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Highlights: [•] Interpreting complex microbiota in infective contexts is a pressing challenge. [•] Potentially, associations can be interpreted spuriously as causal. [•] We argue for the need to include ecological theory in clinical interpretation. [•] Cystic fibrosis lung infections are used as an illustrative model system. [Copyright &y& Elsevier]

Abstract: Inosine triphosphate pyrophosphatase (ITPA), a key enzyme involved in maintaining the purity of cellular nucleoside triphosphate pools, specifically recognizes inosine triphosphate and xanthosine triphosphate (including the deoxyribose forms) and detoxifies them by catalyzing the hydrolysis of a phosphoanhydride bond, releasing pyrophosphate. This prevents their inappropriate use as substrates in enzymatic reactions utilizing (d)ATP or (d)GTP. A human genetic polymorphism leads to the substitution of Thr for Pro32 (P32T) and causes ITPA deficiency in erythrocytes, with heterozygotes having on average 22.5% residual activity, and homozygotes having undetectable activity. This polymorphism has been implicated in modulating patients’ response to mercaptopurines and ribavirin. Human fibroblasts containing this variant have elevated genomic instability upon treatment with base analogs. We find that the wild-type and P32T forms are dimeric in solution and in the crystal structure. This abolishes the previous speculation that the P32T change disrupts dimerization as a mechanism of inactivation. The only difference in structure from the wild-type protein is that the area surrounding Thr32 is disrupted. Phe31 is flipped from the hydrophobic core out into the solvent, leaving a hole in the hydrophobic core of the protein which likely accounts for the reduced thermal stability of P32T ITPA and ultimately leads to its susceptibility to degradation in human cells. Circular dichroism and thermal denaturation studies confirm these structural results. We propose that the dimer of P32T variant subunit with wild-type subunit is degraded in cells similarly to the P32T homodimer explaining the level of loss of ITPA activity in heterozygotes. [Copyright &y& Elsevier]

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination ( FCD) and (ii) sibship structure in relation to an autoimmune ( FCD) and an allergic (asthma) disease. FCD cases ( n = 282) were aged 18-59 years; controls ( n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio ( OR) = 3·11; 95% confidence interval ( CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD ( OR = 0·68; 95% CI: 0·49, 0·95) but not asthma ( OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma ( P trend = 0·04) but not FCD ( P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'. [ABSTRACT FROM AUTHOR]

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18–75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study. [ABSTRACT FROM PUBLISHER]

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003–2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered. [ABSTRACT FROM PUBLISHER]

Highlights: [•] Kallikreins activate plasminogen. [•] Activation is enhanced by GAGs. [•] KLKs act like tPA. [ABSTRACT FROM AUTHOR]

Abstract: Recent findings implicate group II metabotropic glutamate receptors (mGluR2/3) in the reinforcing effects of psychostimulants and have identified these receptors as potential treatment targets for drug addiction. Here, we investigated the effects of mGluR2/3 stimulation on cue- and drug-primed reinstatement in rats with different histories of methamphetamine (METH) self-administration training, under two conditions: 16 daily sessions of short access (90 min/day, ShA), or 8 daily sessions of short access followed by 8 sessions of long access (6 h/day, LgA). Following self-administration and subsequent extinction training, rats were pretreated with the selective mGluR2/3 agonist LY379268 (variable dose, 0–3 mg/kg), exposed to METH-paired cues or a priming injection of METH (1 mg/kg), and tested for reinstatement of METH-seeking behavior. LgA rats self-administered greater amounts of METH during the second half of training, but when pretreated with vehicle, ShA and LgA rats showed cue- and drug-primed reinstatement at equivalent response rates. However, LgA rats demonstrated greater sensitivity to mGluR2/3 stimulation with attenuated responding during cue-induced reinstatement after 0.3 mg/kg and higher doses of LY379268, whereas ShA rats decreased cue-induced reinstatement behavior following 1.0 mg/kg and 3.0 mg/kg LY379268. Additionally, both LgA and ShA rats exhibited decreased METH-primed reinstatement behavior following 0.3 mg/kg and higher doses of LY379268. A separate group of control rats was trained to self-administer sucrose pellets, and demonstrated attenuated cue-induced sucrose-seeking behavior following 1.0 and 3.0 mg/kg LY379268. Together, the results indicate that LY379268 has differential attenuating effects on cue-induced reinstatement behavior in rats with different histories of METH intake. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’. [Copyright &y& Elsevier]

During a simulated haemorrhagic challenge, syncopal symptoms develop sooner when individuals are hyperthermic relative to normothermic. This is due, in part, to a large displacement of blood to the cutaneous circulation during hyperthermia, coupled with inadequate cutaneous vasoconstriction during the hypotensive challenge. The influence of local skin temperature on these cutaneous vasoconstrictor responses is unclear. This project tested the hypothesis that local skin temperature modulates cutaneous vasoconstriction during simulated haemorrhage in hyperthermic humans. Eight healthy participants (four men and four women; 32 ± 7 years old; 75.2 ± 10.8 kg) underwent lower-body negative pressure to presyncope while heat stressed via a water-perfused suit sufficiently to increase core temperature by 1.2 ± 0.2°C. At forearm skin sites distal to the water-perfused suit, local skin temperature was either 35.2 ± 0.6 (mild heating) or 38.2 ± 0.2°C (moderate heating) throughout heat stress and lower-body negative pressure, and remained at these temperatures until presyncope. The reduction in cutaneous vascular conductance during the final 90 s of lower-body negative pressure, relative to heat-stress baseline, was greatest at the mildly heated site (−10 ± 15% reduction) relative to the moderately heated site (−2 ± 12%; P= 0.05 for the magnitude of the reduction in cutaneous vascular conductance between sites), because vasoconstriction at the moderately heated site was either absent or negligible. In hyperthermic individuals, the extent of cutaneous vasoconstriction during a simulated haemorrhage can be modulated by local skin temperature. In situations where skin temperature is at least 38°C, as is the case in soldiers operating in warm climatic conditions, a haemorrhagic insult is unlikely to be accompanied by cutaneous vasoconstriction. [ABSTRACT FROM AUTHOR]

Thick filter cakes have to be removed from the filter in order to keep the pressure drop down to a suitable level for the filtration process of gases. The influence of both, the particulate matter used (phosphate rock, manioc starch and magnesium silicate) and the operating parameters during filtration of these particles from gas on the filter cake removal, was studied. Three filtration velocities were used (0.06, 0.09 and 0.11 m s−1) which were maintained constant until achieve predetermined values of pressure drop (500; 600 and 700 mm of H2O). The cleaning of the filter was performed using the reverse flow technique applying different gas velocities (0.007; 0.015; 0.030; 0.045 and 0.060 m s−1). For all the particulate matters studied, the adhesion force increased with the increment of the filtration gas velocity. The percentage of cake removal for manioc starch and magnesium silicate particles was ∼90% while for phosphate concentrate was ∼60%. Thus, the values of adhesion force per unit area were higher for phosphate concentrate than the other particulate matter. [ABSTRACT FROM PUBLISHER]

Acamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified. In this review, we summarize current clinical data on the safety, efficacy, and pharmacokinetic properties of acamprosate, as well theories on its potential mechanism of action. We also discuss tolerability and patient preference issues and conclude with a discussion of the place of acamprosate in addiction medicine and therapy. [ABSTRACT FROM AUTHOR]

The article discusses candidate treatments for cystic fibrosis (CF) lung disease included in the Cystic Fibrosis Foundation Therapeutics Pipeline in the U.S. A new preparation of inhaled tobramycin (TOBI) called TOBI inhaled powder (TIP) is being developed for treatment of infection. Antinflammatory treatments include N-acetylcysteine, docosahexenoic acid and sildenafil. Also tackled are drugs for mucus alteration/airway surface liquid modulation therapy and stem cell/gene therapy treatments.

The study of the effects of spatially uniform fields on the steady-state properties of Axelrod's model has yielded plenty of counterintuitive results. Here, we reexamine the impact of this type of field for a selection of parameters such that the field-free steady state of the model is heterogeneous or multicultural. Analyses of both one- and two-dimensional versions of Axelrod's model indicate that the steady state remains heterogeneous regardless of the value of the field strength. Turning on the field leads to a discontinuous decrease on the number of cultural domains, which we argue is due to the instability of zero-field heterogeneous absorbing configurations. We find, however, that spatially nonuniform fields that implement a consensus rule among the neighborhood of the agents enforce homogenization. Although the overall effects of the fields are essentially the same irrespective of the dimensionality of the model, we argue that the dimensionality has a significant impact on the stability of the field-free homogeneous steady state. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits. Biospsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n=10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks. The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies. [ABSTRACT FROM AUTHOR]

Background: Urethral stricture description is not standardized. This makes surgical decision-making less reproducible and increases the difficulty of objectively analyzing urethroplasty literature. We developed a standardized system, the UREThRAL stricture score (USS), to quantify the characteristics of anterior urethral stricture disease based on preoperative imaging and intraoperative findings. Methods: To develop the USS, we retrospectively analyzed 95 consecutive patients with urethral strictures who underwent open urethroplasty by a single surgeon (SBB) at Barnes-Jewish Hospital from 2009 to 2011. The USS is a numerical score based on five components of anterior urethral stricture disease that help dictate operative decision-making: (1) (UR)ethral stricture (E)tiology; (2) (T) otal number of strictures; (3) (R)etention (luminal obliteration); (4) (A)natomic location; and (5) (L)ength. Stricture management was categorized by increasing surgical complexity: excision/primary anastomosis (EPA), buccal mucosal graft urethroplasty (BMG), aug-mented anastomotic urethroplasty (AAU), flap urethroplasty, and a combination of flaps and/or grafts. Multinomial logistic regression analysis was used to compare USS to surgical complexity. Results: The mean USS for EPA, BMG, AAU, flap, and combination flaps/grafts was 5.78, 8.82, 9.23, 11.01, and 14.97, respectively. Increasing USS was significantly associated with surgical complex-ity (p < 0.0001). Interpretation: The USS describes the essential factors in deter-mining surgical treatment selection for urethral stricture disease. The USS is a concise, easily applicable system that delineates the clinically significant features of urethral strictures. Valuable com-parison of anterior urethral stricture treatments in clinical practice and in the urological literature could be facilitated by using this novel UREThRAL stricture score. [ABSTRACT FROM AUTHOR]

Abstract: In this study we perform a continuous Morlet wavelet transform method in time series of secondary cosmic rays and 1AU interplanetary medium parameters for the interval from October 2001 to October 2002. The near 13.5-day periodicity was obtained during late 2001, and it was remarkable for muon data. Even though some works have pointed out that the main activations of the 13.5day recurrence in near-Earth solar wind are related, e.g., with the heliosheet crossings or to the occurrence at 1AU of two high speed streams approximately 180° apart in solar longitude per solar rotation, we aim to show that the period of about half the solar rotation during the end months of 2001 present in muon time series was apparently due to the occurrence of non-recurrent interplanetary disturbances. The interconnections among successive Forbush decreases, recovery phases and gradual muon depressions (associated with corotating interaction regions) seem to play an important role in such 13.5-day periodicity. [Copyright &y& Elsevier]

Based on collections in three coast Brazilian states, Hydrosmilodon plagatus sp. nov. and Needhamella mazama sp. nov. are described based on nymphs and adults. Besides the description of these species, new geographic records of the Hermanella complex are presented. The species included are: Hermanella maculipennis (Ulmer, 1920); Hermanella froehlichi Ferreira and Domínguez (1992); Hydrosmilodon gilliesae Thomas & Péru (2004); Hylister plaummani Domínguez and Flowers (1989); Leentvaaria palpalis Demoulin (1966); and Needhamella ehrhadti (Ulmer, 1920). In addition, in this work Leentvaaria palpalis is recorded from Brazil for the first time. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of different instructions for the assessment of maximum walking speed during the ten-meter walking test with chronic stroke subjects. Methods: Participants were instructed to walk under four experimental conditions: (1) comfortable speed, (2) maximum speed (simple verbal command), (3) maximum speed (modified verbal command–“catch a bus”) and (4) maximum speed (verbal command + demonstration). Participants walked three times in each condition and the mean time to cover the intermediate 10 meters of a 14-meter corridor was registered to calculate the gait speed (m/s). Repeated-measures ANOVAs, followed by planned contrasts, were employed to investigate differences between the conditions (α=5%). Means, standard deviations and 95% confidence intervals (CI) were calculated. Results: The mean values for the four conditions were: (1) 0.74m/s; (2) 0.85 m/s; (3) 0.93 m/s; (4) 0.92 m/s, respectively, with significant differences between the conditions (F=40.9; p<0.001). Comfortable speed was significantly slower than the maximum speed, indicating that the participants were able to increase speeds when required. Significant differences were observed between the second condition with the third (p=0.002; 95%CI=-0.13 to -0.03) and the fourth conditions (p=0.004; 95%CI=-0.12 to -0.02) with no differences between the third and fourth conditions (p=1.00; 95%CI=-0.04 to 0.05). Conclusions: The results indicated that simple verbal commands were not sufficient to capture maximum gait speed with chronic stroke subjects. Thus, for clinical assessments and research purposes, where measurements of the maximum gait speed are necessary, modified verbal commands or demonstration strategies could be employed by physical therapists to ensure accurate information. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of different instructions for the assessment of maximum walking speed during the ten-meter walking test with chronic stroke subjects. Methods: Participants were instructed to walk under four experimental conditions: (1) comfortable speed, (2) maximum speed (simple verbal command), (3) maximum speed (modified verbal command–“catch a bus”) and (4) maximum speed (verbal command + demonstration). Participants walked three times in each condition and the mean time to cover the intermediate 10 meters of a 14-meter corridor was registered to calculate the gait speed (m/s). Repeated-measures ANOVAs, followed by planned contrasts, were employed to investigate differences between the conditions (α=5%). Means, standard deviations and 95% confidence intervals (CI) were calculated. Results: The mean values for the four conditions were: (1) 0.74m/s; (2) 0.85 m/s; (3) 0.93 m/s; (4) 0.92 m/s, respectively, with significant differences between the conditions (F=40.9; p<0.001). Comfortable speed was significantly slower than the maximum speed, indicating that the participants were able to increase speeds when required. Significant differences were observed between the second condition with the third (p=0.002; 95%CI=-0.13 to -0.03) and the fourth conditions (p=0.004; 95%CI=-0.12 to -0.02) with no differences between the third and fourth conditions (p=1.00; 95%CI=-0.04 to 0.05). Conclusions: The results indicated that simple verbal commands were not sufficient to capture maximum gait speed with chronic stroke subjects. Thus, for clinical assessments and research purposes, where measurements of the maximum gait speed are necessary, modified verbal commands or demonstration strategies could be employed by physical therapists to ensure accurate information. [ABSTRACT FROM AUTHOR]

Background: Measuring serum 25(OH)D concentration is common in clinical practice despite the questionable reliability of assays. Aims: The aim of the present study was to examine agreement in 25(OH)D concentrations measured by different assays and laboratories, and consider related clinical implications. Methods: Serum samples from 813 participants in the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study) were assayed for 25(OH)D concentration. Duplicate samples from subsets of subjects were sent to different laboratories, two using DiaSorin Liaison (Laboratory A and B) and one using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS - selected here as the nominal gold standard). Pairwise within-assay (both within-laboratory and between-laboratories) and between-assay agreement was examined using Deming regression and Bland-Altman plots. Common 25(OH)D cut-points for classification of vitamin D deficiency were used to compare the different assays. Results: 25(OH)D concentrations measured using Liaison were substantially lower at Laboratory A than at Laboratory B (mean bias −11.60 nmol/L, 95% limits of agreement −46.39, 23.18). Both Liaison assays returned much lower 25(OH)D concentrations than LC-MS/MS (mean bias up to −26.05 nmol/L, 95% limits of agreement of −13.21, 65.31). For Laboratory A participants, 46% (355/765) were classified as vitamin D deficient (25(OH)D <50 nmol/L) using Liaison compared with 17% (128/765) using LC-MS/MS. For Laboratory B participants, the respective figures were 36% (76/209) and 20% (41/209). Hence, between 1-in-5 and 1-in-3 participants were misclassified as 'deficient'. Conclusion: Bias and variability in 25(OH)D measurements sufficient to affect significantly clinical decision-making were found both between-laboratories and between-assays. The adoption of common standards to allow assay calibration is required urgently. [ABSTRACT FROM AUTHOR]

Abstract: Thrombin helps to activate Factor XIII (FXIII) by hydrolyzing the R37-G38 peptide bond. The resultant transglutaminase introduces cross-links into the fibrin clot. With the development of therapeutic coagulation factors, there is a need to better understand interactions involving FXIII. Such knowledge will help predict ability to activate FXIII and thus ability to promote/hinder the generation of transglutaminase activity. Kinetic parameters have been determined for a series of thrombin species hydrolyzing the FXIII (28–41) V34X activation peptides (V34, V34L, V34F, and V34P). The V34P substitution introduces PAR4 character into the FXIII, and the V34F exhibits important similarities to the cardioprotective V34L. FXIII activation peptides containing V34, V34L, or V34P could each be accommodated by alanine mutants of thrombin lacking either the W60d or Y60a residue in the 60-insertion loop. By contrast, FXIII V34F AP could be cleaved by thrombin W60dA but not by Y60aA. FXIII V34P is highly reliant on the thrombin W215 platform for its strong substrate properties whereas FXIII V34F AP becomes the first segment that can maintain its K m upon loss of the critical thrombin W215 residue. Interestingly, FXIII V34F AP could also be readily accommodated by thrombin L99A and E217A. Hydrolysis of FXIII V34F AP by thrombin W217A/E217A (WE) was similar to that of FXIII V34L AP whereas WE could not effectively cleave FXIII V34P AP. FXIII V34F and V34P AP show promise for designing FXIII activation systems that are either tolerant of or greatly hindered by the presence of anticoagulant thrombins. [Copyright &y& Elsevier]

Abstract: Cystic fibrosis (CF) patients suffer typically from bacterial infections of their airways. Whilst current antibiotic-based treatment of these infections has brought much benefit to patients, it has been difficult to make either direct or indirect assessments of the in vivo efficacy of any specific treatment used. Traditional culture-based assessment has for example been rarely used to determine the direct impact of therapy on the bacteria in the airways. Instead, the “success” of a treatment is most often gauged through measures of respiratory and general health. New culture-independent approaches though are emerging that offer much promise here however in allowing a more comprehensive evaluation of antimicrobial efficacy. These new methods offer an opportunity to examine bacterial outcomes rather than host outcomes alone. Application of these novel techniques in a systematic way will lead to the rationalisation and, likely greater still individualisation, of therapy for CF patients. This review discusses host and microbiological factors that may influence antibiotic efficacy. Moreover, the degree to which the inherent complexity of CF respiratory infections complicates the process of determining treatment impact and the need to identify more robust microbiological outcome measures will also be reviewed. [Copyright &y& Elsevier]

Abstract: Two new chemometric electrochemical techniques based on generalized two-dimensional correlation are tested and validated. Two-dimensional cyclic voltammetry (2DCV) involves synchronous and asynchronous correlations between two identical sets of cyclic voltammograms; while correlation electrochemical quartz crystal microbalance (CEQCM) is a hybrid correlation between a set of charge vs. potential curves and a set of mass variation vs. potential curves. A model system with two Fe(III)/Fe(II) pairs is set up to evaluate the reliability and advantages of these two techniques. 2DCV analysis indicates that the charging of poly(vinyl ferrocene)/solution interface (non-faradic process) has a negative influence on the heterogeneous electron transfer (faradic process). CEQCM analysis clearly identifies which Fe(III)/Fe(II) pair is responsible for the mass variation of the poly(vinyl ferrocene) network. This is the first attempt that a two-dimensional correlation has been applied to electrochemical methods. We expect more electrochemical techniques will be expanded into two-dimensional analyses. [Copyright &y& Elsevier]

This review of the considerable evidence linking EpsteineBarr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a doseeresponse relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified. [ABSTRACT FROM AUTHOR]

Muscle spasticity, due to an upper motoneuron lesion, often leads to muscle contractures that limit range of motion and cause increased muscle stiffness. However, the elements responsible for this muscle adaption are unknown. Here we show that muscle tissue is stiffer in contracture compared to age-matched children, implicating the extracellular matrix (ECM). However, titin, the major load-bearing protein within muscle fibres, is not altered in contracture, and individual fibre stiffness is unaltered. Increased ECM stiffness is even more functionally significant given our finding of long in vivo sarcomeres which leads to much larger in vivo forces in muscle contracture. These results may lead to novel therapeutics for treating spastic muscle contracture. [ABSTRACT FROM AUTHOR]

OBJECTIVE: • To assess the impact of primary surgical therapy on local control for patients with lymph-node-positive prostate cancer. METHODS: #x2022; A retrospective analysis from January 1982 to January 2001 identified 192 patients treated by radical retropubic prostatectomy (RRP, N =87), hormonal ablative therapy (ADT, N = 74), or RRP plus adjuvant hormones (RRP + ADT, N = 31). • Statistical analyses were conducted using the Kruskal–Wallis test, chi-squared or Fisher’s exact test, log-rank test and logistic regression with the statistical significance level set at P < 0.05. RESULTS: • The incidence of local relapse in the three treatment groups (RRP, ADT and RRP + ADT) was 40.2%, 59.5% and 12.9%, respectively.• Among those with local relapse, the incidence of symptomatic local relapse (defined as local symptoms secondary to locally recurrent prostate cancer) was 25.7%, 75.0% and 50.0%, respectively. • Logistic regression analysis used to identify predictors of local relapse indicated that patients treated with ADT (OR = 1.96; P = 0.270) had higher odds of having a local relapse whereas patients treated with RRP + ADT (OR = 0.20; P = 0.032) had significantly lower odds of having a local relapse compared with patients treated with RRP (reference group) after adjusting for other significant predictors such as increases in serum PSA at diagnosis (OR = 1.09; P = 0.018) and biochemical failure after primary therapy (OR = 48.3; P < 0.001). • Logistic regression analysis used to identify predictors of symptomatic local relapse, among patients having had a relapse, indicated that patients treated with RRP + ADT (OR = 2.90; P = 0.322) had higher odds of having a symptomatic local relapse whereas patients treated with ADT alone (OR = 8.67; P < 0.001) had significantly higher odds of having a symptomatic local relapse compared with patients treated with RRP(reference group). CONCLUSIONS: • Radical prostatectomy (with adjuvant hormonal therapy) provides improved local control in patients with lymph-nodepositive prostate cancer. • This important endpoint must be considered when determining the optimal treatment of patients with node-positive disease. [ABSTRACT FROM AUTHOR]

Abstract: Duchenne muscular dystrophy is a neuromuscular degenerative disorder caused by the absence of dystrophin protein. It is characterized by progressive muscle weakness and cycles of degeneration/regeneration accompanying chronic muscle damage and repair. Canine models of muscular dystrophy, including the dystrophin-deficient golden retriever muscular dystrophy (GRMD), are the most promising animal models for evaluation of potential therapies, however canine-specific molecular tools are limited. In particular, few immune reagents for extracellular epitopes marking canine satellite cells (muscle stem cells) are available. We generated an antibody to the satellite cell marker syndecan-4 that identifies canine satellite cells. We then characterized isolated satellite cells from GRMD muscle and wildtype muscle by several in vitro metrics, and surprisingly found no significant differences between the two populations. We discuss whether accumulated adverse changes in the muscle environment rather than cell-intrinsic defects may be implicated in the eventual failure of satellite cell efficacy in vivo. [Copyright &y& Elsevier]

Background: Metastasis is associated with poor prognosis for melanoma. The formation of metastases is a multi-step process, in which cancer cells can subsequently acquire the potential to intravasate into the blood or lymph vessels, disseminate through the circulation, extravasate through the endothelium and invade the connective tissue. There is increasing evidence that chemokines have a pivotal role in the dissemination and establishment of melanoma metastasis.Methods: We isolated melanoma cells from melanoma metastasis and performed different migration assays and transendothelial resistance measurements of endothelial monolayers co-cultured with melanoma cells, in order to monitor barrier function and diapedesis and confirmed these results by confocal microscopy.Results: We observed that tumour endothelial cells (ECs) secrete high levels of CXCL9 in all, and CXCL10 in most melanoma metastases. Migration studies revealed that low concentrations of these chemokines induce chemotaxis, whereas high concentrations induce spontaneous migration of melanoma cells (chemokinesis/chemorepulsion) and the disruption of the endothelial barrier, resulting in an accelerated transendothelial migration (TEM). Addition of anti-CXCL9 or anti-CXCR3 antibodies to the co-cultures delayed the TEM of melanoma cells.Conclusion: Our data represent novel mechanisms by which tumour cells in melanoma metastases might use the chemokine-expressing endothelium to leave the tumour and eventually to form additional metastases at distinct sites. [ABSTRACT FROM AUTHOR]

Abstract: In tropical shrimp ponds, the increasing of feed input, concomitantly with the stocking shrimp biomass, induces an eutrophication of the ecosystem. Although difficult to maintain, its stability is required to guarantee the success of the culture. A 110-day period of phytoplankton and bacterioplankton stock and dynamics in an earthen pond (1.2ha area, 1m depth) was monitored using flow cytometry to provide baseline information on community characteristics and ecosystem instability. Seven autotrophic cell types were identified over the whole sampling period. Prokaryotic cells included Synechococcus sp., a group named UNK which presented an atypical new flow cytometric signature and picoeukaryotes (PEUK). Nanophytoplankton cells were represented by 4 groups: NAN1, NAN2, NAN3 and Cryptophytes. During the first part of the survey, picophytoplankton dominated the phytoplanktonic assemblage. The mean abundance of total cells (up to 8×106 cellsmL−1) was among the highest recorded in marine and brackish waters. Bacterial abundance and production ranged from 0.8 to 5.1×107 cellsmL−1 and from 30 to 110μgCL−1 h−1. A shift from pico to nanophytoplankton abundance was observed for a few days from d 96. During this period, heterotrophic bacteria production and abundance suddenly dropped, implying a change in the functioning of the microbial loop. This shift was concomitant with a significant shrimp mortality outbreak due to Vibrio penaeicida, the etiological agent of a disease known as Syndrome 93, which affects the shrimp industry in New Caledonia. This survey suggests that flow cytometric analysis could be used for the monitoring of aquaculture systems to improve our understanding of the complex phytoplankton and bacterial dynamics of these systems and its potential influence on disease development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Since 1993 the participation of Portuguese pharmacies to the national Syringe Exchange Programme (SEP) has remained high. However, no national guidelines or standard procedures are available regarding the provision of this service. We aimed to describe practices and attitudes toward syringe dispensing and other harm reduction strategies in Portuguese pharmacies. METHODS: A cross-sectional survey was conducted using an anonymous self-administered questionnaire. All pharmacies in Portugal (n=2775) were invited to participate. The questionnaire addressed SEP ever involvement and discontinuation; injection equipment policies; problems and needs in service provision. RESULTS: Participation rates were 69.6% among pharmacies involved in SEP and 42.7% in those not involved in the programme. Among current providers, 64.3% followed a strict 'one-for-one' policy and 21.6% established limits on the number of syringes distributed. Syringe selling was reported by 76.2%. One-tenth of pharmacies supervised methadone consumption Problems in service provision were experienced by 12.8% of respondents. Need for increased training and improvement of referral pathways were frequently reported. CONCLUSIONS: Pharmacy-based harm reduction interventions in Portugal have tended to follow strict policies favouring conservative approaches. Training and feedback adaptation seem indispensable to avoid service discontinuation and boost an activity with an essential humanitarian dimension. [ABSTRACT FROM AUTHOR]

Abstract: In this work, we introduce a new analytical form based on the q-exponential function to build three-dimensional reactive surfaces. The quality of this new function is tested by fitting the ab initio potential energy surface (PES) to the ground state Na+HF reaction. The thermal rate constant and reactive probabilities were determined considering this new PES. The obtained properties agree with those found for other PES available in literature. [Copyright &y& Elsevier]

As a new generation of culture-independent analytical strategies emerge, the amount of data on polymicrobial infections will increase dramatically. For these data to inform clinical thinking, and in turn to maximise benefits for patients, an appropriate framework for their interpretation is required. Here, we use cystic fibrosis (CF) lower airway infections as a model system to examine how conceptual and technological advances can address two clinical questions that are central to improved management of CF respiratory disease. Firstly, can markers of the microbial community be identified that predict a change in infection dynamics and clinical outcomes? Secondly, can these new strategies directly characterize the impact of antimicrobial therapies, allowing treatment efficacy to be both assessed and optimized? [ABSTRACT FROM AUTHOR]

This article describes a synthetic route to generate two purine-pyrimidine and pyrimidine heterodinucleosides. Both microwave activated regioselective alkylation using hydride and copper-catalyzed-azide-alkyne-cycloaddition (CuAAC) were used in order to perform the synthesis. [ABSTRACT FROM AUTHOR]

Abstract: Protection–deprotection steps, which are usually needed for regioselective alkylation of pyrimidine deoxynucleosides, can be avoided by choosing the appropriate solvent. The combined effects of low dielectric constant and possible sodium chelation by pyrimidine nucleosides may account for the unexpected regioselectivity observed in THF. [Copyright &y& Elsevier]

Microbes are subjected to selective pressures during chronic infections of host tissues. Pseudomonas aeruginosa isolates with inactivating mutations in the transcriptional regulator LasR are frequently selected within the airways of people with cystic fibrosis (CF), and infection with these isolates has been associated with poorer lung function outcomes. The mechanisms underlying selection for lasR mutation are unknown but have been postulated to involve the abundance of specific nutrients within CF airway secretions. We characterized lasR mutant P. aeruginosa strains and isolates to identify conditions found in CF airways that select for growth of lasR mutants. Relative to wild-type P. aeruginosa, lasR mutants exhibited a dramatic metabolic shift, including decreased oxygen consumption and increased nitrate utilization, that is predicted to confer increased fitness within the nutrient conditions known to occur in CF airways. This metabolic shift exhibited by lasR mutants conferred resistance to two antibiotics used frequently in CF care, tobramycin and ciprofloxacin, even under oxygen-dependent growth conditions, yet selection for these mutants in vitro did not require preceding antibiotic exposure. The selection for loss of LasR function in vivo, and the associated adverse clinical impact, could be due to increased bacterial growth in the oxygen-poor and nitrate-rich CF airway, and from the resulting resistance to therapeutic antibiotics. The metabolic similarities among diverse chronic infection-adapted bacteria suggest a common mode of adaptation and antibiotic resistance during chronic infection that is primarily driven by bacterial metabolic shifts in response to nutrient availability within host tissues. [ABSTRACT FROM AUTHOR]

Stress strongly inhibits proliferation of granule cell precursors in the adult dentate gyrus, whereas voluntary running has the opposite effect. Few studies, however, have examined the possible effects of these environmental manipulations on the maturation and survival of young granule cells. We examined the number of surviving granule cells and the proportion of young neurons that were functionally mature, as defined by seizure-induced immediate-early gene (IEG) expression, in 14- and 21-day-old granule cells in mice that were given access to a running wheel, restrained daily for 2 h, or given no treatment during this period. Treatments began 2 days after BrdU injection, to isolate effects on survival from those on cell proliferation. We found a large increase in granule cell survival in running mice when compared with controls at both time points. In addition, running increased the proportion of granule cells expressing the IEG Arc in response to seizures, suggesting that it speeds incorporation into circuits, i.e., functional maturation. Stressed mice showed no change in Arc expression, compared with control animals, but, surprisingly, showed a transient increase in survival of 14-day-old granule cells, which was gone 7 days later. Examination of cell proliferation, using the endogenous mitotic marker PCNA showed an increase in cell proliferation after 12 days of running but not after 19 days of running. The number of proliferating cells was unchanged 24 h after the 12th or 19th episode of daily restraint stress. These findings demonstrate that running has strong effects on survival and maturation of young granule cells as well as their birth and that stress can have positive but short-lived effects on granule cell survival. Published 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Longwall mining and related subsidence, and watercourse diversion for surface mining operations have the potential to impact on fluvial geomorphic processes and the health of river systems. This is evident in the Isaac River in central Queensland. The scale and likelihood of these impacts are a function of the extent of existing and proposed mining developments and of the ongoing geomorphic, hydrologic and ecological processes within the Isaac River. Understanding the objectives for the river, the past and ongoing processes at work, the cumulative impacts of longwall mining development and the options for managing those impacts is essential for the development of an effective strategy to manage the health of the river system. An assessment has been undertaken to identify and understand the cumulative impacts of mining subsidence and other mining influences on geomorphic processes and waterway health in the Isaac River over a river length of approximately 100 km near Moranbah in central Queensland. The assessment included the development of a vision and objectives for waterway health. The assessment has identified mining and landuse changes that have impacted on the hydrology, geomorphology, ecology and hence the health of the Isaac River. The assessment has then sought to identify the cumulative impact of longwall mining and related subsidence on current stream condition and the proposed vision for the system. The primary impact of longwall mining on the river was found to be associated with sediment transport. The investigation included assessment of total sand available for transport, the volume of sand transported annually and the fluvial process response to subsidence. Recommendations have been developed for the management of the system and for longwall mining to increase system robustness and achieve the river health objectives. [ABSTRACT FROM AUTHOR]

Intestinal alkaline phosphatase (IAP) is an enzyme of the brush border of the enterocyte. The activity of IAP biphasically depends on calcium. Although calcium increases IAP activity, when calcium is higher than 20 mmole/L, IAP activity decreases and the amount of an aggregated form increases. The reversibility of the effect of calcium and the aggregation process are unknown. The isoelectric point of the enzyme was higher in the presence of calcium, but was the same for the enzyme and the aggregated form. The treatment with EGTA after calcium addition did not restore the enzymatic activity but produced desaggregation of the enzyme and increase in the monomeric subunits of IAP. It is concluded that the binding of calcium does not produce important modifications on the structure of the protein, that the inhibitory effect is not reversible and that calcium could be involved in the stability of the structure of the enzyme. [ABSTRACT FROM AUTHOR]

Streambank morphology plays an important role in the ecosystem functions of stream and riparian areas. Large gaps remain in our understanding of the effects of livestock grazing on southwestern stream channels. The purpose of this study was primarily to evaluate the effects of different grazing intensities and different seasons of use on stream- bank morphology in two montane riparian areas in western New Mexico. We did not find significant larger-scale changes to streambanks over the duration of the study. In contrast, we found many smaller-scale changes that had taken place following cattle grazing. Because the smaller-scale changes we observed were not associated with other indicators of streambank alteration such as bank collapse, widening of the active channel, plant community change, or other larger-scale changes, we conclude that the smaller-scale changes we observed were part of the normal geomorphological adjustments made by streambanks and did not ultimately contribute to lasting streambank morphological change. We also stress that care needs to be given to the selection of appropriate response variables when examining streambank change. Livestock can potentially have large impacts on streambanks, and understanding the effects of grazing on streambank morphology is important in order to make good management decisions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pseudomonas aeruginosa with mutations in the transcriptional regulator LasR chronically infect the airways of people with cystic fibrosis (CF), yet the prevalence and clinical implications of lasR mutant infection are unknown. Methods: In an exploratory study, we screened 166 P. aeruginosa isolates from 58 CF patients for LasR inactivation and mucoidy, and compared clinical characteristics among source patients. Results: lasR mutation prevalence was comparable to that of mucoidy, the best-described CF-adapted phenotype, but affected patients were on average approximately 2 years younger. In a regression analysis, lung function decline with age was worse among patients with lasR mutant infection than in those without, similar to the effect of mucoidy. Conclusions: Culture positivity for lasR mutant P. aeruginosa may serve as a marker of early CF adaptive change of prognostic significance. Furthermore, as LasR inactivation alters susceptibility to antibiotics, infection with lasR mutant P. aeruginosa may impact response to therapy. [Copyright &y& Elsevier]

The moving boundary truncation (MBT) method is a time-dependent adaptive method that can significantly reduce the number of grid points needed to perform accurate wave packet propagation while maintaining stability. This work presents a more robust variation of the method. Significant improvements have been made that allow the MBT method to be applied to any potential energy surface and used with any propagation method. The new variation of MBT is applied to the collinear H + H2reaction (using a LEPS potential) to demonstrate the stability and accuracy. Reaction probabilities are calculated for the three-dimensional nonrotating O(3P) + H2and O(3P) + HD reactions to demonstrate that the MBT can be used with a variety of numerical propagation techniques. [ABSTRACT FROM AUTHOR]

In this work, we performed a quantum reactive study using a new potential energy surface (PES) fitted to the Na + HF→NaF + H reaction. The new PES was obtained using the genetic algorithm optimization technique (GAOT). We calculated the reactive probabilities (RP) of the Na + HF system using the new PES. The GAOT RP are compared with the obtained RP using two other PES found to the Na + HF system: Bond Order 5 (BO5) and the generalized simulated annealing (GSA) PES. We found that the GAOT RP are in excellent agreement with the GSA and BO5 RP. It should be point out that the BO5 RP are considered the benchmark of literature. Therefore, the GAOT is shown to be an appropriate method to fit PES of reactive systems. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [ABSTRACT FROM AUTHOR]

We tested the hypothesis that older adults, relative to younger adults, would be more prone to critical reductions in cerebral blood flow and oxygenation upon standing during passive heat stress. Six older (70 ± 4 years, mean ±s.d.) and six younger males (29 ± 4 years) were heated (oesophageal temperature raised 0.5°C) in a water-perfused suit. Blood flow velocity in the middle cerebral artery (MCAv), cerebral oxygenation, mean arterial pressure (MAP) and end-tidal partial pressure of carbon dioxide ( ) were measured continuously before and during 3 min standing in each thermal state. At supine normothermic baseline, MCAv was 47% lower in older participants ( P < 0.001), whilst MAP and cerebral oxygenation were similar between groups ( P > 0.05). Heating lowered the supine MAP more in younger adults, and elevated heart rate only in this group. Upon initial standing in normothermia, older participants had a greater drop in MCAv ( P < 0.05 versus young), a lesser drop in MAP (∼24 and ∼42% in older and younger participants, respectively), but slower recovery of MAP (27.3 ± 6.8 versus 18.6 ± 4.7 s, mean ±s.d., P= 0.004); heating did not exacerbate any postural responses in either age group. During the last minute of standing, MCAv and were lower in older participants, though age differences were not evident in cerebral oxygenation (normothermic or heated). Thus, independent of heat stress, in addition to lower resting MCAv, there are further age-related reductions in MCAv and slower corrections of MAP following standing. However, these asymptomatic changes seem to represent a physiologically acceptable insult which can be well tolerated in otherwise healthy older participants even during heat stress. [ABSTRACT FROM AUTHOR]

Robotic devices can be used for motor control and learning research. In this work, we present the construction, modeling and experimental validation of a bimanual robotic device. We tested some hypotheses that may help to better understand the motor learning processes involved in the interlimb coordination function. The system emulates a bicycle handlebar with rotational motion, thus requiring bilateral upper limb control and a coordinated sequence of joint sub-movements. The robotic handlebar is compact and portable and can register in a fast rate both position and forces independently from arms, including prehension forces. An impedance control system was implemented in order to promote a safer environment for human interaction and the system is able to generate force fields, suitable for implementing motor learning paradigms. The novelty of the system is the decoupling of prehension and manipulation forces of each hand, thus paving the way for the investigation of hand dominance function in a bimanual task. Experiments were conducted with ten healthy subjects, kinematic and dynamic variables were measured during a rotational set of movements. Statistical analyses showed that movement velocity decreased with practice along with an increase in reaction time. This suggests an increase of the task planning time. Prehension force decreased with practice. However, an unexpected result was that the dominant hand did not lead the bimanual task, but helped to correct the movement, suggesting different roles for each hand during a cooperative bimanual task. [ABSTRACT FROM AUTHOR]

Identifying 14-3-3 isoform-specific substrates and functions may be of broad relevance to cell signaling research because of the key role played by this family of proteins in many vital processes. A multitude of ligands have been identified, but the extent to which they are isoform-specific is a matter of debate. Herein we demonstrate, both in vitro and in vivo, a specific, functionally relevant interaction of human 14-3-3γ with the molecular scaffold KSR1, which is mediated by the C-terminal stretch of 14-3-3γ. Specific binding to 14-3-3γ protected KSR1 from epidermal growth factor-induced dephosphorylation and impaired its ability to activate ERK2 and facilitate Ras signaling in Xenopus oocytes. Furthermore, RNA interference-mediated inhibition of 14-3-3γ resulted in the accumulation of KSR1 in the plasma membrane, all in accordance with 14-3-3γ being the cytosolic anchor that keeps KSR1 inactive. We also provide evidence that KSR1-bound 14-3-3γ heterodimerized preferentially with selected isoforms and that KSR1 bound monomeric 14-3-3γ. In sum, we have demonstrated ligand discrimination among 14-3-3 isoforms and shed light on molecular mechanisms of 14-3-3 functional specificity and KSR1 regulation. [ABSTRACT FROM AUTHOR]

To increase understanding of forest carbon cycles and stocks, estimates of total and component (e.g. leaf, branch and trunk) biomass at a range of scales are desirable. Focusing on mixed species forests in central south-east Queensland, two different approaches to the retrieval of biomass from small footprint Light Detection and Ranging (LiDAR) and Compact Airborne Spectrographic Imager (CASI) hyperspectral data were developed and compared. In the first, stems were located using a LiDAR crown openness index, and each was associated with crowns delineated and identified to species using CASI data. The component biomass for individual trees was then estimated using LiDAR-derived height and stem diameter as input to species-specific allometric equations. When summed to give total above-ground biomass (AGB) and aggregated to the plot level, these estimates showed a reasonable correspondence with ground (plot-based) estimates (r 2 = 0.56, RSE = 25.3 Mg ha-1, n = 21) given the complex forest being assessed. In the second approach, a Jackknife linear regression utilizing six LiDAR strata heights and crown cover at the plot-scale produced more robust estimates of AGB that showed a closer correspondence with plot-scale ground data (r 2 = 0.90, RSE = 11.8 Mg ha-1, n = 31). AGB aggregated from the tree-level and Jackknife regression plot-based AGB estimates (for 270 plots - each of 0.25 ha) compared well for more mature homogeneous and open forests. However, at the tree level, AGB was overestimated in taller forests dominated by trees with large spreading crowns, and underestimated AGB where an understorey with a high density of stems occurred. The study demonstrated options for quantifying component biomass and AGB through integration of LiDAR and CASI data but highlighted the requirement for methods that give improved estimation of tree density (by size class distributions) and species occurrence in complex forests. [ABSTRACT FROM AUTHOR]

Aim. This paper is a report of a concept analysis of neonatal neurobehavioural organization for healthy full-term infants. Background. The neonatal period is an opportune time for researchers and clinicians to assess and intervene for optimal neurobehavioural organization. Yet there is inconsistency and lack of clarity in a scientifically grounded definition of neonatal neurobehavioural organization. Clarification of the concept will strengthen research findings that influence practice for optimal infant development. Method. A concept analysis of the literature between 1939 and 2007 ( n = 57) was conducted using Penrod and Hupcey's principle-based concept analysis and Morse's concept clarification. Findings. The concept analysis within and across multiple disciplines revealed: (1) a view of the concept as a holistic phenomenon with multiple dimensions; (2) no agreement on the ideal instrument to operationally define the concept; and (3) consistency in implied meaning, but great variability in terminology. Neonatal neurobehavioural organization was defined as the ability of the neonate to use goal-directed states of consciousness, in reciprocal interaction with the caregiving environment, to facilitate the emergence of differentiating, hierarchical, and coordinated neurobehavioural systems, with ever-increasing resiliency and capacity to learn from complex stimuli. Conclusion. A clear conceptual definition will help the international community to communicate effectively within and between disciplines and to apply evidence-based research findings. It will encourage the development of valid and reliable instruments to capture the concept's multiple dimensions and direct attention to the infant's experience, which sculpts early neurobehavioural organization. [ABSTRACT FROM AUTHOR]

In this paper I have endeavoured to draw attention to what is meant when we refer to a patient as psychotic. It is argued that it is not enough just to be ordinarily sensitive to our patients; we need to tune into the psychotic wavelength with all its implications for understanding and management. Illustrative case-histories are presented from everyday psychiatric work. [ABSTRACT FROM AUTHOR]