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To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3tm2Gfng model, hereafter Shank3/F, Jiang's Shank3tm1Yhj model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan–McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety‐like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory‐gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

The scope of this study is to characterize the mechanical properties of a novel Transformation-Induced Plasticity bainitic steel grade TBC700Y980T. For this purpose, tensile tests are carried out with loading direction 0, 45 and 90° with respect to the L rolling direction. Yield stress is found to be higher than 700 MPa, ultimate tensile strength larger than 1050 MPa and total elongation higher than 15%. Low-cycle fatigue (LCF) tests are carried out under fully reverse axial strain exploring fatigue lives comprised between 102 and 105 fatigue cycles. The data are used to determine the parameters of the Coffin-Manson as well as the cyclic stress-strain curve. No significant stress-induced austenite transformation is detected. The high-cycle fatigue (HCF) behaviour is investigated through load controlled axial tests exploring fatigue tests up to 5 × 106 fatigue cycles at two loading ratios, namely R = −1 and R = 0. At fatigue lives longer than 2 × 105 cycles, the strain life curve determined from LCF tests tends to greatly underestimate the HCF resistance of the material. Apparently, the HCF behaviour of this material cannot be extrapolated from LCF tests, as different damage, cyclic hardening mechanisms and microstructural conditions are involved. In particular, in the HCF regime, the predominant damage mechanism is nucleation of fatigue cracks in the vicinity of oxide inclusions, whereby mean value and scatter in fatigue limit are directly correlated to the dimension of these inclusions. [ABSTRACT FROM AUTHOR]

Aims To assess country- and individual-level correlates of psychological outcomes, and differences among countries in the associations of individual characteristics with psychological outcomes among adults with diabetes. Methods The second Diabetes Attitudes, Wishes and Needs ( DAWN2™) study assessed self-reported characteristics of people with diabetes in 17 countries, including 1368 adults with Type 1 diabetes and 7228 with Type 2 diabetes. In each country, a sample of 500 adults, stratified by diabetes type and treatment, completed a questionnaire incorporating the validated WHO-5 wellbeing index, the WHOQOL- BREF, and the five-item Problem Areas in Diabetes Scale, as well as the newly developed Diabetes Impact on Life Dimensions that assessed impact ranging from very positive to very negative, with no impact as the midpoint. Multilevel regression analyses identified significant ( P < 0.05) independent correlates of psychological outcomes. Results There were significant variations in all outcomes across countries before adjustment for individual-level factors; adjustment reduced between-country disparities. Worse psychological outcomes were associated with more complications, incidence of hypoglycaemia, hypoglycaemic medication, perceived burden of diabetes, family conflict and experience of discrimination. Better psychological outcomes were associated with higher self-rated health, greater access to diabetes education and healthcare, and more psychosocial support from others. The associations of many factors with the outcomes were mediated by modifiable factors. The association of all factors with the outcomes varied across (interacted with) countries, highlighting the need for country-specific analyses. Conclusions Improvements in modifiable risk factors (reductions in burden and increases in support) may lead to better psychological outcomes in adults with diabetes. [ABSTRACT FROM AUTHOR]

Aim: Italian national guidelines on pain management were published in 2010, but there is little information on how effective pain management is in paediatric emergency care, with other countries reporting poor levels. Using headache as an indicator, we described pain assessment in Italian emergency departments and identified predictors of algometric scale use.Methods: All Italian paediatric and maternal and child hospitals participated, plus four general hospitals. Data on all children aged 4-14 years admitted during a one-month period with headache as their chief complaint were abstracted from clinical records. Multivariable analyses identified predictors of algometric assessment, taking into account the cluster study design.Results: We studied 470 admissions. During triage, pain was assessed using a standardised scale (41.5%), informally (15.5%) or was not recorded (42.9%). Only 32.1% of the children received analgesia in the emergency department. The odds ratios for predictors of algometric assessment were non-Italian nationality (3.6), prehospital medication (1.8), admission to a research hospital (7.3) and a more favourable nurses-to-admissions ratio of 10.8 for the highest versus lowest tertile.Conclusion: Despite national guidelines, paediatric pain assessment in Italian emergency care was suboptimal. Hospital variables appeared to be stronger predictors of adequate assessment than patient characteristics. [ABSTRACT FROM AUTHOR]

Chemical extraction, multi-element stable isotopic dilution ( ID) and multi-surface modelling were used to investigate the lability of cadmium ( Cd) and copper ( Cu) in nine types of soil with different properties and contaminated or not with Cd and Cu. The chemical extraction and ID analyses both showed that Cd was more labile than Cu in all the soil types studied. From the ID results, 32.8-93.3% of total Cd and 14.7-71.8% of total Cu were isotopically exchangeable after 3 days of equilibration. A single extraction in 0.43 m HNO3 gave similar results to the 3-day ID assay for Cu in most of the soils and for Cd in the non-calcareous soils. However, an eight-step selective sequential extraction ( SSE) procedure gave different results from the ID assay for both metals. Predictions of the multi-surface model for the amounts of Cd and Cu adsorbed, based on measured metal ion activities in the soil solution and the concentrations of reactive surfaces in the soil, agreed with the ID results. The model predicted that soil organic matter was the predominant sorbent for Cd and Cu in the soils and that manganese oxide was the least important sorbent. The contributions of iron oxides to sorption were predicted to be small except in soil with a high pH and little organic matter. The predicted sorption on different soil components did not match SSE measurements. [ABSTRACT FROM AUTHOR]

ABSTRACT We examine the Atlantic maritime vegetation history from Praia Rei Cortiço, Portugal, to understand natural vegetation patterns and infer climatic conditions during the transition from the last interglacial to early glacial periods. Optically stimulated luminescence dating of quartz grains from sediments surrounding the 1.3-m-thick organic deposit date the section to within 120-89 ka. Pollen data were used to reconstruct the vegetation history and determine a range of possible past climates using an ensemble of seven modern analogue approaches. A five-part environmental sequence transitioned from heath-pine-dominated communities, deciduous hardwood forests and pine forests to heathlands surrounded by steppe-like environments. Mixed temperate and Mediterranean forest elements existed during the last interglacial period at Praia Rei Cortiço, suggesting a proximal limit to these floras. Abundant Fagus pollen (>6%) suggests local beech populations existed within maritime forests of the Iberian Atlantic margin, representing a greater distribution of this genus during interglacial periods than has previously been recognized. Climate reconstructions indicate that variations in moisture availability may have been a major driver of the observed environmental changes. [ABSTRACT FROM AUTHOR]

Aims The second Diabetes Attitudes, Wishes and Needs ( DAWN2) study sought cross-national comparisons of perceptions on healthcare provision for benchmarking and sharing of clinical practices to improve diabetes care. Methods In total, 4785 healthcare professionals caring for people with diabetes across 17 countries participated in an online survey designed to assess diabetes healthcare provision, self-management and training. Results Between 61.4 and 92.9% of healthcare professionals felt that people with diabetes needed to improve various self-management activities; glucose monitoring (range, 29.3-92.1%) had the biggest country difference, with a between-country variance of 20%. The need for a major improvement in diabetes self-management education was reported by 60% (26.4-81.4%) of healthcare professionals, with a 12% between-country variance. Provision of diabetes services differed among countries, with many healthcare professionals indicating that major improvements were needed across a range of areas, including healthcare organization [30.6% (7.4-67.1%)], resources for diabetes prevention [78.8% (60.4-90.5%)], earlier diagnosis and treatment [67.9% (45.0-85.5%)], communication between team members and people with diabetes [56.1% (22.3-85.4%)], specialist nurse availability [63.8% (27.9-90.7%)] and psychological support [62.7% (40.6-79.6%)]. In some countries, up to one third of healthcare professionals reported not having received any formal diabetes training. Societal discrimination against people with diabetes was reported by 32.8% (11.4-79.6%) of participants. Conclusions This survey has highlighted concerns of healthcare professionals relating to diabetes healthcare provision, self-management and training. Identifying between-country differences in several areas will allow benchmarking and sharing of clinical practices. [ABSTRACT FROM AUTHOR]

Background and purpose Recent multiple sclerosis ( MS) prevalence studies classify Italy as a high-risk area without intra-regional latitude effect. Objectives To determine MS prevalence in Verona, Italy, and frequency of myelin oligodendrocyte glycoprotein ( MOG) gene G511C polymorphism and HLA- DRB1*15 locus in a sample of cases and healthy controls. Methods The study area population on the prevalence date (31 December 2001) was 253 208 (133 508 women, 119 700 men). Multiple case sources were examined. Patients fulfilling McDonald's criteria (2001) were included. Crude, age- and sex-specific prevalence rates were computed. MOG G511C polymorphism and HLA- DRB1*15 were determined by standard methods. Results We identified 270 cases of MS yielding a crude prevalence rate of 106.6/100 000 (95% CI: 94-120). Prevalence was higher in women (140.8/100 000) than in men (68.5/100 000). The age-adjusted prevalence rate standardized to the European population was 96.0/100 000. MOG G511C polymorphism did not differ between cases and controls. HLA- DRB1*15 frequency was 58/155 (37%) in cases and 24/157 (15%) in controls ( P < 0.001). There was no HLA- DRB1*15 influence on susceptibility to other autoimmune disorders. Conclusions The high MS prevalence in Verona confirms Italy as a high-risk area with a homogenous distribution across the country. HLA- DRB1*15 is a relevant MS susceptibility locus in the Italian population, possibly with little influence on the occurrence of concomitant autoimmune disorders. [ABSTRACT FROM AUTHOR]

Background Pain markedly activates the hypothalamic-pituitary-adrenal ( HPA) axis and increases plasma corticosterone release interfering significantly with nociceptive behaviour as well as the mechanism of action of analgesic drugs. Aims/Methods In the present study, we monitored the time course of circulating corticosterone in two mouse strains ( C57Bl/6 and Balb/ C) under different pain models. In addition, the stress response was investigated following animal handling, intrathecal (i.t.) manipulation and habituation to environmental conditions commonly used in nociceptive experimental assays. We also examined the influence of within-cage order of testing on plasma corticosterone. Results Subcutaneous injection of capsaicin precipitated a prompt stress response whereas carrageenan and complete Freund's adjuvant induced an increased corticosterone release around the third hour post-injection. However, carrageenan induced a longer increased corticosterone in C57Bl/6 mice. In partial sciatic nerve ligation, neuropathic pain model corticosterone increased only in the first days whereas mechanical hypersensitivity remained much longer. Animal handling also represents an important stressor whereas the i.t. injection per se does not exacerbate the handling-induced stress response. Moreover, the order of testing animals from the same cage does not interfere with plasma corticosterone levels in the intrathecal procedure. Animal habituation to the testing apparatus also does not reduce the immediate corticosterone increase as compared with non-habituated mice. Conclusion Our data indicate that HPA axis activation in acute and chronic pain models is time dependent and may be dissociated from evoked hyperalgesia. Therefore, HPA-axis activation represents an important variable to be considered when designing experimental assays of persistent pain as well as for interpretation of data. [ABSTRACT FROM AUTHOR]

The paper describes a test rig designed to check and assess the accuracy of the incremental hole drilling (IHD) method. An external load produces a controlled linearly through thickness variable uniaxial stress field (reference bending stress), known with good accuracy, that can be applied and removed at each hole increment. After the separation between the bending relaxed strain from the residual stress relaxed strain, it is possible to reproduce the bending stress distribution in order to have complete confidence of the residual stress measurement. The bending verification of the IHD method was already proposed by other investigators before, but residual stress measurements were then performed on independent configurations. The proposed testing procedure gives a 'real time' verification of the residual stress measurement. Any experimental malfunctioning due to the operator inexperience, or any error during the stress calculation from the relaxed strain would produce an evident difference between the expected reference bending stress and the IHD bending stress output. Moreover, the reference bending stress helped for understanding that the not perfect hole cylindrical shape causes an underestimate of the predicted stress near the surface. A zero depth offset correction was proposed. This correction was tested on the reference bending stress, and then applied to the residual stress prediction. Three shot peening residual stresses IHD measurements were successfully validated by means of the bending stress; moreover, they were in good agreement with independent X-ray diffraction measures also proposed in the paper. [ABSTRACT FROM AUTHOR]

Aim: To estimate absolute and relative incidence rates of hypoglycaemia when using once-daily evening or morning regimens of insulin glargine (glargine) versus once-daily evening NPH insulin (NPH) using individual patient data (IPD). Materials and methods: Randomized controlled trials with accessible IPD and including white European people with type 2 diabetes (T2DM) using glargine or NPH once-daily (with oral glucose-lowering drugs) were identified. Two study pools were analysed: evening glargine versus evening NPH (pool 1); and morning glargine versus evening NPH (pool 2). The number-needed-to-treat to avoid hypoglycaemia was calculated for glargine versus NPH. Results: In study pool 1 (n = 2711), the risk of nocturnal hypoglycaemia was approximately halved with glargine compared with NPH [odds ratios (OR): 0.44–0.52, p < 0.001–0.047]. This led to a significant reduction in anytime risk of symptomatic hypoglycaemia [plasma glucose (PG) <3.9 mmol/l, OR: 0.64, p = 0.018; PG <2.0 mmol/l, OR: 0.51, p < 0.001]. In study pool 2 (n = 470), although a strong numerical reduction in all types of nocturnal hypoglycaemia was observed (OR: 0.16–0.64), statistical significance was reached only for symptomatic hypoglycaemia with PG <3.9 mmol/l (p < 0.001). Eight (pool 1) or five (pool 2) people with T2DM needed to use glargine rather than NPH to avoid one person from experiencing a nocturnal symptomatic hypoglycaemic event within a median of about 25 weeks of starting insulin. Conclusions: This meta-analysis of open-label studies provides confidence that reductions of around 50% of risk for nocturnal hypoglycaemia can be achieved with using glargine instead of NPH. [ABSTRACT FROM AUTHOR]

Competition for uptake and/or efflux transporters can be responsible for drug interactions. Cetirizine is mainly eliminated unchanged in urine through both glomerular filtration and tubular secretion. The aim of this study was to investigate whether the eutomer, levocetirizine, and the distomer, dextrocetirizine, have a similar tubular secretion. The renal clearance associated with tubular secretion was calculated from the renal clearance of levocetirizine and dextrocetirizine obtained in a study in healthy volunteers. The values of the unbound fraction in plasma were obtained in an in vitro study of the binding of 14C-cetirizine and 14C-levocetirizine to human plasma proteins using equilibrium dialysis and chiral high-performance liquid chromatography (HPLC) with on-line liquid scintillation counting. The unbound fraction was 0.074 for levocetirizine and 0.141 for dextrocetirizine. The tubular secretion of dextrocetirizine (44.5 mL/min) is higher than that of levocetirizine (23.1 mL/min), which may have consequences for drug interactions at the renal level. The higher tubular secretion for dextrocetirizine may be due to the higher free fraction available for secretion or to a higher affinity for (a) renal transporter(s) mediating the secretion pathway. [ABSTRACT FROM AUTHOR]

Aims To determine the cost-effectiveness of adding pioglitazone to existing treatment regimens in patients with Type 2 diabetes with a history of macrovascular disease who are at high risk of further cardiovascular events. Methods We conducted two analyses. A within-trial cost-effectiveness analysis (CEA) based on data from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) Study was performed to estimate the impact of additional pioglitazone treatment on life expectancy, quality-adjusted life expectancy (QALE) and macrovascular events. PROactive data was then used as a basis for a lifetime modelling analysis using a modified version of the validated CORE diabetes model that simulated the same outcomes over a 35-year time horizon. We accounted for direct medical costs from a health-care payer perspective and related these to the clinical outcomes from the study. Costs and benefits were discounted at 3.5% per annum and extensive sensitivity analyses were performed to account for uncertainty in input parameters. Results (i) Within-trial CEA: compared with placebo, pioglitazone was associated with improved life expectancy (undiscounted 0.0109 years), increased QALE [0.0190 quality-adjusted life years (QALYs)] and slightly higher costs ( pound102 per patient). After a mean treatment period of 3 years, the incremental cost-effectiveness ratio (ICER) of pioglitazone vs. placebo was pound5396 per QALY gained. The ICERs were relatively insensitive to cost and utility values and were most sensitive to event rates in the pioglitazone arm. (ii) Long-term CEA: pioglitazone was associated with improvements in clinical outcomes based on model projections beyond the PROactive Study. Patients treated with pioglitazone could expect improved life expectancy (undiscounted 0.406 years), increased QALE (0.152 QALYs) and higher costs of care ( pound619 per patient) compared with those on existing treatment alone. The base case analysis indicated that the ICER of pioglitazone vs. placebo was pound4060 per QALY gained. The cost-effectiveness acceptability curve showed there was an 84.3% likelihood that pioglitazone would be considered cost-effective in the UK using a willingness-to-pay threshold of pound30 000 per QALY gained. These long-term results were most sensitive to variation in the time horizon, the duration of cardiovascular benefit of pioglitazone, and changes in mortality rates. Conclusions The addition of pioglitazone to existing therapy in patients with Type 2 diabetes at high risk of further cardiovascular events is cost-effective and represents good value for money by currently accepted standards in the UK. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) is extensively expressed in multiple sclerosis lesions suggesting that regulatory variants of the COX-2 gene could be implicated in multiple sclerosis (MS). Screening of the proximal 5′ regulatory region and genotyping of −765G>C and −62C>G showed that polymorphisms in this COX-2 region are unlikely to be involved in MS susceptibility. [ABSTRACT FROM AUTHOR]

The most frequent localization is the duodenum (79% of patients), followed by the jejunum and ileum (18%); in rare cases (3%) the diverticula are diffused in all segments of the small bowel [2]. For stable patients with contained perforations, nonoperative treatment (bowel rest, intravenous fluids and antibiotics) has been successfully reported [6]; for larger peridiverticular abscesses, CT-guided percutaneous drainage may be required [7]. South Med J 1988; 81: 1386 - 91. 4 Falidas E, Vlachos K, Mathioulakis S, Archontovasilis F, Villias C. Multiple giant diverticula of the jejunum causing intestinal obstruction: report of a case and review of the literature. [Extracted from the article]

Granulomatous slack skin (GSS) represents a rare variant of mycosis fungoides, histologically characterized by a variably deep T helper lymphocytes infiltrate with alteration of the dermal elastic tissue and consequent elastolysis, elastophagocytosis and numerous giant cells. Clinically, a development of unelastic, slack skin, especially on flexural areas, is observed. Hereby, we describe a man with a 12-year history of GSS. In 2002, for practical (limitation of movement, deambulation) and cosmetic reasons, he underwent the surgical excision of loose and sagging skinfold over inguinal area, and, afterwards, of the opposite affected inguinal skin. The surgical treatment of bilateral inguinal hernia with reposition of inguinal dislocated vasculature is also reported. In both cases the excised material confirmed the former diagnosis of GSS and revealed a very deep, muscular infiltrate of neoplastic lymphocytes. One year later, a new excision of GSS on the axillae was made. Now, after 2 years, deambulation keeps improving, although an initial relapse of the inguinal slack skin has been observed. [ABSTRACT FROM AUTHOR]

The aim of this study was to review modifications of the endogenous pathways (e.g. enzyme elevations, normal body constituent depletion or higher formation/excretion of endogenous metabolites) which could be ascribed to enzyme induction by antiepileptic drugs (AEDs). Information on older (e.g. phenobarbital, phenytoin and carbamazepine) and newer drugs (where information is available) is discussed together with clinical implications. The enzymes involved in the endogenous pathways and induced by the AEDs will not be limited to the hepatic microsomal enzymes; extrahepatic enzymes and/or enzymes present in other subcellular fractions will also be discussed, if pertinent. The induction of endogenous pathways by AEDs has been taken into account in the past, but much less emphasis has been given compared with the extensive literature on induction by AEDs of the metabolism of concomitantly administered drugs, either of the same or of different classes. Not all of the endogenous pathways examined and induced by AEDs appear to result in serious clinical consequences (e.g. induction of hepatic ALP, increased excretion of d-glucaric acid or of 6 β-hydroxycortisol). In some cases, induction of some pathways (e.g. increase of high-density lipoprotein cholesterol or of conjugated bilirubin) might even be a beneficial side-effect, however enzyme induction is considered rather a detrimental aspect for an AED, as induction is generally a broad and a non-specific phenomenon. The new AEDs have generally less induction potential than the older agents. Yet some (felbamate, topiramate, oxcarbazepine and lamotrigine) have the potential for inducing enzymes, whereas others (levetiracetam, gabapentin and vigabatrin) appear to be completely devoid of enzyme inducing characteristics, at least as far as the enzymes investigated are concerned. [ABSTRACT FROM AUTHOR]

The present study focuses on the effect of microstructural gradients on the fatigue crack growth resistance of Ti-6Al-4V and Ti-6242 titanium alloys. Sharp microstructural gradients from fine-grained bimodal to coarse-grained lamellar microstructures were obtained by heat treating only a portion of fine-grained plates in the β single-phase field using a high-frequency induction coil. For fatigue crack growth from a bimodal into a lamellar microstructure, it was found that the initial crack extension past the microstructural transition within the lamellar microstructure shows the same crack growth resistance as the reference bimodal microstructure. Similarly, for fatigue crack growth from a lamellar into a bimodal microstructure, the initial crack extension past the microstructural transition within the bimodal microstructure shows same crack growth resistance as the reference lamellar microstructure. Based on detailed crack front profile investigations using optical light and scanning electron microscopy as well as heat tinting procedures, these findings can be mainly attributed to the effect of the crack front geometry. [ABSTRACT FROM AUTHOR]

This paper is aimed at evaluating the influence of bi-modal and lamellar microstructures on the behaviour of small cracks emanating from notches inα+β titanium Ti-6Al-4V alloy. Pulsating four point bending tests were performed at a nominal stress ratio of 0.1 and a frequency of 15 Hz on double-edge-notched specimens. The conditions of initiation and early propagation of fatigue cracks were investigated at two relatively high nominal stress levels corresponding to 88 and 58% of the 0.2% material yield stress. Crack closure effects were measured by an extensometric technique and discussed. Variations in crack aspect ratio were determined and considered in theΔKcalculation. Corresponding results were discussed by considering the effect of the yielded region at the notch tip calculated by elastic–plastic finite element modelling of the fatigue tests. The importance of the bi-modal and lamellar microstructures on the material damage was highlighted and correlated to the observed oscillations in the crack growth rate. The crack growth rate data obtained were compared with those measured using standard C(T) specimens (long crack). [ABSTRACT FROM AUTHOR]

Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels ( tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (≥3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2–3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1–1.2 L/kg), larger for fexofenadine (5.4–5.8 L/kg) and particularly large for desloratadine (≈ 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (≈ 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84–95% (faeces) and 8–15% (urine) for 14C-mizolastine. The absolute bioavailability is 50–65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions. [ABSTRACT FROM AUTHOR]

This paper is aimed at evaluating the behaviour of small cracks emanating from notches in the Ti-6Al-4V alloy. Pulsating four point bending tests were performed at a nominal stress ratio of 0.1 and a frequency of 15 Hz on prismatic specimens with a central hole. The conditions of initiation and early propagation of fatigue cracks were investigated at two relatively high nominal stress levels corresponding to 56.6 and 100% of the 0.2% yield stress of the material. Microstructural effects were discussed. To this purpose a specific device based on the ‘in situ’ detection of cracks by photomicroscopy was developed. Corresponding results were analysed quantitatively considering the effect of the yielded region at the notch tip by elastic–plastic finite element modelling. Furthermore, information regarding the sites of fatigue crack initiation and propagation path were discussed on the basis of careful fractographic analysis of the specimens. The importance of the two phase α, β microstructure on the material damage was highlighted and correlated to the observed oscillations in the crack growth rate. Mechanically and microstructurally long cracks were correlated by linear-elastic fracture mechanics. [ABSTRACT FROM AUTHOR]

This study compared clinical and functional outcomes after treatment with botulinum toxin A (BTX-A) and BTX-A with casting in children with dynamic equinus foot. Ten children (seven males, three females; mean age 6 years 4 months, SD 2 years 7 months; range 4 to 11 years) with mild spastic diplegia and independent walking were divided into two groups: group 1, BTX-A and group 2, BTX-A plus casting. BTX-A was injected in the triceps surae bilaterally at multiple sites while the children were sedated with mask anaesthesia. Dysport toxin was used, 15 to 20 IU/kg in each muscle. Immediately after injection an ankle-foot orthosis was applied to children in group 1 and a cast to children in group 2. Clinical assessment using the Ashworth scale, Gross Motor Function Measure (GMFM), range of movement measurement, and gait analysis was performed before treatment and 1, 4, and 12 months after treatment. Spasticity decreased significantly at 1-month examination in both groups (p = 0.002), at 4-month examinations (Wilcoxon test p = 0.003), and 12 month (p = 0.052) examinations in group 2. GMFM highlighted a significant improvement in group 2 at the 4-month examination (p = 0.052 for standing,p = 0.007 for walking). Gait analysis showed a significant increase in the walking speed in group 2 (p = 0.04). No change was detected in ankle kinematics and kinetics or in muscular activity during the gait cycle. We confirmed that BTX-A reduces spasticity and improves functional performance in standing and walking; association with casting provides more marked and enduring results. [ABSTRACT FROM AUTHOR]

Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [ABSTRACT FROM AUTHOR]

1Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l−1 and AUC (0, th) 144 nmol l−1h, mean MDL Cmax 183 nmol l−1 and AUC 2627 nmol l−1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l−1 and AUC 10512 nmol l−1h, MDL concentrations below limit of quantitation). 5We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism. [ABSTRACT FROM AUTHOR]

A mobile positioning system based on GSM signals analysis and on a cooperative stochastic optimization algorithm is presented. The proposed technique is intended as a backup solution in those applicative scenarios where the GPS system fails to work (e.g., urban canyons). The hardware architecture of the system and the positioning algorithm are described and validated by means of a numerical assessment. © 2008 Wiley Periodicals, Inc. Microwave Opt Technol Lett 50: 2128–2130, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.23568 [ABSTRACT FROM AUTHOR]

In this letter, the structure of the prototype of a smart antenna working in the 2.4-GHz band is described. The radiating structure is composed by an eight-element linear array with a finite reflecting plane and its adaptive behavior is obtained by means of a set of electronically driven vector modulators that control the array weights. The antenna system is equipped with a control software based on a particle swarm optimizer algorithm that enables the system to adapt to the complex interference scenario. A selected set of numerical and experimental results are reported and discussed to assess the effectiveness of the proposed architecture. © 2008 Wiley Periodicals, Inc. Microwave Opt Technol Lett 50: 1715–1716, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.23459 [ABSTRACT FROM AUTHOR]