which could not be achieved in humans with reasonable dosages. There did not appear to be a dose-response relation. The magnitude of damage, when found, was in the range encompassing the effects of many commonly used substances. The absence in vitro of excretory and detoxifying systems present in vivo, as well as several negative reports, cast doubt on the relevance of in vitro results. In 21 chromosomal studies in vivo, 310 subjects were examined. Of these, 126 were treated with pure LSD; the other 184 were exposed to illicit, "alleged" LSD. A maximum of only 18 of 126 (14.29 percent) of the subjects in the group exposed to pure LSD showed higher frequency of chromosome aberration than the controls. In contrast, a maximum of 90 of 184 (48.91 percent) of the subjects taking illicit LSD showed an increase in frequency of aberrations. Of all the subjects reported to have chromosome damage, only 18 of the 108 (16.67 percent) were exposed to pure LSD. The frequency of individuals with chromosomal damage reported among illicit drug users was more than triple that associated with the use of pharmacologically pure LSD. We conclude that chromosome damage, when found, was related to the effects of drug abuse in general and not, as initially reported, to LSD alone. We believe that pure LSD ingested in moderate dosages does not produce chromosome damage detectable by available methods. No significant work on carcinogenic potential of LSD has been reported so far. No cause-and-effect relation and no increase in the incidence of neoplasia among LSD users have been demonstrated. Case reports (three in 4.0 years) of leukemia and other neoplasia in this population are rare. The results of early chromosome studies suggested that true genetic damage might be a consequence of LSD exposure. The comprehensive evidence from studies on drosophila indicates no mutagenic effect from 0.28 to 500 microg of LSD per milliliter and a definite mutagenic effect from 2,000 to 10,000 microg/ml; this is consistent with a threshold response or a sigmoid dose-effect relation. We believe that LSD is, in fact, a weak mutagen, effective only in extremely high doses; it is unlikely to be mutagenic in any concentration used by human subjects. Circular dichroism experiments suggested that the specific mechanism of action of LSD on DNA may be a direct interaction resulting in conformational changes in the DNA helix. These changes are unlikely to result in a decrease of internal stability sufficient to cause breakage of chromosomes, but they may be the physical basis of the weak mutagenicity. Early chromosomal studies implicated LSD as a potential cause of congenital malformations, fetal wastage, and germinal chromosome damage. First reports of a teratogenic effect in hamsters and rats have not been confirmed. A review of 15 rodent studies indicated a wide range of individual, strain, and species susceptibility to the effects of LSD. The applicability of such investigations to man is doubtful. In a study of human pregnancies, those exposed to illicit LSD had an elevated rate of spontaneous abortions. There is no reported instance of a malformed child born to a woman who ingested pure LSD; there are six cases of malformation associated with exposure to illicit LSD, four of which have similar limb defects. Given, however, the high frequency of unexplained "spontaneous" birth defects, the rare occurrence of malformed infants born to women who used illicit LSD may be coincidental. While there is no evidence that pure LSD is teratogenic in man, the use of any drug during pregnancy requires that its potential benefits significantly outweigh its potential hazards. From our own work and from a review of the literature, we believe that pure LSD ingested in moderate doses does not damage chromosomes in vivo, does not cause detectable genetic damage, and is not a teratogen or a carcinogen in man. Within these bounds, therefore, we suggest that, other than during pregnancy, there is no present contraindication to the continued controlled experimental use of pure LSD. Note added in proof: A brief review has been brought to our attention. Although based on a sample of only 15 studies the author reached conclusions similar to our own (92).


Microsatellite instability is uncommon in lymphoepithelioma-like carcinoma of the lung.
Primary lymphoepithelioma-like carcinoma of the lung (LELC) shares some morphologic and clinical characteristics with malignancies associated with microsatellite instability (MSI). The aims of our study were to determine the MSI status in LELC and compare these findings with stage I non-small cell lung carcinoma (NSCLC) with marked lymphocytic host response (MLHR). We assessed MSI by a DNA-based polymerase chain reaction assay using mononucleotide (BAT25 and BAT26) and dinucleotide (D2S123, D5S346, and D17S250) repeats. MSI was detected in 2 (29%) of 7 LELC cases with only 1 marker (D17S250), and in 3 (19%) of 16 NSCLC cases with MLHR with only 2 markers (1D2S123 and 2 D17S250). Loss of heterozygosity (LOH) was detected at 1 or 2 of 3 dinucleotide repeats in 11 NSCLC cases (69%) with MLHR and 3 LELC cases (43%) (P = .36). The overall frequencies of LOH in NSCLC with MLHR were 29% and 19% in LELC (P = .55). MSI is very uncommon in LELC, indicating that MSI is not an important event in carcinogenesis for this tumor subtype. The presence of LOH suggests a probable role of tumor suppressor genes in LELC carcinogenesis.


Cervical Distraction-Stabilization Using an Intervertebral Spacer Screw and String-of Pearl (SOP™) Plates in 16 Dogs With Disc-Associated Wobbler Syndrome.
To retrospectively investigate a novel surgical technique using the Fitz Intervertebral Traction Screw (FITS) combined with string-of-pearl (SOP™) locking plates for the treatment of Disc Associated Wobbler Syndrome (DAWS). Case series (n = 16). Ventral approach and fenestration of the affected disc(s), nuclear extirpation, and insertion of the FITS device to the level of the dorsal annulus was followed by application of one or two 3.5 mm SOP™ plates. Autogenous cancellous bone graft was placed between adjacent vertebrae. Long-term followup (>12months) via telephone or examination was attempted for all dogs. Case records of 16 dogs were reviewed. All dogs had Type II disc disease with a single site in 13 dogs and multiple sites in 3 dogs. Mean ± SD age was 75 ± 38 months and body weight was 34 ± 7 kg. Fifteen of the 16 dogs had significantly improved neurologic status (P =.01) at 6 weeks. Seven of the 16 dogs were examined at 24-36 months with 6 considered normal and 1 had mild ataxia. Postoperative radiographic intervertebral distraction was significant (P = .01). Radiographic bridging was recorded in 10/16 dogs at 6 weeks and in 7 dogs available for follow-up at 5-36 months. Computed tomography in 3 dogs at 24-36 months and postmortem with histology in 1 dog confirmed bone-bridging. Complications were not considered clinically significant and included implant loosening (2 dogs, both single plates) and minor end-plate subsidence (8 dogs). Application of the FITS device in combination with 2 ventral SOP™ locking plates and autogenous cancellous bone graft was associated with excellent outcomes in dogs treated for DAWS in this small case series.


Antioxidant activity of raspberry (Rubus fruticosus) leaves extract and its effect on oxidative stability of sunflower oil.
Efficacy of R. fruticosus leaves extract in stabilizing sunflower oil during accelerated storage has been studied. Extracts of R. fruticosus were prepared in different solvents which methanolic extract yield with 15.43 % was higher than water and acetone ones (11.87 and 6.62 %, respectively). Methanolic extract was chosen to evaluate its thermal stability at 70 °C in sunflower oil, due to the highest yield, antioxidant and antiradical potential and also high content of phenolic compounds campared to other solvents. So, different concentrations of methanolic extract (200, 400, 600, 800 and 1,000 ppm) were added to sunflower oil. BHA and BHT at 200 ppm served as standards besides the control. Peroxide value (PV) and thiobarbituric acid (TBA) were taken as parameters for evaluation of effectiveness of R. fruticosus leaves extract in stabilization of sunflower oil. Moreover, antioxidant activity index (AAI) of the extract at 120 °C at rancimat were conducted. Results from different parameters were in agreement with each other, suggesting the highest efficiency of 1,000 ppm of the extract followed by BHT, BHA and other concentrations of the extract. Results reveal the R. fruticosus leaves extract to be a potent antioxidant for stabilization of sunflower oil.


Evidencing a reaction intermediate in the formation of the Eu(III) bimetallic complex with p-tert-butylcalix[8]arene.
In view of the very few mechanistic information available on the complex formation between lanthanide ions and calixarenes, we study here the reaction mechanism leading to the formation of the bimetallic complex between Eu(III) and p-tert-butylcalix[8]arene (b-LH8). We show that in dmf, the 1 : 1 complex [Eu(b-LH6)(NO3)(dmf)4] partially dissociates into a compound A which is an important intermediate in the formation of bimetallic [Eu2(b-LH2)(dmf)5]. Several spectroscopic (ES-MS, visible, luminescence, FT-IR) and conductometric techniques are combined with variable-temperature and variable-pressure experiments to demonstrate that in absence of base, intermediate A is the cationic species [Eu(b-LH6)(dmf)4]+. The thermodynamic parameters of the dissociation reaction, K5(298) = (4 +/- 1) x 10(-5) M, delta H0 = +16 +/- 3 kJ mol(-1), delta S0 = -30 +/- 11 J mol(-1) K(-1) as well as the reaction volume delta V0 = +9.4 +/- 0.9 cm3 mol(-1) are evaluated and rationalized. In presence of triethylamine, intermediate A deprotonates to generate the neutral species A' = [Eu(b-LH5)(dmf)4], which, in turn, further reacts with europium nitrate to yield the bimetallic complex. In addition, the pKas of the parent calixarene LH8, of b-LH8 and of p-iso-propylcalix[8]arene are determined in dmf, as well as the association constant between b-LH8 and triethylamine, K assoc = (9 +/- 1) x 10(3) M(-1).


DNA protein crosslink proteolysis repair: From yeast to premature ageing and cancer in humans.
DNA-protein crosslinks (DPCs) are a specific type of DNA lesion consisting of a protein covalently and irreversibly bound to DNA, which arise after exposure to physical and chemical crosslinking agents. DPCs can be bulky and thereby pose a barrier to DNA replication and transcription. The persistence of DPCs during S phase causes DNA replication stress and genome instability. The toxicity of DPCs is exploited in cancer therapy: many common chemotherapeutics kill cancer cells by inducing DPC formation. Recent work from several laboratories discovered a specialized repair pathway for DPCs, namely DPC proteolysis (DPCP) repair. DPCP repair is carried out by replication-coupled DNA-dependent metalloproteases: Wss1 in yeast and SPRTN in metazoans. Mutations in SPRTN cause premature ageing and liver cancer in humans and mice; thus, defective DPC repair has great clinical ramifications. In the present review, we will revise the current knowledge on the mechanisms of DPCP repair and on the regulation of DPC protease activity, while highlighting the most significant unresolved questions in the field. Finally, we will discuss the impact of faulty DPC repair on disease and cancer therapy.


Interoperability of medical device information and the clinical applications: an HL7 RMIM based on the ISO/IEEE 11073 DIM.
Medical devices are essential to the practice of modern healthcare services. Their benefits will increase if clinical software applications can seamlessly acquire the medical device data. The need to represent medical device observations in a format that can be consumable by clinical applications has already been recognized by the industry. Yet, the solutions proposed involve bilateral mappings from the ISO/IEEE 11073 Domain Information Model (DIM) to specific message or document standards. Considering that there are many different types of clinical applications such as the electronic health record and the personal health record systems, the clinical workflows, and the clinical decision support systems each conforming to different standard interfaces, detailing a mapping mechanism for every one of them introduces significant work and, thus, limits the potential health benefits of medical devices. In this paper, to facilitate the interoperability of clinical applications and the medical device data, we use the ISO/IEEE 11073 DIM to derive an HL7 v3 Refined Message Information Model (RMIM) of the medical device domain from the HL7 v3 Reference Information Mode (RIM). This makes it possible to trace the medical device data back to a standard common denominator, that is, HL7 v3 RIM from which all the other medical domains under HL7 v3 are derived. Hence, once the medical device data are obtained in the RMIM format, it can easily be transformed into HL7-based standard interfaces through XML transformations because these interfaces all have their building blocks from the same RIM. To demonstrate this, we provide the mappings from the developed RMIM to some of the widely used HL7 v3-based standard interfaces.


S-100 positive cells in human arterial intima and in atherosclerotic lesions.
The presence of previously unrecognised cells has been detected during ultrastructural investigations of normal and atherosclerotic human aortic intima. These cells show many of the morphological features of dendritic cells. Because dendritic cells can be stained positively for S-100, the aim of this study was to determine whether S-100 immunoreactive cells can be detected in the arterial wall, and if so, how they are distributed in normal intima and in atherosclerotic lesions. Paraffin sections of human aorta and carotid artery were stained with S-100 antibody, using an immunoperoxidase technique. In areas of the arterial wall without histological signs of atherosclerosis, S-100 positive cells were found but they were relatively few compared with the much greater numbers of S-100 positive cells showing dendritic cell morphology in atherosclerotic lesions. Different atherosclerotic lesions were found to contain different numbers of S-100 positive cells. In fatty steaks and in uncomplicated atheromatous plaques, many S-100 positive cells were present, but in complicated atherosclerotic lesions fewer such cells were found. Although the nature of these S-100 positive dendritic cells needs further clarification, the results suggest that these cells play an important role in the development of atherosclerotic lesions, and may represent antigen presenting dendritic cells in human arteries. If the S-100 positive cells prove to be part of the family of antigen presenting dendritic cells, the findings have important implications for understanding atherogenesis and offer a link between immune mechanisms and atherosclerotic lesion formation.


Is parental age related to the risk of Alzheimer's disease?
Advanced maternal and paternal age were investigated as putative risk factors for AD in 198 clinically diagnosed Alzheimer patients and in 198 randomly selected healthy controls. No significant differences in average age of fathers and of mothers at birth of the subject were observed. The risk of AD was not significantly different across categories of maternal and paternal age. The association with parental age was not different for sporadic and familial AD. These findings do not support the view of a maternal or paternal age effect on AD.


Sexual orientation and drug use in a longitudinal cohort study of U.S. adolescents.
Adolescents with a minority sexual orientation (e.g., lesbian, gay, and bisexual) are more likely to use substances than their heterosexual peers. This study aimed to increase understanding of the development of drug use in this vulnerable population by: 1) comparing longitudinal patterns of past-year illicit drug use (e.g., marijuana, cocaine, and ecstasy) and misuse of prescription drugs among minority sexual orientation youth relative to heterosexual youth and, 2) examining how sexual orientation sub-group, gender, and age relate to variation in the risk of drug use. Data come from the Growing Up Today Study, a community-based cohort of U.S. adolescents who were assessed three times between 1999 and 2005 with self-administered questionnaires when they ranged in age from 12 to 23 years (N=12,644; 74.9% of the original cohort). Multivariable repeated measures generalized estimating equations using modified Poisson regression were used to estimate relative risks. Participants indicating their sexual orientation was mostly heterosexual, bisexual, or lesbian/gay were more likely than completely heterosexual youth to report past-year illicit drug use and misuse of prescription drugs. Gender was an important modifier; bisexual females were most likely to report drug use. Age was also an important modifier of risk; differences in drug use between minority sexual orientation and heterosexual youth were larger during adolescence (12-17 years) than during emerging adulthood (18-23 years). Research must focus on identifying reasons why minority sexual orientation youth are at disproportionate risk for drug use. Such information is essential for developing interventions that are critically needed to reduce drug use in this population. Efforts need to begin early because large sexual orientation disparities in drug use are evident by adolescence.


The combination of prednisone and colchicine in patients with primary sclerosing cholangitis.
Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of the biliary tract. The cause of the disease is unknown, and no effective medical treatment exists. In this study, 12 patients received a combination of low-dose prednisone (10 mg/day) and colchicine (0.6 mg bid). Their course was compared with that of a group of concurrent historical controls. At 6 and 12 months, there was significantly more improvement in liver test results over baseline values in patients receiving prednisone and colchicine than in the untreated controls. At 24 months, however, no significant differences in biochemical tests were appreciated between treated and untreated patients. Analysis of serial liver biopsies showed no differences in histologic change in the two groups. During the 2 yr of follow-up, there were two deaths in the control group but none in the treated group. Four untreated patients developed ascites; gastrointestinal bleeding developed in three untreated patients, one of whom developed ascites. In contrast, in the treated group, ascites and bleeding developed in only one patient. We conclude that the combination of colchicine and prednisone does not retard histologic progression or progression of standard liver tests after 2 yr of therapy. There is a trend toward less clinical deterioration and improved survival after 2 yr of treatment. On the basis of these findings, we would not advocate empiric use of these drugs for patients with primary sclerosing cholangitis, but suggest that, if they are to be used at all in PSC, they be evaluated in a controlled clinical trial as treatment for this as yet incurable disease.


Wireless computing and health care.
Wireless computing technology has progressed sufficiently that it is now being incorporated into health care communications. These advances are linked to major improvements in general computer capabilities, the introduction of global satellite systems, and changes in government regulation of airwave access. This article describes some of these advances and their application in health care settings.


A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer.
Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs.