Propranolol attenuates cognitive, learning, and memory deficits in a murine model of traumatic brain injury.
β-blockers have been shown to improve survival after traumatic brain injury (TBI); however, the impact of continuous dosage of β-blockers on cognitive function has not been elucidated. We hypothesized that a daily dose of propranolol can improve memory, learning, and cognitive function following TBI. Twenty male C57BL mice were subjected to a cortical-controlled moderate TBI. Two hours after TBI, animals were randomly allocated to either the β-blocker group (n = 10) or the placebo group (n = 10). Mice in the β-blocker group received intraperitoneal 4 mg/kg propranolol every 24 hours for 7 days while the placebo group received 4 mg/kg normal saline. Baseline novel object recognition and classic maze tests were done prior to TBI and then daily from Day 1 through 7 after TBI. Animals were sacrificed on Day 7. Serum biomarkers were measured using ELISA and brain sections were analyzed using western blot and hematoxylin and eosin staining. Both the β-blocker and placebo groups had lower recognition index scores compared with the baseline following TBI. β-blocker mice had significantly higher novel object recognition scores compared with placebo mice 2 days after TBI. The β-blocker group required less time to complete the maze-test compared to placebo group after Day 4. There was no difference regarding the serum levels of IL-1β, IL-6, and TNF-α. The β-blocker group had lower levels of UCHL-1 and higher levels of Hsp-70 in brain lysate. Hematoxylin and eosin staining revealed that more neurons in the hippocampal-CA1 area underwent apoptosis in the placebo group compared with the β-blocker group. Postinjury propranolol administration results in improved memory, learning and cognitive functions in a murine model of moderate TBI. Propranolol increases the expression of antiapoptotic protein (Hsp-70) and decreases cell death in the hippocampal-CA1 area compared with the placebo.


Evaluation of a commercial enzyme-linked immunosorbent assay for detection of Borrelia burgdorferi exposure in dogs.
To evaluate the effectiveness of a commercially available ELISA kit for detecting antibodies against Borrelia burgdorferi in dogs. Banked sera from 440 military working dogs were used for serologic analyses. Serum samples were analyzed for antibodies against B burgdorferi by use of a commercially available ELISA and subsequently by western blot analysis as a confirmatory test. Results from the ELISA indicated that 89 (20%) samples were positive for exposure to B burgdorferi or canine Lyme disease vaccine, and 351 (80%) were negative. Follow-up testing by western blot analysis indicated that results for 109 (25%) samples were positive and 331 (75%) were negative for exposure. All samples that had positive results on the ELISA also had positive results on western blot analysis (true positives). Of the 351 samples that had negative results on the ELISA, only 331 had negative results on western blot analysis (true negatives). The remaining 20 samples had positive results on western blot analysis. By use of a standard 2 x 2 table, it was determined that the ELISA had a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. The commercial ELISA kit evaluated in this study appeared to lack adequate sensitivity for detecting all potential cases of borreliosis in dogs. The ELISA was also unable to discriminate natural exposure from exposure attributable to vaccination, which could complicate interpretation of positive results and treatment of dogs with clinical signs.


[Ichthyc biodiversity of seagrass meadows from the Northwest coast of Cariaco Gulf, Venezuela].
Seagrasses are highly productive coastal ecosystems with a high diversity and abundance of fishes, very important to support artisanal fisheries. We analyzed the fish community structure of Thalassia testudinum in the communities of Manzanillo (M) and La Brea (LB), Northwest coast of Cariaco Gulf, Venezuela. Samples were taken monthly (Nov. 2006-Oct. 2007) from each place, using a beach net. A total of 34 810 fishes were captured, grouped into 13 orders, 36 families and 83 species. In both areas (M and LB), the number of species was similar, but a variation in their abundance was found: a total of 55 species and 13 210 organisms for M, and 58 species and 21 600 organisms for LB. The most abundant species and those with the highest biomasses in both areas were: Nicholsina usta, Haemulon boschmae, H. steindachneri, Harengula jaguana, Halichoeres bivittatus and Hemiramphus brasiliensis. The occasional visitors were the most frequent community components with a 59%, the cyclical and permanent residents were represented by the 22% and 19%, respectively. The H'n average for M was of 1.71+/-0.64bits/ind., while for LB was of 1.95+/-0.51bits/ind. The diversity values were directly related to the evenness and inversely related to the dominance. The low values of similarity indexes among localities allow us to assert that these fish communities are dissimilar, because of the structure of each Thalassia meadow and their connectivity with other systems.


The inactivation of ornithine transcarbamoylase by N delta-(N'-sulpho-diaminophosphinyl)-L-ornithine.
Phaseolotoxin, a tripeptide inhibitor of ornithine transcarbamoylase, is a phytotoxin produced by Pseudomonas syringae pv. phaseolicola, the causal agent of halo-blight in beans. In vivo the toxin is cleaved to release N delta-(N'-sulpho-diaminophosphinyl)-L-ornithine, the major toxic chemical species present in diseased leaf tissue. This paper reports on the interaction between N delta-(N'-sulpho-diaminophosphinyl)-L-ornithine and ornithine transcarbamoylase. N delta-(N'-Sulpho-diaminophosphinyl)-L-ornithine was found to be a potent inactivator of the enzyme, in contrast with phaseolotoxin, which previously has been reported to inhibit the enzyme reversibly. Inactivation by N delta-(N'-[35S]sulpho-diaminophosphinyl)-L-ornithine resulted in the incorporation of 35S into ethanol-precipitated protein. The stoicheiometry of 35S incorporation was approximately 1 mol/mol of active sites. Inactivation was second-order and a rate constant of 10(6) M-1 X s-1 at 0 degree C in 50 mM-Tris/HCl, pH 9.0, was obtained. Carbamoyl phosphate, a substrate of ornithine transcarbamoylase, protected the enzyme from inactivation. A dissociation constant of 3 microM for the enzyme-carbamoyl phosphate complex was calculated. L-Ornithine, the second substrate for ornithine transcarbamoylase, protected the enzyme only at high concentrations. The results are consistent with N delta-(N'-sulpho-diaminophosphinyl)-L-ornithine being a potent affinity label that binds via the carbamoyl phosphate-binding site of ornithine transcarbamoylase. Cleavage of phaseolotoxin to N delta-(N'-sulpho-diaminophosphinyl)-L-ornithine in vivo appears to be an important function in the physiology of the disease.


Predominance of Atopobium vaginae at Midtrimester: a Potential Indicator of Preterm Birth Risk in a Nigerian Cohort.
Preterm birth (PTB) is the largest contributor to infant death in sub-Saharan Africa and globally. With a global estimate of 773,600, Nigeria has the third highest rate of PTB worldwide. There have been a number of microbiome profiling studies to identify vaginal microbiomes suggestive of preterm and healthy birth outcome. However, studies on the pregnancy vaginal microbiome in Africa are sparse with none performed in Nigeria. Moreover, few studies have considered the concurrent impact of steroid hormones and the vaginal microbiome on pregnancy outcome. We assessed two key determinants of pregnancy progression to gain a deeper understanding of the interactions between vaginal microbiome composition, steroid hormone concentrations, and pregnancy outcome. Vaginal swabs and blood samples were prospectively collected from healthy midtrimester pregnant women. Vaginal microbiome compositions were assessed by analysis of the V3-V5 region of 16S rRNA genes, and potential functional metabolic traits of identified vaginal microbiomes were imputed by PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states) analysis, while plasma estradiol (E2) and progesterone (P1) levels were quantified by the competitive enzyme-linked immunosorbent assay (ELISA). PTB vaginal samples were characterized by increased microbial richness, high diversity, and depletion of lactobacilli compared to term delivery samples. Women who delivered preterm were characterized by an Atopobium vaginae-dominated vagitype. High relative abundance of Atopobium vaginae at the midtrimester was highly predictive of PTB (area under the receiving operator characteristics [AUROC] of 0.983). There was a marked overlap in the range of plasma E2 and P1 values between term and PTB groups.IMPORTANCE Giving birth too soon accounts for half of all newborn deaths worldwide. Clinical symptoms alone are not sufficient to identify women at risk of giving birth too early, as such a pragmatic approach to reducing the incidence of preterm birth entails developing early strategies for intervention before it materializes. In view of the role played by the vaginal microbiome and maternal steroid hormones in determining obstetric outcome, we assessed the vaginal microbiome composition and steroid hormone during pregnancy and examined their relationship in predicting preterm birth risk in Nigerian women. This study highlights a potential early-driver microbial marker for prediction of preterm birth risk and supports the notion that vaginal microbiome composition varies across populations. A knowledge of relevant preterm birth microbial markers specific to populations would enhance the development of personalized therapeutic interventions toward restoring a microbiome that optimizes reproductive health fitness, therefore reducing the incidence of preterm birth.


Reforming perspectives: MSN graduates' knowledge, attitudes and awareness of self-transformation.
Socialization includes internalization of attitudes and values critical to the development of a professional identity. Resocialization relates to the returning registered nurse student's development of professional values and roles. Nurse educators' challenge is to consider socialization/resocialization as a formation/re-formation process. The purpose of this article is to report findings from a replication qualitative descriptive study that examined the process of change in knowledge and attitudes of recent MSN graduates using Mezirow's (1994)Transformative Learning Theory. Findings substantiated the changes in attitudes, knowledge and skills of MSN graduates identified by Cragg and Andrusyszyn (2005). Results further inform nurse educators of the process of transformation in MSN graduates according to Mezirow's Phases of Perspective Transformation.


Condom use among people living with HIV/AIDS attending Abejukolo General Hospital in Kogi State, North Central Nigeria.
Condom programming is an integral component in a range of HIV/AIDS prevention strategies and with repeated sexual contact among HIV-discordant couples, 98-100% of those who used latex condoms correctly and consistently did not become infected. The objective of this study is to determine condom use among people living with HIV/AIDS (PLWHA). This is a cross-sectional survey carried out among 231 PLWHA and receiving care and treatment at General Hospital Abejukolo in Kogi State, Nigeria. The research instrument was interviewer-administered questionnaire. The data obtained were analysed using EPI-INFO version 3.4.1 software and P-value of < 0.05 was significant for the study. About three-quarters (70.6%) of the respondents had ever used condom. Reasons given by respondents who did not use condom were: Desire for children (39.7%), and reduction of sexual pleasure (17.7%) and partner preference. More than half (56.0%) of the respondents with multiple partners did not use condom. About half 119 (51.5%) have used condom in the last sexual encounter. Gender, literacy level and disclosure of HIV status to partners significantly influence condom use during sexual intercourse. The poor uptake of condom among PLWHA underscores the need for government and other stakeholders in the management of HIV/AIDS to provide more enlightenment opportunities to address the gaps in condom use and disclosure of HIV status to partners.


[Neurotransplantation of the fetal tissue and compensatory-restorative processes in the recipient nervous system].
Last years the allogenic neurografting starts to be use in clinic for the treatment of some diseases connected with organic and functional disorders of CNS. This review is devoted to analysis of the literature data and the results of own investigations about the influence of the immature nervous tissue grafts of the different genesis on the compensatory-restorative processes in the central nervous system of mammalian recipients with different models of nervous diseases, mainly the brain traumas. Besides it, the physiological-active substances of developmental brain, the donor materials alternative to allogenic solid and suspensions grafts, the ways to prevent the xenogenic nervous tissue rejection without immune suppressive therapy were analyze. The conception about mechanisms of neurografts influence on the recipient brain was suggested.


Shell disease does not affect biochemical profiles of the North Sea brown shrimp Crangon crangon.
The brown shrimp Crangon crangon is a key component of the North Atlantic coastal food web and an important target species for the fishery economy. As the brown shrimp contains large amounts of protein and essential fatty acids, its consumption makes it a beneficial choice for humans. Commercially harvested crustaceans like C. crangon are frequently affected by bacterial shell disease, with necrotizing erosions and ulcerations of the cuticle. To determine whether shell disease influences the nutritional value of C. crangon, total protein and lipid contents, as well as fatty acid compositions of muscle tissue and hepatopancreas, together with the hepatosomatic index, were examined in healthy and affected individuals. The biochemical composition of the tissues did not differ significantly between the 2 groups. Also, the hepatosomatic index, as an indicator of energy reserves in shrimps, was similar between healthy and affected animals. Our results indicate that the nutritional value of C. crangon is not affected by shell disease, as long as it remains superficial as in the present study.


[Changes in heat shock protein synthesis and thermotolerance of Arabidopsis thaliana seedlings as a result of inhibition of Hsp90 by geldanamycin].
The influence of geldanamycin (GA), which is a specific inhibitor of heat shock protein Hsp90 activities, on synthesis of Hsp70 and Hsp90 and thermotolerance of Arabidopsis thaliana seedlings has been studied. Incubation of seedlings with GA was shown to induce synthesis of these stress proteins under normal conditions. Treatment of seeds with the Hsp90 inhibitor resulted in the elevated constitutive levels of Hsp70 and Hsp90 in seedlings as well as increased induction of their synthesis under heat shock, at that the effect of GA increased with its concentration. These up-regulation of Hsp promoted thermotolerance of seedlings. The obtained results are considered as evidence for autoregulation of heat shock protein synthesis and regulation of plant tolerance by Hsp90.


Two forms of autosomal chronic granulomatous disease lack distinct neutrophil cytosol factors.
Chronic granulomatous diseases of childhood (CGD) are a group of disorders of phagocytic cell superoxide (O2.-) production (respiratory burst). Anion exchange chromatography separated from normal neutrophil cytosol a 47-kilodalton neutrophil cytosol factor, NCF-1, that restored activity to defective neutrophil cytosol from most patients with autosomally inherited CGD in a cell-free O2.--generating system. A 65-kilodalton factor, NCF-2, restored activity to defective neutrophil cytosol from one patient with autosomal CGD. NCF-1, NCF-2, and a third cytosol fraction, NCF-3, were inactive alone or in pairs, but together replaced unfractionated cytosol in cell-free O2.- generation. Neutrophils deficient in NCF-1, but not NCF-2, did not phosphorylate the 47-kilodalton protein. It is proposed that NCF-1, NCF-2, and NCF-3 are essential for generation of O2.- by phagocytic cells and that genetic abnormalities of these cytosol components can result in the CGD phenotype.


Progress in selective oxidative dehydrogenation of light alkanes to olefins promoted by boron nitride catalysts.
Conversion of light alkanes into industrial chemical olefins via oxidative dehydrogenation (ODH) is a promising route because of favorable thermodynamic and kinetic characteristics, but encounters difficulties in selectivity control for olefins because of over-oxidation reactions that produce a substantial amount of undesired carbon oxides. Compared to widely-developed metal oxide-based catalysts, functionalized boron nitride has recently been shown as a competitive system in the ODH of light alkanes because of its more superior selectivity toward olefins as well as negligible formation of CO2. It is also characterized by high productivity to light olefins, remarkable catalyst stability, superior anti-oxidation ability, and excellent thermal conductivity. This feature article highlights the recent developments in applying boron nitride towards the ODH reaction of light alkanes. By correlating structural character with catalytic behavior, we expect to provide more insights into the catalytic nature of boron nitride-based materials in ODH reactions. Finally, we envisage perspective directions for boron-based ODH catalysts.


Cyclic nucleotide-independent protein kinases bound to cytoplasmic and nuclear polyribosomes in non-infected and adenovirus-infected HeLa cells.
Cyclic nucleotide-independent protein kinase activity bound to cytoplasmic and nuclear polyribsomes from non-infected and adenovirus-infected HeLa cells was compared. The enzymes catalysed the incorporation of phosphate from gamma-(32)P-labelled ATP or GTP into acid-precipitable material in the absence of exogenous substrates. Their activity was not affected by cyclic AMP or cyclic GMP and was not inhibited by a cyclic nucleotide-dependent protein kinase-inhibitor protein. The kinases are tightly bound to polyribosomes of either origin from infected and non-infected cells, since treatment with 0.5m-NaCl did not dissociate the activity. The enzymes and the enzyme-associated endogenous substrates of cytoplasmic polyribosomes are significantly different from those of the nucleus, and adenovirus infection of the cells did not alter the nature of the enzymes or the substrates at 18-20h after infection. Nuclear kinases catalysed 3-4-fold more phosphate incorporation than did the cytoplasmic kinases. They did not phosphorylate endogenous substrates in the cytoplasmic preparations, and vice versa, which suggests that such substrates for cytoplasmic and nuclear kinases are specific. Polyacrylamide-gel electrophoresis of the phosphorylated proteins revealed the presence of a higher number of endogenous substrates in the nuclear preparation. The nuclear kinases phosphorylated all histones from HeLa cells, but the cytoplasmic ones phosphorylated predominantly the histone of mol.wt. 12000. Bovine heart kinase phosphorylated several low-molecular-weight cytoplasmic proteins and no nuclear proteins. With a DEAE-cellulose column either enzyme activity could be resolved into a number of peaks. The substrate specificities of these peaks indicate that there are at least two different forms of the enzyme in each preparation of polyribosomes.


A simple in vitro assay for assessing the efficacy, mechanisms and kinetics of anti-prion fibril compounds.
Prion diseases are caused by the conversion of normal cellular prion proteins (PrP) into lethal prion aggregates. These prion aggregates are composed of proteinase K (PK) resistant fibrils and comparatively PK-sensitive oligomers. Currently there are no anti-prion pharmaceuticals available to treat or prevent prion disease. Methods of discovering anti-prion molecules rely primarily on relatively complex cell-based, tissue slice or animal-model assays that measure the effects of small molecules on the formation of PK-resistant prion fibrils. These assays are difficult to perform and do not detect the compounds that directly inhibit oligomer formation or alter prion conversion kinetics. We have developed a simple cell-free method to characterize the impact of anti-prion fibril compounds on both the oligomer and fibril formation. In particular, this assay uses shaking-induced conversion (ShIC) of recombinant PrP in a 96-well format and resolution enhanced native acidic gel electrophoresis (RENAGE) to generate, assess and detect PrP fibrils in a high throughput fashion. The end-point PrP fibrils from this assay can be further characterized by PK analysis and negative stain transmission electron microscopy (TEM). This cell-free, gel-based assay generates metrics to assess anti-prion fibril efficacy and kinetics. To demonstrate its utility, we characterized the action of seven well-known anti-prion molecules: Congo red, curcumin, GN8, quinacrine, chloropromazine, tetracycline, and TUDCA (taurourspdeoxycholic acid), as well as four suspected anti-prion compounds: trans-resveratrol, rosmarinic acid, myricetin and ferulic acid. These findings suggest that this in vitro assay could be useful in identifying and comprehensively assessing novel anti-prion fibril compounds. Abbreviations: PrP, prion protein; PK, proteinase K; ShIC, shaking-induced conversion; RENAGE, resolution enhanced native acidic gel electrophoresis; TEM, transmission electron microscopy; TUDCA, taurourspdeoxycholic acid; BSE, bovine spongiform encephalopathy; CWD, chronic wasting disease; CJD, Creutzfeldt Jakob disease; GSS, Gerstmann-Sträussler-Scheinker syndrome; FFI, fatal familial insomnia; PrPc, cellular prion protein; recPrPC, recombinant monomeric prion protein; PrPSc, infectious particle of misfolded prion protein; RT-QuIC, real-time quaking-induced conversion; PMCA, Protein Misfolding Cyclic Amplification; LPS, lipopolysaccharide; EGCG, epigallocatechin gallate; GN8, 2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide; DMSO, dimethyl sulfoxide; ScN2A, scrapie infected neuroblastoma cells; IC50, inhibitory concentration for 50% reduction; recMoPrP 23-231, recombinant full-length mouse prion protein residues 23-231; EDTA; PICUP, photo-induced cross-linking of unmodified protein; BSA, bovine serum albumin;; PMSF, phenylmethanesulfonyl fluoride.


A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2.
The proteins encoded by two groups of conserved genes, the Polycomb and trithorax groups, have been proposed to maintain, at the level of chromatin structure, the expression pattern of homeotic genes during Drosophila development. To identify new members of the trithorax group, we screened a collection of deficiencies for intergenic noncomplementation with a mutation in ash1, a trithorax group gene. Five of the noncomplementing deletions uncover genes previously classified as members of the Polycomb group. This evidence suggests that there are actually three groups of genes that maintain the expression pattern of homeotic genes during Drosophila development. The products of the third group appear to be required to maintain chromatin in both transcriptionally inactive and active states. Six of the noncomplementing deficiencies uncover previously unidentified trithorax group genes. One of these deficiencies removes 25D2-3 to 26B2-5. Within this region, there are two, allelic, lethal P-insertion mutations that identify one of these new trithorax group genes. The gene has been called little imaginal discs based on the phenotype of mutant larvae. The protein encoded by the little imaginal discs gene is the Drosophila homologue of human retinoblastoma binding protein 2.


Regulation of gamma-aminobutyric acid/barbiturate receptor-gated chloride ion flux in brain vesicles by phospholipase A2: possible role of oxygen radicals.
Preincubation of brain membranes with phospholipase A2 (PLA2) has been shown previously to affect the binding characteristics of various recognition sites associated with the gamma-aminobutyric acid (GABA) receptor complex. In the present study, we have investigated the effects of PLA2 (from Naja naja siamensis venom) on the functional activity of the GABA receptor/chloride ion channel. PLA2 (0.001-0.02 U/mg protein) preincubation decreased pentobarbital-induced 36Cl- efflux and muscimol-induced 36Cl- uptake in rat cerebral cortical synaptoneurosomes. The effect of PLA2 was prevented by EGTA and two nonselective PLA2 inhibitors, mepacrine and bromophenacyl bromide. The removal of free fatty acids by addition of bovine serum albumin both prevented and reversed the effect of PLA2. Products of the catalytic activity of PLA2, such as the unsaturated free fatty acids, arachidonic and oleic acids, mimicked the effect of PLA2. However, the saturated fatty acid, palmitic acid, and lysophosphatidyl choline had no effect on pentobarbital-induced 36Cl- efflux. Because unsaturated free fatty acids are highly susceptible to peroxidation by oxygen radicals, the role of oxygen radicals was investigated. Xanthine plus xanthine oxidase, a superoxide radical generating system, mimicked the effect of PLA2, whereas the superoxide radical scavenger, superoxide dismutase, diminished the effects of PLA2 and arachidonic acid on pentobarbital-induced 36Cl- efflux. Similarly, the effect of PLA2 was also inhibited by methanol (1 mM), a scavenger of the hydroxyl radical, and by catalase. These data indicate that exogenously added PLA2 induces alterations in membrane phospholipids, possibly promoting the generation of oxygen radicals and fatty acid peroxides which can ultimately modulate GABA/barbiturate receptor function in brain.


Neurodegeneration in diabetic retinopathy: Potential for novel therapies.
The complex pathology of diabetic retinopathy (DR) affects both vascular and neural tissue. The characteristics of neurodegeneration are well-described in animal models but have more recently been confirmed in the clinical setting, mostly by using non-invasive imaging approaches such as spectral domain optical coherence tomography (SD-OCT). The most frequent observations report loss of tissue in the nerve fiber layer and inner plexiform layer, confirming earlier findings from animal models. In several cases the reduction in inner retinal layers is reported in patients with little evidence of vascular lesions or macular edema, suggesting that degenerative loss of neural tissue in the inner retina can occur after relatively short durations of diabetes. Animal studies also suggest that neurodegeneration leading to retinal thinning is not limited to cell death and tissue loss but also includes changes in neuronal morphology, reduced synaptic protein expression and alterations in neurotransmission, including changes in expression of neurotransmitter receptors as well as neurotransmitter release, reuptake and metabolism. The concept of neurodegeneration as an early component of DR introduces the possibility to explore alternative therapies to prevent the onset of vision loss, including neuroprotective therapies and drugs targeting individual neurotransmitter systems, as well as more general neuroprotective approaches to preserve the integrity of the neural retina. In this review we consider some of the evidence for progressive retinal neurodegeneration in diabetes, and explore potential neuroprotective therapies.


Afatinib After Progression on Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer.
After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown. We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib. After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017). Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.


Transient bilateral blindness following blepharoplasty.
A case of bilateral transient visual loss following elective four-lid blepharoplasty is described. Postoperative retrobulbar hemorrhages developed sequentially and were immediately treated by decompression, restoring full vision. The critical importance of supervised postoperative observation and immediate availability of medical help is underscored. The etiology of retrobulbar hemorrhage following blepharoplasty, the steps necessary to reduce its incidence, and the treatment of this complication are discussed.


The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.
The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial. The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables. The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.


The CONSENSUS study: protocol for a mixed methods study to establish which outcomes should be included in a core outcome set for oropharyngeal cancer.
The incidence of oropharyngeal cancer is increasing in the developed world. This has led to a large rise in research activity and clinical trials in this area, yet there is no consensus on which outcomes should be measured. As a result, the outcomes measured often differ between trials of comparable interventions, making the combination or comparison of results between trials impossible. Outcomes may also be 'cherry-picked', such that favourable results are reported, and less favourable results withheld. The development of a minimum outcome reporting standard, known as a core outcome set, goes some way to addressing these problems. Core outcome sets are ideally developed using a patient-centred approach so that the outcomes measured are relevant to patients and clinical practice. Core outcome sets drive up the quality and relevance of research by ensuring that the right outcomes are consistently measured and reported in trials in specific areas of health or healthcare. This is a mixed methods study involving three phases to develop a core outcome set for oropharyngeal cancer clinical trials. Firstly, a systematic review will establish which outcomes are measured in published oropharyngeal cancer randomised controlled trials (RCTs). Secondly, qualitative interviews with patients and carers in the UK and the USA will aim to establish which outcomes are important to these stakeholders. Data from these first two stages will be used to develop a comprehensive list of outcomes to be considered for inclusion in the core outcome set. In the third stage, patients and clinicians will participate in an iterative consensus exercise known as a Delphi study to refine the contents of the core outcome set. This protocol lays out the methodology to be implemented in the CONSENSUS study. A core outcome set defines a minimum outcome reporting standard for clinical trials in a particular area of health or healthcare. Its consistent implementation in oropharyngeal cancer clinical trials will improve the quality and relevance of research. This study is registered at the National Institute for Health Research (NIHR) Clinical Research Network (CRN) portfolio, ID 13823 (17 January 2013).


The Effect of Market-Based Economic Factors on the Adoption of Orphan Drugs Across Multiple Countries.
Orphan drugs are designed to treat rare disease. Multiple countries have approved regulations that support the creation of new orphan drugs. The regulations directly and indirectly affect orphan drug markets and contribute to classifying a country as being more or less market based. A more market-based country is recognized as functioning closest to free market principles, where the actions of supply, demand, and pricing operate with minimal government involvement. However, little information exists on how country market differences affect the adoption of these orphan drugs. This study argues that relationships exist between country market-based economic factors and the adoption of orphan drugs. This research uses a combination of qualitative and quantitative methods, drawing on orphan drug adoption of 13 marketed orphan drugs in France, Germany, Spain, the UK, and the US. Results show a statistically significant but negative relationship between the degree to which a country is market based and the adoption of orphan drugs. Results suggest that governments and regulators in less market-based countries support market factors that result in a more efficient delivery of orphan drug products to patients with rare diseases.


Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial.
The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Long-chain omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that omega-3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation. To determine whether omega-3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis. Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007. Psychosis detection unit of a large public hospital in Vienna, Austria. Eighty-one individuals at ultra-high risk of psychotic disorder. A 12-week intervention period of 1.2-g/d omega-3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months. The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of omega-6 to omega-3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition. Seventy-six of 81 participants (93.8%) completed the intervention. By study's end (12 months), 2 of 41 individuals (4.9%) in the omega-3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). omega-3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups. Long-chain omega-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states. Trial Registration clinicaltrials.gov Identifier: NCT00396643.


Presence of Toxoplasma gondii in Drinking Water from an Endemic Region in Southern Mexico.
Toxoplasmosis can be acquired through the ingestion of contaminated drinking water with oocysts of Toxoplasma gondii, highly resistant to the routinely disinfection processes; based on chlorination commonly used in the water supply industry. The aim of this study was to determine the presence of T. gondii DNA in samples of public drinking water from an endemic region of southern Mexico. In total 74 samples of water (5 L each) were collected from the three well fields (I, II, and III) and 71 independent wells, distributing public drinking water to the city of Merida Yucatan, after passing through the chlorination process. Water samples were filtered and concentrated by a sucrose solution, then DNA was extracted and evaluated through a nested-PCR (nPCR) specific for T. gondii. Positive samples were detected in 5.4% (4/74) of the water samples. This is the first report of the presence of T. gondii DNA in public drinking water from a large city in southern Mexico, where their consumption without any postpurification treatment could pose a risk for acquiring the infection in the urban population.


Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice.
Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5-/-;Ldlr-/- mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5-/-;Ldlr-/- mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5-/- mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5-/- cells, except for a slight increase in PGE2 secretion in Elovl5-/- cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5-/-;Ldlr-/- mice.


Demonstration of a compressive-sensing Fourier-transform on-chip spectrometer.
We demonstrate compressive-sensing (CS) spectroscopy in a planar-waveguide Fourier-transform spectrometer (FTS) device. The spectrometer is implemented as an array of Mach-Zehnder interferometers (MZIs) integrated on a photonic chip. The signal from a set of MZIs is composed of an undersampled discrete Fourier interferogram, which we invert using l1-norm minimization to retrieve a sparse input spectrum. To implement this technique, we use a subwavelength-engineered spatial heterodyne FTS on a chip composed of 32 independent MZIs. We demonstrate the retrieval of three sparse input signals by collecting data from restricted sets (8 and 14) of MZIs and applying common CS reconstruction techniques to this data. We show that this retrieval maintains the full resolution and bandwidth of the original device, despite a sampling factor as low as one-fourth of a conventional (non-compressive) design.


Comparison of Iroquois gene expression in limbs/fins of vertebrate embryos.
In Drosophila, Iroquois (Irx) genes have various functions including the specification of the identity of wing veins. Vertebrate Iroquois (Irx) genes have been reported to be expressed in the developing digits of mouse limbs. Here we carry out a phylogenetic analysis of vertebrate Irx genes and compare expression in developing limbs of mouse, chick and human embryos and in zebrafish pectoral fin buds. We confirm that the six Irx gene families in vertebrates are well defined and that Clusters A and B are duplicates; in contrast, Irx1 and 3, Irx2 and 5, and Irx4 and 6 are paralogs. All Irx genes in mouse and chick are expressed in developing limbs. Detailed comparison of the expression patterns in mouse and chick shows that expression patterns of genes in the same cluster are generally similar but paralogous genes have different expression patterns. Mouse and chick Irx1 are expressed in digit condensations, whereas mouse and chick Irx6 are expressed interdigitally. The timing of Irx1 expression in individual digits in mouse and chick is different. Irx1 is also expressed in digit condensations in developing human limbs, thus showing conservation of expression of this gene in higher vertebrates. In zebrafish, Irx genes of all but six of the families are expressed in early stage pectoral fin buds but not at later stages, suggesting that these genes are not involved in patterning distal structures in zebrafish fins.


Electron dynamics in charge-transfer-to-solvent states of aqueous chloride revealed by Cl- 2p resonant Auger-electron spectroscopy.
Charge-transfer-to-solvent (CTTS) excited states of aqueous chloride are studied by a novel experimental approach based on resonant inner-shell photoexcitation, Cl(-)aq 2p --> e(i), i = 1-4, which denotes a series of excitations to lowest and higher CTTS states. These states are clearly identified through the occurrence of characteristic spectator Auger decays to double Cl 3p valence-hole states, where the CTTS states can be more stabilized as compared to single Cl(-)aq 2p core excitations and optical valence excitations. Furthermore, we have found for the first time that the CTTS electron e(i) bound by a single Cl 2p hole not only behaves as a spectator e(i) --> e'(i), bound by a double valence-hole state before relaxation of the excited electron (i) itself, but also shows electron dynamics to the relaxed lowest state, e(i) --> e'(1*). This interpretation is supported by ab initio calculations. The key to performing photoelectron and Auger-electron spectroscopy studies from aqueous solutions is the use of a liquid microjet in ultrahigh vacuum in conjunction with synchrotron radiation.


Wavelet representations for monitoring changes in teeth imaged with digital imaging fiber-optic transillumination.
Digital imaging fiber-optic transillumination (DI-FOTI) is a novel method to detect and monitor dental caries, using light, a charge-coupled device (CCD) camera, and computer-controlled image acquisition. The advantages of DIFOTI over radiography include: no ionizing radiation, no film, real-time diagnosis, and higher sensitivity in detection of early lesions not apparent to X-ray, as demonstrated in vitro. Here, we present a method of processing DIFOTI images, acquired at different times, for monitoring changes. Of central importance to this application is pattern matching of image frames that is invariant to translation and rotation of a tooth, relative to the field of view of the imaging camera, and that is robust to changes in illumination source intensity. Our method employs: 1) wavelet modulus maxima representations for segmentation of teeth images; 2) first and second moments of gray level representations of DIFOTI images in the spatial domain, to estimate tooth location and orientation; and 3) multiresolution wavelet magnitude representations for quantitative monitoring. Even with illumination source intensity variation, it is demonstrated in vitro that such wavelet representations can facilitate detection of simulated clinical changes in light transmission that cannot be detected in the spatial domain.


Endothelin-evoked Release of Arachidonic Acid from Mouse Astrocytes in Primary Culture.
In striatal astrocytes, receptors for the vasoactive peptide endothelin (ET) are associated with several intracellular signalling pathways: ET-1 increases the breakdown of phosphoinositides, induces a sustained influx of Ca2+ and inhibits the isoproterenol-induced formation of cAMP (Marin et al., J. Neurochem., 56, 1270 - 1275, 1991). In the present study, it will be shown that ET-1 and ET-3 markedly stimulate the release of arachidonic acid (AA) from cultured astrocytes from the mouse striatum (EC50=3 and 7 nM for ET-1 and ET-3, respectively), mesencephalon and cerebral cortex. The ET-1-evoked release of AA probably resulted from the activation of a phospholipase A2, since it required extracellular Ca2+ and was prevented by mepacrine but not by RHC 80267, an inhibitor of diacylglycerol lipase. The ET-1-induced release of AA was shown to be partially mediated by a guanine nucleotide-binding protein sensitive to pertussis toxin but not to cholera toxin. A cAMP-dependent process is not involved since the ET-1-evoked release of AA was not affected when cells were incubated with either isoproterenol or 8-bromo-cAMP. The ET-1-evoked release of AA could be mimicked by the co-application of a calcium ionophore and a protein kinase C activator. However, staurosporine, a potent inhibitor of protein kinase C, which blocked the release of AA induced by the combined application of ionomycin and phorbol 12-myristate 12-acetate (PMA), was without effect on the ET-1-evoked response, indicating that protein kinase C is not directly involved in the ET-1-induced release of AA. Furthermore, the responses induced by ET-1 and by PMA were found to be additive. These results suggest that (1) ET-1 receptors are coupled to the release of AA by a mechanism independent of both protein kinase C activation and the adenylate cyclase pathway, possibly via the activation of phospholipase A2, (2) different mechanisms (or different phospholipase A2 subtypes) are involved in the control of AA release in astrocytes.


Weather variability influences color and phenolic content of pigmented baby leaf lettuces throughout the season.
The lack of consistency in homogeneous color throughout the season of pigmented baby leaf lettuce is a problem for growers because of the rejection of the product and consequently the economic loss. Changes in color as well as individual and total phenolic composition and content as a response to the climatic variables were studied following the analysis of three pigmented baby leaf lettuces over 16 consecutive weeks from February to May, which corresponded to the most important production season in winter in Europe. Color and phenolic content were significantly (P ≤ 0.001) affected by cultivar, harvest week, and climatic variables that occurred in the last week before harvest. Radiation and temperature showed positive correlations with the content of phenolic acids and flavonoids that increased in all three cultivars as the season progressed. Cyanidin-3-O-(6''-O-malonyl)-glucoside content showed positive correlations with temperature and radiation but only in Batavia cultivars whereas in red oak leaf the correlation was with cold temperatures. Regarding hue angle, a positive correlation was shown with the number of hours at temperatures lower than 7 °C. A relationship between hue angle and the content of anthocyanins was not possible to establish. These results suggest that the colorimetric measurement of color cannot be used as a good indicator of anthocyanin accumulation because other pigments such as chlorophylls and carotenoids may contribute as well to the leaf color of pigmented lettuce. This study provides information about the impact of genotype and environment interactions on the biosynthesis of phenolic compounds to explain the variability in the leaf color and product appearance.


Effect of pH and amiloride on the intrarenal formation of kinins.
Changes in urinary kallikrein excretion are assumed to reflect changes in intrarenal formation of kinins. Yet factors that alter the enzymatic activity of renal kallikrein and kininases may alter the concentration of kinins in the nephron independent of amount of kallikrein excreted. In anesthetized rats, we measured excretion of urinary kallikrein (kininogenase activity) and kinin excretion during altered urinary pH and after amiloride, which reportedly inhibits urinary kallikrein. In rats fed a low sodium diet, urine was acidified by intravenous 0.28 M sodium sulfate. This decreased urinary pH from 6.1 +/- 0.09 to 5.3 +/- 0.17 and urinary kinin excretion from 28.0 +/- 9.0 to 10.5 +/- 5.0 pg/min. Urinary kallikrein excretion doubled from 43.0 +/- 5.0 to 82.5 +/- 13.5 ng/min. The optimum pH of kallikrein is congruent to 8.5, so the decreased excretion of urinary kinins is probably secondary to decreased kininogenase activity at lower urinary pH. Amiloride decreased urinary kinins from 35.5 +/- 7.3 to 18.2 +/- 2.5 pg/min and kallikrein from 18.7 +/- 4.9 to 9.3 +/- 1.8 ng/min, while urinary pH increased from 6.7 +/- 0.07 to 7.3 +/- 0.07. The depressed excretion of kallikrein and kinins with amiloride may not have been due to inhibition of kallikrein, since amiloride (1 mM) did not inhibit the kininogenase activity of rat urinary kallikrein (congruent to 1.2 nM) on dog or rat kininogen in vitro. We conclude that changes in urinary kallikrein may not reflect changes in intrarenal formation of kinins. These data also indicate that kallikrein excretion increases and kinin formation decreases when urine is acidified in the distal nephron and that there may be a link between the kallikrein-kinin system and the renal mechanisms affected by amiloride.


Sports Concussion Management: part II.
Millions of concussions occur every year in the United States. The public interest in concussion has increased after a number of high-profile deaths in high school athletes from sports-related head trauma and in some professional athletes from chronic traumatic encephalopathy. One of the most active areas of research in sports medicine during the last decade has been the evaluation and management of concussion. In this second article of a two-part series, we provide an overview of the latest scientific advances in concussion research. This overview includes an update on the pathobiological changes that occur during concussion and the results of biomechanical studies. In addition, to aid the practicing clinician, we review the literature on proven and currently studied concussion risk factors, including a history of concussion, fatigue, and age. Genetic polymorphisms and biomarkers may provide risk-prediction capability, but at present the research remains inconclusive. Diffusion tensor imaging and functional magnetic resonance imaging are promising technologies that reveal more sophisticated data about the impact of concussion on the brain. We review the existing literature on the application of these neuroimaging modalities to sports concussion. An update from the Fourth International Conference on Concussion in Sport, with highlights of new recommendations, and the presentation of the third edition of the Sports Concussion Assessment Tool to evaluate acute concussion, concludes our review.


A population-based nested case control study on recurrent pneumonias in children with severe generalized cerebral palsy: ethical considerations of the design and representativeness of the study sample.
In children with severe generalized cerebral palsy, pneumonias are a major health issue. Malnutrition, dysphagia, gastro-oesophageal reflux, impaired respiratory function and constipation are hypothesized risk factors. Still, no data are available on the relative contribution of these possible risk factors in the described population. This paper describes the initiation of a study in 194 children with severe generalized cerebral palsy, on the prevalence and on the impact of these hypothesized risk factors of recurrent pneumonias. A nested case-control design with 18 months follow-up was chosen. Dysphagia, respiratory function and constipation will be assessed at baseline, malnutrition and gastro-oesophageal reflux at the end of the follow-up. The study population consists of a representative population sample of children with severe generalized cerebral palsy. Inclusion was done through care-centres in a predefined geographical area and not through hospitals. All measurements will be done on-site which sets high demands on all measurements. If these demands were not met in "gold standard" methods, other methods were chosen. Although the inclusion period was prolonged, the desired sample size of 300 children was not met. With a consent rate of 33%, nearly 10% of all eligible children in The Netherlands are included (n = 194). The study population is subtly different from the non-participants with regard to severity of dysphagia and prevalence rates of pneumonias and gastro-oesophageal reflux. Ethical issues complicated the study design. Assessment of malnutrition and gastro-oesophageal reflux at baseline was considered unethical, since these conditions can be easily treated. Therefore, we postponed these diagnostics until the end of the follow-up. In order to include a representative sample, all eligible children in a predefined geographical area had to be contacted. To increase the consent rate, on-site measurements are of first choice, but timely inclusion is jeopardized. The initiation of this first study among children with severe neurological impairment led to specific, unexpected problems. Despite small differences between participants and non-participating children, our sample is as representative as can be expected from any population-based study and will provide important, new information to bring us further towards effective interventions to prevent pneumonias in this population.


Challenges, Facilitators, and Recommendations for Implementation of Home Dialysis in the Veterans Health Administration: Patient, Caregiver, and Clinician Perceptions.
Home dialysis confers similar survival and greater quality of life than in-center hemodialysis for adults with ESKD but remains underutilized. We examined challenges and facilitators to implementation of home dialysis and identified stakeholder-centered strategies for improving it. We conducted a qualitative, cross-sectional, multisite evaluation that included five geographically dispersed Veterans Health Administration (VHA) home dialysis programs. Participants included patients with ESKD receiving home dialysis, their informal caregivers, and home dialysis staff. Semistructured telephone interviews were conducted and audio-recorded from 2017 through 2018, to assess perceived barriers and facilitators to patient home dialysis use in VHA. Transcribed interviews were analyzed thematically by each participant group. Participants included 22 patients receiving home dialysis (18 on peritoneal dialysis [PD] and four hemodialysis [HD]); 20 informal caregivers, and 19 home dialysis program staff. Ten themes emerged as challenges to implementing home dialysis, of which six (60%) spanned all groups: need for sterility, burden of home dialysis tasks, lack of suitable home environment, physical side effects of home dialysis, negative psychosocial effects of home dialysis, and loss of freedom. Four themes (40%), identified only by staff, were insufficient self-efficacy, diminished peer socialization, geographic barriers, and challenging health status. Twelve themes emerged as facilitators to implementing home dialysis, of which seven (58%) spanned all groups: convenience, freedom, avoidance of in-center HD, preservation of autonomy, adequate support, favorable disposition, and perceptions of improved health. Two themes (17%) common among patients and staff were adequate training and resources, and physical and cognitive skills for home dialysis. Recommendations to promote implementation of home dialysis common to all participant groups entailed incorporating mental health care services, offering peer-to-peer coaching, increasing home visits, providing health data feedback, and reducing patient burden. Stakeholder-centered challenges were rigorously identified. Facilitators and recommendations can inform efforts to support home dialysis implementation.


The cross-cultural utility of foreign- and locally-derived normative data for three WHO-endorsed neuropsychological tests for South African adolescents.
Interpretation of neuropsychological tests may be hampered by confounding sociodemographic factors and by using inappropriate normative data. We investigated these factors in three tests endorsed by the World Health Organization: the Grooved Pegboard Test (GPT), the Children's Color Trails Test (CCTT), and the WHO/UCLA version of the Auditory Verbal Learning Test (AVLT). In a sample of 12-15-year-old, Afrikaans- and English-speaking adolescents from the Cape Town region of South Africa, analyses of covariance (ANCOVAs) demonstrated that quality of education was the sociodemographic factor with the biggest influence on test performance, and that age also significantly influenced GPT and CCTT performance. Based on those findings, we provide appropriately stratified normative data for the age group in question. Comparisons between diagnostic interpretations made using foreign normative data versus those using the current local data demonstrate that it is imperative to use appropriately stratified normative data to guard against misinterpreting performance.


Molecular Weight Analysis of Blue Shark (Prionace glauca) Collagen Hydrolysates by GPC-LS; Effect of High Molecular Weight Hydrolysates on Fibroblast Cultures: mRNA Collagen Type I Expression and Synthesis.
High molecular weight (Mw) collagen hydrolysates have been demonstrated to produce a higher synthesis of collagen type I mRNA. Mw determination is a key factor maximizing the effect of collagen hydrolysates on collagen type I synthesis by fibroblasts. This work aimed to achieve a high average Mw in Blue Shark Collagen Hydrolysate, studying different hydrolysis parameters by GPC-LS analysis and testing its effect on mRNA Type I collagen expression. Analysis revealed differences in blue shark collagen hydrolysates Mw depending on hydrolysis conditions. Papain leads to obtaining a significantly higher Mw hydrolysate than Alcalase at different times of hydrolysis and at different enzyme/substrate ratios. Besides, the time of the hydrolysis factor is more determinant than the enzyme/substrate ratio factor for obtaining a higher or lower hydrolysate Mw when using Papain as the enzyme. Contrary, Alcalase hydrolysates resulted in similar Mw with no significant differences between different conditions of hydrolysis assayed. Blue shark collagen hydrolysate showing the highest Mw showed neither cytotoxic nor proliferation effect on fibroblast cell culture. Besides, it exhibited an increasing effect on both mRNA expression and pro-collagen I production.


Dipicolinic acid: a strong anchoring group with tunable redox and spectral behavior for stable dye-sensitized solar cells.
Dipicolinic acid was investigated as a new anchoring group for DSSCs. A pilot dye (PD2) bearing this new anchoring group was found to adsorb significantly stronger to TiO2 than its cyanoacrylic acid analogue. The electrolyte composition was found to have a strong effect on the photoelectrochemical properties of the adsorbed dye in the device, allowing the dye LUMO energy to be tuned by 0.5 eV. Using a pyridine-free electrolyte, panchromatic absorption of the dye on TiO2 extending to 900 nm has been achieved. Solar cells using PD2 and a Co(bpy)3 based electrolyte showed unique stability under simulated sunlight and elevated temperatures.


[Relationship between disaster stress and peptic ulcers].
There had been several reports about the increasing of peptic ulcers under a large-scale disaster or a war. But in human, it was still unclear that a severe psychological stress itself cause peptic ulcer independently of two major causes (Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs). After Great East Japan earthquake in March 11th, 2011, one of the five most powerful earthquakes in the world since modern record keeping began in 1900, we also noticed remarkable increasing of patients with peptic ulcer in wide stricken area. Reports after this gigantic earthquake gave us two new important viewpoints. Disaster (psychological) stress possibly induce peptic ulcer independently of two major causes. And, people living in refugee shelter immediately after a disaster are strong risk group of peptic ulcer bleeding as well as an intake of anti-thrombotic agents.


Delivery of DNA vaccines: an overview on the use of biodegradable polymeric and magnetic nanoparticles.
Vaccination offers a cost-effective approach to the control of endemic infectious and a less invasive treatment modality against cancers. Since the discovery that injecting DNA encoding antigens (expressed in vivo) results in the induction of CD8 T cells as well as antibody mediated immunity, researchers have tried to develop methods to consistently enhance this immunity to disease protective levels in humans. Adsorption, coformulation, or encapsulation with particles has been found to both stabilize DNA formulations, through preventing rapid degradation, and provide vaccine adjuvanting effects, largely due to effective uptake of particulate materials by antigen presenting cells. Recently, it has been shown that nanoparticles, as opposed to microparticles, based DNA vaccine carriers are preferentially taken up by dendritic cells resulting in the induction of maximal levels of combined humoral and cellular immunity.


RETRACTED: Chiral Majorana fermion modes in a quantum anomalous Hall insulator-superconductor structure.
Majorana fermion is a hypothetical particle that is its own antiparticle. We report transport measurements that suggest the existence of one-dimensional chiral Majorana fermion modes in the hybrid system of a quantum anomalous Hall insulator thin film coupled with a superconductor. As the external magnetic field is swept, half-integer quantized conductance plateaus are observed at the locations of magnetization reversals, giving a distinct signature of the Majorana fermion modes. This transport signature is reproducible over many magnetic field sweeps and appears at different temperatures. This finding may open up an avenue to control Majorana fermions for implementing robust topological quantum computing.


Piloplex, a new long-acting pilocarpine polymer salt. B: Comparative study of the visual effects of pilocarpine and Piloplex eye drops.
Induced accommodation and changes in vision (distance and near) were measured monocularly and binocularly in 9 young healthy volunteers in a double blind study after administering to them pilocarpine hydrochloride 4%, Piloplex 3.4, and saline eye drop instillations. Piloplex 3.4, a new long-acting pilocarpine polymer salt, and pilocarpine hydrochloride 4% (both contain equal amounts of pilocarpine-3.4%) induced changes in vision and accommodation. These changes were greater with pilocarpine hydrochloride than with Piloplex. The maximum changes occurred half an hour after instillation and the effect vanished after an additional period up to 3 hours. The changes were greater when measured monocularly than binocularly. Piloplex initiates a prolonged hypotensive effect which lasts for 12 hours. Patients with glaucoma are thus able to use Piloplex on a twice-daily schedule. Consequently, visual disturbances occur only once a day in contrast to pilocarpine hydrochloride given 4 times a day, which induces 3 visual disturbances during the day.


Few infected CD4+ T cells but a high proportion of replication-competent provirus copies in asymptomatic human immunodeficiency virus type 1 infection.
The virus load in CD4+ T cells from six asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected individuals was determined by limiting-dilution analysis with a sensitive virus isolation procedure and the polymerase chain reaction (PCR). Both methods allowed detection of one HIV-1-infected cell among 10(5) uninfected cells. The number of provirus-containing CD4+ T cells was found to be 1 per 4,000 to 150,000 (median, 1 per 29,000), as determined by virus isolation and 1 per 2,500 to 26,000 (median, 1 per 12,000), as determined by PCR. Infected cells contained an average of 1 to 2 provirus copies, and a high proportion of the provirus copies (1 in 1 to 1 in 6; median, 1 in 2) were replication competent. The results suggest that only a few CD4+ T cells are likely to be lost as a direct consequence of the presence of HIV-1 in infected cells in asymptomatic individuals and that additional mechanisms may contribute to the depletion of CD4+ T cells observed in vivo.


Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral?
This article considers the use and modality of iron therapy to treat iron deficiency in patients with heart failure, an aspect of care which has received relatively little attention compared with the wider topic of anaemia management. Iron deficiency affects up to 50% of heart failure patients, and is associated with poor quality of life, impaired exercise tolerance, and mortality independent of haematopoietic effects in this patient population. The European Society of Cardiology Guidelines for heart failure 2012 recommend a diagnostic work-up for iron deficiency in patients with suspected heart failure. Iron absorption from oral iron preparations is generally poor, with slow and often inefficient iron repletion; moreover, up to 60% of patients experience gastrointestinal side effects. These problems may be exacerbated in heart failure due to decreased gastrointestinal absorption and poor compliance due to pill burden. Evidence for clinical benefits using oral iron is lacking. I.v. iron sucrose has consistently been shown to improve exercise capacity, cardiac function, symptom severity, and quality of life. Similar findings were observed recently for i.v. ferric carboxymaltose in patients with systolic heart failure and impaired LVEF in the double-blind, placebo-controlled FAIR-HF and CONFIRM-HF trials. I.v. iron therapy may be better tolerated than oral iron, although confirmation in longer clinical trials is awaited. Routine diagnosis and management of iron deficiency in patients with symptomatic heart failure regardless of anaemia status is advisable, and, based on current evidence, prompt intervention using i.v. iron therapy should now be considered.


Multitasking as a choice: a perspective.
Performance decrements in multitasking have been explained by limitations in cognitive capacity, either modelled as static structural bottlenecks or as the scarcity of overall cognitive resources that prevent humans, or at least restrict them, from processing two tasks at the same time. However, recent research has shown that individual differences, flexible resource allocation, and prioritization of tasks cannot be fully explained by these accounts. We argue that understanding human multitasking as a choice and examining multitasking performance from the perspective of judgment and decision-making (JDM), may complement current dual-task theories. We outline two prominent theories from the area of JDM, namely Simple Heuristics and the Decision Field Theory, and adapt these theories to multitasking research. Here, we explain how computational modelling techniques and decision-making parameters used in JDM may provide a benefit to understanding multitasking costs and argue that these techniques and parameters have the potential to predict multitasking behavior in general, and also individual differences in behavior. Finally, we present the one-reason choice metaphor to explain a flexible use of limited capacity as well as changes in serial and parallel task processing. Based on this newly combined approach, we outline a concrete interdisciplinary future research program that we think will help to further develop multitasking research.


Impact of scale space search on age- and gender-related changes in MRI-based cortical morphometry.
In magnetic resonance imaging based brain morphometry, Gaussian smoothing is often applied to increase the signal-to-noise ratio and to increase the detection power of statistical parametric maps. However, most existing studies used a single smoothing filter without adequately justifying their choices. In this article, we want to determine the extent for which performing a morphometry analysis using multiple smoothing filters, namely conducting a scale space search, improves or decreases the detection power. We first compared scale space search with single-filter analysis through a simulated population study. The multiple comparisons in our four-dimensional scale space searches were corrected for using a unified P-value approach. Our results illustrate that, compared with a single-filter analysis, a scale space search analysis can properly capture the variations in analysis results caused by variations in smoothing, and more importantly, it can obviously increase the sensitivity for detecting brain morphometric changes. We also show that the cost of an increased critical threshold for conducting a scale space search is very small. In the second experiment, we investigated age and gender effects on cortical volume, thickness, and surface area in 104 normal subjects using scale space search. The obtained results provide a perspective of scale space theory on the morphological changes with age and gender. These results suggest that, in exploratory studies of aging, gender, and disease, conducting a scale space search is essential, if we are to produce a complete description of the structural changes or abnormalities associated with these dimensions.


Assessing BPSD with the support of the NPI-NH: a discourse analysis of clinical reasoning.
ABSTRACTBackground:The ability of nursing staff to assess and evaluate behavioral and psychological symptoms of dementia (BPSD) to determine when intervention is needed is essential. In order to assist with the assessment process, the current use of the Neuropsychiatric Inventory Nursing Home version (NPI-NH) is internationally accepted. Even though the NPI-NH is thoroughly validated and has several advantages, there are also various challenges when implementing this system in practice. Thus, the aim of this study was to explore clinical reasoning employed by assistant nurses when utilizing the NPI-NH as a tool to assess frequency and severity of BPSD in individuals with advanced dementia. Twenty structured assessment sessions in which assistant nurses used the NPI-NH were audio recorded and analyzed with a discourse analysis focusing on the activities in the communication. Four categories were identified to convey assistant nurses' clinical reasoning when assessing and evaluating BPSD using the NPI-NH: considering deteriorations in ability and awareness, incorporating individual and contextual factors, overcoming variations in behaviors and ambiguous formulations in the instrument, and sense-making interactions with colleagues. The NPI-NH served as a supportive frame and structure for the clinical reasoning performed during the assessment. The clinical reasoning employed by assistant nurses became a way to reach a consensual and broader understanding of the individual with dementia, with the support of NPI-NH as an important framework.


Percutaneous treatment of ductal origin of the distal pulmonary artery in low-weight newborns.
We sought to evaluate the role of percutaneous techniques in the treatment of ductal origin of a distal pulmonary artery (PA) in low-weight infants. Various surgical approaches have been proposed, however, they are highly challenging and risky in neonates. We treated 5 infants weighing < 3 kg with ductal origin of the PA associated with other congenital heart disease. Procedures were performed under general anesthesia and orotracheal intubation. A total of 7 coronary stents were used. Median procedure and fluoroscopy times were 100 and 8 minutes, respectively. Oxygen saturation increased significantly in all cases (p = 0.026). Both procedural and postprocedural courses were uneventful and the patients were discharged 7-10 days post procedure. During a follow up of 4-12 months, the results remained stable. Two subjects underwent complete corrective surgery 6 months after stent implantation at a weight of 7-9 kg. Ductus arteriosus with the stent inside were completely removed by surgeons who did not report any difficulty. Three subjects await surgery. Percutaneous management of the ductal origin of the pulmonary artery is a safe and efficacious palliative approach.


Direct measurement of the rhythmic motions of the human head identifies a third rhythm.
Central to the osteopathic cranial field, and at the same time controversial, is the concept of a unique rhythmic movement believed to originate from a primary respiratory mechanism (PRM). Further, the PRM is reported to manifest as a cranial rhythmic impulse (CRI) on the living human skull. This study explores the rhythmic oscillations of the human head measured directly as physical movements. The aim is to investigate the existence of a third rhythm distinct from the head movements caused by respiratory breathing and arterial pulsing, in an objective and purely experimental study. In 50 healthy individuals, rhythmic oscillations of the head were measured in real-time for 42 min in a supine resting state without any intervention. A newly developed machine for tracking rhythmic movements was used for measurements. In all individuals, a third rhythm was distinguished as separate from the arterial and respiratory rhythm at all times. The third rhythm was observed as a dynamic physiological phenomenon with a narrow range in resting healthy individuals with a mean of 6.16 cycles/minute (4.25-7.07). The significant contribution to the amplitude of the measured movements was the respiratory breathing and this third rhythm, whereas the contribution from the arterial pulsing were minor. The present study demonstrates the existence, and normative range of a third physical rhythm detected on the human head. Having developed an objective approach to studying this third rhythm might form the future basis for clinical and physiological studies of craniosacral function and dysfunction.


Cross-modal Action Complexity: Action- and Rule-related Memory Retrieval in Dual-response Control.
Normally, we do not act within a single effector system only, but rather coordinate actions across several output modules (cross-modal action). Such cross-modal action demands can vary substantially with respect to their complexity in terms of the number of task-relevant response combinations and to-be-retrieved stimulus-response (S-R) mapping rules. In the present study, we study the impact of these two types of cross-modal action complexity on dual-response costs (i.e., performance differences between single- and dual-action demands). In Experiment 1, we combined a manual and an oculomotor task, each involving four response alternatives. Crucially, one (unconstrained) condition involved all 16 possible combinations of response alternatives, whereas a constrained condition involved only a subset of possible response combinations. The results revealed that preparing for a larger number of response combinations yielded a significant, but moderate increase in dual-response costs. In Experiment 2, we utilized one common lateralized auditory (e.g., left) stimulus to trigger incompatible response compounds (e.g., left saccade and right key press or vice versa). While one condition only involved one set of task-relevant S-R rules, another condition involved two sets of task-relevant rules (coded by stimulus type: noise/tone), while the number of task-relevant response combinations was the same in both conditions. Here, an increase in the number of to-be-retrieved S-R rules was associated with a substantial increase in dual-response costs that were also modulated on a trial-by-trial basis when switching between rules. Taken together, the results shed further light on the dependency of cross-modal action control on both action- and rule-related memory retrieval processes.


Interobserver and intraobserver variability in the response evaluation of cancer therapy according to RECIST and WHO-criteria.
Response Evaluation Criteria In Solid Tumors (RECIST) and WHO-criteria are used to evaluate treatment effects in clinical trials. The purpose of this study was to examine interobserver and intraobserver variations in radiological response assessment using these criteria. Thirty-nine patients were eligible. Each patient's series of CT images were reviewed. Each patient was classified into one of four categories according RECIST and WHO-criteria. To examine interobserver variation, response classifications were independently obtained by two radiologists. One radiologist repeated the procedure on two additional different occasions to examine intraobserver variation. Kappa statistics was applied to examine agreement. Interobserver variation using RECIST and WHO-criteria were 0.53 (95% CI 0.33-0.72) and 0.60 (0.39-0.80), respectively. Response rates (RR) according to RECIST obtained by reader A and reader B were 33% and 21%, respectively. RR according to WHO-criteria obtained by reader A and reader B were 33% and 23% respectively. Intraobserver variation using RECIST and WHO-criteria ranged between 0.76-0.96 and 0.86-0.91, respectively. Radiological tumor response evaluation according to RECIST and WHO-criteria are subject to considerable inter- and intraobserver variability. Efforts are necessary to reduce inconsistencies from current response evaluation criteria.


Impact of feed intake during late gestation on piglet birth weight and reproductive performance: a dose-response study performed in gilts.
The effects of increasing feed intake (1.8, 2.3, 2.8, and 3.3 kg/d) during late gestation of gilts on piglet birth weight and female reproductive performance were evaluated. A total of 977 gilts were fed a diet based on corn-soybean meal (3.29 Mcal ME per kg and 0.64% standardized ileal digestible lysine) from day 90 of gestation until farrowing. Gilts were weighed on days 90 and 112 of gestation, at farrowing and weaning. Born alive and stillborn piglets were weighed within 12 h of birth. Colostrum yield (CY), lactation feed intake, and litter growth rate were measured in a randomly selected subsample of 245 gilts. The data were analyzed using generalized linear mixed models. As expected, gains in body weight (BW) were different at day 112 (P < 0.001) with the greatest values observed in the 3.3 kg/d treatment. As feed intake increased during late gestation, BW, body condition score (BCS), backfat (BF), and Caliper unit also increased between day 112 and weaning (P < 0.001). No differences were found among treatments in total number of piglets born, mummified fetuses, sum of born alive and stillborn piglets, and within-litter birth weight CV (P > 0.05). Tendencies for quadratic effect of feed intake were observed for born alive piglets (P = 0.079), average birth weight of piglets (P = 0.083), and litter weight (P = 0.059). Gilts with lower feed intake during late gestation had reduced percentages of stillborn piglets than gilts with greater feed intakes. The CY decreased linearly (P < 0.05) as the feed intake was increased. No differences among treatments were found at weaning in individual piglet weight and litter weight, as well as in percentage of weaned piglets (P > 0.05). Lactation feed intake decreased as gestation feeding level increased (P < 0.05). No differences in the subsequent cycle were observed among treatments for farrowing rate, retention rate up to the next farrowing, number of total piglets born, born alive, stillborn piglets, and mummified fetuses (P > 0.05). In conclusion, increased feed intake from day 90 of gestation until farrowing resulted in increased maternal BW gain and stillborn rate, but reduced CY and lactation feed intake. A slight increase in birth weight was observed for the 2.3 kg/d treatment. Furthermore, litter growth and subsequent female reproductive performance were not affected by feed intake during late gestation.


Results of a workplace health campaign: what can be achieved?
Effective health promotion in the workplace is now essential because of the rising health-related costs for businesses, the increasing pressure arising from international competition, prolonged working lives, and the aging of the work force. The basic problem of prevention campaigns is that the target groups are too rarely reached and sustainable benefits too rarely achieved. In 2011, we carried out a broad-based health and fitness campaign to assess how many personnel could be motivated to participate in a model study under nearly ideal conditions. 1010 personnel were given the opportunity to participate in various kinds of sports, undergo sports-medicine examinations, attend monthly expert lectures, and benefit from nutritional offerings and Intranet information during work hours. Pseudonymized questionnaires were used to classify the participants according to their exercise behavior as non-active, not very active, and very active. The participants' subjective responses (regarding, e.g., health, exercise, nutrition, and the factors that motivated them to participate in sports or discouraged them from doing so) were recorded, as were their objective data (measures of body size and strength). The duration of the study was one year. 490 of the 1010 personnel (48.5%, among whom 27.2% were nonactive, 44.1% not very active, and 28.7% very active) participated in the initial questionnaire and testing. By the end of the study, this figure had dropped to 17.8%; diminished participation affected all three groups to a comparable extent. A comparison of dropouts and non-dropouts revealed that older age was a stable predictor for drop-out (bivariate odds ratio [OR] 1.028, p = 0.006; multivariate OR 1.049, p = 0.009). The study participants reported beneficial effects on their health and health awareness, performance ability, psychological balance, stress perception, exercise and dietary behavior. Even under optimal conditions and with high use of staff resources, this model study (which cannot be universally implemented) did not lead to comprehensive and sustained personnel participation. This finding suggests that the currently available prevention instruments are insufficient for the effective and cost-efficient promotion of health and fitness in the workplace.


The role of the partner and relationship satisfaction on treatment outcome in patients with chronic fatigue syndrome.
Cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) leads to a significant decrease in CFS-related symptoms and disability. The primary objective of this study was to explore whether partners' solicitous responses and patients' and partners' perceived relationship satisfaction had an effect on treatment outcome. The treatment outcome of a cohort of 204 consecutively referred patients treated with CBT was analysed. At baseline, CFS patients completed the Maudsley Marital Questionnaire. The Checklist Individual Strength subscale Fatigue and the Sickness Impact Profile total scores completed by CFS patients post-treatment were used as measures of clinically significant improvement. Partners completed the Family Response Questionnaire, the Maudsley Marital Questionnaire, the Brief Illness Perception Questionnaire, and the Causal Attribution List. Logistic regression analyses were performed with clinically significant improvement in fatigue and disability as dependent variables and scores on questionnaires at baseline as predictors. Solicitous responses of the partner were associated with less clinically significant improvement in fatigue and disability. Partners more often reported solicitous responses when they perceived CFS as a severe condition. Patients' relationship dissatisfaction was negatively associated with clinically significant improvement in fatigue. Partners' solicitous responses and illness perceptions at the start of the therapy can negatively affect the outcome of CBT for CFS. We emphasize the importance of addressing this in therapy.


Cost-effectiveness of laparoscopy in children.
Laparoscopy may offer fast recovery and improved cosmesis, but its cost has been perceived as excessive. To analyze the total hospital costs of laparoscopy vs open surgery. Retrospective cost-effectiveness analysis evaluating all cases performed in a 36-month period (September 1995 to August 1998). Cases were evaluated for operative time, itemized cost of supplies, and length of hospitalization. Operations performed by pediatric surgeons in a tertiary care children's hospital. Consecutive children undergoing laparoscopic or open appendectomies, cholecystectomies, fundoplications, and splenectomies. Patients were not randomized to laparoscopy, or open surgery. Laparoscopic procedures performed with a core set of reusable equipment and a limited number of disposable instruments. Cost surplus of laparoscopy was evaluated, and compared with savings associated with decreased hospital stay, to obtain cost-effectiveness of laparoscopy per procedure. There were 26 laparoscopic and 359 open appendectomies; 33 laparoscopic and 3 open cholecystectomies; 16 laparoscopic and 18 open fundoplications; and 16 laparoscopic and 7 open splenectomies. Excess operating costs per procedure were $442.00 for appendectomy, $634.60 for fundoplication, $847.50 for cholecystectomy, and $1551.30 for splenectomy. Hospital stay was decreased for all laparoscopies, resulting in an overall savings per laparoscopic procedure of $2369.90 for appendectomy, $5390.90 for fundoplication, $1161.00 for cholecystectomy, and $858.90 for splenectomy. Laparoscopy is cost-effective, particularly for fundoplication, appendectomy, and cholecystectomy. Detailing the costs of supplies, operating time, and length of stay allows interinstitutional comparison and critical cost-analysis of laparoscopy. With a more selective use of reusable instruments and further shortening of operative time, the global savings of laparoscopy may increase.


[The tricarboxylic acid cycle and the genetic code].
Application of quantum--mechanical calculations of interaction energy of nitrous bases in DNA triplets to genetic code permits division of codons and pertinent amino acids into two groups. The first one corresponds to the upper energetic level 150-170 kJ/mole per base pair (per a triplet codon on the average). The second group corresponds to the low energetic level 88/92 kJ/mole per base pair. Comparing this grouping of amino acids with their incorporations into the cycle of tricarboxylic acids it turns out that the majority of amino acids of the first group are incorporated into the cycle via acetyl-KoA. Most amino acids of the second group are incorporated directly. It seems that the ways of amino acids introduction into the cycle of tricarboxylic acids are to a certain degree predetermined by energetic interactions of nitrous bases in the genetic codons.


Blood Cell In Vitro Cytokine Production in Response to Lipopolysaccharide Stimulation in a Healthy Population: Effects of Age, Sex, and Smoking.
Immune system functionality has been commonly assessed by a whole-blood or isolated-cell stimulation assay. The aim of this study was to determine whether cytokine production in whole-blood-stimulated samples is influenced by age, sex, and smoking. A descriptive cross-sectional study in 253 healthy participants aged 18-55 years was conducted. Whole blood samples were stimulated for 24 h with LPS and concentrations of IL-6, IL-10, and TNF-α were determined in the culture media. Among parameters considered, statistical regression analysis indicated that smoking (change in R2 = 0.064, p < 0.001) and sex (change in R2 = 0.070, p < 0.001) were the main predictors for IL-10 production, with higher values for women and non-smokers. Age was also found to be a significant predictor (change in R2 = 0.021, p < 0.001), with higher values for younger ages. Age (change in R2 = 0.089, p = 0.013) and smoking (change in R2 = 0.037, p = 0.002) were found to be negative predictors for IL-6 production. Regarding TNF-α-stimulated production, age (change in R2 = 0.029, p = 0.009) and smoking (change in R2 = 0.022, p = 0.022) were found to be negative predictors. Furthermore, sex (change in R2 = 0.016, p = 0.045) was found to be a significant predictor, with lower values for women. In conclusion, sex, age, and smoking were found to be independent determinants of stimulated cytokine production. While female sex is associated with higher IL-10 and lower TNF-α production, aging and smoking are associated with lower IL-6, IL-10, and TNF-α production.


Brain activity in the right-frontal pole and lateral occipital cortex predicts successful post-operatory outcome after surgery for anterior glenoumeral instability.
Shoulder apprehension is more complex than a pure mechanical problem of the shoulder, creating a scar at the brain level that prevents the performance of specific movements. Surgery corrects for shoulder instability at the physical level, but a re-dislocation within the first year is rather common. Predicting which patient will be likely to have re-dislocation is therefore crucial. We hypothesized that the assessment of neural activity at baseline and follow-up is the key factor to predict the post-operatory outcome. 13 patients with shoulder apprehension (30.03 ± 7.64 years) underwent clinical and fMRI examination before and one year after surgery for shoulder dislocation contrasting apprehension cue videos and control videos. Data analyses included task-related general linear model (GLM) and correlations imaging results with clinical scores. Clinical examination showed decreased pain and increased shoulder functions for post-op vs. pre-op. Coherently, GLM results show decreased activation of the left pre-motor cortex for post-surgery vs. pre-surgery. Right-frontal pole and right-occipital cortex activity predicts good recovery of shoulder function measured by STT. Our findings demonstrate that beside physical changes, changes at the brain level also occur one year after surgery. In particular, decreased activity in pre-motor and orbito-frontal cortex is key factor for a successful post-operatory outcome.


Buflomedil for intermittent claudication.
Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. To evaluate the available evidence on the efficacy of buflomedil for IC. We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched November 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2007), MEDLINE (1966 to November 2007), International Pharmaceutical Abstracts (IPA) (from inception to November 2007), Science Citation Index (from inception to November 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.


Valuing and Integrating Informal Care as a Core Component of Long-Term Care for Older People: A Comparison of Recent Developments in Italy and Spain.
The international long-term care (LTC) debate has recently been focusing on how to strengthen home care provision. In this regard, a major role has been played by informal care and how to best integrate it in a holistic care approach. Italy and Spain, usually labeled as "familialist" or "family-based" care models, have been promoting national reforms or actions to support the integration of "informal" actors into the overall LTC system. Through a comparative review of recent trends observed in the two care regimes, this article aims at contributing to improve our cross-national understanding of how LTC is changing across Europe, identifying the basic approaches adopted in Italy and Spain and highlighting both their strengths and drawbacks.


Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary.
Sulfonimidamides (SIAs) and sulfoximines (SOIs) have attracted attention due to their potential in agriculture and in medicinal chemistry as bioisosteres of biologically active compounds, and new synthetic methods are needed to access and explore these compounds. Herein, we present a light-promoted generation of perfluorinated aromatic nitrenes, from perfluorinated azides, that subsequently are allowed to react with sulfinamides and sulfoxides, generating achiral and chiral SIAs and SOIs. One of the enantiopure SIAs was evaluated as a novel chiral auxiliary in Grignard additions to the imines yielding the product in up to 96:4 diastereomeric ratio.


Avoidance motivation and choking under pressure in soccer penalty shootouts.
The purpose of this study was to examine the relationships between shot valence, avoidance behavior, and performance in soccer penalty shootouts. Video analyses were conducted with all penalty shootouts ever held in the World Cup, the European Championships, and the UEFA Champions League (n = 36 shootouts, 359 kicks). Shot valence was assessed from the potential consequences of a shot outcome as follows: Shots where a goal instantly leads to victory were classified as positive valence shots and shots where a miss instantly leads to loss as negative valence shots. Avoidance behavior was defined as looking away from the goalkeeper or preparing the shot quickly (thus speeding up the wait). The results showed that avoidance behavior occurred more with negative valence shots than with positive shots and that players with negative valence shots performed worse than those with positive shots. Thus, avoidance motivation may help explain why professional athletes occasionally choke under pressure.