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This article presents improvements of large-signal RF power performance at Ka-band of gallium nitride high electron mobility transistors (HEMTs) utilizing a scandium aluminum nitride barrier. Three samples were fabricated and measured having different passivation schemes, including gallium nitride, silicon nitride, and aluminum gallium nitride. The pinning of the Fermi level against the valence band reduced the gain and output power density of the gallium nitride passivated device, resulting in 4.5 W/mm at a drain bias of 32 V. With silicon nitride alone as the passivation, dc/RF dispersion was reduced, and gain increased significantly, boosting the output power for this device to 8.0 W/mm at 28 V, though at the cost of a reduced breakdown voltage. Adding an epitaxial aluminum gallium nitride passivating layer increased the maximum bias voltage that the devices can operate at compared to devices with the silicon nitride passivation. When biased at 40 V, the output power of the devices reached 10.8 W/mm at 30 GHz. These devices show the importance of the passivation design to large-signal RF performance in scandium aluminum nitride-based HEMTs and will help guide further improvements. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing orthopedic surgery are at risk of post-operative complications and needing Medical Emergency Team (MET) review. We assessed the frequency of, and associations with MET calls in orthopedic patients, and whether this was associated with increased in-hospital morbidity and mortality.Methods: Retrospective cohort study of patients admitted over four years to a University teaching hospital using hospital administrative and MET call databases.Results: Amongst 6344 orthopedic patients, 55.8% were female, the median (IQR) age and Charlson comorbidity index were 66 years (47-79) and 3 (1-5), respectively. Overall, 54.5% of admissions were emergency admissions, 1130 (17.8%) were non-operative, and 605 (9.5%) patients received a MET call. The strongest independent associations with receiving a MET call was the operative procedure, especially hip and knee arthroplasty. Common MET triggers were hypotension (37.5%), tachycardia (25.0%) and tachypnoea (9.1%). Patients receiving a MET call were at increased risk of anemia, delirium, pressure injury, renal failure and wound infection. The mortality of patients who received a MET call was 9.8% compared with 0.8% for those who did not. After adjusting for pre-defined co-variates, requirement for a MET call was associated with an adjusted odd-ratio of 9.57 (95%CI 3.1-29.7) for risk of in-hospital death.Conclusions: Approximately 10% of orthopedic patients received a MET call, which was most strongly associated with major hip and knee arthroplasty. Such patients are at increased risk of morbidity and in-hospital mortality. Further strategies are needed to more pro-actively manage at-risk orthopedic patients. [ABSTRACT FROM AUTHOR]

Objectives: There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. Methods: Twelve children (seven girls and five boys) aged 7–10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re‐align the genu varum in three children. Results: Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21‐q22.3 were confirmed. Re‐alignment was accomplished in our group of patients. Conclusion: The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2–3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases. [ABSTRACT FROM AUTHOR]

Background:Doctors’ continuing professional development (CPD) training needs are known to be strongly influenced by national and local contextual characteristics. Given the changing national demographic profile and government-mandated changes to primary care health care provision, this study aimed to investigate Irish General Practitioners’ (GPs) perceptions of, and preferences for, current and future CPD programmes. Methods:A cross-sectional questionnaire, using closed- and open-ended questions, was administered to Irish GPs, focusing on training needs analysis; CPD course content; preferred format and the learning environment. Results:The response rate was 719/1000 (71.9%). GPs identified doctor-patient communication as the most important and best-performed GP skill. Discrepancies between perceived importance (high) and current performance (low) emerged for time/workload management, practice finance and business skills. GPs identified clinically-relevant primary care topics and non-clinical topics (stress management, business skills, practice management) as preferences for future CPD. Flexible methods for CPD delivery were important. Gender and practice location (urban or rural) significantly influenced CPD participation and future course preference. Conclusion:The increasing diversity of services offered in the Irish primary care setting, in both clinical and non-clinical areas, should be tailored based to include GP practice location and structure. [ABSTRACT FROM AUTHOR]

Thin film composites (TFCs) of poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(methyl methacrylate) (PMMA) chain-tethered poly(vinylidene fluoride)-poly(dimethylsiloxane) (PVDF-PDMS) were prepared as a gas separation membrane. PDMS was coated on the PVDF support using a dip coating method. PHEMA and PMMA were then grafted on PVDF-PDMS substrate by atom transfer radical polymerization. The PVDF-PDMS-PHEMA and PVDF-PDMS-PMMA trilayer membranes were studied by attenuated total reflection Fourier transform infrared spectroscopy, scanning electron microscopy, atomic force microscopy, water contact angle measurement, and X-ray photoelectron spectroscopy. The results of separation tests indicated that the CO/N selectivity of PVDF-PDMS-PHEMA and PVDF-PDMS-PMMA TFCs increased by ∼2 and ∼3 times, respectively, compared to the solvent-extracted PVDF-PDMS support. [ABSTRACT FROM AUTHOR]

Colorectal cancer remains a leading cause of cancer-related death in Europe. Approximately one-quarter of patients have synchronous hepatic metastases and metachronous liver metastases occur in a further 30%. The scope of surgery in management of colorectal metastases has evolved to include selected patients with extra-hepatic disease for whom R0 resection is considered feasible; however, locoregional treatments are increasingly recognised as viable management options in those patients deemed unsuitable for surgery and there is an expanding body of evidence regarding their ability to achieve local control and increase progression-free survival in the liver. Locoregional therapies increasingly practised in the management of unresectable liver metastatic colorectal cancer (mCRC) include percutaneous ablation, primarily in the form of radiofrequency ablation or microwave ablation, although there remains a lack of data regarding long-term outcome. Radio-embolisation (RE) is the most comprehensively studied embolisation technique in the context of colorectal liver metastases, predominantly using yttrium 90 (90Y). The data published to date suggests that 90Y represents a safe and effective cytoreductive modality. The optimal dose and timing of therapies remains uncertain and further studies are required to determine its relationship with systemic treatment. Irinotecan-loaded drug-eluting beads (DEBIRI) transcatheter arterial chemo-embolisation (TACE) represents a further therapy with considerable potential. There is evidence of improved overall survival in the salvage setting. As with the other therapies discussed, further research is required to elucidate the optimal role and timing of these treatments within the increasingly crowded space of therapies for mCRC. [ABSTRACT FROM AUTHOR]

The current manuscript experimentally investigates the mechanical and wears properties of three different phenolic polymer nanocomposites. Samples are made of 1, 2 and 3 wt.% of well-dispersed silica nanoparticles in a phenolic resin. Firstly, it was found that for the phenolic polymer, the Young’s modulus steadily increased as the weight percent of silica nanoparticles was increased except for 3 wt.% nanoparticle filled samples. For the phenolic polymer with 1 and 2 wt.% nano silica, Young’s modulus was increased 7% and 12.5%, respectively in comparison with the neat phenolic resin. However, for samples with 3% nanosilica this value showed a reduction about 13.5% and 2.7% in comparison to 2% nanoparticle filled samples and pure samples, respectively. Secondly, the presence of 2 wt.% nano silica particles increased the hardness of the phenolic polymer by 27.3% compared with the pure phenolic resin. Also, it was shown by the results of scratch tests that nano silica has almost no effect on the coefficient of the friction and wear rates. [ABSTRACT FROM AUTHOR]

Emissions of particulate matter (PM) from vehicle and industrial sources constitute a hazard to human health. Here, we apply biomagnetic monitoring to (a) discriminate between potential PM10 sources around a steelworks and (b) examine magnetic source differentiation for a combined, U.K.-based, magnetic data set (steelworks, roadside, power-generating site). Tree leaves (sampled September 2009, as passive PM receptors) and putative sources were subjected to rapid magnetic characterization (magnetic remanence measurements). Fuzzy cluster analysis of the combined data set identified three clusters, showing that particulates emitted from vehicle fleets (e.g., diesel/petrol), and from different industrial processes can be magnetically differentiated. Cluster analysis of the steelworks leaf receptors and potential sources identified seven magnetic groupings. Leaves from one PM "hotspot" showed no affinity with any available source sample, suggesting an as yet untested PM source. These data indicate the value of fast, inexpensive magnetic techniques for particulate source discrimination and indication of "missing" sources. [ABSTRACT FROM AUTHOR]

The sources and fluxes of sediment to the Great Barrier Reef lagoon from north-eastern Australian rivers have been the subject of much concern and study, with the large catchments of the Burdekin and Fitzroy Rivers thought to be the key sources at present. Here, the utility of newly developed magnetic ‘fingerprinting’ methods for identifying sediment provenance, both onshore and offshore, and in association with individual large flood events, is investigated. Within the Burdekin catchment, sediments are mobilized from different subcatchments by runoff generated by intense, localized rainfall events. Magnetic measurements were made on untreated and acid-treated samples of river channel sediments within the Burdekin River subcatchments and from the estuarine and inner shelf depocentres of Burdekin River sediments. The acid treatment removes all discrete magnetic particles and coatings, and leaves magnetic inclusions (protected within host silicate grains) as the basis of the measured magnetic signature of a sample. The magnetic properties of the acid-treated samples display statistically distinct sediment provenance groupings. Sand samples from the Upper Burdekin River appear magnetically distinct from samples from tributaries of the Burdekin (e.g. Hann Creek, Fanning River) and also from nearby coastal rivers, including the Haughton. Suspended sand samples from a Burdekin flood event in 2000 appear to have a different source compared with those from floods in 1998 and 1999. Comparisons of the terrestrial, acid-treated sand fractions with the same, acid-treated, sand-size fractions from transects taken offshore suggest that the surface sediments in Upstart Bay and Bowling Green Bay have different sources. Some of these sources are as yet unidentified but may represent the unsampled, lower-discharge south-western Burdekin subcatchments, and/or along-shore drift of sand from the south, perhaps even from the Fitzroy River, over millennial timescales of cyclone pumping. The magnetic inclusion method precludes any obfuscation or confounding of sediment source, which might arise from hydraulic sorting and/or post-depositional magnetic diagenesis or authigenesis. [ABSTRACT FROM AUTHOR]

Oxygen isotope records from stalagmites in caves in southern China, interpreted as proxy rainfall records reflecting the intensity of the East Asian summer monsoon, indicate gradual monsoon weakening for the last ∼9000 years, as also documented for the Indian monsoon. Coupled with high-precision dating, the speleothem proxy records have been used to test monsoon links with orbital forcing, solar changes, iceberg discharges in the North Atlantic, ocean currents and atmospheric methane. However, these 'benchmark' cave records do not match other published, dated E Asian proxy rainfall records (specifically here, independently calibrated rainfall records from loess/palaeosol magnetic properties, and cave oxygen isotope intercomparisons), which show variable E Asian monsoon intensity through the entire Holocene. The strong correlation of the cave records with the extraregional Indian monsoon record yet their mismatch with these other dated Chinese rainfall records might be reconciled if the speleothem isotope variations reflect not changes in Holocene rainfall amount but in rainfall source. Declining Holocene influence of isotopically lighter, Indian monsoon-sourced moisture over China would have resulted in increasing proportions of isotopically heavier rainfall, sourced from the more oceanic E Asian monsoon. Individual speleothems may thus regionally record Holocene changes in Indian monsoon intensity and isotopic influence. Conversely, the other Chinese proxy records described here reflect changes in rainfall amount, and thus in E Asian summer monsoon intensity. For the Holocene, the E Asian and the Indian monsoon responses to orbital forcing are likely to have differed, specifically due to E Asian internal feedbacks and the seasonal contrasts between the two monsoon systems. [ABSTRACT FROM AUTHOR]

Uttered language does not necessarily reflect the planned communications of schizophrenia patients, nor do their delusions necessarily reflect basic failures of inferential reasoning. The role of inhibitory failure in the production of speech and the role of primary experiences of discrepancy between intention and action, and between experience–based expectations and perceived realities account for many of the clinical phenomena that have led to the conclusion that these patients have a ‘thought’ disorder, or a ‘disturbed’ mind. The alternatives and the evidence are summarized in this paper. [ABSTRACT FROM AUTHOR]

Background: Gene sequencing is the 'gold standard' for resistance testing in the clinic. We present evidence that clinically misleading results arise with mixed viral populations due to intrasample variability. Methods: An HW+ patient taking nelfinavir presented with mixed populations of virus ar codons 30, 63 and 90 of protease. RNA was re-extracted from plasma and 20 aliquots of cDNA prepared. Each aliquot, including the original cDNA, was sequenced twice, using different ABI310 Genetic Analysers and two primers. Electropherograms were compared for the 42 sequences. Results: All aliquots were sequenced successfully, but produced inconsistent results at mixed codons. A codon is uninterpretable ('N') if no peak dominates at one position. Codons 36, 71, 77 and 84 gave identical results with homozygous bases in all 42 samples. Codon 30 was wild-type (WT) in 29/42, mutant (MT) in 3/42 and 'N' in 10/42. Codon 46 was WT in 37/42 and 'N' in 5/42. Codon 63 was WT in 1/42, MT in 33/42 and 'N' in 8/42. Codon 90 was WT in 4/42, MT in 29/42 and 'N' in 9/21. Conclusions: The 42 sequences should have been identical, but in the presence of a mixed population of virus there is marked variability. Over-amplification of a minor WT population may result in masking of the true dominant MT codon. A false WT could result in a failing regimen being continued or an inactive drug being prescribed. Background: Gene sequencing is the 'gold standard' for resistance testing in the clinic. We present evidence that clinically misleading results arise with mixed viral populations due to intrasample variability. Methods: An HW+ patient taking nelfinavir presented with mixed populations of virus ar codons 30, 63 and 90 of protease. RNA was re-extracted from plasma and 20 aliquots of cDNA prepared. Each aliquot, including the original cDNA, was sequenced twice, using different ABI310 Genetic Analysers and two primers. Electropherograms were compared for the 42 sequences. Results: All aliquots... [ABSTRACT FROM AUTHOR]

Presents a forum on the interpretation of the magnetic susceptibility record of Chinese loess-paleosol sequences. Comments; Reply.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values 0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r2=0.008; rs10043986-rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10−4 and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10−4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case–Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in ∼30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1l and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia. [ABSTRACT FROM AUTHOR]

The article focuses on the study on pharmacokinetic variability as an important consideration in treatment failure and current approaches to address the problem towards HIV-positive patients. Despite the exposure to most antiretroviral agents and consequently receiving salvage therapy, noticeable number of patients who fail the treatment is growing. Regimens are associated with increased potential for toxicity and serious drug interactions. Reasons of treatment failure is presented.

Objectives: Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting (MDM). Study Design: Retrospective analysis of the association of MDM discussion with survival. Methods: All newly diagnosed cancer patients from 2009 to 2012, presenting to a large regional cancer service in South West Victoria, Australia (620 colorectal, 657 breast, 593 lung and 511 haematological) were recorded and followed up to 5 years after diagnosis. Treatment patterns and survival of patients whose treatment was discussed at an MDM compared to those who were not, were explored. Results: The proportion of patients presented to an MDM within 60 days after diagnosis was 56% (n = 366) for breast cancer, 59% (n = 363) for colorectal cancer, 27% (n = 137) for haematological malignancies and 60% (n = 355) for lung cancer. Seventy-three percent (n = 886) of patients discussed at an MDM had their tumour stage recorded in their medical records while only 52% (n = 604) of patients not discussed had their tumour stage recorded (P < 0.01). We found for haematological and lung cancer patients that those presented to an MDM prior to treatment had a significant reduction in mortality (lung cancer hazard ratio [HR] 0.62, 95% confidence interval [Cl] 0.50-0.76, P < 0.01) (haematological cancer HR 0.58, 95% Cl 0.35-0.96, P = 0.03) compared to patients whose cases were not discussed at an MDM after adjusting for the potential cofounders of age, stage, comorbidities and treatment. This was not the case for colorectal and breast cancer patients where there was no significant difference. Conclusion: MDM discussion has been recommended as best practice in the management of cancer patients, however, from a public health perspective this creates potential issues around access and resources. It is likely that MDM presentation patterns and outcomes across tumour streams are linked in complex ways. We believe that our data would demonstrate that these patterns differ across tumour streams and that more detailed work is required to better allocate relatively scarce and potentially costly MDM resources to tumour streams and patient groups that may get the most benefit. [ABSTRACT FROM AUTHOR]

Several aspects of social and emotional functioning are abnormal in people with eating disorders. The aim of the present study was to measure facial emotional expression in patients with eating disorders and healthy controls whilst playing a therapeutic video game (Playmancer) designed to train individuals in emotional regulation. Participants were 23 ED patients (11 AN, 12 BN) and 11 HCs. ED patients self reported more anger at baseline but expressed less facial expression of anger during the Playmancer game. The discrepancy between self-report and non-verbal expression may lead to problems in social communication. Copyright © 2012 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

Several aspects of social and emotional functioning are abnormal in people with eating disorders. The aim of the present study was to measure facial emotional expression in patients with eating disorders and healthy controls whilst playing a therapeutic video game (Playmancer) designed to train individuals in emotional regulation. Participants were 23 ED patients (11 AN, 12 BN) and 11 HCs. ED patients self reported more anger at baseline but expressed less facial expression of anger during the Playmancer game. The discrepancy between self-report and non-verbal expression may lead to problems in social communication. Copyright © 2012 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10−7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10−9). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10−11, odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10−13, OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb region of 2q33-35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial subtype of MDD. This 451 kb region includes CREB1, an attractive susceptibility gene for MDD and related disorders. Sequence variations in the CREB1 promoter and intron 8 have been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying CREB1 as a sex-limited susceptibility gene for unipolar Mood Disorders. These findings implicate the cAMP signaling pathway in the pathophysiology of Mood Disorders and related conditions. [ABSTRACT FROM AUTHOR]

Aims Since α1-acid glycoprotein (AGP) levels may be raised during HIV infection, we have examined in vitro the effect of increasing the concentration of AGP on the intracellular accumulation of the HIV protease inhibitors saquinavir (SQV), ritonavir (RTV) and indinavir (IDV). Methods U937 cells (5 × 106 cells in 5 ml RPMI growth medium) were incubated at 37 °C for 18 h with [14C]-SQV (0.1 µCi), [3H]-RTV and [3H]-IDV (0.135 µCi) to a final concentration of 1 µm in the presence of 0, 0.5 and 2.0 mg ml-1 AGP. Following extraction in 60% methanol the intracellular drug concentration was determined by liquid scintillation counting. Results Binding to AGP (2.0 mg ml-1) reduced the mean intracellular concentration of SQV from 31.5 µm to 7.4 µm (P < 0.0001; 95% CI 19.4–28.8). RTV concentration was also reduced (8.8 µm to 1.6 µm; P < 0.0001; 95% CI 5.4–9.0) as was the concentration of IDV (3.0 µm to 1.5 µm; P < 0.0001; 95% CI 1.1–1.9). Conclusions Reduced intracellular protease inhibitor concentrations in the presence of increasing concentrations of AGP will certainly impact on the antiviral activity in vitro. However, since protease inhibitors are high clearance drugs, free drug concentration will likely remain unaffected in the presence of elevated AGP during chronic oral dosing although there will be an increase in total plasma drug concentration. [ABSTRACT FROM AUTHOR]

Intensity of isometric muscle contractions was measured in alcoholic subjects with cirrhosis (N = 42), nonalcoholic subjects with cirrhosis (N = 33), and normal controls (N = 31). Muscle strength and endurance were comparable in the alcoholic and nonalcoholic cirrhotic subjects for all variables. Both cirrhotic groups were inferior to normal controls for all variables. The quantity x frequency (Q x F) index reported for the period during peak alcohol consumption correlated with 6 muscle-force variables, accounting for 9-20% of the variance. Alcoholic and nonalcoholic cirrhotic subjects did not differ in Quality of Life Inventory (QOLI) scales. Significant correlations, however, were found for the alcoholic cirrhotic subjects but not for the nonalcoholic cirrhotic subjects between quality-of-life indices and muscle strength and endurance. Muscle weakness is thus differentially associated with quality of life in alcoholic cirrhotic subjects as compared with nonalcoholic subjects with cirrhosis even though level of strength and endurance in the two groups is comparable. [ABSTRACT FROM AUTHOR]

Epileptic encephalopathies (EE) are a heterogeneous group of epilepsy syndromes associated with severe cognitive and behavioral disturbances. Amongst others, genes encoding neuronal ion channels have been identified as candidate genes for EE. Using next generation sequencing, we identified four different de novo mutations in KCNA2, encoding the voltage-gated potassium channel KV1.2. Voltage-gated potassium channels play an essential role in neuronal excitability, control the resting membrane potential and thresholds for action potential generation of a neuron and are responsible for repolarizing membranes back to resting values after action potential generation. Therefore, mutations in potassium channel-encoding genes have been shown to alter the neuronal excitability and cause different epilepsy syndromes, including EE. Here, we identified four independently occurring de novo KCNA2 mutations in six EE patients, with one mutation recurring three times. Four of the studied patients presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild-moderate ID, delayed speech development and sometimes ataxia. Functional studies were performed using an automated two-microelectrode voltage-clamp oocyte system. The two mutations associated with this phenotype revealed an almost complete loss-of-function with a dominant negative effect. Two further cases with KCNA2 mutations in the voltage sensor presented with an even more severe EE phenotype. These mutations caused a dramatic gain-of-function effect leading to permanent opening of KV1.2 channels. Therefore, KCNA2 is a novel gene involved in human neurodevelopmental disorders causing the clinical phenotype by two different mechanisms: (i) increasing the excitability or (ii) electrical silencing of KV1.2-expressing neurons. [ABSTRACT FROM AUTHOR]