Classification of neck movement patterns related to whiplash-associated disorders using neural networks.
This paper presents a new method for classification of neck movement patterns related to Whiplash-associated disorders (WAD) using a resilient backpropagation neural network (BPNN). WAD are a common diagnosis after neck trauma, typically caused by rear-end car accidents. Since physical injuries seldom are found with present imaging techniques, the diagnosis can be difficult to make. The active range of the neck is often visually inspected in patients with neck pain, but this is a subjective measure, and a more objective decision support system, that gives a reliable and more detailed analysis of neck movement pattern, is needed. The objective of this study was to evaluate the predictive ability of a BPNN, using neck movement variables as input. Three-dimensional (3-D) neck movement data from 59 subjects with WAD and 56 control subjects were collected with a ProReflex system. Rotation angle and angle velocity were calculated using the instantaneous helical axis method and motion variables were extracted. A principal component analysis was performed in order to reduce data and improve the BPNN performance. BPNNs with six hidden nodes had a predictivity of 0.89, a sensitivity of 0.90 and a specificity of 0.88, which are very promising results. This shows that neck movement analysis combined with a neural network could build the basis of a decision support system for classifying suspected WAD, even though further evaluation of the method is needed.


The management of hepatorenal syndrome.
The hepatorenal syndrome (HRS) is a common complication in advanced liver cirrhosis, and often occurs in patients with ascites and severe circulatory dysfunction. HRS is a functional renal failure which was believed to be the end result of progressive splanchnic vasodilatation. However, recent data have implicated a role of reduced cardiac output as well as endothelial dysfunction in the etiology of HRS. Type 1 HRS is associated with a poor prognosis and often occurs in conjunction with microcirculatory dysfunction in other organs, including the heart, brain and liver. The treatment of type 1 HRS has centered around vasoconstrictors and intravenous hydration, traditionally midodrine and albumin. However, new vasoconstrictors (specifically vasopressin analogues), transjugular intrahepatic portacaval shunts, and albumin dialysis have been introduced as potential therapies. This review will discuss new advances in the diagnosis and pathogenesis of HRS, with an emphasis on the management.


Natural recovery and treatment-seeking in pathological gambling: results of two U.S. national surveys.
Pathological gambling is described in DSM-IV as a chronic and persisting disorder, but recent community-based longitudinal studies that have highlighted the transitory nature of gambling-related problems have called into question whether this is an accurate characterization. This emerging evidence of high rates of recovery coupled with low rates of treatment-seeking for pathological gambling suggests that natural recovery might be common. The purpose of the present study was to document the rates of recovery, treatment-seeking, and natural recovery among individuals with DSM-IV pathological gambling disorder in two large and representative U.S. national surveys. Prevalences of recovery, treatment-seeking, and natural recovery were estimated among individuals from the Gambling Impact and Behavior Study (N=2,417) and the National Epidemiologic Survey on Alcohol and Related Conditions (N=43,093) who reported a lifetime history of DSM-IV pathological gambling disorder (N=21 and N=185, respectively). Among individuals with a lifetime history of DSM-IV pathological gambling, 36%-39% did not experience any gambling-related problems in the past year, even though only 7%-12% had ever sought either formal treatment or attended meetings of Gamblers Anonymous. About one-third of the individuals with pathological gambling disorder in these two nationally representative U.S. samples were characterized by natural recovery. Pathological gambling may not always follow a chronic and persisting course. A substantial portion of individuals with a history of pathological gambling eventually recover, most without formal treatment. The results of large epidemiological surveys of pathological gambling may eventually overturn the established wisdom about pathological gambling disorder.


Genome analysis of the moss Physcomitrella patens (Hedw.) B.S.G.
A wild-type (WT) strain of the moss Physcomitrella patens (Hedw.) B.S.G., two mutants derived from it (PC22 and P24), and a somatic hybrid, PC22(+)P24, were analysed. Staining of metaphases revealed 54 +/- 2 chromosomes in the somatic hybrid and 27 chromosomes in the wild type and the two mutants. Using flow cytometry (FCM), DNA contents were calculated to be 0.6 pg (WT, PC22), 1.2 pg (P24), and 1.6 pg (PC22(+)P24) per nucleus, respectively. Southern hybridization provided evidence for at least one family of highly repetitive DNA and, furthermore, revealed different amounts of repetitive DNA in the four genotypes. However, these sequences cannot account for the 100% increase in the nuclear DNA amount in mutant P24, relative to wild type. In FCM analyses every moss genotype generated just one single peak of fluorescence, indicating an arrest in the cell cycle during the daytime. Thermal denaturation of wild-type DNA revealed a G+C content of 34.6% for total DNA and 38.6% for plastid DNA. A cDNA library of 1.2 x 10(6) independent clones was established, from which sequences homologous to cab and rbcS, respectively, were isolated. These genes show significant homologies to those of higher plants, and, likewise, comprise multigene families. No restriction fragment length polymorphisms could be detected between the four moss genotypes using these cDNA probes.


[The role of co-inhibitory signals driven by CTLA-4 in immune system].
Key players on the immunosurveillance program, T cells are regulated by their surface receptors such as T-cell receptor (TCR), and costimulatory molecules, optimizing T-cell activation. Some of these costimulatory molecules, such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), induce inhibitory effects on T cells. By "inhibiting the inhibitor" CTLA-4-blocking monoclonal antibodies represent a novel class of weapons against cancers. To better understand the promising future and the limits of this immunotherapy, this review dissects the molecular inhibitory mechanisms induced by CTLA-4 in T cells.


Using positive youth development constructs to design a drug education curriculum for junior secondary students in Hong Kong.
This paper outlines the design of a new curriculum for positive youth development (P.A.T.H.S. II) in Hong Kong. The paper discusses the conceptual base for designing a drug-education curriculum for junior-secondary students using four positive youth development constructs--cognitive competence, emotional competence, beliefs in the future, and self-efficacy. The program design is premised on the belief that adolescents do have developmental assets; therefore, the curriculum is designed to develop their psychosocial competencies. The goal of the curriculum is to develop the selfhood of these youths and ultimately achieve the goal of successful adolescent development.


Halofuginone-coated urethral catheters prevent periurethral spongiofibrosis in a rat model of urethral injury.
Urethral strictures are from periurethral spongiofibrosis that develops as a result of urethral trauma, disease, or iatrogenic injury. The spongy tissue that surrounds the strictured urethra has an altered ratio of collagen, with increased collagen type I relative to type III. We evaluated the ability of a urethral catheter that was coated with halofuginone (HF), a potent type I collagen inhibitor, to prevent spongiofibrosis formation in a rat model. HF was coated on silicone catheters and release kinetics were measured. Success of impregnation was evaluated with scanning electron microscopy, serial weights, and drug elution data. Urethral strictures were induced in rats using electrocautery. Half the animals had placement of an HF-coated catheter while the others had uncoated silicone controls. Animals were sacrificed at predetermined time points, and urethral tissue was either processed for staining with Masson trichrome and anti-alpha-1 collagen or digested to determine HF concentration. Serum drug levels were also determined in treated animals. Slides were graded by a pathologist who was blinded to treatment to determine collagen deposition. HF was coated successfully on silicone catheters. Local urethral concentration of HF was tenfold higher than serum concentration in treated rats. Animals with HF-coated catheters had no new type I collagen deposition after urethral injury. Control animals had increased periurethral collagen type I deposition, typical of urethral stricture formation. HF can be coated successfully on silicone catheters. HF successfully inhibits periurethral type I collagen deposition after urethral injury. This may become an important therapy to prevent urethral stricture formation or recurrence after endoscopic therapy.


Broadly tunable continuous-wave orange-red source based on intracavity-doubled Cr4+:forsterite laser.
The operation of a room-temperature, continuous-wave, intracavity frequency-doubled Cr4+:forsterite laser capable of producing broadly tunable output in the orange-red region of the electromagnetic spectrum is described. Intracavity doubling was achieved in a periodically poled lithium niobate crystal that had gratings with different periods. Tunable second-harmonic output could be obtained between 613 and 655 nm. At a wavelength of 630 nm, intracavity doubling yielded as much as 45 mW of continuous-wave output. To the author's knowledge, this represents the highest second-harmonic-power generation obtained to date with a continuous-wave Cr4+:forsterite laser.


Gene prediction in novel fungal genomes using an ab initio algorithm with unsupervised training.
We describe a new ab initio algorithm, GeneMark-ES version 2, that identifies protein-coding genes in fungal genomes. The algorithm does not require a predetermined training set to estimate parameters of the underlying hidden Markov model (HMM). Instead, the anonymous genomic sequence in question is used as an input for iterative unsupervised training. The algorithm extends our previously developed method tested on genomes of Arabidopsis thaliana, Caenorhabditis elegans, and Drosophila melanogaster. To better reflect features of fungal gene organization, we enhanced the intron submodel to accommodate sequences with and without branch point sites. This design enables the algorithm to work equally well for species with the kinds of variations in splicing mechanisms seen in the fungal phyla Ascomycota, Basidiomycota, and Zygomycota. Upon self-training, the intron submodel switches on in several steps to reach its full complexity. We demonstrate that the algorithm accuracy, both at the exon and the whole gene level, is favorably compared to the accuracy of gene finders that employ supervised training. Application of the new method to known fungal genomes indicates substantial improvement over existing annotations. By eliminating the effort necessary to build comprehensive training sets, the new algorithm can streamline and accelerate the process of annotation in a large number of fungal genome sequencing projects.


When is a pregnancy nonviable and what criteria should be used to define miscarriage?
In 2011, the first systematic review of the evidence behind the diagnostic criteria for miscarriage was published. It states, "findings were limited by the small number and poor quality of the studies," and concluded that further studies were, "urgently required before setting future standards for the accurate diagnosis of early embryonic demise." This implies that data used to define criteria to diagnose miscarriage are unreliable. The 2011 Irish Health Service executive review into miscarriage misdiagnosis highlighted this issue. In parallel to these publications a multicenter prospective study was published examining cut-off values for mean sac diameter (MSD) and embryo size to define miscarriage. The authors also published evidence on expected findings when ultrasonography is repeated at an interval. This led to guidance on diagnostic criteria for miscarriage in the UK changing. These new criteria state miscarriage be considered only when: an empty gestation sac has an MSD of ≥ 25 mm (with no obvious yolk sac), or embryonic crown rump length ≥ 7 mm (the latter without evidence of fetal heart activity). If in doubt, repeating scans at an interval is emphasized. It is axiomatic that decisions about embryonic viability must not be open to doubt. So it is surprising how little evidence exists to support previous guidance. Any clinician working in this area knows of women being wrongly informed that their pregnancy has failed. This cannot be acceptable and guidance in this area must be "failsafe."


Radicals derived from histone hydroperoxides damage nucleobases in RNA and DNA.
Exposure of individual histone proteins (H1, H2A, H2B, H3, or H4) and histone octamers (consisting of two molecules each of H2A, H2B, H3, and H4) to hydroxyl radicals, generated by gamma-irradiation, in the presence of O(2) generates protein-bound hydroperoxides in a dose-dependent fashion; this is in accord with previous studies with other proteins. These histone hydroperoxides are stable in the absence of exogenous catalysts (e.g., heat, light, and transition metal ions), but in the presence of these agents decompose rapidly to give a variety of radicals which have been identified by EPR spin trapping. Histone hydroperoxide-derived radicals generated on decomposition of the hydroperoxides with Cu(+) react with both pyrimidine and purine nucleobases. Thus, with uridine the histone hydroperoxide-derived radicals undergo addition across the C(5)-C(6) double bond of the pyrimidine ring to give cross-linked adduct species which have been identified by EPR spectroscopy. HPLC analysis of the products generated on reaction of histone hydroperoxide-derived radicals with 2'-deoxyguanosine, or intact calf thymus DNA, has shown that significant levels of the mutagenic oxidized DNA base 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) are formed, with the yield dependent on the individual histone protein, the presence of hydroperoxide functions, and the concentration of metal ion. These studies demonstrate that initial oxidative damage to individual histone proteins or histone octamers can result in the transfer of oxidative damage to associated DNA via the formation and subsequent decomposition of protein hydroperoxides to reactive radicals, and provide a novel route for the formation of mutagenic lesions in DNA.


Microsatellite analysis of Damask rose (Rosa damascena Mill.) accessions from various regions in Iran reveals multiple genotypes.
Damask roses (Rosa damascena Mill.) are mainly used for essential oil production. Previous studies have indicated that all production material in Bulgaria and Turkey consists of only one genotype. Nine polymorphic microsatellite markers were used to analyze the genetic diversity of 40 accessions of R. damascena collected across major and minor rose oil production areas in Iran. All microsatellite markers showed a high level of polymorphism (5-15 alleles per microsatellite marker, with an average of 9.11 alleles per locus). Cluster analysis of genetic similarities revealed that these microsatellites identified a total of nine different genotypes. The genotype from Isfahan province, which is the major production area, was by far the most common genotype (27/40 accessions). It was identical to the Bulgarian genotype. Other genotypes (each represented by 1-4 accessions) were collected from minor production areas in several provinces, notably in the mountainous Northwest of Iran. This is the first study that uncovered genetic diversity within Damask rose. Our results will guide new collection activities to establish larger collections and manage the Iranian Damask rose genetic resources. The genotypes identified here may be directly useful for breeding.


Analysis of the influence of cell heterogeneity on nanoparticle dose response.
Understanding the effect of variability in the interaction of individual cells with nanoparticles on the overall response of the cell population to a nanoagent is a fundamental challenge in bionanotechnology. Here, we show that the technique of time-resolved, high-throughput microscopy can be used in this endeavor. Mass measurement with single-cell resolution provides statistically robust assessments of cell heterogeneity, while the addition of a temporal element allows assessment of separate processes leading to deconvolution of the effects of particle supply and biological response. We provide a specific demonstration of the approach, in vitro, through time-resolved measurement of fibroblast cell (HFF-1) death caused by exposure to cationic nanoparticles. The results show that heterogeneity in cell area is the major source of variability with area-dependent nanoparticle capture rates determining the time of cell death and hence the form of the exposure–response characteristic. Moreover, due to the particulate nature of the nanoparticle suspension, there is a reduction in the particle concentration over the course of the experiment, eventually causing saturation in the level of measured biological outcome. A generalized mathematical description of the system is proposed, based on a simple model of particle depletion from a finite supply reservoir. This captures the essential aspects of the nanoparticle–cell interaction dynamics and accurately predicts the population exposure–response curves from individual cell heterogeneity distributions.


Transcriptional profiling of developing mouse epidermis reveals novel patterns of coordinated gene expression.
The mammalian epidermis is the first line of defense against external environmental challenges including dehydration. The epidermis undergoes a highly intricate developmental program in utero, transforming from a simple to a complex stratified epithelium. During this process of stratification and differentiation, epidermal keratinocytes express a defined set of structural proteins, mainly keratins, whose expression is controlled by largely unknown mechanisms. In order to identify novel factors contributing to epidermal morphogenesis, we performed a global transcriptional analysis of the developing mouse epidermis after separating it from the underlying dermis (E12.5-E15.5). Unexpectedly, the recently identified genes encoding secreted peptides dermokine (Dmkn), keratinocyte differentiation-associated protein (krtdap), and suprabasin (Sbsn) as well as a largely uncharacterized embryonic keratin (Krt77), were among the most highly differentially expressed genes. The three genes encoding the secreted proteins form a cluster in an approximately 40-Kb locus on human chromosome 19 and the syntenic region on mouse chromosome 7 known as the stratified epithelium secreted peptides complex (SSC). Using whole mount in situ hybridization, we show that these genes show a coordinated spatio-temporal expression pattern during epidermal morphogenesis. The expression of these genes initiates in the nasal epithelium and correlates with the initiation of other epidermal differentiation markers such as K1 and loricrin (Byrne et al. [1994] Development 120:2369-2383), as well as the initiation of barrier formation. Our observations reveal a coordinated mode of expression of the SSC genes as well as the correlation of their initiation in the nasal epithelium with the initiation of barrier formation at this site.


Partial purification from hot dogs of N-nitroso compound precursors and their mutagenicity after nitrosation.
Hot dogs contain apparent N-nitroso compounds (ANC) and ANC precursors (ANCP). ANCP purification was followed by nitrosation, sulfamic acid treatment, and analysis for ANC. Aqueous hot dog extracts were adsorbed on silica gel, which was eluted with MeCN and MeOH. The MeOH eluate was adsorbed on cation exchange resin (H+ form) and eluted with NH4OH. Eluted ANCP traveled at moderate speeds in high-performance liquid chromatography (HPLC) on amino and Pb2+ columns. Gas chromatography-mass spectrometry (GC-MS) of trimethylsilyl (TMS) derivatives of crude water extract indicated the presence of glycerol, phosphate, lactic acid, and two monosaccharides. GC-MS of TMS derivatives of Pb2+ column HPLC eluates indicated that ANCP included 1-deoxy-N-1-glucosyl glycine. The nitrosated NH4OH eluate showed 4x background mutagenic activity for Salmonella typhimurium TA-100. Un-nitrosated fractions showed 2x background activity. Although tryptophan nitrosation gave 88% ANC yield, tryptophan is probably not a major ANCP in hot dogs. Hot dog patties prepared with or without sucrose or glucose showed similar ANC and ANCP levels. We discuss possible implications of these findings for the etiology of colon cancer.


Evolution of crystallins for a role in the vertebrate eye lens.
The camera eye lens of vertebrates is a classic example of the re-engineering of existing protein components to fashion a new device. The bulk of the lens is formed from proteins belonging to two superfamilies, the α-crystallins and the βγ-crystallins. Tracing their ancestry may throw light on the origin of the optics of the lens. The α-crystallins belong to the ubiquitous small heat shock proteins family that plays a protective role in cellular homeostasis. They form enormous polydisperse oligomers that challenge modern biophysical methods to uncover the molecular basis of their assembly structure and chaperone-like protein binding function. It is argued that a molecular phenotype of a dynamic assembly suits a chaperone function as well as a structural role in the eye lens where the constraint of preventing protein condensation is paramount. The main cellular partners of α-crystallins, the β- and γ-crystallins, have largely been lost from the animal kingdom but the superfamily is hugely expanded in the vertebrate eye lens. Their structures show how a simple Greek key motif can evolve rapidly to form a complex array of monomers and oligomers. Apart from remaining transparent, a major role of the partnership of α-crystallins with β- and γ-crystallins in the lens is to form a refractive index gradient. Here, we show some of the structural and genetic features of these two protein superfamilies that enable the rapid creation of different assembly states, to match the rapidly changing optical needs among the various vertebrates.


Gelam Honey Attenuates the Oxidative Stress-Induced Inflammatory Pathways in Pancreatic Hamster Cells.
Purpose. Type 2 diabetes consists of progressive hyperglycemia and insulin resistance, which could result from glucose toxicity, inflammatory cytokines, and oxidative stress. In the present study we investigated the effect of Gelam honey and quercetin on the oxidative stress-induced inflammatory pathways and the proinflammatory cytokines. Methods. HIT-T15 cells were cultured and preincubated with the extract of Gelam honey (20, 40, 60, and 80 μg/mL), as well as quercetin (20, 40, 60, and 80 μM), prior to stimulation by 20 and 50 mM glucose. Results. HIT-T15 cells cultured under hyperglycemic condition showed a significant increase in the inflammatory pathways by phosphorylating JNK, IKK-β, and IRS-1 at Ser307 (p < 0.05). There was a significant decrease in the phosphorylation of Akt at Ser473 (p < 0.05). Pretreatment with Gelam honey and quercetin reduced the expression of phosphorylated JNK, IKK-β, and IRS-1, thereby significantly reducing the expression of proinflammatory cytokines like TNF-α, IL-6, and IL-1β (p < 0.05). At the same time there was a significant increase in the phosphorylated Akt showing the protective effects against inflammation and insulin resistance (p < 0.05). In conclusion, our data suggest the potential use of the extract from Gelam honey and quercetin in modulating the inflammation induced insulin signaling pathways.


Orange juice consumption and its effect on blood lipid profile and indices of the metabolic syndrome; a randomised, controlled trial in an at-risk population.
Data from epidemiological and in vitro studies suggest that orange juice (OJ) may have a positive impact on lipid metabolism. However, there have been reports in the media claiming detrimental consequences of 100% juice consumption, including weight-gain and adverse effects on insulin sensitivity and blood lipid profile. The effect of daily OJ consumption was assessed using a randomised, placebo-controlled, single-blinded, parallel group design. Thirty-six overweight, but otherwise healthy men (40-60 years; 27-35 kg m(-2)) with elevated fasting serum cholesterol (5-7 mmol l(-1)), were recruited from the general UK population. None were using nutritional strategies or medication to lower their cholesterol, nor were regular consumers of citrus products. Assessment of BMI, HOMA-IR, and circulating lipid (total cholesterol, low-density lipoprotein, high-density lipoprotein, non-esterified fatty acids, triacylglycerol, apolipoprotein-A1 and apolipoprotein-B) concentrations, was made when fasted before (V1) and after a 12-week intervention (V2), during which participants consumed 250 ml per d of OJ or an energy and sugars-matched orange-flavoured drink (control). The two groups were matched at V1 with respect to all parameters described above. Although triacylglycerol concentration was similar between the groups at both visits, a trend for the change in this variable to differ between groups was observed (P = 0.060), with those in control exhibiting a significant increase in triacylglycerol at V2, compared with V1. In OJ, those with the highest initial triacylglycerol concentration showed the greatest reduction at V2 (R(2) = 0.579; P < 0.001), whereas there was no correlation between these variables in controls (R(2) = 0.023; P = 0.548). Twelve weeks consumption of 250 ml per d of OJ did not adversely affect insulin sensitivity, circulating lipids or body weight.


Brain activity and language assessment using event-related potentials: development of a clinical protocol.
To test the validity of a new computerized task to assess children's receptive vocabulary, event-related potentials (ERPs) were recorded from 56 typically developing children ranging in age from 5 to 12 years. This ERP-computerized vocabulary task does not require a child to give a verbal or motor (i.e. pointing) response. Single pictures, from an existing standardized test of receptive vocabulary, were presented on a computer screen and simultaneously named either correctly (congruent) or incorrectly (incongruent) via a computer. As predicted, the N400 amplitude was found to be significantly higher to the incongruent picture-word pair (i.e. the child knew it was an incorrect pairing) than to the congruent picture-word pair (i.e. the child knew it was a correct pairing). This effect was found for each of the four age groups (5 to 6 years, 7 to 8 years, 9 to 10 years, 11 to 12 years). This task accurately estimated current receptive vocabulary in typically developing children. Although still in the development stage, it may eventually serve as an adjunct to a thorough neurological and neurodevelopmental assessment of some children presenting with moderate to severe cerebral palsy.


Liver-cell patterning lab chip: mimicking the morphology of liver lobule tissue.
A lobule-mimetic cell-patterning technique for on-chip reconstruction of centimetre-scale liver tissue of heterogeneous hepatic and endothelial cells via an enhanced field-induced dielectrophoresis (DEP) trap is demonstrated and reported. By mimicking the basic morphology of liver tissue, the classic hepatic lobule, the lobule-mimetic-stellate-electrodes array was designed for cell patterning. Through DEP manipulation, well-defined and enhanced spatial electric field gradients were created for in-parallel manipulation of massive individual cells. With this liver-cell patterning labchip design, the original randomly distributed hepatic and endothelial cells inside the microfluidic chamber can be manipulated separately and aligned into the desired pattern that mimicks the morphology of liver lobule tissue. Experimental results showed that both hepatic and endothelial cells were orderly guided, snared, and aligned along the field-induced orientation to form the lobule-mimetic pattern. About 95% cell viability of hepatic and endothelial cells was also observed after cell-patterning demonstration via a fluorescent assay technique. The liver function of CYP450-1A1 enzyme activity showed an 80% enhancement for our engineered liver tissue (HepG2+HUVECs) compared to the non-patterned pure HepG2 for two-day culturing.


Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery.
The risk of preoperative anemia in patients undergoing heart surgery has not been described precisely. Specifically, the impact of low hemoglobin per se or combined with other risk factors on postoperative outcome is unknown. Thus, we determined the effects of low preoperative hemoglobin and comorbidities on postoperative adverse outcomes in patients with coronary artery bypass graft in a large comprehensive multicenter study. The Multicenter Study of Perioperative Ischemia investigated 5065 patients with coronary artery bypass graft at 70 institutions worldwide, collecting approximately 7500 data points per patient. In 4804 patients who received no preoperative transfusions, we determined the association between lowest preoperative hemoglobin levels and in-hospital cardiac and noncardiac morbidity and mortality and the impact of concomitant risk factors, assessed by EuroSCORE, on this effect. In patients with EuroSCORE < 4 (n=2054), only noncardiac outcomes were increased, whereas patients with EuroSCORE > or = 4 (n=2750) showed an increased incidence of all postoperative events, starting at hemoglobin < 11 g/dL. Low preoperative hemoglobin was an independent predictor for noncardiac (renal > cerebral; P<0.001) outcomes, whereas the increase in cardiac events was due to other factors associated with preoperative anemia. Anemic patients undergoing cardiac surgery have an increased risk of postoperative adverse events. Importantly, the extent of preexisting comorbidities substantially affects perioperative anemia tolerance. Therefore, preoperative risk assessment and subsequent therapeutic strategies, such as blood transfusion, should take into account both the individual level of preoperative hemoglobin and the extent of concomitant risk factors.


The good and the bad collagens of fibrosis - Their role in signaling and organ function.
Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression. We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively. We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM.


An accurate measure of the instantaneous discharge probability, with application to unitary joint-even analysis.
We present an estimate for the instantaneous discharge probability of a neurone, based on single-trial spike-train analysis. By detecting points where the neurone abruptly changes its firing rate and treating them specially, the method is able to achieve smooth estimates yet avoid the blurring of significant changes. This estimate of instantaneous discharge probability is then applied to the method of unitary event analysis. We show that the unitary event analysis as originally conceived is highly sensitive to firing-rate nonstationarities and covariations, but that it can be considerably improved if calculations of statistical significance use an instantaneous discharge probability instead of a firing-rate estimate based on averaging across multiple trials.


Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates.
In a multi-target complex network, the links (L(ij)) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K(i), K(m), IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.


Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2-mediated signalling.
Merkel cells are mechanosensory cells involved in tactile discrimination. Merkel cells have been primarily studied in the murine back skin, where they are found in specialized structures called touch domes located around primary hair follicles. Yet, little is known about the morphogenesis of Merkel cells in areas of the skin devoid of hair, such as the glabrous paw skin. Here, we describe Merkel cell formation in the glabrous paw skin during embryogenesis. We first found in the glabrous paw skin that Merkel cells were specified at E15.5, 24 hours later, compared to in the back skin. Additionally, by performing lineage-tracing experiments, we found that unlike in the back skin, SOX9(+) cells do not give rise to Merkel cells in the glabrous paw skin. Finally, we compared the transcriptomes of Merkel cells in the back and the glabrous paw skin and showed that they are similar. Genetic and transcriptome studies showed that the formation of Merkel cells in both regions was controlled by similar regulators. Among them was FGFR2, an upstream factor of MAPK signalling that was reported to have a critical function in Merkel cell formation in the back skin. Here, we showed that FGFR2 is also required for Merkel cell development in the glabrous paw skin. Taken together, our results demonstrate that Merkel cells in the murine back skin and glabrous paw skin are similar, and even though their formation is controlled by a common genetic programme, their precursor cells might differ.


Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation.
Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.


Work stress, smoking status, and smoking intensity: an observational study of 46,190 employees.
To examine the relation between work stress, as indicated by the job strain model, and the effort-reward imbalance model, and smoking. Ten municipalities and 21 hospitals in Finland. Binary logistic regression models for the prevalence of smoking were related to survey responses of 37,309 female and 8881 male Finnish public sector employees aged 17-65. Separate multinomial logistic regression models were calculated for smoking intensity for 8130 smokers. In addition, binary logistic regression models for ex-smoking were fitted among 16,277 former and current smokers. In all analyses, adjustments were made for age, basic education, occupational status, type of employment, and marital status. Respondents with high effort-reward imbalance or lower rewards were more likely to be smokers. Among smokers, an increased likelihood of higher intensity of smoking was associated with higher job strain and higher effort-reward imbalance and their components such as low job control and low rewards. Smoking intensity was also higher in active jobs in women, in passive jobs, and among employees with low effort expenditure. Among former and current smokers, high job strain, high effort-reward imbalance, and high job demands were associated with a higher likelihood of being a current smoker. Lower effort was associated with a higher likelihood of ex-smoking. This evidence suggests an association between work stress and smoking and implies that smoking cessation programmes may benefit from taking into account the modification of stressful features of work environment.


Exploring the needs and challenges of parents and their children in childhood epilepsy care: A qualitative study.
Because of the nature of epilepsy, and the unpredictability of seizure recurrence, epilepsy requires long-term treatment with medications. As a consequence, epilepsy has a negative pervasive impact in children with epilepsy (CWE), and their parents. Hence, our aim was to explore the needs and challenges of parents and their CWE. In-depth interviews (IDIs) were conducted with 15 families (12 mothers and 3 fathers) and 15 CWE (aged 8-18 years). Data were transcribed verbatim and thematically analyzed using the descriptive phenomenology approach. The experiences of parents and their CWE could be divided into two time frames: "experiences during a child's first seizure" and "experiences whilst growing up with epilepsy". Parents' main concerns and worries were regarding their child's physical health, psychological and emotional wellbeing, academic achievement, and future. The children's main concerns were restrictions imposed, their interpersonal relationship with peers, and being independent in the future. Parents reported that they needed epilepsy-related information, continuity of care, and a parental support group, while CWE reported that their main needs were independence and autonomy. The views of parents and their child with epilepsy were similar in physical functioning and academic achievement. However, parents and children had different views on how epilepsy impacted on the child emotionally, as well as behavioral and interpersonal relationship with peers.


MR imaging of tumor microcirculation: promise for the new millennium.
Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is a method of imaging the physiology of the microcirculation. A series of recent clinical studies have shown that DCE MRI can measure and predict tumor response to therapy. Recent advances in MR technology provide the enhanced spatial and temporal resolution that allow the application of this methodology in the management of cancer patients. The September issue of this journal provided a microcirculation section to update readers on this exciting and challenging topic. Evidence is mounting that DCE MRI-based measures correlate well with tumor angiogenesis. DCE MRI has already been shown in several types of tumors to correlate well with traditional outcome measures, such as histopathologic studies, and with survival. These new measures are sensitive to tumor physiology and to the pharmacokinetics of the contrast agent in individual tumors. Moreover, they can present anatomical images of tumor microcirculation at excellent spatial resolution. Several issues have emerged from recent international workshops that must be addressed to move this methodology into routine clinical practice. First, is complex modeling of DCE MRI really necessary to answer clinical questions reliably? Clinical research has shown that, for tumors such as bone sarcomas, reliable outcome measures of tumor response to chemotherapy can be extracted from DCE MRI by methods ranging from simple measures of enhancement to pharmacokinetic models. However, the use of similar methods to answer a different question-the differentiation of malignant from benign breast tumors-has yielded contradictory results. Thus, no simple, one-size-fits-all-tumors solution has yet been identified. Second, what is the most rational and reliable data collection procedure for the DCE MRI evaluation? Several groups have addressed population variations in some key variables, such as tumor T(1)0 (T(1) prior to contrast administration) and the arterial input function C(a)(t) for contrast agent, and how they influence the precision and accuracy of DCE MRI outcomes. However, despite these potential complications, clinical studies in this section show that some tumor types can be assessed by relatively simple dynamic measures and analyses. The clinical scenario and tumor type may well determine the required complexity of the DCE MRI exam procedure and its analysis. Finally, we suggest that a consensus on naming conventions (nomenclature) is needed to facilitate comparison and analysis of the results of studies conducted at different centers. J. Magn. Reson. Imaging 10:903-907, 1999.


Metabolic synchronization by traveling waves in yeast cell layers.
The coordination of cellular behavior is a prerequisite of functionality of tissues and organs. Generally, this coordination occurs by signal transduction, neuronal control, or exchange of messenger molecules. The extent to which metabolic processes are involved in intercellular communication is less understood. Here, we address this question in layers of resting yeast cells and report for the first time the observation of intercellular glycolytic waves. We use a combined experimental and theoretical approach and explain the radial velocity of the waves to arise from the substrate gradient due to local substrate addition. Our results show that metabolic processes introduce an additional level of local intercellular coordination.


A Novel Microfluidic Point-of-Care Biosensor System on Printed Circuit Board for Cytokine Detection.
Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H₂O₂ depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes.


A route to small clusters: a twisted half-hexagram-shaped M4(OH)4 cluster and its capacity for hosting closed-shell metals.
By combining different oxidation states, coordination indices and bridging systems, it has been possible to obtain the structurally novel M4(OH)4 cluster core (M = transition metal) found in the organometallic compound (NBu4)2[PtIVPt(C6Cl5)8(μ2-OH)2(μ3-OH)2] (1). The cluster is formed by two (μ3-OH) and two (μ2-OH) units that bond platinum atoms in different oxidation states. The cluster core geometry can best be described as a half-hexagram. Compound 1 is an excellent precursor for preparing heterometallic clusters since it can host d10 or s2 Lewis-acid metal centers through Pt→M dative bonds, as demonstrated by its reaction with Ag(i) to produce the heterometallic [Ag2PtIVPt(C6Cl5)8(μ2-OH)2(μ3-OH)2] (2), which has four unbridged Pt-Ag bonds.


Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk.
We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p < 0.05). Median FTV in ctDNA-positive patients was significantly higher compared to those who were ctDNA-negative (p < 0.05). FTV and ctDNA trajectories in individual patients showed a general decrease during NAC. Exploratory analysis showed that adding ctDNA information early during treatment to FTV-based predictors resulted in numerical but not statistically significant improvements in performance for pCR prediction (e.g., AUC 0.59 vs. 0.69, p = 0.25). In contrast, ctDNA-positivity after NAC provided significant additive value to FTV in identifying patients with increased risk of metastatic recurrence and death (p = 0.004). In this pilot study, we demonstrate that ctDNA and FTV were correlated measures of tumor burden. Our preliminary findings based on a limited cohort suggest that ctDNA at surgery improves FTV as a predictor of metastatic recurrence and death. Validation in larger studies is warranted.


Explicit incorporation of equity considerations into economic evaluation of public health interventions.
Health equity is one of the main avowed objectives of public health policy across the world. Yet economic evaluations in public health (like those in health care more generally) continue to focus on maximizing health gain. Health equity considerations are rarely mentioned. Health economists rely on the quasi-egalitarian value judgment that 'a QALY is a QALY'--that is QALYs are equally weighted and the same health outcome is worth the same no matter how it is achieved or to whom it accrues. This value judgment is questionable in many important circumstances in public health. For example, policy-makers may place rather little value on health outcomes achieved by infringing individual liberties or by discriminating on the basis of age, sex, or race. Furthermore, there is evidence that a majority of the general public wish to give greater weight to health gains accruing to children, the severely ill, and, to a lesser extent, the socio-economically disadvantaged. This paper outlines four approaches to explicit incorporation of equity considerations into economic evaluation in public health: (i) review of background information on equity, (ii) health inequality impact assessment, (iii) analysis of the opportunity cost of equity, and (iv) equity weighting of health outcomes. The first three approaches can readily be applied using standard methods of health technology assessment, where suitable data are available; whereas approaches for generating equity weights remain experimental. The potential benefits of considering equity are likely to be largest in cases involving: (a) interventions that target disadvantaged individuals or communities and are also relatively cost-ineffective and (b) interventions to encourage lifestyle change, which may be relatively ineffective among 'hard-to-reach' disadvantaged groups and hence may require re-design to avoid increasing health inequalities.


Genetic and epigenetic alterations in normal and sensitive COPD-diseased human bronchial epithelial cells repeatedly exposed to air pollution-derived PM2.5.
Even though clinical, epidemiological and toxicological studies have progressively provided a better knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects, further in vitro studies on relevant cell systems are still needed. Hence, aiming of getting closer to the human in vivo conditions, primary human bronchial epithelial cells derived from normal subjects (NHBE) or sensitive chronic obstructive pulmonary disease (COPD)-diseased patients (DHBE) were differentiated at the air-liquid interface. Thereafter, they were repeatedly exposed to air pollution-derived PM2.5 to study the occurrence of some relevant genetic and/or epigenetic endpoints. Concentration-, exposure- and season-dependent increases of OH-B[a]P metabolites in NHBE, and to a lesser extent, COPD-DHBE cells were reported; however, there were more tetra-OH-B[a]P and 8-OHdG DNA adducts in COPD-DHBE cells. No increase in primary DNA strand break nor chromosomal aberration was observed in repeatedly exposed cells. Telomere length and telomerase activity were modified in a concentration- and exposure-dependent manner in NHBE and particularly COPD-DHBE cells. There were a global DNA hypomethylation, a P16 gene promoter hypermethylation, and a decreasing DNA methyltransferase activity in NHBE and notably COPD-DHBE cells repeatedly exposed. Changes in site-specific methylation, acetylation, and phosphorylation of histone H3 (i.e., H3K4me3, H3K9ac, H3K27ac, and H3S10ph) and related enzyme activities occurred in a concentration- and exposure-dependent manner in all the repeatedly exposed cells. Collectively, these results highlighted the key role played by genetic and even epigenetic events in NHBE and particularly sensitive COPD-DHBE cells repeatedly exposed to air pollution-derived PM2.5 and their different responsiveness. While these specific epigenetic changes have been already described in COPD and even lung cancer phenotypes, our findings supported that, together with genetic events, these epigenetic events could dramatically contribute to the shift from healthy to diseased phenotypes following repeated exposure to relatively low doses of air pollution-derived PM2.5.


Pueraria mirifica phytoestrogens improve dyslipidemia in postmenopausal women probably by activating estrogen receptor subtypes.
Impaired lipid metabolism is an important health problem in postmenopausal women with insufficient estrogens, because dyslipidemia is a risk factor for development of atherosclerosis and the incidence of cardiovascular disease markedly increases after menopause. Pueraria mirifica (PM), a Thai herb, has been noticed as a source of phytoestrogens, estrogen-mimicking plant compounds. However, the clinical effects of PM on lipid metabolism and the underlying molecular mechanisms remain undetermined. Therefore, we examined the effects of PM on serum lipid parameters in a randomized, double-blind, placebo-controlled clinical trial. Nineteen postmenopausal women were randomly assigned to receive oral administration of PM powder or placebo. After 2 months of treatment, the PM group showed a significant increase in serum concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-1 (34% and 40%, respectively), and a significant decrease in low-density lipoprotein (LDL) cholesterol and apo B (17% and 9%, respectively), compared with baseline measurements. Moreover, significant decreases were observed in the ratios of LDL cholesterol to HDL cholesterol (37%) and apo B to apo A-1 (35%). Next, we determined the effects of PM phytoestrogens on the activation of estrogen receptor (ER)-mediated transactivation by transient expression assays of a reporter gene in cultured cells. Among PM phytoestrogens, miroestrol and coumestrol enhanced both ERalpha- and ERbeta-mediated transactivation, whereas other phytoestrogens, including daidzein and genistein, preferentially enhanced ERbeta-mediated transactivation. In conclusion, PM has a beneficial effect on lipid metabolism in postmenopausal women, which may result from the activation of gene transcription through selective binding of phytoestrogens to ERalpha and ERbeta.


Healthcare utilization and costs of patients with rosacea in an insured population.
Rosacea is a chronic, relapsing dermatologic condition that affects an estimated 14 million people in the U.S. However, there is little data in the literature on the healthcare utilization and costs of patients with rosacea in insured populations. This retrospective, observational, cohort study used the MarketScan databases to identify a rosacea cohort of patients with medical and prescription drug claims between 2002 and 2005. Inclusion criteria were (1) age 30 years and older, (2) at least one medical claim with a primary or secondary diagnosis of rosacea (ICD-9-CM 695.3), (3) at least one pharmacy claim for a rosacea topical or systemic prescription drug, (4) a 6-month clean period prior to index drug and 12 months continuous enrollment after the index drug. Propensity score matching was used to match the rosacea cohort to a control group of patients without rosacea. Disease severity during the 6-month preperiod was assessed by the Charlson Comorbidity Index (CCI), the Chronic Disease Score (CDS), and the Elixhauser Index (EI). Healthcare utilization rates and costs were determined by the type of care for the 12-month postperiod. Costs were calculated for the 12-month post-period and adjusted to reflect 2005 costs. Healthcare utilization rates and costs were reported for inpatient hospital admissions, physician office visits, emergency room visits, other outpatient services, and outpatient pharmacy prescriptions. Both total healthcare and rosacea-related rates and costs were reported. There were no rosacea-related inpatient admissions and very few emergency department visits. More rosacea patients had a specialist visit than a primary care physician visit. The average number of rosacea-related prescriptions, for all patients, was 3.4 (SD 2.7) per year. Total annual healthcare expenditures for the rosacea patient cohort were $735 more than for the matched controls ($6,458 vs. $5,723). Of the total healthcare costs, annual rosacea-related expenditures were $276; approximately 70% of rosacea-related expenditures were due to prescription drugs. Topical drugs were the index drugs for 77% of rosacea patients with branded metronidazole, which is the most common topical drug. Of the 23% of rosacea patients with an oral index drug, generic antibiotic dosage forms of tetracyclines were the most common oral index drug therapy. This is the first extensive study of rosacea and its impact on healthcare utilization and costs in an insured population. Although rosacea is a common illness that does not have much financial impact on its sufferers, rosacea patients incurred slightly higher direct total healthcare costs than matched controls.


Ion channel genes and human neurological disease: recent progress, prospects, and challenges.
What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are "paroxysmal disorders" whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.


Effects of inactivation and constitutive expression of the unfolded- protein response pathway on protein production in the yeast Saccharomyces cerevisiae.
One strategy to obtain better yields of secreted proteins has been overexpression of single endoplasmic reticulum-resident foldases or chaperones. We report here that manipulation of the unfolded-protein response (UPR) pathway regulator, HAC1, affects production of both native and foreign proteins in the yeast Saccharomyces cerevisiae. The effects of HAC1 deletion and overexpression on the production of a native protein, invertase, and two foreign proteins, Bacillus amyloliquefaciens alpha-amylase and Trichoderma reesei endoglucanase EGI, were studied. Disruption of HAC1 caused decreases in the secretion of both alpha-amylase (70 to 75% reduction) and EGI (40 to 50% reduction) compared to the secretion by the parental strain. Constitutive overexpression of HAC1 caused a 70% increase in alpha-amylase secretion but had no effect on EGI secretion. The invertase levels were twofold higher in the strain overexpressing HAC1. Also, the effect of the active form of T. reesei hac1 was tested in S. cerevisiae. hac1 expression caused a 2.4-fold increase in the secretion of alpha-amylase in S. cerevisiae and also slight increases in invertase and total protein production. Overexpression of both S. cerevisiae HAC1 and T. reesei hac1 caused an increase in the expression of the known UPR target gene KAR2 at early time points during cultivation.


The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders.
Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy.


Isolation and characterization of ten mutator alleles of the mitochondrial DNA polymerase-encoding MIP1 gene from Saccharomyces cerevisiae.
Ten mutator alleles of MIP1, the gene encoding mitochondrial (mt) DNA polymerase, have been isolated after in vitro random mutagenesis. Five mutations causing a 100-400-fold increase in the frequency of erythromycin-resistant (ErR) mt mutants in yeast mapped to the 3'-5' exonuclease (Exo) domain, and mainly to the three conserved motifs Exo1, Exo2 and Exo3 of this domain, highlighting the importance of proofreading in accurate mt DNA replication. The essential role of the invariant glutamate at the Exo1 site was confirmed and the participation of four amino acids (aa) in the 3'-5' Exo function revealed. Another mutation that is located between the Exo1 and Exo2 sites produced an extremely strong mutator phenotype associated with impaired DNA replication, but could be assigned neither to a conserved aa nor to a conserved portion of the 3'-5' exonuclease domain. The importance of the polymerization domain in accurate mt DNA replication was pointed out by three mutator mutations. Two of these severely impaired mt DNA replication and were assigned to a subdomain of the polymerase which probably corresponds to the 'fingers' module of the Klenow (large) fragment of Escherichia coli DNA polymerase I (PolIk). The third, which did not alter the efficiency of DNA replication, was located at the active center of the polymerization reaction. Finally, the mutation, R1001I, mapped to the C-terminal part of the MIP1 protein which has no counterpart in prokaryotic DNA polymerases.


Lectin-binding sites on the plasma membranes of rabbit spermatozoa. Changes in surface receptors during epididymal Maturation and after ejaculation.
MODIFICATIONS IN RABBIT SPERM PLASMA MEMBRANES DURING EPIDIDYMAL PASSAGE AND AFTER EJACULATION WERE INVESTIGATED BY USED OF THREE LECTINS: concanavalin A (Con A); Ricinus communis I (RCA(I)); and wheat germ agglutinin (WGA). During sperm passage from caput to cauda epididymis, agglutination by WGA drastically decreased, and agglutination by RCA(I) slightly decreased, although agglutination by Con A remained approximately unchanged. After ejaculation, spermatozoa were agglutinated to a similar degree or slightly less by Con A, WGA, and RCA(I), compared to cauda epididymal spermatozoa. Ultrastructural examination of sperm lectin-binding sites with ferritin- lectin conjugates revealed differences in the densities of lectin receptors in various sperm regions, and changes in the same regions during epididymal passage and after ejaculation. Ferritin-RCA(I) showed abrupt changes in lectin site densities between acrosomal and postacrosomal regions of sperm heads. The relative amounts of ferritin-RCA(I) bound to heads of caput epididymal or ejaculated spermatozoa. Tail regions were labeled by ferritin RCA(I) almost equally on caput and cauda epididymal spermatozoa, but the middle-piece region of ejaculated spermatozoa was slightly more densely labeled than the principal-piece region, and these two regions on ejaculated spermatozoa were labeled less than on caput and cuada epididymal spermatozoa. Ferritin-WGA densely labeled the acrosomal region of caput epididymal spermatozoa, although labeling of cauda epidiymal spermatozoa was relatively sparse except in the apical area of the acrosomal region. Ejaculated spermatozoa bound only a few molecules of ferritin-WGA, even at the highest conjugate concentrations used. Caput epididymal, but not cauda epididymal or ejaculated spermatozoa, bound ferritin-WGA in the tail regions. Dramatic differences in labeling densities during epididymal passage and after ejaculation were not found with ferritin-Con A.


A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies.
Impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction characterize autism spectrum disorders (ASDs). Seventy consecutive patients with an ASD diagnosis (DSM-IV criteria, >/= 6 years-old) who presented to the Genetic Centers of America for outpatient genetic/developmental evaluations from 2005-2007 were examined. Patients were evaluated using CLIA-approved Laboratory Cooperation of America (LabCorp) testing for: serum testosterone, serum free testosterone, % free testosterone, serum/plasma dehydroepiandrosterone (DHEA), androstendione, and follicle-stimulating hormone (FSH). Morning blood samples collected following an overnight fast, compared to the pertinent reference means, showed significantly increased relative mean levels for: serum testosterone (158%), serum free testosterone (214%), percent free testosterone (121%), DHEA (192%), and androstenedione (173%). By contrast, compared to the pertinent reference mean, the relative mean level of FSH (51%) was significantly decreased. Additionally, at least one of the androgen attributes examined exceeded its recognized laboratory age- and sex-specific reference range in 81.4% (57 of 70) of the patients examined. With respect to their age- and sex-specific reference ranges, females had significantly higher overall mean relative testosterone and relative free testosterone levels than males. Increased androgens in patients diagnosed with ASDs may involve cyclical interactions between the androgen and the transsulfuration pathways, particularly following mercury exposure. A review of therapies that have significantly improved clinical outcomes in ASD patients indicates they share commonality in helping lower androgens. Thus, androgens should be routinely clinically measured in patients with an ASD diagnosis and appropriate androgen-lowering therapies considered for those who have significantly elevated levels.


Educational techniques used in occupational therapy treatment of cumulative trauma disorders of the elbow, wrist, and hand.
This study examined patient education techniques used by occupational therapists when treating cumulative trauma disorders (CTDs) of the elbow, wrist, and hand. A self-administered survey was sent to 232 registered occupational therapists whose primary area of practice was hand therapy. The questionnaire sought information about specific content areas and methods (i.e., media, format) used to educate patients about preventing the recurrence of CTDs in the elbow, wrist, and hand. One hundred twenty-eight therapists responded to the survey. A majority of respondents (n = 116) reported that patient education content area consisted of anatomy of the joint, the CTD disease process, and job modification. Verbal instruction, illustrations, and pamphlets and handouts were the most frequently used forms of educational media. A majority of respondents (n = 111) also reported that individual interaction was the most common format of patient education. The findings indicate that a majority of therapists use the same patient education techniques with regard to content areas, media, and format, regardless of the area being treated (i.e., elbow, wrist, hand). Furthermore, it appears that therapists with specialty training in CTDs more frequently include anatomy of the elbow, job modification, and proper body mechanics in the content of their patient education about the elbow.


An unprecedented coastwide toxic algal bloom linked to anomalous ocean conditions.
A coastwide bloom of the toxigenic diatom Pseudo-nitzschia in spring 2015 resulted in the largest recorded outbreak of the neurotoxin, domoic acid, along the North American west coast. Elevated toxins were measured in numerous stranded marine mammals and resulted in geographically extensive and prolonged closures of razor clam, rock crab, and Dungeness crab fisheries. We demonstrate that this outbreak was initiated by anomalously warm ocean conditions. Pseudo-nitzschia australis thrived north of its typical range in the warm, nutrient-poor water that spanned the northeast Pacific in early 2015. The seasonal transition to upwelling provided the nutrients necessary for a large-scale bloom; a series of spring storms delivered the bloom to the coast. Laboratory and field experiments confirming maximum growth rates with elevated temperatures and enhanced toxin production with nutrient enrichment, together with a retrospective analysis of toxic events, demonstrate the potential for similarly devastating ecological and economic disruptions in the future.


Molecular organization of Drosophila neuroendocrine cells by Dimmed.
In Drosophila, the basic-helix-loop-helix protein DIMM coordinates the molecular and cellular properties of all major neuroendocrine cells, irrespective of the secretory peptides they produce. When expressed by nonneuroendocrine neurons, DIMM confers the major properties of the regulated secretory pathway and converts such cells away from fast neurotransmission and toward a neuroendocrine state. We first identified 134 transcripts upregulated by DIMM in embryos and then evaluated them systematically using diverse assays (including embryo in situ hybridization, in vivo chromatin immunoprecipitation, and cell-based transactivation assays). We conclude that of eleven strong candidates, six are strongly and directly controlled by DIMM in vivo. The six targets include several large dense-core vesicle (LDCV) proteins, but also proteins in non-LDCV compartments such as the RNA-associated protein Maelstrom. In addition, a functional in vivo assay, combining transgenic RNA interference with MS-based peptidomics, revealed that three DIMM targets are especially critical for its action. These include two well-established LDCV proteins, the amidation enzyme PHM and the ascorbate-regenerating electron transporter cytochrome b(561-1). The third key DIMM target, CAT-4 (CG13248), has not previously been associated with peptide neurosecretion-it encodes a putative cationic amino acid transporter, closely related to the Slimfast arginine transporter. Finally, we compared transcripts upregulated by DIMM with those normally enriched in DIMM neurons of the adult brain and found an intersection of 18 DIMM-regulated genes, which included all six direct DIMM targets. The results provide a rigorous molecular framework with which to describe the fundamental regulatory organization of diverse neuroendocrine cells.


Asymmetries in intermanual transfer of training and motor overflow in adults with Down's syndrome and nonhandicapped children.
A sequential finger-lifting task was used to examine asymmetries in intermanual transfer of training and motor overflow in Down's syndrome adults and young, nonhandicapped children. Both groups exhibited more interlimb transfer of training from the left hand to the right hand than the reverse. This finding provides evidence for left-hemisphere specialization for the organization and control of sequential movement. While the motor overflow results were less compelling, they provide some evidence for left-hemisphere dominance for movement control in Down's syndrome persons. It is suggested that perhaps the same neural mechanisms are responsible for motor overflow and transfer of training asymmetries.


Whole genome sequencing of a banana wild relative Musa itinerans provides insights into lineage-specific diversification of the Musa genus.
Crop wild relatives are valuable resources for future genetic improvement. Here, we report the de novo genome assembly of Musa itinerans, a disease-resistant wild banana relative in subtropical China. The assembled genome size was 462.1 Mb, covering 75.2% of the genome (615.2Mb) and containing 32, 456 predicted protein-coding genes. Since the approximate divergence around 5.8 million years ago, the genomes of Musa itinerans and Musa acuminata have shown conserved collinearity. Gene family expansions and contractions enrichment analysis revealed that some pathways were associated with phenotypic or physiological innovations. These include a transition from wood to herbaceous in the ancestral Musaceae, intensification of cold and drought tolerances, and reduced diseases resistance genes for subtropical marginally distributed Musa species. Prevalent purifying selection and transposed duplications were found to facilitate the diversification of NBS-encoding gene families for two Musa species. The population genome history analysis of M. itinerans revealed that the fluctuated population sizes were caused by the Pleistocene climate oscillations, and that the formation of Qiongzhou Strait might facilitate the population downsizing on the isolated Hainan Island about 10.3 Kya. The qualified assembly of the M. itinerans genome provides deep insights into the lineage-specific diversification and also valuable resources for future banana breeding.


Forecasting influenza outbreak dynamics in Melbourne from Internet search query surveillance data.
Accurate forecasting of seasonal influenza epidemics is of great concern to healthcare providers in temperate climates, as these epidemics vary substantially in their size, timing and duration from year to year, making it a challenge to deliver timely and proportionate responses. Previous studies have shown that Bayesian estimation techniques can accurately predict when an influenza epidemic will peak many weeks in advance, using existing surveillance data, but these methods must be tailored both to the target population and to the surveillance system. Our aim was to evaluate whether forecasts of similar accuracy could be obtained for metropolitan Melbourne (Australia). We used the bootstrap particle filter and a mechanistic infection model to generate epidemic forecasts for metropolitan Melbourne (Australia) from weekly Internet search query surveillance data reported by Google Flu Trends for 2006-14. Optimal observation models were selected from hundreds of candidates using a novel approach that treats forecasts akin to receiver operating characteristic (ROC) curves. We show that the timing of the epidemic peak can be accurately predicted 4-6 weeks in advance, but that the magnitude of the epidemic peak and the overall burden are much harder to predict. We then discuss how the infection and observation models and the filtering process may be refined to improve forecast robustness, thereby improving the utility of these methods for healthcare decision support.


Qualitative SERS analysis of G-quadruplex DNAs using selective stabilising ligands.
Nucleic acids are of key biological importance due to their range of functions and ability to form various different structures, with an example of emerging significance being quadruplexes formed by guanine-rich sequences. These guanine rich sequences are found in different regions of the genome such as telomeres, gene promoters and introns and UTRs of mRNAs. Here a new approach has been developed that utilises surface enhanced Raman scattering (SERS) for the detection of the formation of G-quadruplexes. Three G-quadruplex stabilising ligands that each have their own unique SERS response were used in this study and their ability to act as reporters assessed. A SERS response was only obtained from the ligands in the absence of G-quadruplex formation. This resulted in an "on/off" method which was successfully used to qualitatively detect the formation of G-quadruplex using quadruplex-forming sequences such as human telomeric and C-MYC promoter DNAs. The unique SERS spectra of each stabilising ligand offer the potential for use of SERS to study higher order DNA structures. This work shows that the ligands used can act simultaneously as a potential therapeutic stabilising agent and a SERS reporter, therefore allowing the use of SERS as a method of analysis of the formation of G-quadruplex DNAs.


Adverse health experiences, environmental attitudes, and pesticide usage behavior of farm operators.
Water pollution from agricultural pesticides continues to be a public concern. Given that the use of such pesticides on the farm is largely governed by voluntary behavior, it is important to understand what drives farmer behavior. Health belief models in public health and social psychology argue that persons who have adverse health experiences are likely to undertake preventive behavior. An analogous hypothesis set was tested here: farmers who believe they have had adverse health experiences from pesticides are likely to have heightened concerns about pesticides and are more likely to take greater precautions in dealing with pesticides. This work is based on an original survey of a population of 2700 corn and soybean growers in Maryland, New York, and Pennsylvania using the U.S. Department of Agriculture data base. It was designed as a mail survey with telephone follow-up, and resulted in a 60 percent response rate. Farm operators report experiencing adverse health problems they believe are associated with pesticides that is equivalent to an incidence rate that is higher than the reported incidence of occupational pesticide poisonings, but similar to the reported incidence of all pesticide poisonings. Farmers who report experiencing such problems have more heightened concerns about water pollution from fertilizers and pesticides, and illness and injury from mixing, loading, and applying pesticides than farmers who have not experienced such problems. Farmers who report experiencing such problems also are more likely to report using alternative pest management practices than farmers who do not report having such problems. This implies that farmers who have had such experiences do care about the effects of application and do engage in alternative means of pest management, which at least involve the reduction in pesticide use.


Tiotropium Respimat inhaler and the risk of death in COPD.
Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).


Collagen fiber anchoring platforms for percutaneous devices.
In this study, we investigated the use of perforated sheet platforms to improve the attachment of percutaneous devices to surrounding tissues. The model platform was created by a poly(methyl methacrylate) (PMMA) sheet with a matrix of 200-microm diameter perforations covering the groove (width, 3 mm; depth, 0.5 mm) prepared on the PMMA cylinder (diameter, 10 mm; length, 6 mm). Velour cuffs from peritoneal dialysis catheters were used as controls. Specimens were implanted percutaneously in rats, harvested with the surrounding tissues at 4 weeks after surgery, and subjected to mechanical tests and histological observations. The attachment strength of the experimental specimens to tissue was 138.4 +/- 123.6 kPa (n = 5, mean SD); although it was greater than the 67.23 +/- 45.78 kPa (n = 5) of the controls, no statistical significance was found. Histological observations of the experimental specimens revealed the collagen fibers originating from the surrounding tissues, passing through the perforations of the sheet, merging into the collagen fibers running behind the sheet, and thus anchoring the tissues to the device. In contrast, such anchoring of collagen fibers was not evident in the controls. These results suggest that the proposed perforated sheet structures are effective for soft tissue attachment.


Phonics training for English-speaking poor readers.
The reading skills of 16% of children fall below the mean range for their age, and 5% of children have significant and severe reading problems. Phonics training is one of the most common reading treatments used with poor readers, particularly children. To measure the effect of phonics training and explore the impact of various factors, such as training duration and training group size, that might moderate the effect of phonics training on literacy-related skills in English-speaking poor readers. We searched CENTRAL, MEDLINE, Embase, 12 other databases, and three trials registers up to May 2018. We also searched reference lists of included studies and contacted experts in the field to identify additional studies. We included studies that used randomisation, quasi-randomisation, or minimisation to allocate participants to a phonics intervention group (phonics training only or phonics training plus one other literacy-related skill) or a control group (no training or non-literacy training). Participants were English-speaking poor readers with word reading one standard deviation below the appropriate level for their age (children, adolescents, and adults) or one grade or year below the appropriate level (children only), for no known reason. Participants had no known comorbid developmental disorder, or physical, neurological, or emotional problem. We used standard methodological procedures expected by Cochrane. We included 14 studies with 923 participants in this review. Studies took place in Australia, Canada, the UK, and the USA. Six of the 14 included studies were funded by government agencies and one was funded by a university grant. The rest were funded by charitable foundations or trusts. Each study compared phonics training alone, or in conjunction with one other reading-related skill, to either no training (i.e. treatment as usual) or alterative training (e.g. maths). Participants were English-speaking children or adolescents, of low and middle socioeconomic status, whose reading was one year, one grade, or one standard deviation below the level expected for their age or grade for no known reason. Phonics training varied between studies in intensity (up to four hours per week), duration (up to seven months), training group size (individual and small groups), and delivery (human and computer). We measured the effect of phonics training on seven primary outcomes (mixed/regular word reading accuracy, non-word reading accuracy, irregular word reading accuracy, mixed/regular word reading fluency, non-word reading fluency, reading comprehension, and spelling). We judged all studies to be at low risk of bias for most risk criteria, and used the GRADE approach to assess the quality of the evidence.There was low-quality evidence that phonics training may have improved poor readers' accuracy for reading real and novel words that follow the letter-sound rules (standardised mean difference (SMD) 0.51, 95% confidence interval (CI) 0.13 to 0.90; 11 studies, 701 participants), and their accuracy for reading words that did not follow these rules (SMD 0.67, 95% CI 0.26 to 1.07; 10 studies, 682 participants). There was moderate-quality evidence that phonics training probably improved English-speaking poor readers' fluency for reading words that followed the letter-sounds rules (SMD 0.45, 95% CI 0.19 to 0.72; 4 studies, 224 participants), and non-word reading fluency (SMD 0.39, 95% CI 0.10 to 0.68; 3 studies, 188 participants), as well as their accuracy for reading words that did not follow these rules (SMD 0.84, 95% CI 0.30 to 1.39; 4 studies, 294 participants). In addition, there was low-quality evidence that phonics training may have improved poor readers' spelling (SMD 0.47, 95% CI -0.07 to 1.01; 3 studies, 158 participants), but only slightly improve their reading comprehension (SMD 0.28, 95% CI -0.07 to 0.62; 5 studies, 343 participants). Phonics training appears to be effective for improving literacy-related skills, particularly reading fluency of words and non-words, and accuracy of reading irregular words. More studies are needed to improve the precision of outcomes, including word and non-word reading accuracy, reading comprehension, spelling, letter-sound knowledge, and phonological output. More data are also needed to determine if phonics training in English-speaking poor readers is moderated by factors such as training type, intensity, duration, group size, or administrator.


Marginal Fit of All-Ceramic Crowns Before and After Cementation: An In Vitro Study.
The marginal integrity of all-ceramic crowns for anterior and posterior teeth were evaluated. A total of 60 ceramic crowns (In-Ceram Alumina, IPS e.max Press, and Lava) were fabricated for the epoxy resin maxillary first central incisor and first molar and divided into three groups (n = 20). The crowns were measured at the facial, lingual, mesial, and distal finish lines (52 points) before and after cementation using scanning electron microscopy. The results were analyzed using one-way analysis of variance, paired samples t test, and independent t test. The mean values of marginal gaps were within acceptable clinical limits before and after cementation. The values of the anterior crowns at the buccal finish line were higher than those at the proximal finish line areas (P < .05). However, these were insignificant at four measurement areas for posterior crowns (P > .05). Marginal gaps of crowns at the anterior teeth were higher than at the posterior teeth for all groups.


[Calcium carbonate for the treatment of hyperphosphatemia in chronic hemodialysis patients].
Hyperphosphatemia in chronic hemodialysis patients is usually treated with aluminium containing phosphate binders. In recent years there has been increasing evidence of serious complications due to aluminium accumulation. We have investigated a new calcium carbonate preparation with an HCl-resistant capsule designed to prevent gastrointestinal side effects. Its phosphate binding capacity in comparison to aluminium chloride hydroxide was investigated in 17 chronic hemodialysis patients. The dose of the phosphate binder was adjusted regularly so that the serum phosphorus levels were below 1.8 mmol/l. The mean dose of aluminium chloride hydroxide was 3.36 g/day and of calcium carbonate 4.96 g/day. The mean (+/- SD) serum calcium level was 2.58 +/- 0.11 mmol/l under aluminium chloride hydroxide and 2.50 +/- 0.25 mmol/l under calcium carbonate. The mean phosphorus level was 1.69 +/- 0.31 mmol/l under aluminium chloride hydroxide and 1.71 +/- 0.33 under calcium carbonate. Serum aluminium fell from 64.5 +/- 14.4 micrograms/l to 28.5 +/- 17.5 micrograms/l after 3 months.


New advances in on-line sample preconcentration by capillary electrophoresis using dynamic pH junction.
The small injection volumes and narrow dimensions characteristic of microseparation techniques place constraints on concentration sensitivity that is required for trace chemical analyses. On-line sample preconcentration techniques using dynamic pH junction and its variants have emerged as simple yet effective strategies for enhancing concentration sensitivity of weakly ionic species by capillary electrophoresis (CE). Dynamic pH junction offers a convenient format for electrokinetic focusing of dilute sample plugs directly in-capillary for improved detection without off-line sample pretreatment. In this report, we highlight new advances in dynamic pH junction which have been reported to enhance method performance while discussing challenges for future research.


Frequency analysis of air and skin temperature in neonates in servo-controlled incubators.
To test a new system designed for digital recording of skin and air temperature, thereby allowing analysis of cyclic changes in temperature in neonates in servo-controlled incubators. Analysis of cyclic changes of serial skin and air temperature in asymptomatic infants in servo-controlled incubators adjusting heat output to the patient's temperature. In nine asymptomatic neonates ranging from 25 to 40 weeks of gestational age, analysis showed peaks of coherence (squared correlation) between skin and air temperature measurements at periods ranging between 1.5 and 3 h. We have established a new system to study cyclic changes in skin and air temperature in neonates in servo-controlled incubators. The analysis of this pilot study suggests that the most important changes in skin and air temperature in asymptomatic neonates occur at a periodicity of 1.5 to 3 h, which is similar to that previously described for neonatal temperature. Additional data are required to determine whether this new system may be useful in neonatal care.


The brave new world of coordination frameworks.
In 1994 the field of coordination frameworks was still in its infancy and yet to give birth to its offspring research field of metal-organic frameworks (MOFs). Studies by Zaworotko and Ciani served to illustrate both the simplicity and the complexity of these remarkable structures.


Personnel administration: in-service training at the nonprofessional level.
A growing shortage of professional librarians has caused library administrators in all types of libraries to take a hard look at their interpretation of what constitutes professional work. The Free Library of Philadelphia is no exception, and in recent years it has evolved formal position classifications providing for the employment of nonlibrarians in positions formerly classed as professional as well as in the usual clerical and desk assignments. Conceived primarily out of necessity, these classifications and assignments are now readily accepted by the Library's staff, and there is little likelihood that earlier interpretations of professional and nonprofessional duties will ever be revived. This article outlines the Free Library's classification and training plan for nonprofessionals.


Osmotic blood-brain barrier disruption: CT and radionuclide imaging.
To compare CT and radionuclide imaging of osmotic blood-brain barrier disruption. To develop a quantitative method for imaging osmotic blood-brain barrier disruption and to see if iopamidol could be safely given intravenously in conjunction with blood-brain barrier disruption. Forty-five blood-brain barrier disruption procedures were imaged with CT and radionuclide scans. The scans were evaluated with visual and quantitative scales. Patients were observed for adverse effects after blood-brain barrier disruption. There was a 4% rate of seizures in this study. There was good agreement between visual CT and radionuclide grading systems. Quantitative methods to grade disruption did not add useful information to visual interpretations. Nonionic iodine-based contrast medium has a lower incidence of seizures when injected intravenously in conjunction with osmotic blood-brain barrier disruption than ionic contrast material. Contrast-enhanced CT is the preferred method to image disruption because it has better spatial resolution than radionuclide techniques.


An Insight Into the Involvement of Mothers of Low Socioeconomic Status in Scottish Primary School Health Education Activities.
School-based health activities that involve parents are more likely to be effective for child health and well-being than activities without a parent component. However, such school-based interventions tend to recruit the most motivated parents, and limited evidence exists surrounding the involvement of hard-to-reach parents with low socioeconomic status (SES). Mothers remain responsible for the majority of family care; therefore, this study investigated mothers with low SES to establish the reasons and barriers to their involvement in school-based health activities and to propose strategies to increase their involvement in those activities. Interviews were conducted with mothers with low SES, who were typically not involved in school-based health activities (n = 16). An inductive-deductive approach to hierarchical analysis revealed that there are several barriers resulting in mothers being less involved, particularly due to issues surrounding the schools' Parent Councils and the exclusivity of school-based events. Efforts made by the school to promote health activities and involve parents in such activities were revealed, alongside recommendations to improve on these practices. The findings offer multiple ways in which future school-based health interventions can recruit and involve mothers with low SES.


A Spatial Dashboard for Alzheimer's Disease in New South Wales.
This paper illustrates a proof of concept scenario for the application of comprehensive data visualisation methods in the rapidly changing aged care sector. The scenario we explored is population ageing and the dementias with an emphasis on the spatial effects of change over time at the Statistical Area 2 (SA2) level for the state of New South Wales. We did this using a combination of methods, culminating in the use of the Tableau software environment to explore the intersections of demography, epidemiology and their formal cost of care implications. In addition, we briefly illustrate how key infrastructure data can be included in the same data management context by showing how service providers can be integrated and mapped in conjunction with other analyses. This is an innovative and practical approach to some of the complex issues already faced in the health and aged care sectors which can only become more pronounced as population ageing progresses.


Impact of non-compliant balloons on long-term clinical outcomes in coronary bifurcation lesions: results from the COBIS (COronary BIfurcation Stent) II registry.
Non-compliant balloons provide uniform radial force along the vessel wall at any inflation pressure. As a result, the use of non-compliant balloons may reduce side branch complications and optimise stent deployment. We sought to investigate the impact of non-compliant balloons on the long-term clinical outcomes of patients undergoing a coronary bifurcation intervention. A total of 2,897 patients treated with drug-eluting stents for bifurcation lesions were enrolled. Non-compliant balloons were used in 752 patients (26%). During a median three-year follow-up, major adverse cardiac events (MACE: cardiac death, myocardial infarction, or target lesion revascularisation) occurred less frequently in the non-compliant balloon group than in the compliant balloon group (8.2% versus 10.9%; p=0.03). After propensity score matching (710 pairs), the use of non-compliant balloons resulted in a lower rate of side branch dissection (0.1% versus 1.1%; p=0.046) and a higher rate of procedural success (79.0% versus 73.9%; p=0.01). The use of non-compliant balloons was associated with a lower risk of MACE (HR 0.64, 95% CI: 0.46-0.91; p=0.01) and cardiac death (HR 0.14, 95% CI: 0.03-0.64; p=0.01). The use of non-compliant balloons was associated with favourable procedural and long-term clinical outcomes in patients receiving coronary bifurcation intervention.