Heterotrimeric guanosine triphosphate-binding protein-coupled modulatory actions of motilin on K+ channels and postsynaptic γ-aminobutyric acid receptors in mouse medial vestibular nuclear neurons.
Some central nervous system neurons express receptors of gastrointestinal hormones, but their pharmacological actions are not well known. Previous anatomical and unit recording studies suggest that a group of cerebellar Purkinje cells express motilin receptors, and motilin depresses the spike discharges of vestibular nuclear neurons that receive direct cerebellar inhibition in rats or rabbits. Here, by the slice-patch recording method, we examined the pharmacological actions of motilin on the mouse medial vestibular nuclear neurons (MVNs), which play an important role in the control of ocular reflexes. A small number of MVNs, as well as cerebellar floccular Purkinje cells, were labeled with an anti-motilin receptor antibody. Bath application of motilin (0.1 μm) decreased the discharge frequency of spontaneous action potentials in a group of MVNs in a dose-dependent manner (K(d) , 0.03 μm). The motilin action on spontaneous action potentials was blocked by apamin (100 nm), a blocker of small-conductance Ca(2+) -activated K(+) channels. Furthermore, motilin enhanced the amplitudes of inhibitory postsynaptic currents (IPSCs) and miniature IPSCs, but did not affect the frequencies of miniature IPSCs. Intracellular application of pertussis toxin (PTx) (0.5 μg/μL) or guanosine triphosphate-γ-S (1 mm) depressed the motilin actions on both action potentials and IPSCs. Only 30% of MVNs examined on slices obtained from wild-type mice, but none of the GABAergic MVNs that were studied on slices obtained from vesicular γ-aminobutyric acid transporter-Venus transgenic mice, showed such a motilin response on action potentials and IPSCs. These findings suggest that motilin could modulate small-conductance Ca(2+) -activated K(+) channels and postsynaptic γ-aminobutyric acid receptors through heterotrimeric guanosine triphosphate-binding protein-coupled receptor in a group of glutamatergic MVNs.


Synaptopathy in the Aging Cochlea: Characterizing Early-Neural Deficits in Auditory Temporal Envelope Processing.
Aging listeners, even in the absence of overt hearing loss measured as changes in hearing thresholds, often experience impairments processing temporally complex sounds such as speech in noise. Recent evidence has shown that normal aging is accompanied by a progressive loss of synapses between inner hair cells and auditory nerve fibers. The role of this cochlear synaptopathy in degraded temporal processing with age is not yet understood. Here, we used population envelope following responses, along with other hair cell- and neural-based measures from an age-graded series of male and female CBA/CaJ mice to study changes in encoding stimulus envelopes. By comparing responses obtained before and after the application of the neurotoxin ouabain to the inner ear, we demonstrate that we can study changes in temporal processing on either side of the cochlear synapse. Results show that deficits in neural coding with age emerge at the earliest neural stages of auditory processing and are correlated with the degree of cochlear synaptopathy. These changes are seen before losses in neural thresholds and particularly affect the suprathreshold processing of sound. Responses obtained from more central sources show smaller differences with age, suggesting compensatory gain. These results show that progressive cochlear synaptopathy is accompanied by deficits in temporal coding at the earliest neural generators and contribute to the suprathreshold sound processing deficits observed with age.SIGNIFICANCE STATEMENT Aging listeners often experience difficulty hearing and understanding speech in noisy conditions. The results described here suggest that age-related loss of cochlear synapses may be a significant contributor to those performance declines. We observed aberrant neural coding of sounds in the early auditory pathway, which was accompanied by and correlated with an age-progressive loss of synapses between the inner hair cells and the auditory nerve. Deficits first appeared before changes in hearing thresholds and were largest at higher sound levels relevant to real world communication. The noninvasive tests described here may be adapted to detect cochlear synaptopathy in the clinical setting.


Complete sequence and genomic annotation of carrot torradovirus 1.
Carrot torradovirus 1 (CaTV1) is a new member of the genus Torradovirus within the family Secoviridae. CaTV1 genome sequences were obtained from a previous next-generation sequencing (NGS) study and were compared to other members and tentative new members of the genus. The virus has a bipartite genome, and RACE was used to amplify and sequence each end of RNA1 and RNA2. As a result, RNA1 and RNA2 are estimated to contain 6944 and 4995 nucleotides, respectively, with RNA1 encoding the proteins involved in virus replication, and RNA2 encoding the encapsidation and movement proteins. Sequence comparisons showed that CaTV1 clustered within the non-tomato-infecting torradoviruses and is most similar to motherwort yellow mottle virus (MYMoV). The nucleotide sequence identities of the Pro-Pol and coat protein regions were below the criteria established by the ICTV for demarcating species, confirming that CaTV1 should be classified as a member of a new species within the genus Torradovirus.


Comparison of Unipolar and Bipolar Voltage Mapping for Localization of Left Atrial Arrhythmogenic Substrate in Patients With Atrial Fibrillation.
Background: Presence of left atrial low voltage substrate in bipolar voltage mapping is associated with increased arrhythmia recurrences following pulmonary vein isolation for atrial fibrillation (AF). Besides local myocardial fibrosis, bipolar voltage amplitudes may be influenced by inter-electrode spacing and bipole-to-wavefront-angle. It is unclear to what extent these impact low voltage areas (LVA) in the clinical setting. Alternatively, unipolar electrogram voltage is not affected by these factors but requires advanced filtering. Objectives: To assess the relationship between bipolar and unipolar voltage mapping in sinus rhythm (SR) and AF and identify if the electrogram recording mode affects the quantification and localization of LVA. Methods: Patients (n = 28, 66±7 years, 46% male, 82% persistent AF, 32% redo-procedures) underwent high-density (>1,200 sites, 20 ± 10 sites/cm2, using a 20-pole 2-6-2 mm-spaced Lasso) voltage mapping in SR and AF. Bipolar LVA were defined using four different thresholds described in literature: <0.5 and <1 mV in SR, <0.35 and <0.5 mV in AF. The optimal unipolar voltage threshold resulting in the highest agreement in both unipolar and bipolar mapping modes was determined. The impact of the inter-electrode distance (2 vs. 6 mm) on the correlation was assessed. Regional analysis was performed using an 11-segment left atrial model. Results: Patients had relevant bipolar LVA (23 ± 23 cm2 at <0.5 mV in SR and 42 ± 26 cm2 at <0.5 mV in AF). 90 ± 5% (in SR) and 85 ± 5% (AF) of mapped sites were concordantly classified as high or low voltage in both mapping modes. Discordant mapping sites located to the border zone of LVA. Bipolar voltage mapping using 2 vs. 6 mm inter-electrode distances increased the portion of matched mapping points by 4%. The unipolar thresholds (y) which resulted in a high spatial concordance can be calculated from the bipolar threshold (x) using following linear equations: y = 1.06x + 0.26mV (r = 0.994) for SR and y = 1.22x + 0.12mV (r = 0.998) for AF. Conclusion: Bipolar and unipolar voltage maps are highly correlated, in SR and AF. While bipole orientation and inter-electrode spacing are theoretical confounders, their impact is unlikely to be of clinical importance for localization of LVA, when mapping is performed at high density with a 20-polar Lasso catheter.


Urocortin 3 Levels Are Impaired in Overweight Humans With and Without Type 2 Diabetes and Modulated by Exercise.
Urocortin3 (UCN3) regulates metabolic functions and is involved in cellular stress response. Although UCN3 is expressed in human adipose tissue, the association of UCN3 with obesity and diabetes remains unclear. This study investigated the effects of Type 2 diabetes (T2D) and increased body weight on the circulatory and subcutaneous adipose tissue (SAT) levels of UCN3 and assessed UCN3 modulation by a regular physical exercise. Normal-weight (n = 37) and overweight adults with and without T2D (n = 98 and n = 107, respectively) were enrolled in the study. A subset of the overweight subjects (n = 39 for each group) underwent a supervised 3-month exercise program combining both moderate intensity aerobic exercise and resistance training with treadmill. UCN3 levels in SAT were measured by immunofluorescence and RT-PCR. Circulatory UCN3 in plasma was assessed by ELISA and was correlated with various clinical and metabolic markers. Our data revealed that plasma UCN3 levels decreased in overweight subjects without T2D compared with normal-weight controls [median; 11.99 (0.78-86.07) and 6.27 (0.64-77.04), respectively; p < 0.001], whereas plasma UCN3 levels increased with concomitant T2D [median; 9.03 (0.77-104.92) p < 0.001]. UCN3 plasma levels were independently associated with glycemic index; fasting plasma glucose and hemoglobin A1c (r = 0.16 and r = 0.20, p < 0.05, respectively) and were significantly different between both overweight, with and without T2D, and normal-weight individuals (OR = 2.11 [1.84-4.11, 95% CI] and OR = 2.12 [1.59-3.10, 95% CI], p < 0.01, respectively). Conversely, the UCN3 patterns observed in SAT were opposite to those in circulation; UCN3 levels were significantly increased with body weight and decreased with T2D. After a 3-month supervised exercise protocol, UCN3 expression showed a significant reduction in SAT of both overweight groups (2.3 and 1.6-fold change; p < 0.01, respectively). In conclusion, UCN levels are differentially dysregulated in obesity in a tissue-dependent manner and can be mitigated by regular moderate physical exercise.


Prevalence of BoHV-1 seropositive and BVD virus positive bulls on Irish dairy farms and associations between bull purchase and herd status.
BVD and IBR are contagious viral diseases highly prevalent in Irish cattle. Despite their significant reproductive and economic impact very little is known about the BVD and IBR status of stock bulls (a bull used for breeding purposes). There are still a high proportion of dairy farms in Ireland that rely on the use of a bull for breeding cattle and ensuring the fertility of the bulls is of paramount importance for the efficiency of the farms. The prevalence of BoHV-1 and BVD in stock bulls in Irish dairy herds has never been investigated. The objectives of this study therefore were: (i) to provide descriptive, observational data on the use of stock bulls on Irish dairy farms; (ii) to investigate the BVD and BoHV1 status of a sub-set of stock bulls; (iii) to investigate factors associated with BVD and BoHV1 status of stock bulls and (iv) to investigate factors associated with dairy herd status for BVD and BoHV1, including any associations with the use of stock bull. A total of 529 blood samples from bulls involved in the dairy breeding process were analysed for BVD virus using RT-PCR, and BoHV-1 antibodies by ELISA test. A total of 305 different dairy herds took part in the study and the overall BVD and BoHV-1 herd status was determined by ELISA using four bulk tank milk samples over the 2009 lactation. Logistic regression was used to investigate the associations between the stock bulls and BVD and BoHV-1 herd and individual status. Of the 305 total participating farms, 235 farms (77 %) had at least one bull and 167 farms had purchased bulls. Two bulls (0.4 %) out of 529 tested were found positive for BVD virus and 87 (16.7 %) tested seropositive for BoHV-1. Some significant associations were identified between the purchase of bulls and both viral diseases. Purchased bulls were three times more likely to be seropositive for BoHV-1 than homebred bulls. In the same way, herds with purchased bulls were three times more likely to be classified as seropositive for BVD and four times more likely to have evidence of recent BoHV-1 circulation than farms where all the bulls were homebred. The prevalence of BoHV-1 and BVD in stock bulls in Irish dairy herds has never been investigated. This study highlights the widespread use of stock bulls in Irish dairy herds, as well as the high rate of exchange of bulls between farms. Significant associations were found between the origin of the bull and their serological BoHV-1 status. In keeping with these results, bulls with higher number movements between farms were more likely to be seropositive for BoHV-1.


CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.
Inflammatory markers are raised in cross-sectional studies of depressed patients and may represent an important mediating factor for behaviour, neural plasticity and brain structure. We undertook a systematic review of longitudinal studies, investigating whether raised inflammatory markers indicate an increased risk of subsequent depressive symptoms. We searched three databases (1970-2012) for longitudinal studies with repeat data on CRP or IL-6 levels and subsequent depressive symptoms. We calculated effect sizes using a mixed-effects model, with separate meta-analyses for inflammatory markers and age groups. We identified eight papers for CRP (14,832 participants) and three for IL-6 (3695 participants). There was a significant association between increased CRP and depressive symptoms (weighted-mean effect size 'unadjusted r'=0.069, p<0.0005; 'adjusted r'=0.046, p<0.0005), with moderate heterogeneity between studies (Q=11.21, p=0.08, I(2)=46.5). For IL-6 the weighted-mean effect size was smaller ('unadjusted r'=0.045, p-value=0.007; 'adjusted r'=0.097, p-value=0.06). The meta-analysis was based on a relatively small number of studies (particularly for IL-6) and only two inflammatory markers. There was moderate heterogeneity between studies and some evidence of publication bias. Raised inflammatory markers have a small but significant association with the subsequent development of depressive symptoms. This is a robust effect which remains significant after adjustment for age and a wide range of factors associated with risk for depression. Our results support the hypothesis that there is a causal pathway from inflammation to depression.


Influence of human skin injury on regeneration of sensory neurons.
The regeneration of sensory nerve fibres is regulated by trophic factors released from their target tissue, particularly the basal epidermis, and matrix molecules. Means to modulate this response may be useful for the treatment of neuromas and painful hypertrophic scars and of sensory deficits in skin grafts and flaps. We have developed an in vitro model of sensory neuron regeneration on human skin in order to study the mechanisms of sensory dysfunction in pathological conditions. Adult rat sensory neurons were co-cultured with unfixed cryosections of normal or injured (crushed) human skin for 72 h. Neurons were immunostained for growth-associated protein-43 and the neurite lengths of neuronal cell bodies situated in various skin regions were measured. Two-way analysis of variance was performed. Neurites of sensory cell bodies on epidermis of normal skin were the shortest, with a mean +/- SEM of 75+/-10 micrometer, whereas those of cells on the dermo-epidermal junction were the longest, with a mean +/- SEM of 231+/-18 micrometer. Neurons on the dermo-epidermal junction of injured skin had significantly longer neurites than those on the same region of normal skin (mean +/- SEM = 289+/-21 micrometer). Regeneration of sensory neurons may be influenced by extracellular matrix molecules, matrix-binding growth factors and trophic factors. Altered substrate or trophic factors in injured skin may explain the increase of neurite lengths. This in vitro model may be useful for studying the molecular mechanisms of sensory recovery and the development of neuropathic pain following peripheral nerve injury.


Comparison of life cycle carbon dioxide emissions and embodied energy in four renewable electricity generation technologies in New Zealand.
In order to make the best choice between renewable energy technologies, it is important to be able to compare these technologies on the basis of their sustainability, which may include a variety of social, environmental, and economic indicators. This study examined the comparative sustainability of four renewable electricity technologies in terms of their life cycle CO2 emissions and embodied energy, from construction to decommissioning and including maintenance (periodic component replacement plus machinery use), using life cycle analysis. The models developed were based on case studies of power plants in New Zealand, comprising geothermal, large-scale hydroelectric, tidal (a proposed scheme), and wind-farm electricity generation. The comparative results showed that tidal power generation was associated with 1.8 g of CO2/kWh, wind with 3.0 g of CO2/kWh, hydroelectric with 4.6 g of CO2/kWh, and geothermal with 5.6 g of CO2/kWh (not including fugitive emissions), and that tidal power generation was associated with 42.3 kJ/kWh, wind with 70.2 kJ/kWh, hydroelectric with 55.0 kJ/kWh, and geothermal with 94.6 kJ/kWh. Other environmental indicators, as well as social and economic indicators, should be applied to gain a complete picture of the technologies studied.


Renal transplantation at the University of Minnesota during the 1980s.
1. There have been 1,225 renal allografts performed at the University of Minnesota between January 1, 1980 and May 31, 1987. Significant risk factors for graft survival include donor type, retransplantation, and age at time of transplant. In addition, diabetes is a significant risk factor in patient survival. 2. Three immunosuppressive regimens have been used during this time period: AZA + P + ALG, CsA + P, and CsA + AZA + P (+ ALG for CAD grafts). The 3 protocols have been received by 411, 205, and 356 primary renal allograft recipients, respectively. No overall differences between the therapies exist with respect to graft or patient survival. However, females, recipients of CAD organs (especially the recipient with diabetes), and patients 18-50 years of age at transplant have improved graft survival results using CsA + AZA + P (+ ALG). Females and the 18-50-year-old recipients also have improved results with respect to patient survival. 3. The 3 protocols [AZA + P + ALG; CsA + P; and CsA + AZA + P + ALG] have been used for 125, 112, and 174 primary recipients of CAD organs, respectively. Recipients of CsA + AZA + P + ALG have significantly better graft survival overall in the diabetic and poorly matched subgroups. Other high-risk (but small sample size) subgroups show statistically nonsignificant, but clinically important, improvements. These groups include patients over 50 years of age, patients with preformed antibodies, as well as those with compatible ABO blood types. Similar trends exist with respect to patient survival. 4. Risk factor analysis of all patients receiving CsA + AZA + P (+ ALG) indicates that donor type, retransplantation, and age at the time of transplant are still serious risk factors for graft survival. Only age at transplant influences patient survival significantly. 5. The failure to find any significant risk factors in primary recipients of CAD organs in the CsA + AZA + P(+ ALG) era, combined with the generally consistent good graft and patient survival rates, suggest that the traditionally high-risk patient can be successfully transplanted with excellent results. 6. Pediatric patients can be successfully transplanted with results equivalent to 18-50-year-old patients and better than those recipients over 50 years of age at the time of transplant. Random transfusions and combination therapy are at least as good as DST and AZA + P + ALG.


[Revised prevention strategies for persons with (functional) hypo- or asplenie].
The Dutch guideline for the preventions of infections in persons with (functional) hypo- or asplenie has been revised, recommending adjustments for the use of vaccinations and antibiotics. The spleen has an important function in the defence against infections. Around 1,000 splenectomies are performed in the Netherlands every year. Three different groups of patients are distinguished: (a) persons with a partially or completely removed spleen after surgery or embolization; (b) persons with congenital asplenia; and (c) a heterogeneous group of patients, who may have functional hyposplenie or asplenia due to an underlying condition or specific treatments. Patients with asplenia have an increased risk of severe infections by encapsulated bacteria, including in particular Streptococcus pneumoniae, but also Haemophilus influenzae type b and Neisseria meningitides may lead to an increased risk S.pneumoniae causes up to 90% of the infections, which makes it the most important infectious agent in patients with asplenia. A number of preventive measures are recommended to prevent infections in patients with hypo- or asplenie, including the use of vaccinations and antibiotics and patient counselling.


The human sexual response cycle: brain imaging evidence linking sex to other pleasures.
Sexual behavior is critical to species survival, yet comparatively little is known about the neural mechanisms in the human brain. Here we systematically review the existing human brain imaging literature on sexual behavior and show that the functional neuroanatomy of sexual behavior is comparable to that involved in processing other rewarding stimuli. Sexual behavior clearly follows the established principles and phases for wanting, liking and satiety involved in the pleasure cycle of other rewards. The studies have uncovered the brain networks involved in sexual wanting or motivation/anticipation, as well as sexual liking or arousal/consummation, while there is very little data on sexual satiety or post-orgasmic refractory period. Human sexual behavior also interacts with other pleasures, most notably social interaction and high arousal states. We discuss the changes in the underlying brain networks supporting sexual behavior in the context of the pleasure cycle, the changes to this cycle over the individual's life-time and the interactions between them. Overall, it is clear from the data that the functional neuroanatomy of sex is very similar to that of other pleasures and that it is unlikely that there is anything special about the brain mechanisms and networks underlying sex.


Demosaicking by alternating projections: theory and fast one-step implementation.
Color image demosaicking is a key process in the digital imaging pipeline. In this paper, we study a well-known and influential demosaicking algorithm based upon alternating projections (AP), proposed by Gunturk, Altunbasak and Mersereau in 2002. Since its publication, the AP algorithm has been widely cited and compared against in a series of more recent papers in the demosaicking literature. Despite good performances, a limitation of the AP algorithm is its high computational complexity. We provide three main contributions in this paper. First, we present a rigorous analysis of the convergence property of the AP demosaicking algorithm, showing that it is a contraction mapping, with a unique fixed point. Second, we show that this fixed point is in fact the solution to a constrained quadratic minimization problem, thus, establishing the optimality of the AP algorithm. Finally, using the tool of polyphase representation, we show how to obtain the results of the AP algorithm in a single step, implemented as linear filtering in the polyphase domain. Replacing the original iterative procedure by the proposed one-step solution leads to substantial computational savings, by about an order of magnitude in our experiments.


Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease.
The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of intravenous glutathione in Parkinson's disease (PD) patients. This was a randomized, placebo-controlled, double-blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen. Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks. Twenty-one subjects were randomly assigned, 11 to glutathione and 10 to placebo. One subject who was assigned to glutathione withdrew from the study for personal reasons prior to undergoing any postrandomization efficacy assessments. Glutathione was well tolerated and there were no withdrawals because of adverse events in either group. Reported adverse events were similar in the two groups. There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the glutathione group (P = 0.54). Glutathione was well tolerated and no safety concerns were identified. Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.


Randomised controlled trial of fractionated and unfractionated prednisolone regimens for dogs with immune-mediated haemolytic anaemia.
A randomised non-blinded non-inferiority trial was conducted to determine whether treatment with an unfractionated regimen of oral prednisolone was inferior to a fractionated regimen for dogs with primary immune-mediated haemolytic anaemia. Dogs received the same total daily dose of prednisolone as unfractionated (group 1, starting at 4 mg/kg orally once daily) or fractionated (group 2, starting at 2 mg/kg orally twice daily) doses. Questionnaires were administered to owners to assess adverse effects and quality of life (QoL). End points included survival to eight weeks, and changes in QoL and clinicopathological parameters over time. Thirty-nine dogs were enrolled in the study, of which 5 were withdrawn and 17 were assigned to each group. The number of cases recruited was insufficient to determine whether unfractionated treatment was inferior to fractionated. Total serum bilirubin decreased more rapidly in dogs in group 2, whereas polydipsia improved more rapidly in group 1. Blood pressure and score for polyuria were higher in dogs in group 2 over time, whereas lymphocyte concentration was lower. Administration of the same total daily dose of prednisolone as an unfractionated dose resulted in fewer adverse effects but the effect on survival could not be assessed in this study.


The diversity and evolution of nematodes (Pharyngodonidae) infecting New Zealand lizards.
Host-parasite co-evolutionary studies can shed light on diversity and the processes that shape it. Molecular methods have proven to be an indispensable tool in this task, often uncovering unseen diversity. This study used two nuclear markers (18S rRNA and 28S rRNA) and one mitochondrial (cytochrome oxidase subunit I) marker to investigate the diversity of nematodes of the family Pharyngodonidae parasitizing New Zealand (NZ) lizards (lygosomine skinks and diplodactylid geckos) and to explore their co-evolutionary history. A Bayesian approach was used to infer phylogenetic relationships of the parasitic nematodes. Analyses revealed that nematodes parasitizing skinks, currently classified as Skrjabinodon, are more closely related to Spauligodon than to Skrjabinodon infecting NZ geckos. Genetic analyses also uncovered previously undetected diversity within NZ gecko nematodes and provided evidence for several provisionally cryptic species. We also examined the level of host-parasite phylogenetic congruence using a global-fit approach. Significant congruence was detected between gecko-Skrjabinodon phylogenies, but our results indicated that strict co-speciation is not the main co-evolutionary process shaping the associations between NZ skinks and geckos and their parasitic nematodes. However, further sampling is required to fully resolve co-phylogenetic patterns of diversification in this host-parasite system.


Mitochondrial Replacement Therapy: Are Mito-nuclear Interactions Likely To Be a Problem?
It has been suggested that deleterious interactions between the mitochondrial and nuclear genomes could pose a problem for mitochondrial replacement therapy (MRT). This is because the mitochondrial genome is placed in a novel nuclear environment using this technique. In contrast, it is inherited with half the mother's genome during normal reproduction, a genome that it is relatively compatible with, since the mother is alive. Here, I review the evidence of whether mito-nuclear interactions are likely to pose a problem for MRT. The majority of the available experimental evidence, both in humans and other species, suggests that MRT is not harmful. These results are consistent with population genetic theory, which predicts that deleterious mito-nuclear interactions are unlikely to be much more prevalent in individuals born to MRT than normal reproduction, particularly in a species such as humans with low population differentiation. This is because selection is unlikely to be strong enough to establish significant linkage disequilibrium between the mitochondrial and nuclear genomes. These results are supported by a meta-analysis of 231 cases, from a variety of animals, in which the mitochondrial DNA (mtDNA) from one strain has been introgressed into the nuclear background of another strain of the same species. Overall, there is little tendency for introgression of mtDNA to be harmful.


Efficiency maximization in solar-thermochemical fuel production: challenging the concept of isothermal water splitting.
Widespread adoption of solar-thermochemical fuel production depends on its economic viability, largely driven by the efficiency of use of the available solar resource. Herein, we analyze the efficiency of two-step cycles for thermochemical hydrogen production, with emphasis on efficiency. Owing to water thermodynamics, isothermal H2 production is shown to be impractical and inefficient, irrespective of reactor design or reactive oxide properties, but an optimal temperature difference between cycle steps, for which efficiency is the highest, can be determined for a wide range of other operating parameters. A combination of well-targeted pressure and temperature swing, rather than either individually, emerges as the most efficient mode of operation of a two-step thermochemical cycle for solar fuel production.


Acetylcholine receptor antibody in Thai generalized myasthenia gravis patients.
The authors studied acetylcholine receptor antibody (AChR Ab) in twenty-six Thai patients diagnosed as having generalized myasthenia gravis and fifteen control cases. AChR Ab assay was done by radio-immunoassay technique and reported by titer in nmole/L. The positive result was defined by titer more than 0.5 nmole/L. In the myasthenia gravis group, age ranged from 18 to 64 years old with mean of 34 years old. The female: male ratio was 4.2:1. Duration of disease before taking blood sample ranged from 1 month to 14 years with a mean of 3.9 year The AChR Ab could be detected in 21 out of 26 patients (80.7%). In the control group, tests were all negative. The results of the test made the sensitivity of 80.7% and specificity of 100%. The positive predictive value was 100%, the negative predictive value was 75%, and the prevalence was 60.3%. There was no correlation between AChR Ab titer and clinical features. This test is a very valuable test in case of uncertainly in the diagnosis of myasthenia gravis.


Testing alternative methods for purging genetic load using the housefly (Musca domestica L.).
When a population faces long-term inbreeding, artificial selection, in principle, can enhance natural selection processes for purging the exposed genetic load. However, strong purge pressures might actually decrease fitness through the inadvertent fixation of deleterious alleles and allelic combinations. We tested lines of the housefly (Musca domestica L.) for the effectiveness of artificial selection to promote the adaptation to small population size. Specifically, replicate populations were held at average census sizes of 54 for nine generations or 30 for 14 generations while being subjected to artificial selection pressure for increased fitness in overall mating propensity (i.e., the proportion of virgin male-female pairs initiating copulation within 30 min), while also undergoing selection to create differences among lines in multivariate components of courtship performance. In the 14-generation experiment, a subset of the lines were derived from a founder-flush population (i.e., derived from three male-female pairs). In both experiments, we also maintained parallel non-selection lines to assess the potential for natural purging through serial inbreeding alone. Sub-populations derived from a stock newly derived from the wild responded to artificial selection for increased mating propensity, but only in the short-term, with eventual rebounds back to the original levels. Serial inbreeding in these lines simply reduced mating propensity. In sub-populations derived from the same base population, but 36 generations later, both artificial selection and serial inbreeding increased mating propensity, but mainly to restore the level found upon establishment in the laboratory. Founder-flush lines responded as well as the non-bottlenecked controls, so we base our major conclusions on the comparisons between fresh-caught and long-term laboratory stocks. We suggest that the effectiveness of the alternative purge protocols depended upon the amount of genetic load already exposed, such that prolonged periods of relaxed or altered selection pressures of the laboratory rendered a population more responsive to purging protocols.


Treatment expectations versus outcomes among orthognathic surgery patients.
As a followup to a longitudinal study of orthognathic surgery patients who had participated in a study of alternative approaches to surgical preparation, 27 patients were administered questionnaires regarding postsurgical changes in their oral, general, and psychological well-being. Age and sex had minimal effect on the patients' responses. Diagnosis, surgery type, and complications did not influence postoperative patient reports. Esthetic improvement was most often cited as a motive for surgery and most likely to be achieved. Fewer postoperative problems were experienced than expected, although interpersonal problems increased for some patients. Oral and general health problems declined significantly after surgery; the greatest improvements were found in occlusion and appearance of teeth and facial profile. Satisfaction with outcomes reflected these improvements in patient well-being. Exceptions to these generally favorable outcomes and the implications for patient preparation for orthognathic surgery are discussed.


Reliability, validity, and responsiveness of the Lysholm knee scale for various chondral disorders of the knee.
The Lysholm knee scale is a condition-specific outcome measure that was originally designed to assess ligament injuries of the knee. The purpose of this study was to determine the psychometric properties of the Lysholm knee scale for various chondral disorders of the knee. Test-retest reliability, internal consistency, content validity, criterion validity, construct validity, and responsiveness to change were determined for the Lysholm knee scale within subsets of an overall study population of 1657 patients with chondral disorders of the knee. The study population was a heterogeneous group of patients with various types of traumatic and degenerative chondral lesions, including isolated lesions and those associated with meniscal and ligament injuries. The overall Lysholm knee scale and six of the eight domains had acceptable test-retest reliability (intraclass correlation coefficient = 0.91) and internal consistency (Cronbach alpha = 0.65). The overall Lysholm knee scale demonstrated acceptable floor (0%) and ceiling (0.7%) effects; however, the floor effects for the domain of squatting and the ceiling effects for the domains of limp, instability, support, and locking were unacceptable (>30%). There was acceptable criterion validity with significant (p < 0.05) correlations between the overall Lysholm knee scale and the physical functioning, role-physical, and bodily pain domains of the Short Form-12 scale; the pain, stiffness, and function domains of the Western Ontario and McMaster Universities Osteoarthritis Index; and the Tegner activity scale. The overall Lysholm knee scale had acceptable construct validity, with all nine hypotheses demonstrating significance (p < 0.05), and it had acceptable responsiveness to change (effect size, 1.16; standardized response mean, 1.10), with large effects (> or = 0.80) for the domains of pain, limping, swelling, and squatting and a small effect (> or = 0.20) for the domain of instability. The Lysholm knee scale demonstrated overall acceptable psychometric performance for outcomes assessment of various chondral disorders of the knee, although some domains demonstrated suboptimal performance. Psychometric testing of other condition-specific knee instruments in patients with chondral disorders of the knee would be helpful to allow for comparison of psychometric properties.


Responsiveness to change [corrected] due to supportive-expressive group therapy, improvement in mood and disease progression in women with metastatic breast cancer.
To compare the responsiveness of six questionnaires using three hypotheses of change: (i) change due to supportive-expressive group therapy (SEGT), (ii) improved mood defined as a small effect size (.2) on Profile of Mood States (POMS) Total Mood Disturbance score and (iii) progression of disease. Data from the "Breast Expressive-Supportive Therapy" study, a multicentre randomized controlled trial of change due to SEGT versus standard of care in women with metastatic breast cancer were used. Questionnaires studied were: POMS, Impact of Event Scale, Psychosocial Adjustment to Illness Scale (PAIS), EORTC QLQ-C30, Mental Adjustment to Cancer and a Pain visual analog scale (VAS). Responsiveness to change was evaluated using the standardized response mean. POMS was used as the standard. POMS was the most responsive questionnaire to change due to SEGT. Questionnaires measuring psychosocial attributes were responsive to improvement in mood. EORTC QLQ-C30, PAIS, PAIN VAS and MAC were the most responsive to disease progression. More responsive questionnaires were associated with the smallest sample size required to detect an effect. Responsiveness to change is context specific. The POMS was the most responsive questionnaire to psychosocial therapy.


Complex patterns of divergence among green-sensitive (RH2a) African cichlid opsins revealed by Clade model analyses.
Gene duplications play an important role in the evolution of functional protein diversity. Some models of duplicate gene evolution predict complex forms of paralog divergence; orthologous proteins may diverge as well, further complicating patterns of divergence among and within gene families. Consequently, studying the link between protein sequence evolution and duplication requires the use of flexible substitution models that can accommodate multiple shifts in selection across a phylogeny. Here, we employed a variety of codon substitution models, primarily Clade models, to explore how selective constraint evolved following the duplication of a green-sensitive (RH2a) visual pigment protein (opsin) in African cichlids. Past studies have linked opsin divergence to ecological and sexual divergence within the African cichlid adaptive radiation. Furthermore, biochemical and regulatory differences between the RH2aα and RH2aβ paralogs have been documented. It thus seems likely that selection varies in complex ways throughout this gene family. Clade model analysis of African cichlid RH2a opsins revealed a large increase in the nonsynonymous-to-synonymous substitution rate ratio (ω) following the duplication, as well as an even larger increase, one consistent with positive selection, for Lake Tanganyikan cichlid RH2aβ opsins. Analysis using the popular Branch-site models, by contrast, revealed no such alteration of constraint. Several amino acid sites known to influence spectral and non-spectral aspects of opsin biochemistry were found to be evolving divergently, suggesting that orthologous RH2a opsins may vary in terms of spectral sensitivity and response kinetics. Divergence appears to be occurring despite intronic gene conversion among the tandemly-arranged duplicates. Our findings indicate that variation in selective constraint is associated with both gene duplication and divergence among orthologs in African cichlid RH2a opsins. At least some of this variation may reflect an adaptive response to differences in light environment. Interestingly, these patterns only became apparent through the use of Clade models, not through the use of the more widely employed Branch-site models; we suggest that this difference stems from the increased flexibility associated with Clade models. Our results thus bear both on studies of cichlid visual system evolution and on studies of gene family evolution in general.


Real-World Emissions from Conventional Passenger Cars.
It has long been recognized that vehicles emit more pollutants than allowed under the new car emission standards. Further tightening of the certification standards based on existing test procedures does not directly address the largest sources of emissions. This study attempts to quantify vehicle emissions by source, in order to prioritize future policymaking. Several new sets of data are used in conjunction with regulatory emission models to characterize the lifetime emissions from the average Model Year (MY)93 vehicle. Special attention is paid to two of the largest sources of real-world emissions: (1) high-power driving by cars with properly functioning emissions controls, and (2) cars with malfunctioning emissions controls. Emissions are projected to MY2000 and 2010, based on estimates of the effectiveness of recently adopted and proposed regulatory policies. These new policies are projected to reduce total emissions substantially.


Protein interfaces in signaling regulated by arginine methylation.
Posttranslational modifications are well-known effectors of signal transduction. Arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains. A probable role of arginine methylation in signal transduction is emerging with the identification of new arginine-methylated proteins. However, the functional consequences of arginine methylation and its mode of regulation remain unknown. The identification of the protein arginine methyltransferase family and the development of methylarginine-specific antibodies have raised renewed interest in this modification during the last decade. Arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine-methylated proteins implicated in a variety of cellular processes, including signaling by interferon and cytokines, and in T cell signaling. We discuss these recent advances and the role of arginine methylation in signal transduction.


True histiocytic lymphoma following therapy for lymphoblastic neoplasms.
True histiocytic lymphomas (THLs) are rare tumors in which the malignant cells show morphologic and immunophenotypic evidence of histiocytic differentiation. We describe THLs that arose after therapy for one case of T-lineage lymphoblastic lymphoma (LyL) and two cases of acute lymphoblastic leukemia (ALL) (both CD10+, one pre-B phenotype). The lymphoblastic neoplasms were not unusual in any way, and responded well to standard therapy. The THLs arose 10 to 20 months after complete remission was achieved for the lymphoblastic neoplasms, at which time there was still no clinical or pathologic evidence of the lymphoblastic neoplasms. All three THLs exhibited clinical and morphologic features of malignancy. Neoplastic cells in the THLs had abundant eosinophilic vacuolated cytoplasm and pleomorphic nuclei, and expressed histiocytic antigens in the absence of lymphocyte-specific lineage markers. Because THLs are rare neoplasms, their occurrence after otherwise successful therapy for lymphoblastic neoplasms in these three cases may constitute a distinct clinicopathologic entity.


Self-trapped leaky waves in lattices: discrete and Bragg soleakons.
We propose lattice soleakons: self-trapped waves that self-consistently populate slowly-attenuating leaky modes of their self-induced defects in periodic potentials. Two types, discrete and Bragg, lattice soleakons are predicted. Discrete soleakons that are supported by combination of self-focusing and self-defocusing nonlinearities propagate robustly for long propagation distances. They eventually abruptly disintegrate because they emit power to infinity at an increasing pace. In contrast, Bragg soleakons self-trap by only self-focusing nonlinearity. Also, they do not disintegrate because they emit power at a decreasing rate.


Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group.
Patients with oligometastatic disease (OMD) often have controllable symptoms, and cures are possible. Technical improvements in surgery and radiotherapy have introduced the option of metastasis-directed ablative therapies as an adjunct or alternative to standard-of-care systemic therapies. Several clinical trials and registries are investigating the benefit of these therapeutic approaches across several cancer sites. This requires that patients are correctly included and followed with appropriate imaging. This article discusses the evidence and offers recommendations for the implementation of standard-of-care (Response Evaluation Criteria in Solid Tumours measurements on computed tomography [CT], magnetic resonance imaging [MRI] and bone scintigraphy) and advanced imaging modalities (functional, metabolic and radionuclide targeted) for identifying and following up patients with OMD. Imaging requirements for recognising OMD vary with tumour type, metastatic location, and timing of measurement in relation to previous treatment. At each point in the disease cycle (diagnosis, response assessment and follow-up), imaging must be tailored to the clinical question and the context of prior treatment. The differential use of whole-body approaches such as 18F-FDG-positron emission tomography (PET)/CT, diffusion-weighted MRI, 18F-Choline-PET/CT and 68Ga-prostate specific membrane antigen-PET/CT require rationalisation depending on clinical risk assessment. Optimal standardised imaging approaches will enable OMD trials to document patterns of disease progression and outcomes of treatment. Quality assured and quality controlled imaging data included in databases such as the European Organisation for Research and Treatment of Cancer Imaging platform for the Oligocare trial (a prospective, large-scale observational basket study being set up to collect outcome data from patients with OMD treated with radiation therapy) will establish a large and high-quality imaging warehouse for future research.


Comparison of 128-SP-QAM and PM-16QAM in long-haul WDM transmission.
We investigate 128-level set-partitioning quadrature amplitude modulation (128-SP-QAM) experimentally and compare the performance to polarization-multiplexed 16QAM both at the same bit rate and at the same symbol rate. Using a recirculating loop we study both single channel and wavelength-division multiplexing (WDM) transmission and demonstrate a reach of up to 2680 km at a bit-error rate of 10(-3) for 128-SP-QAM. We confirm that 128-SP-QAM has an increased sensitivity compared to PM-16QAM and show that the maximum transmission distance can be increased by more than 50 % at the same bit rate for both single channel and WDM transmission. We also investigate the performance at the same symbol rate as a possible fall back solution in a degrading link.


Development and validation of a liquid chromatography-mass spectrometry assay for the quantitation of IPTG in E. Coli fed-batch cultures.
IPTG (Isopropyl-beta-d-1-thiolgalactopyranoside) is a gratuitous inducer commonly used for the overexpression of heterologous recombinant proteins in Escherichia coli. A reliable method has been developed for the determination of IPTG in E.coli fed-batch fermentation samples with a minimal sample treatment. Analysis was performed in single ion monitoring positive mode using ESI source. The extracted ion was 261 m/z and the retention time of IPTG was 12.4 min with a total run time in samples of 30 min. The flow was directed to mass spectrometer 11 min after the start of the run and diverted from mass spectrometer after 14.5 min in order to avoid interference of salts and other metabolites. The assay was validated for medium and intracellular matrices and linear calibration curves of 3 orders of magnitude were obtained (R(2) >or= 0.99). Quality control samples were analyzed and showed precision and accuracy within the limits according to FDA Guidelines for analytical method validation. Recovery for both matrices was between 95.8 and 113.5%. The limit of detection (LOD) was set at 0.02 microM being the 0.1% of the lowest IPTG concentration used for induction of recombinant protein overexpression. The developed procedure has been applied to determine the IPTG distribution profiles in medium and intracellular samples in high cell density induced cultures for the production of the recombinant protein rhamnulose-1-phosphate aldolase (RhuA).


Degenerative disc disease as a cause of back pain in the thalassaemic population: a case-control study using MRI and plain radiographs.
The aim of this study was to test our observation that back pain in thalassemic patients could be caused by premature and extensive lumbar degenerative disc disease, when compared to non-thalassemic patients with back pain. Sixteen thalassemic patients with their sex- and age-matched controls were recruited into the study, 12 with thalassemia major, and 4 with thalassemia intermedia. Both the thalassemia patients and control subjects suffered from back pain, which was subjective rather than measured/pain scored. All subjects underwent magnetic resonance (MR) imaging of the lumbar spine, and 11 of the cases and 8 controls had lumbar spine radiographs. Each lumbar disc was scored for radiographic appearances and MR features of disc degeneration and disc protrusion. Proportion values for these parameters and median scores were derived at each disc level, and were analyzed and compared. There was a statistically-significant difference between proportion values of cases and controls for the MR features (P value=0.01, n=16) and the radiographic features (P value=0.01, n=11 cases, n=8 controls) of disc degeneration. The median disc level scores for the thalassemic group were uniformly high across all lumbar discs, and at all levels except at L 4/5. The control group conversely demonstrated a predilection for disc degeneration at L4/5 level. The distribution of lumbar disc degeneration in thalassemic patients with back pain is more extensive, severe and multi-level in nature compared to matched controls, and disc degeneration should be considered as a significant cause of back pain in this population group.


Bayesian Reconstruction of Two-Sex Populations by Age: Estimating Sex Ratios at Birth and Sex Ratios of Mortality.
The original version of Bayesian reconstruction, a method for estimating age-specific fertility, mortality, migration and population counts of the recent past with uncertainty, produced estimates for female-only populations. Here we show how two-sex populations can be similarly reconstructed and probabilistic estimates of various sex ratio quantities obtained. We demonstrate the method by reconstructing the populations of India from 1971 to 2001, Thailand from 1960 to 2000, and Laos from 1985 to 2005. We found evidence that in India, sex ratio at birth exceeded its conventional upper limit of 1.06, and, further, increased over the period of study, with posterior probability above 0.9. In addition, almost uniquely, we found evidence that life expectancy at birth (e0) was lower for females than for males in India (posterior probability for 1971-1976 equal to 0.79), although there was strong evidence for a narrowing of the gap through to 2001. In both Thailand and Laos, we found strong evidence for the more usual result that e0 was greater for females and, in Thailand, that the difference increased over the period of study.


Ruptured ectopic pregnancy diagnosed with computed tomography.
The rupture of ectopic pregnancy (EP) still remains the primary and direct cause of death in the first trimester of pregnancy. Ultrasonography is known to be a modality of choice in EP diagnostics. We found a severe discrepancy between the frequency of ectopic pregnancies (EP) and the number of available computed tomography (CT) examinations. A 29-year-old woman was admitted to the emergency department with a history of abdominal pain, nausea, vomiting and collapse. Sonographic findings of a suspected EP were unclear. Moreover, not all features of intrauterine pregnancy were present. Due to the patient's life-threatening condition, an emergency multi-slice CT with MPR and VRT reconstructions was performed, revealing symptoms of a ruptured EP. In the right adnexal area, a well-vascularized, solid-cystic abnormal mass lesion was found. Intraperitoneal hemorrhage was confirmed intraoperatively, and the right fallopian tube with a tubal EP was resected. In the surgery in situ, as well as in the pathological examination of the tumor mass, a human embryo of approximately 1.5 cm in length (beginning of the 8(th) week of gestation) was found. Although ultrasonography still remains the first-line imaging examination in EP diagnostics, sometimes the findings of suspected EPs are unclear and not sufficient. The rupture of EP, with serious bleeding and symptoms of shock, may require an emergent pelvic and abdominal CT inspection. A clear correlation was found between the macroscopic CT images and the intraoperatively sampled material.


Casein addition to a whey-based formula has limited effects on gut function in preterm pigs.
Preterm infants are susceptible to necrotizing enterocolitis (NEC). Using preterm pigs, we determined whether a whey-casein-based formula would be superior to a formula based on whey protein alone. Twenty cesarean-derived preterm pigs (92% gestation) were given total parenteral nutrition for 36 h followed by 30 h of enteral feeding with whey [protein fraction of milk formula based on whey (WHEY); n = 11] or casein and/or whey [protein fraction of milk formula based on a combination of casein and whey (CASEIN); n = 9]-based formulas. Sugar absorptive function was investigated at 6 and 30 h after initiation of enteral feeding using bolus feedings with galactose and mannitol. Pigs were killed after the last in vivo sugar absorption test and evaluated for NEC and the mid intestine was used for ex vivo measurements of hexose absorption. Microbiota profile and short chain fatty acid (SCFA) levels were studied in gut contents. Severity of NEC lesions was similar between diet groups but galactose absorption was markedly higher in CASEIN than in WHEY (P < 0.01) although only 6 h after the start of the enteral feeding period. There were no differences in ex vivo (14)C-D-glucose uptake, digestive enzymes, microbiota profile, or SCFA concentration. Casein may transiently stimulate intestinal sugar absorption but has limited effects on gut structure, microbiota, and NEC in preterm pigs.


Revision of Gangesia (Cestoda: Proteocephalidea) in the Indomalayan region: morphology, molecules and surface ultrastructure.
Tapeworms of Gangesia Woodland, 1924 (Cestoda: Proteocephalidea) parasitic in freshwater fishes in the Indomalayan Region were critically reviewed. Evaluation of type specimens and newly collected materials from Bangladesh, Cambodia and India, as well as critical examination of extensive literature have shown that only the following four species, instead of 48 nominal species of Gangesia and Silurotaenia Nybelin, 1942 reported from this region (36 new synonymies proposed), are valid: Gangesia bengalensis (Southwell, 1913), type-species of the genus and most common parasite of Wallago attu (Siluridae), G. macrones Woodland, 1924 typical of Sperata seenghala (Bagridae), both species characterized by the possession of two circles of hooks on the rostellum-like organ and several rows of hooklets on the anterior margins of suckers; G. agraensis Verma, 1928 from W. attu (typical host), which has the scolex with only one circle of hooks and 1-3 incomplete rows of tiny hooklets on the suckers; and G. vachai (Gupta and Parmar, 1988) n. comb. from several catfishes, which possesses 4-6 circles of hooks and 5-11 rows of hooklets on the anterior half of suckers. Scolex morphology, including surface ultrastructure (microtriches), of all but one species (G. vachai) is described for the first time using scanning electron microscopy. A phylogenetic analysis based on the partial sequences encoding the large nuclear ribosomal subunit RNA gene has shown that three Indomalayan species, namely G. bengalensis, G. macrones and G. vachai, form a monophyletic group within Gangesia, whereas G. agraensis tends to form a clade with the Palaearctic species of the genus. A table with differential characters of all species from the Indomalayan Region is also provided together with a key to identification of genera of the subfamily Gangesiinae. The present study demonstrates that species of Silurotaenia do not occur in the Indomalayan region.


Two-dimensional hybrid photonic/plasmonic crystal cavities.
We present a 2-D plasmonic crystal design with visible band-gap by combining a 2-D photonic crystal with TM band-gap and a silver surface. Simulations show that the presence of the silver surface gives rise to an expanded band-gap. A plasmonic crystal defect cavity with Q ~300 and mode volume ~1.9x10(-2) (λ/n) (3) can be formed using our design. The total Q of such a cavity is determined by both the radiative loss of the dielectric component, as well as absorption loss to the metal. We provide design criteria for the optimization of the total Q to allow high radiative or extraction efficiency.


Constitutively active forms of c-Jun NH2-terminal kinase are expressed in primary glial tumors.
The c-Jun NH(2)-terminal kinases (JNKs) have a role both in promoting apoptosis and tumorigenesis. The JNKs are encoded by three separate genes (JNK1, 2, and 3), which are spliced alternatively to create 10 JNK isoforms that are either M(r) 55,000 or 46,000 in size. However, the functional significance and distinct role for each splice variant remains unclear. We have noted previously that 86% of primary human glial tumors show activation of almost exclusively the M(r) 55,000 isoforms of JNK. To further study which isoforms are involved, we constructed glutathione S-transferase fusion proteins for all 10 JNK isoforms and examined kinase activity with or without the activating upstream kinase. Surprisingly, five JNK isoforms demonstrate autophosphorylation activity, and in addition, all four JNK2 isoforms (either M(r) 55,000 or 46,000) show a high basal level of substrate kinase activity in the absence of the upstream kinase, especially a M(r) 55,000 JNK2 isoform. Examination revealed autophosphorylation activity at the T-P-Y motif, which is critical for JNK activation, because a mutant lacking the dual phosphorylation sites did not show autophosphorylation or basal kinase activity. Using green fluorescence protein-JNK expression vectors, transient transfection into U87MG cells demonstrates that although the JNK1 isoforms localize predominantly to the cytoplasm, the JNK2 isoforms localize to the nucleus and are phosphorylated, confirming the constitutive activation seen in vitro. We then examined which JNK isoforms are active in glial tumors by performing two-dimensional electrophoresis. This revealed that the M(r) 55,000 isoforms of JNK2 are the principal active JNK isoforms present in tumors. Collectively, these results suggest that these constitutively active JNK isoforms play a significant role in glial tumors. Aside from epidermal growth factor receptor vIII, this is the only other kinase that has been shown to be basally active in glioma. The presence of constitutively active JNK isoforms may have implications for the design of inhibitors of the JNK pathway.


Duration of androgen suppression in the treatment of prostate cancer.
The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer. We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429. A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)


Evaluation of cardiovascular disease in patients with systemic arterial hypertension in relation to age and sex: a retrospective study in a south Indian population.
Systemic arterial hypertension manifests as constant elevation of blood pressure and is considered to be an important cardiovascular risk factor. Systemic evaluation of cardiovascular diseases in patients with systemic arterial hypertension is imperative for prevention. The objective of the present study was to investigate and inter-relate sex and age with systemic arterial hypertension and cardiovascular diseases. Medical records of patients with systemic arterial hypertension and cardiovascular disease were evaluated. Data from the medical records were recorded in a prescribed protocol and the data were analyzed and correlated to the patients' age and sex. A total of 170 medical records for patients who visited the cardiology department were reviewed. Of these, 50 patients had systemic arterial hypertension and 19 of this subset had cardiovascular diseases. When we correlated systemic arterial hypertension with age, we observed that patients in the 51-60 years age group were more prone to systemic arterial hypertension (36%). Most of the patients with both systemic arterial hypertension and cardiovascular disease were female and in the 61-70 years age group, while among males the highest rate of occurrence was seen in the 51-60 years age group. The correlation coefficient (r) was 0.62, indicating a moderate, positive, linear relationship between systemic arterial hypertension and cardiovascular disease. A majority of patients with systemic arterial hypertension may develop cardiovascular disease and, as age increases, the tendency to develop hypertension also increases.


Inhibition of the Receptor for Advanced Glycation End Products Enhances the Cytotoxic Effect of Gemcitabine in Murine Pancreatic Tumors.
Pancreatic ductal adenocarcinoma (PDAC) remains a very difficult cancer to treat. Recent in vitro and in vivo studies suggest that the activation of the receptor for advanced glycation end products (RAGE) by its ligands stimulates pancreatic cancer cell proliferation and tumor growth. Additional studies show that, in the RAGE ligand, the high mobility group box 1 (HMGB1) protein plays an important role in chemoresistance against the cytotoxic agent gemcitabine by promoting cell survival through increased autophagy. We hypothesized that blocking the RAGE/HMGB1 interaction would enhance the cytotoxic effect of gemcitabine by reducing cell survival and autophagy. Using a preclinical mouse model of PDAC and a monoclonal antibody (IgG 2A11) as a RAGE inhibitor, we demonstrate that RAGE inhibition concurrent with gemcitabine treatment enhanced the cytotoxic effect of gemcitabine. The combination of IgG 2A11 and gemcitabine resulted in decreased autophagy compared to treatment with gemcitabine combined with control antibodies. Notably, we also observed that RAGE inhibition protected against excessive weight loss during treatment with gemcitabine. Our data suggest that the combination of gemcitabine with a RAGE inhibitor could be a promising therapeutic approach for the treatment of pancreatic cancer and needs to be further investigated.


Associations between oral complications and days to death in palliative care patients.
Adverse oral symptoms gradually appear in advanced cancer patients as the disease progresses. We retrospectively investigated the associations between the incidence of oral problems and the days to death (DTD) in patients receiving palliative care. The dental assessment sheets and medical charts of 105 patients who had been admitted into the palliative care unit at our hospital were examined. Case data included evaluations of organic and functional oral conditions at the time of admission for all patients. The cohort was divided into two groups according to the DTD as the short group (<28 days from the time of dental assessment until death) and the long group (≥28 days). We compared the incidences of organic and functional oral problems between these groups. Dry mouth, tongue inflammation, and bleeding spots were significantly more frequent in the short group than in the long group (78 vs. 54% for dry mouth, 67 vs. 46% for tongue inflammation, 35 vs. 14% for bleeding spots, respectively; p < 0.05). Tongue coating and candidiasis were comparable between the two groups. Dysphagia was significantly more common in the short group (43%) than in the long group (20%) (p = 0.01), as was assistance with oral health care (76 vs. 50%) (p = 0.01). Our findings suggest that, during palliative care, oral complications appear more frequently when the DTD period is shorter. These symptoms may be useful indicators when deciding on the proper timing of intensive oral care intervention to decrease oral problems and pain in terminally ill patients.


The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population.
The aim was to investigate the frequency of genetic polymorphisms of cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit1 (VKORC1) and determine the effect of these polymorphisms on warfarin dose requirements in pediatric patients. Fifty-eight pediatric patients with cardiac disease, thrombophilia, or other conditions, taking a stable warfarin dose, aged 0.2-18 years, and with international normalized ratio (INR) between 2 and 3 and 149 healthy children as a control group were included in this prospective, observational study. Patients receiving drugs that interact with warfarin, having chronic liver or renal disease, obesity, or thyroid dysfunctions were excluded. Polymerase chain reaction (real time and restriction fragment length polymorphism) was used to analyze the CYP2C9*2, CYP2C9*3, and VKORC1 polymorphisms. The ideal warfarin dose was calculated according to the patient's age, height, and the presence of CYP2C9*2, CYP2C9*3, and VKORC1 genetic polymorphisms. The mean daily administered doses and ideal doses were compared. Analysis of variance, Student's t-test, logistic regression analysis, and Pearson's correlation analysis were used for statistical analyses. The frequency of the CYP2C9 and VKORC1 genetic polymorphisms was determined as CYP2C9*1/*1 (54.6%), *1/*2 (16.4%), *1/*3 (24.2%), *2/*3 (2.9%), *3/*3 (1.9%), wild-type VKORC1 (26.6%), heterozygote alleles (52.7%), and mutant alleles (20.8%). Patients with allelic variants were found to require lower warfarin doses, and a 64.5% correlation was found between the calculated ideal doses and the administered warfarin doses. Considering CYP2C9 and VKORC1 genetic polymorphisms prior to commencing warfarin treatment will make it easier to reach target INRs and reduce the rate of complications.


The defence of body weight: a physiological basis for weight regain after weight loss.
Although weight loss can usually be achieved by restricting food intake, the majority of dieters regain weight over the long-term. In the hypothalamus, hormonal signals from the gastrointestinal tract, adipose tissue and other peripheral sites are integrated to influence appetite and energy expenditure. Diet-induced weight loss is accompanied by several physiological changes which encourage weight regain, including alterations in energy expenditure, substrate metabolism and hormone pathways involved in appetite regulation, many of which persist beyond the initial weight loss period. Safe effective long-term strategies to overcome these physiological changes are needed to help facilitate maintenance of weight loss. The present review, which focuses on data from human studies, begins with an outline of body weight regulation to provide the context for the subsequent discussion of short- and long-term physiological changes which accompany diet-induced weight loss.


Collagenase treatment of Dupuytren's contracture using a modified injection method: a prospective cohort study of skin tears in 164 hands, including short-term outcome.
Treatment of Dupuytren's contracture (DC) with collagenase Clostridium histolyticum (CCH) consists of injection followed by finger manipulation. We used a modified method, injecting a higher dose than recommended on the label into several parts of the cord, which allows treatment of multiple joint contractures in 1 session and may increase efficacy. We studied the occurrence of skin tears and short-term outcome with this procedure. We studied 164 consecutive hands with DC, palpable cord, and extension deficit of ≥ 20º in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint (mean patient age 70 years, 82% men). A hand surgeon injected all the content of 1 CCH vial (approximately 0.80 mg) into multiple spots in the cord and performed finger extension under local anesthesia after 1 or 2 days. A nurse recorded skin tears on a diagram and conducted a standard telephone follow-up within 4 weeks. A hand therapist measured joint contracture before injection and at a median of 23 (IQR: 7-34) days after finger extension. A skin tear occurred in 66 hands (40%). The largest diameter of the tear was ≤ 5 mm in 30 hands and > 10 mm in 14 hands. Hands with skin tear had greater mean pretreatment MCP extension deficit than those without tear: 59º (SD 26) as opposed to 32º (SD 23). Skin tear occurred in 21 of 24 hands with MCP contracture of ≥ 75º. All tears healed with open-wound treatment. No infections occurred. Mean improvement in total (MCP + PIP) extension deficit was 55º (SD 28). Skin tears occurred in 40% of hands treated with collagenase injections, but only a fifth of them were larger than 1 cm. Tears were more likely in hands with severe MCP joint contracture. All tears healed without complications. Short-term contracture reduction was good.


Fermented goat milk consumption improves melatonin levels and influences positively the antioxidant status during nutritional ferropenic anemia recovery.
The aim of the current study was to assess the influence of fermented goat or cow milk on melatonin levels and antioxidant status and during anemia recovery. Eighty male Wistar rats were placed on a pre-experimental period of 40 days and randomly divided into two groups, a control group receiving normal-Fe diet (45 mg kg(-1)) and the Fe-deficient group receiving low-Fe diet (5 mg kg(-1)). Then, the rats were fed with fermented goat or cow milk-based diets with a normal-Fe content or Fe-overload (450 mg kg(-1)) for 30 days. After 30 days of feeding the fermented milks, the total antioxidant status (TAS) was higher in both groups of animals fed fermented goat milk with the normal-Fe content. Plasma and urine 8-OHdG were lower in control and anemic rats fed fermented goat milk. Melatonin and corticosterone increased in the anemic groups during Fe replenishment with both fermented milks. Urine isoprostanes were lower in both groups fed fermented goat milk. Lipid and protein oxidative damage were higher in all tissues with fermented cow milk. During anemia instauration, an increase in melatonin was observed, a fact that would improve the energy metabolism and impaired inflammatory signaling, however, during anemia recovery, fermented goat milk had positive effects on melatonin and TAS, even in the case of Fe-overload, limiting the evoked oxidative damage.


A new nonenzymatic method and device to obtain a fat tissue derivative highly enriched in pericyte-like elements by mild mechanical forces from human lipoaspirates.
Adipose tissue contains multipotent elements with phenotypic and gene expression profiles similar to human mesenchymal stem cells (hMSCs) and pericytes. The chance of clinical translation of the multilineage potential of these cells is delayed by the poor/negligible cell survival within cryopreserved lipoaspirates, the difficulty of ex vivo expansion, and the complexity of current Good Manufacturing Practice (cGMP) requirements for expanded cells. Hence, availability of a minimally manipulated, autologous, hMSC/pericyte-enriched fat product would have remarkable biomedical and clinical relevance. Here, we present an innovative system, named Lipogems, providing a nonexpanded, ready-to-use fat product. The system uses mild mechanical forces in a completely closed system, avoiding enzymes, additives, and other manipulations. Differently from unprocessed lipoaspirate, the nonexpanded Lipogems product encompasses a remarkably preserved vascular stroma with slit-like capillaries wedged between adipocytes and stromal stalks containing vascular channels with evident lumina. Immunohistochemistry revealed that Lipogems stromal vascular tissue included abundant cells with pericyte/hMSC identity. Flow cytometry analysis of nonexpanded, collagenase-treated Lipogems product showed that it was comprised with a significantly higher percentage of mature pericytes and hMSCs, and lower amount of hematopoietic elements, than enzymatically digested lipoaspirates. Differently from the lipoaspirate, the distinctive traits of freshly isolated Lipogems product were not altered by cryopreservation. Noteworthy, the features of fresh product were retained in the Lipogems product obtained from human cadavers, paving the way to an off-the-shelf strategy for reconstructive procedures and regenerative medicine. When placed in tissue culture medium, the Lipogems product yielded a highly homogeneous adipose tissue-derived hMSC population, exhibiting features of hMSCs isolated from other sources, including the classical commitment to osteogenic, chondrogenic, and adipogenic lineages. Moreover, the transcription of vasculogenic genes in Lipogems-derived adipose tissue hMSCs was enhanced at a significantly greater extent by a mixture of natural provasculogenic molecules, when compared to hMSCs isolated from enzymatically digested lipoaspirates.


[The effect of maternal exposure to dioxin on fetal steroidogenesis in the steroidogenic organs].
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposed to pregnant or lactational mother impairs the reproduction and development of the pups. The defect is a serious problem, because it is caused by TCDD at much lower doses than that needed for acute toxicity in the mother. However, the toxic mechanism underlying the defect remains to be obscure. We have previously revealed that maternal exposure to TCDD (1 microg/kg) causes a reduction in luteinizing hormone in the fetal pituitary, leading to the reduced expression of testicular steroidogenic proteins such as steroidogenic acute-regulatory protein (StAR) and cytochrome P450 (CYP) 17. In addition, we have provided evidence that such a reduction imprints defects in sexual behaviors at adulthood. In this study, we investigated TCDD effect on fetal steroidogenesis in the extra-gonadal tissues. Even when pregnant Wistar rats at gestational day (GD) 15 were orally treated with TCDD (0.25, 1 or 3 microg/kg), neither expression of StAR nor CYP17 mRNA was affected in the adrenal gland, placenta and hypothalamus of male fetuses (GD20). However, TCDD induced placental StAR (3 microg/kg) and adrenal CYP17 mRNAs (0.25 microg/kg) in female fetuses. Therefore, our study suggests that while TCDD gives damage to male fetal steroidogenesis in a testis-specific manner, the dioxin enhances the steroidogenesis of the fetal adrenal gland and placenta in females. Thus, the mechanism whereby TCDD exerts its endocrine-disrupting properties is considered to differ, at least partially, between male and female fetuses.


Antiproliferative and Cytotoxic Activities of Fluorescein-A Diagnostic Angiography Dye.
Fluorescein is a fluorescent dye used as a diagnostic tool in various fields of medicine. Although fluorescein itself possesses low toxicity, after photoactivation, it releases potentially toxic molecules, such as singlet oxygen (1O2) and, as we demonstrate in this work, also carbon monoxide (CO). As both of these molecules can affect physiological processes, the main aim of this study was to explore the potential biological impacts of fluorescein photochemistry. In our in vitro study in a human hepatoblastoma HepG2 cell line, we explored the possible effects on cell viability, cellular energy metabolism, and the cell cycle. We observed markedly lowered cell viability (≈30%, 75-2400 μM) upon irradiation of intracellular fluorescein and proved that this decrease in viability was dependent on the cellular oxygen concentration. We also detected a significantly decreased concentration of Krebs cycle metabolites (lactate and citrate < 30%; 2-hydroxyglutarate and 2-oxoglutarate < 10%) as well as cell cycle arrest (decrease in the G2 phase of 18%). These observations suggest that this photochemical reaction could have important biological consequences and may account for some adverse reactions observed in fluorescein-treated patients. Additionally, the biological activities of both 1O2 and CO might have considerable therapeutic potential, particularly in the treatment of cancer.


Assessment of DNA double-strand breaks induced by intravascular iodinated contrast media following in vitro irradiation and in vivo, during paediatric cardiac catheterization.
Paediatric cardiac catheterizations may result in the administration of substantial amounts of iodinated contrast media and ionizing radiation. The aim of this work was to investigate the effect of iodinated contrast media in combination with in vitro and in vivo X-ray radiation on lymphocyte DNA. Six concentrations of iodine (15, 17.5, 30, 35, 45, and 52.5 mg of iodine per mL blood) represented volumes of iodinated contrast media used in the clinical setting. Blood obtained from healthy volunteers was mixed with iodinated contrast media and exposed to radiation doses commonly used in paediatric cardiac catheterizations (0 mGy, 70 mGy, 140 mGy, 250 mGy and 450 mGy). Control samples contained no iodine. For in vivo experimentation, pre and post blood samples were collected from children undergoing cardiac catheterization, receiving iodine concentrations of up to 51 mg of iodine per mL blood and radiation doses of up to 400 mGy. Fluorescence microscopy was performed to assess γH2AX-foci induction, which corresponded to the number of DNA double-strand breaks. The presence of iodine in vitro resulted in significant increases of DNA double-strand breaks beyond that induced by radiation for ≥ 17.5 mg/mL iodine to blood. The in vivo effects of contrast media on children undergoing cardiac catheterization resulted in a 19% increase in DNA double-strand breaks in children receiving an average concentration of 19 mg/mL iodine to blood. A larger investigation is required to provide further information of the potential benefit of lowering the amount of iodinated contrast media received during X-ray radiation investigations.


Twenty-eight years of clinical experience with implantable neuroprostheses for various applications.
Since 1973, the author has been implanting neural stimulators and later drug pumps to restore or improve motor function and modulate pain, spasticity, and seizures in patients with spinal cord and brain injury, cerebral palsy, stroke, and multiple sclerosis. During these 28 years, many physicians, biomedical engineers, and manufactures have realized worthwhile successes. Many lessons have been learned to improve operative techniques to ensure safety, low infection, and improved results for implant patients. The relationships between manufacturers and physicians have varied. Problems arise with patents, royalties, confidentiality, publishing, and liability insurance. There has been a need to patent ideas and intellectual properties; however, some of the patented concepts have been published previously but missed by the patent author and patent office. This has led to vigorous legal battles, consuming money with time delays, or resulting in surrendering worthwhile projects. There is a need for a responsible, independent appeals board to review these disputed patent claims. Then their findings should be admissible at the Patent Office and if necessary in court.


In situ study of binding of copper by fulvic acid: comparison of differential absorbance data and model predictions.
This study examined the binding of copper(II) by Suwannee River fulvic acid (SRFA) using the method of differential absorbance that was used at environmentally-relevant concentrations of copper and SRFA. The pH- and metal-differential spectra were processed via numeric deconvolution to establish commonalities seen in the changes of absorbance caused by deprotonation of SRFA and its interactions with copper(II) ions. Six Gaussian bands were determined to be present in both the pH- and Cu-differential spectra. Their maxima were located, in the order of increasing wavelengths at 208 nm, 242 nm, 276 nm, 314 nm, 378 nm and 551 nm. The bands with these maxima were denoted as A0, A1, A2, A3, A4 and A5, respectively. Properties of these bands were compared with those existing in the spectra of model compounds such as sulfosalicylic acid (SSA), tannic acid (TA), and polystyrenesulfonic acid-co-maleic acid (PSMA). While none of the features observed in differential spectra of the model compound were identical to those present in the case of SRFA, Gaussian bands A1, A3 and possibly A2 were concluded to be largely attributable to a combination of responses of salicylic- and polyhydroxyphenolic groups. In contrast, bands A4 and A5 were detected in the differential spectra of SRFA only. Their nature remains to be elucidated. To examine correlations between the amount of copper(II) bound by SRFA and changes of its absorbance, differential absorbances measured at indicative wavelengths 250 nm and 400 nm were compared with the total amount of SRFA-bound copper estimated based on Visual MINTEQ calculations. This examination showed that the differential absorbances of SRFA in a wide range of pH values and copper concentrations were strongly correlated with the concentration of SRFA-bound copper. The approach presented in this study can be used to generate in situ information concerning the nature of functional groups in humic substances engaged in interactions with metals ions. This information can be useful for further elaboration and development of detailed theoretic models that describe the complexation of metals in the environment.


Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study.
The incidence of breast cancer among women in Shanghai, a traditionally low-risk population, has increased substantially over the past 20 years. To evaluate the association of menstrual and reproductive factors with breast cancer risk and the influence of these factors on the temporal trend of breast cancer incidence, we analyzed data from the Shanghai Breast Cancer Study, a population-based case-control study of breast cancer recently completed among Chinese women in urban Shanghai. In-person interviews were completed for 1,459 women newly diagnosed with breast cancer between ages 25 and 64 and for 1,556 controls frequency-matched to cases by age. Unconditional logistic regression was employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) related to menstrual and reproductive factors. Earlier menarcheal age, nulliparity, and later age at first live birth were associated with increased risk of breast cancer among both pre- and post-menopausal women, while never having breast-fed and later age at menopause were associated with elevated risk only among post-menopausal women. Among controls, 32% of younger women (</=40 years) and 24% of older women (>40 years) reported starting menarche at age of 13 or younger, and this factor contributed to 44% of cases diagnosed among younger women and 26% to 28% of cases in older women. Older age at first live birth or at menopause explained a considerable portion of cases diagnosed in older, but not younger, women. Our study suggests that the changes in menstrual and reproductive patterns among women in Shanghai have contributed to the recent increase in breast cancer incidence, particularly among younger women.


The value of bedside ocular ultrasound assessment of optic nerve sheath diameter in the detection of increased intracranial pressure in patients presenting to the emergency room with headache.
Headache is one of the most important complaints in emergency room (ER) admissions, and the rate of the increase in intracranial pressure in these cases should not be overlooked. This study was performed to investigate the value of the measurement of optic nerve sheath diameter (ONSD) by ocular ultrasound in ER patients with the complaint of headache and increase in intracranial pressure regarding this. : A total of 100 patients who applied to the ER with the complaint of headache were included in this prospective study. Fifty patients with increased ONSD (≥5 mm) and 50 patients with normal ONSD (<5 mm) were obtained. ONSD measurements were performed with 7.5-10 MHz linear probe and closed-eye technique. In addition to this, all patients underwent cranial computerized tomography (CT) examinations, and CT results were compared with the results of the ocular ultrasound. The median right and left ONSD values were detected to be 4.3 mm (3.6-5.5 mm) and 4.4 mm (3.6-5.6 mm) in patients whose cranial CT results were within normal limits. However, the median right and left ONSD values were detected to be 5.5 mm (5.1-6.3 mm) and 5.5 mm (5.1-6.4 mm) in patients whose cranial CT examination results were abnormal. In all cases with abnormal CT findings, the right and the left ONSD measurements were significantly higher (P < 0.001). Furthermore, ONSD value in the ipsilateral side with the lesion was significantly higher than the contralateral side (P < 0.001). Bedside ocular ultrasound is a noninvasive and easily applicable method in ER for the detection and evaluation of intracranial hypertension with headache.


Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs.
Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others. Efavirenz-based treatment is generally well-tolerated in children, although some experience persistent concentration problems, as well as sleep disturbances, psychotic reactions, and seizures. In an effort to link basic with clinical research, parameters associated with efavirenz brain exposure are discussed, and factors that increase efavirenz levels are explored in depth as they are expected to contribute to NPAE risk. These include the role of modifiable and nonmodifiable risk factors such as diet, weight, and drug-drug interactions and sex, age, and ethnicity/pharmacogenetics. In addition to NPAEs, this review explores what is known about antiretroviral (ARV) drugs being used for recreational purposes. Although multiple ARV drugs are covered, special attention is devoted to efavirenz given that the majority of reports of NPAEs and illicit use of ARV drugs concern efavirenz. The evolving molecular mechanistic basis of NPAEs and abuse of efavirenz point to a complex and polymodal receptor pharmacology. Animal studies to date primarily point to a serotonergic mechanism of action. Recently emerging associations between HIV-associated neurocognitive disorder and efavirenz use, and possible contributions of the mitochondrial-immune-inflammatory-redox cascade are explored in the context of the signaling mechanisms that appear to be involved.


Determinants and Determination of Carotenoid Bioavailability from Infant Food Formulas and Adult Nutritionals Including Liquid Dairy Products.
Carotenoids are typically tetraterpenoid phytochemicals that cannot be synthesized by humans, some of which such as β-carotene can be metabolized into vitamin A. Sufficient carotenoid intake and tissue levels have been associated with several health benefits including the reduction of cardiovascular diseases and some types of cancer and also the amelioration of age-related macular degeneration. Carotenoids and their metabolites have also been related to reduced inflammation and oxidative stress via interacting with transcription factors, such as NF-κB and Nrf-2, as well as with the nuclear receptors retinoic acid receptor/retinoid X receptor, implicated in immune functions and cellular differentiation. Therefore, carotenoids are important for growth and development. They could mark beneficial constituents in infant food formulas and adult nutritionals, the latter typically constituting protein-rich liquid foods targeting meal replacements. Carotenoids may be present by nature (typically below 20 μg/100 mL) or following fortification (up to 200 μg/100 mL), such as for lutein and β-carotene. However, carotenoid bioavailability may be low and variable, especially in low-fat items. Although most infant foods and adult nutritionals are rich in lipids and proteins, facilitating absorption and availability of carotenoids, unfortunately, very little data is available. In addition, carotenoid detection for such lipid-rich matrices may be challenging as a result of low concentrations and matrix effects. This review aims to highlight considerations for carotenoid bioavailability from infant food formula and adult nutritionals as well as summarize detection methods for carotenoids from these items.


Addressing overtreatment of screen detected DCIS; the LORIS trial.
Overdiagnosis, and thus overtreatment, are inevitable consequences of most screening programmes; identification of ways of minimising the impact of overdiagnosis demands new prospective research, in particular the need to separate clinically relevant lesions that require active treatment from those that can be safely left alone or monitored and only need treated if they change characteristics. Breast cancer screening has led to a large increase in ductal carcinoma in situ (DCIS) diagnoses. This is a widely heterogeneous disease and most DCIS detected through screening is of high cytonuclear grade and therefore likely to be important clinically. However, the historic practice of surgical treatment for all DCIS is unlikely to be optimal for lower risk patients. A clearer understanding of how to manage DCIS is required. This article describes the background and development of 'The low risk' DCIS trial (LORIS), a phase III trial of surgery versus active monitoring. LORIS will determine if it is appropriate to manage women with screen detected or asymptomatic, low grade and intermediate grade DCIS with low grade features, by active monitoring rather than by surgical treatment.


Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling.
Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures. The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [18F]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment-insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI). WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (ρ = 0.83 vs -0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR's or revised QUICKI's (ρ = 0.67 vs -0.58 and 0.59; both nonsignificant) in the test dataset. Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals.


Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study.
The Mediterranean dietary pattern is believed to protect against cancer, although evidence from cohort studies that have examined particular cancer sites is limited. We aimed to explore the association between adherence to a relative Mediterranean diet (rMED) and incident gastric adenocarcinoma (GC) within the European Prospective Investigation into Cancer and Nutrition study. The study included 485,044 subjects (144,577 men) aged 35-70 y from 10 European countries. At recruitment, dietary and lifestyle information was collected. An 18-unit rMED score, incorporating 9 key components of the Mediterranean diet, was used to estimate rMED adherence. The association between rMED and GC with respect to anatomic location (cardia and noncardia) and histologic types (diffuse and intestinal) was investigated. A calibration study in a subsample was used to control for dietary measurement error. After a mean follow-up of 8.9 y, 449 validated incident GC cases were identified and used in the analysis. After stratification by center and age and adjustment for recognized cancer risk factors, high compared with low rMED adherence was associated with a significant reduction in GC risk (hazard ratio: 0.67; 95% CI: 0.47, 0.94). A 1-unit increase in the rMED score was associated with a decreased risk of GC of 5% (95% CI: 0.91, 0.99). There was no evidence of heterogeneity between different anatomic locations or histologic types. The calibrated results showed similar trends (overall hazard ratio for GC: 0.93; 95% CI: 0.89, 0.99). Greater adherence to an rMED is associated with a significant reduction in the risk of incident GC.