Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver.
Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.


Accuracy of 16-row multidetector computed tomography for the assessment of coronary artery stenosis.
Multidetector computed tomography (MDCT) has been proposed as a noninvasive method to evaluate coronary anatomy. To determine the diagnostic accuracy of 16-row MDCT for the detection of obstructive coronary disease based exclusively on quantitative analysis and performed in a multicenter study. Eleven participating sites prospectively enrolled 238 patients who were clinically referred for nonemergency coronary angiography from June 2004 through March 2005. Following a low-dose MDCT scan to evaluate coronary artery calcium, 187 patients with an Agatston score of less than 600 underwent contrast-enhanced MDCT. Conventional angiography was performed 1 to 14 days after MDCT. Conventional angiographic and MDCT studies were analyzed by independent core laboratories. Segment-based and patient-based sensitivities and specificities for the detection of luminal stenosis of more than 50% (of luminal diameter) and more than 70% (of luminal diameter) based on quantitative coronary angiography. Of 1629 nonstented segments larger than 2 mm in diameter, there were 89 (5.5%) in 59 (32%) of 187 patients with stenosis of more than 50% by conventional angiography. Of the 1629 segments, 71% were evaluable on MDCT. After censoring all nonevaluable segments as positive, the sensitivity for detecting more than 50% luminal stenoses was 89%; specificity, 65%; positive predictive value, 13%; and negative predictive value, 99%. In a patient-based analysis, the sensitivity for detecting patients with at least 1 positive segment was 98%; specificity, 54%; positive predictive value, 50%; and negative predictive value, 99%. After censoring all nonevaluable segments as positive, the sensitivity for detecting more than 70% luminal stenoses was 94%; specificity, 67%; positive predictive value, 6%; and negative predictive value, 99%. In a patient-based analysis, the sensitivity for detecting patients with at least 1 positive segment was 94%; specificity, 51%; positive predictive value, 28%; and negative predictive value, 98%. The results of this study indicate that MDCT coronary angiography performed with 16-row scanners is limited by a high number of nonevaluable cases and a high false-positive rate. Thus, its routine implementation in clinical practice is not justified. Nevertheless, given its high sensitivity and negative predictive value, 16-row MDCT may be useful in excluding coronary disease in selected patients in whom a false-positive or inconclusive stress test result is suspected.


H-2 restriction as a consequence of intentional priming. Frequency analysis of alloantigen-restricted, trinitrophenyl-specific cytotoxic T lymphocyte precursors within thymocytes of normal mice.
An in vitro acute-depletion protocol was used to detect trinitrophenyl (TNP)-specific, allo-major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) within thymocytes of inbred mice. After removal of alloreactivity, the negatively selected cells could be sensitized to become TNP-specific, allo-MHC-restricted cytotoxic T cells. A precursors frequency analysis revealed a three- to ninefold lower frequency of allo-MHC-restricted CTL precursors (CTL-P) as compared to self-MHC-restricted CTL-P. The specificity analysis of clonally distributed allo-MHC-restricted CTL-P excluded cross-reactivity as an explanation of allo-MHC restriction. These results provide direct evidence that thymic T cells are composed of a mixture of self-MHC- and allo-MHC-restricted immunocompetent T cells and that antigen-driven selection of precommitted T cells dictates the H-2-restriction phenotype, i.e., H-2 restriction is a consequence of priming.


Endovascular Treatment for Ruptured Vertebral Artery Dissecting Aneurysms: Results from Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2.
In treating ruptured vertebral artery dissecting aneurysms (VADAs), neuroendovascular therapy (NET) represented by coil obliteration is considered to be a reliable intervention. However, there has been no multi-center based study in this setting so far. In this article, results of NET for ruptured VADA obtained from Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2 were assessed to elucidate the factors associated with favorable outcome. A total of 213 in JR-NET1 and 381 patients in JR-NET2 with ruptured VADA were included, and they were separately analyzed because several important datasets such as vasospasm and site of dissecting aneurysms in relation to the posterior inferior cerebellar artery (PICA) were collected only in JR-NET1. The ratio of poor World Federation of Neurosurgical Societies (WFNS) grade (4 and 5) was 48.8% and 53.9%, and the ratio of favorable outcome (modified Rankin scale, mRS 0 to 2) at 30 days after onset was 61.1 % and 49.1% in JR-NET1 and 2, respectively. In both studies, poor WFNS grade and procedural complication were independently correlated as negative factors for favorable outcome. In JR-NET1, PICA-involved lesion was also designated as a negative factor while elderly age and absence of postprocedural antithrombotic therapy was detected as other negative factors in JR-NET2. The ratios of favorable outcome in poor grade patients were 25.4% in JR-NET1 and 31.3% in JR-NET2, which seemed compatible with the previous studies. These results may provide a baseline data for the NET in this disease and could be useful for validating the benefits of novel devices.


Recombinant therapeutic protein production in cultivated mammalian cells: current status and future prospects.
Recombinant therapeutic proteins produced in mammalian cells represent a major class of biopharmaceuticals. In recent years, their demand has increased dramatically and is now driving the development of a variety of improvements to maximize their expression in mammalian cells. Advances in media- and process optimization have already resulted in more than 100-fold improvement in yield, but further insights and subsequent targeted modifications with respect to the general biology of cells (genomics, physiology, selection and adaptation) in bioreactors are hoped to further improve protein yields and quality in the near future.:


Telomerase dysregulation in the hippocampus of a rat model of depression: normalization by lithium.
Telomeres are protective DNA-protein complexes at the ends of each chromosome, maintained primarily by the enzyme telomerase. Shortening of the blood leukocyte telomeres is associated with aging, several chronic diseases, and stress, eg, major depression. Hippocampus is pivotal in the regulation of cognition and mood and the main brain region of telomerase activity. Whether there is telomere dysfunction in the hippocampus of depressed subjects is unknown. Lithium, used in the treatment and relapse prevention of mood disorders, was found to protect against leukocyte telomere shortening in humans, but the mechanism has not been elucidated. To answer the questions whether telomeres are shortened and the telomerase activity changed in the hippocampus and whether lithium could reverse the process, we used a genetic model of depression, the Flinders Sensitive Line rat, and treated the animals with lithium. Telomere length, telomerase reverse transcriptase (Tert) expression, telomerase activity, and putative mediators of telomerase activity were investigated in the hippocampus of these animals. The naïve Flinders Sensitive Line had shorter telomere length, downregulated Tert expression, reduced brain-derived neurotrophic factor levels, and reduced telomerase activity compared with the Flinders Resistant Line controls. Lithium treatment normalized the Tert expression and telomerase activity in the Flinders Sensitive Line and upregulated β-catenin. This is the first report showing telomere dysregulation in hippocampus of a well-defined depression model and restorative effects of lithium treatment. If replicated in other models of mood disorder, the findings will contribute to understanding both the telomere function and the mechanism of lithium action in hippocampus of depressed patients.


Effect of supplementation of drumstick (Moringa oleifera) and amaranth (Amaranthus tricolor) leaves powder on antioxidant profile and oxidative status among postmenopausal women.
Menopause is a gradual three-stage process that concludes with the end of periods and reproductive life. The antioxidant enzyme system get affected in postmenopause due to deficiency of estrogen, which has got antioxidant properties. The objective of the present study was therefore, to analyze the effect of supplementation of drumstick and amaranth leaves powder on blood levels of antioxidant and marker of oxidative stress. Ninety postmenopausal women aged 45-60 years were selected and divided into three groups viz. Group I, II and III having thirty subjects in each group. The subjects of group II and III were supplemented daily with 7 g drumstick leaves powder (DLP) and 9 g amaranth leaves powder (ALP), respectively for a period of 3 months in their diet. The subjects of group I was not given supplementation. Serum retinol, serum ascorbic acid, glutathione peroxidase, superoxide dismutase and malondialdehyde were analyzed before and after supplementation. Fasting blood glucose and haemoglobin level of the subjects were also analyzed. The data revealed that supplementation of DLP and ALP significantly increased serum retinol (8.8 % and 5.0 %), serum ascorbic acid (44.4 % and 5.9 %), glutathione peroxidase (18.0 % and 11.9 %), superoxide dismutase (10.4 % and 10.8) whereas decrease in marker of oxidative stress i.e. malondialdehyde (16.3 % and 9.6 %) in postmenopausal women of group II and group III, respectively. A significant (p ≤ 0.01) decrease was also observed in fasting blood glucose level (13.5 % and 10.4 %) and increase in haemoglobin (17.5 % and 5.3 %) in group II and group III, respectively. The results indicated that these plants possess antioxidant property and have therapeutic potential for the prevention of complications during postmenopause.


Stereoselective arene formation.
While aromatic hydrocarbons are ubiquitous in organic chemistry, they are typically not associated with chirality and stereoisomerism. Due to the planarity and symmetry of simple arenes, methods to assemble aromatic rings are not routinely considered for the stereoselective synthesis of chiral compounds. The aim of this tutorial review is to contrast this common perception with the counterintuitive circumstance that stereoselective arene formation offers a means to stereoselectively prepare an exceptional range of chiral aromatic structures. The versatility of these methods across various types of molecular scaffolds allows to control stereocentre configuration, helical chiral compounds, the configuration of rotationally restricted stereogenic axes, planar chiral molecules or curved polyaromatic systems. Furthermore, stereoselective arene formation holds great promise for the selective construction of extended but structurally well-defined chiral structures.


The relationship between stunting and overweight among children from South Africa: Secondary analysis of the National Food Consumption Survey--Fortification Baseline I.
Globally, in children the prevalence of overweight and obesity is increasing, and this is associated with an increased risk of non-communicable diseases in adulthood. There is a need to examine the growing trends of overweight and obesity in children and their consequences in low- and middle-income countries. To describe the prevalence of, and determine the relationship between, stunting and overweight among children in two provinces of South Africa. Secondary data analysis was conducted on anthropometric measurements of 36-119-month-old children from Gauteng and Mpumalanga provinces (N=519) participating in the South African National Food Consumption Survey--Fortification Baseline I (2005). The International Obesity Task Force (IOTF) body mass index (BMI) reference percentiles were used to determine overweight and obesity. The World Health Organization standards were used to derive z-scores. The prevalence of overweight was 12.0% (IOTF BMI≥25 kg/m2), including 3.7% obesity (IOTF BMI≥30 kg/m2). The predominantly urban Gauteng Province had a significantly higher prevalence of overweight children (14.1%) compared with Mpumalanga (6.3%) (p=0.0277). The prevalence of stunting was 17.0% (16.5% Gauteng, 18.2% Mpumalanga; p>0.05). There was a significant correlation (r=-0.32) between BMI and height-for-age z-scores (p<0.0001). In the obese group, 68.4% were stunted, while in the normal and underweight group only 13.6% were stunted. Stunted children were more likely to be obese. Further research is necessary for clarity on the physiological mechanisms of this relationship. In the interim, prevention of stunting requires priority.


Anti-Toxoplasma antibodies in Egyptian rheumatoid arthritis patients.
To assess seroprevalence of anti-Toxoplasma gondii antibodies; both IgG and IgM in Egyptian rheumatoid arthritis (RA) patients versus a non-RA group and to compare anti-Toxoplasma antibodies seroprevalence among RA patients receiving traditional treatment and RA patients treated with biologic drug. 60 RA patients and 60 healthy controls were enrolled in the study. Patients were categorized into two groups: one group included 30 patients receiving disease modifying anti-rheumatic drugs (DMARDs), while the other group included 30 patients receiving biologic agent, infliximab, a TNF-α antagonist. Serum samples of all investigated persons were examined for anti-Toxoplasma antibodies. RA activity markers including rheumatoid factor, anti-cyclic citrullinated protein antibodies, C reactive protein, ESR in addition to disease activity score 28 (DAS28) of RA patients were also evaluated to explore their association with Toxoplasma seropositivity. Anti-Toxoplasma IgG antibodies were detected among 46/60 RA patients (76.7%) versus 29/60 controls (48.3%), (p = 0.001). Anti-Toxoplasma IgG titre was higher among RA group [median, (range) = 232.940 (8.949-653.242) IU/ml] than among controls [median, (range) = 68.820 (2.450-318.945) IU/ml], (p < 0.001). No difference was detected among RA patients either on traditional or biologic treatment regarding anti-Toxoplasma IgG antibodies. No positive anti-Toxoplasma IgM was detected. A positive correlation was detected between anti-Toxoplasma IgG titre and disease activity markers. Higher seroprevalence of anti-Toxoplasma IgG antibodies among RA patients compared to controls reflects an association between latent Toxoplasma infection and RA. Our findings support previous studies and necessitate future large-scale studies to elucidate the exact role of Toxoplasma whether a trigger of autoimmunity in RA or an effect of immunosuppression.


Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family.
The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated alphaA-crystallin we used the bioinformatics tool of the ExPASy server. Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n=30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n=96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended alpha-helical structure is predicted in this region. The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the alphaA-crystallin for functional integrity in the lens.


Efficacy of manual therapy treatments for people with cervicogenic dizziness and pain: protocol of a randomised controlled trial.
Cervicogenic dizziness is a disabling condition characterised by postural unsteadiness that is aggravated by cervical spine movements and associated with a painful and/or stiff neck. Two manual therapy treatments (Mulligan's Sustained Natural Apophyseal Glides (SNAGs) and Maitland's passive joint mobilisations) are used by physiotherapists to treat this condition but there is little evidence from randomised controlled trials to support their use. The aim of this study is to conduct a randomised controlled trial to compare these two forms of manual therapy (Mulligan glides and Maitland mobilisations) to each other and to a placebo in reducing symptoms of cervicogenic dizziness in the longer term and to conduct an economic evaluation of the interventions. Participants with symptoms of dizziness described as imbalance, together with a painful and/or stiff neck will be recruited via media releases, advertisements and mail-outs to medical practitioners in the Hunter region of NSW, Australia. Potential participants will be screened by a physiotherapist and a neurologist to rule out other causes of their dizziness. Once diagnosed with cervciogenic dizziness, 90 participants will be randomly allocated to one of three groups: Maitland mobilisations plus range-of-motion exercises, Mulligan SNAGs plus self-SNAG exercises or placebo. Participants will receive two to six treatments over six weeks. The trial will have unblinded treatment but blinded outcome assessments. Assessments will occur at baseline, post-treatment, six weeks, 12 weeks, six months and 12 months post treatment. The primary outcome will be intensity of dizziness. Other outcome measures will be frequency of dizziness, disability, intensity of cervical pain, cervical range of motion, balance, head repositioning, adverse effects and treatment satisfaction. Economic outcomes will also be collected. This paper describes the methods for a randomised controlled trial to evaluate the effectiveness of two manual therapy techniques in the treatment of people with cervicogenic dizziness for which there is limited established evidence-based treatment. ACTRN12611000073909.


Promotoras Can Facilitate Use of Recreational Community Resources: The Mi Corazón Mi Comunidad Cohort Study.
Limited research has documented interventions aimed at promoting use of existing recreational community resources among underserved populations. This study (HEART [Health Education Awareness Research Team] Phase 2) reports findings of an intervention (Mi Corazón Mi Comunidad) where community health workers facilitated use of diet and exercise programming at local recreational facilities among Mexican American border residents. The aim was to evaluate overall attendance rates and to assess which factors predicted higher attendance. The design was a cohort study. From 2009 to 2013, a total of 753 participants were recruited across 5 consecutive cohorts. The intervention consisted of organized physical activity and nutrition programming at parks and recreational facilities and a free YWCA membership. Attendance at all activities was objectively recorded. Regression analyses were used to evaluate whether demographic factors, health status, and health beliefs were associated with attendance. Results Participants included mostly females at high risk for cardiovascular disease (72.4% were overweight/obese and 64% were [pre-]hypertensive). A total of 83.6% of participants attended at least one session. On average, total attendance was 21.6 sessions (range: 19.1-25.2 sessions between the different cohorts), including 16.4 physical activity and 5.2 nutrition sessions. Females (p = .003) and older participants (p < .001) attended more sessions. Participants low in acculturation (vs. high) attended on average seven more sessions (p = .003). Greater self-efficacy (p < .001), perceived benefits (p = .038), and healthy intentions (p = .024) were associated with higher attendance. Conclusions The intervention was successful in promoting use of recreational facilities among border residents at high risk for cardiovascular disease. Findings were similar across five different cohorts.


Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression.
Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear, induction of endogenous retroelements (EREs) has been hypothesised. Using RNA sequencing (RNA-seq), we compared the transcription of EREs in bone marrow HSCs from a new cohort of MDS and chronic myelomonocytic leukaemia (CMML) patients before and after 5-AZA treatment with HSCs from healthy donors and AML patients. We further examined ERE transcription using the most comprehensive annotation of ERE-overlapping transcripts expressed in HSCs, generated here by de novo transcript assembly and supported by full-length RNA-seq. Consistent with prior reports, we found that treatment with 5-AZA increased the representation of ERE-derived RNA-seq reads in the transcriptome. However, such increases were comparable between treatment responses and failures. The extended view of HSC transcriptional diversity offered by de novo transcript assembly argued against 5-AZA-responsive EREs as determinants of the outcome of therapy. Instead, it uncovered pre-treatment expression and alternative splicing of developmentally regulated gene transcripts as predictors of the response of MDS and CMML patients to 5-AZA treatment. Our study identifies the developmentally regulated transcriptional signatures of protein-coding and non-coding genes, rather than EREs, as correlates of a favourable response of MDS and CMML patients to 5-AZA treatment and offers novel candidates for further evaluation.


Disease distribution of beta 2-glycoprotein I-dependent anticardiolipin antibodies in rheumatic diseases.
We investigated the clinical significance of IgG beta 2-glycoprotein I (GPI)-dependent anticardiolipin antibodies (aCL) in rheumatic diseases. Three hundred and seventeen patients were entered. They consisted of 133 patients with SLE, 60 with RA, 45 with SSc, 37 with PM, 23 with overlap syndrome (overlap), and 19 with unclassified connective tissue disease (UCTD). IgG beta 2-GPI-dependent aCL were examined by ELISA. While IgG beta 2-GPI-dependent aCL were detected in 13% of patients with SLE, these aCL were positive in two patients with SSc, two with overlap and 14 with UCTD. A significant association between IgG beta 2-GPI-dependent aCL and thrombosis was found. Clinical manifestations were studied in 32 patients with secondary APS based on SLE and 14 with primary APS (PAPS). Incidence of malar rash, arthritis, renal disorder, leucopenia, immunological disorders and hypocomplementemia were significantly less frequent in patients with PAPS. IgG beta 2-GPI-dependent aCL were detected in all patients with PAPS and in 34% of secondary APS. This difference was significant. These data suggest that IgG beta 2-dependent aCL are useful for identifying a subset in patients with APS.


Prognostic value of cervical nodal tumor volume in nasopharyngeal carcinoma: Analysis of 1230 patients with positive cervical nodal metastasis.
To investigate the variability and prognostic value of nodal tumor volume (NTV) in nasopharyngeal carcinoma (NPC). Data on 1230 patients with newly diagnosed stage T1-4N1-3M0 NPC treated with definitive radiation therapy with or without chemotherapy at a single cancer center were reviewed. NTV was determined from dose volume histogram (DVH) data. X-tile analysis was applied to identify the optimal cut-off points for the NTV with respect to regional recurrence-free survival (RRFS). Correlations between the TNM classification system, NTV and RRFS were assessed using a Cox regression model. Cross-validation based on receiver operating characteristic (ROC) curve analysis was applied to compare the prognostic predictive validity of NTV and N categories. Within a median follow-up of 49.9 (range, 1.27-76.40) months, 61/1230 (5%) patients developed regional recurrence and 154 (12.5%) developed distant metastasis. NTV values of 7.2 cc and 35.7 cc were identified as the optimal cut-off points. Patients with larger NTV had poorer prognosis. Compared with the N category, NTV was better at determining RRFS for patients with NPC. Hazard ratios increased with NTV, ranging from 1.86 (95% confidence interval [95% CI], 0.92-3.78) for NTV between 7.2 cc to 35.7 cc, and 3.67 (95% CI, 1.58-8.50) for NTV > 35.7 cc. With both NTV and N category in the same Cox regression model, only NTV remained statistically significant in the RRFS of NPC. The validation results with ROC curves also revealed that, NTV was superior to N category for predicting RRFS with significantly larger area under the ROC curve. NTV offers important prognostic value for treatment outcomes in NPC, especially regional control. Volumetric analysis of nodal involvement may assist selection of patients with poor prognosis.


Review of EEG-based pattern classification frameworks for dyslexia.
Dyslexia is a disability that causes difficulties in reading and writing despite average intelligence. This hidden disability often goes undetected since dyslexics are normal and healthy in every other way. Electroencephalography (EEG) is one of the upcoming methods being researched for identifying unique brain activation patterns in dyslexics. The aims of this paper are to examine pros and cons of existing EEG-based pattern classification frameworks for dyslexia and recommend optimisations through the findings to assist future research. A critical analysis of the literature is conducted focusing on each framework's (1) data collection, (2) pre-processing, (3) analysis and (4) classification methods. A wide range of inputs as well as classification approaches has been experimented for the improvement in EEG-based pattern classification frameworks. It was uncovered that incorporating reading- and writing-related tasks to experiments used in data collection may help improve these frameworks instead of using only simple tasks, and those unwanted artefacts caused by body movements in the EEG signals during reading and writing activities could be minimised using artefact subspace reconstruction. Further, support vector machine is identified as a promising classifier to be used in EEG-based pattern classification frameworks for dyslexia.


Injuries and injury prevention during foot marching.
Since the beginning of recorded history, Soldiers have carried arms and equipment on their bodies. More recently, loads have substantially increased, driven by improvements in weapons technology and personal protection. As Soldier loads increase, there are increases in energy cost, altered gait mechanics, increased stress on the musculoskeletal system, and more rapid fatigue, factors that may increase the risk of injury. Common injuries and symptoms experienced by Soldiers on load-carriage missions include foot blisters, metatarsalgia, knee problems, and back problems. This article discusses these problems, providing diagnoses, injury mechanisms, and preventive measures. In general, lighter loads, improving load distribution, using appropriate physical training, selecting proper equipment, and using specific prevention techniques will facilitate load carriage and provide Special Operations Forces with a higher probability of mission success.


The relationship between population-level exposure to alcohol advertising on television and brand-specific consumption among underage youth in the US.
We investigated the population-level relationship between exposure to brand-specific advertising and brand-specific alcohol use among US youth. We conducted an internet survey of a national sample of 1031 youth, ages 13-20, who had consumed alcohol in the past 30 days. We ascertained all of the alcohol brands respondents consumed in the past 30 days, as well as which of 20 popular television shows they had viewed during that time period. Using a negative binomial regression model, we examined the relationship between aggregated brand-specific exposure to alcohol advertising on the 20 television shows [ad stock, measured in gross rating points (GRPs)] and youth brand-consumption prevalence, while controlling for the average price and overall market share of each brand. Brands with advertising exposure on the 20 television shows had a consumption prevalence about four times higher than brands not advertising on those shows. Brand-level advertising elasticity of demand varied by exposure level, with higher elasticity in the lower exposure range. The estimated advertising elasticity of 0.63 in the lower exposure range indicates that for each 1% increase in advertising exposure, a brand's youth consumption prevalence increases by 0.63%. At the population level, underage youths' exposure to brand-specific advertising was a significant predictor of the consumption prevalence of that brand, independent of each brand's price and overall market share. The non-linearity of the observed relationship suggests that youth advertising exposure may need to be lowered substantially in order to decrease consumption of the most heavily advertised brands.


The clinical, forensic and treatment outcome factors of patients with autism spectrum disorder treated in a forensic intellectual disability service.
To describe the characteristics of those with autism spectrum disorder (ASD) treated within a forensic intellectual disability hospital and to compare them with those without ASD. Service evaluation of a cohort of 138 patients treated over a 6-year period. Of the 138, 42 had an ASD. Personality disorders and harmful use or dependence on drugs were significantly lower in the ASD group. The ASD group was less likely to be subject to criminal sections or restriction orders. Self-harm was significantly higher in the ASD group. There were no differences in the length of stay and direction of care pathway. Although the ASD and non-ASD groups differ on clinical and forensic characteristics, their treatment outcomes appear similar. This suggests that the diagnostic category of ASD alone may be inadequate in predicting the treatment outcome. There is a case to identify distinct typologies within the ASD group.


When emotional valence modulates audiovisual integration.
We constantly integrate the information that is available to our various senses. The extent to which the mechanisms of multisensory integration are subject to the influences of attention, emotion, and/or motivation is currently unknown. The "ventriloquist effect" is widely assumed to be an automatic crossmodal phenomenon, shifting the perceived location of an auditory stimulus toward a concurrently presented visual stimulus. In the present study, we examined whether audiovisual binding, as indicated by the magnitude of the ventriloquist effect, is influenced by threatening auditory stimuli presented prior to the ventriloquist experiment. Syllables spoken in a fearful voice were presented from one of eight loudspeakers, while syllables spoken in a neutral voice were presented from the other seven locations. Subsequently, participants had to localize pure tones while trying to ignore concurrent visual stimuli (both the auditory and the visual stimuli here were emotionally neutral). A reliable ventriloquist effect was observed. The emotional stimulus manipulation resulted in a reduction of the magnitude of the subsequently measured ventriloquist effect in both hemifields, as compared to a control group exposed to a similar attention-capturing, but nonemotional, manipulation. These results suggest that the emotional system is capable of influencing multisensory binding processes that have heretofore been considered automatic.


Dorsal medullary cavernous hemangioma presenting as obstinate hiccups and its surgical treatment: illustrative case.
Hiccups are characterized by involuntary, intermittent, repetitive, myoclonic, and spasmodic contractions of the diaphragm. Hiccups are termed "intractable" when they last for over 1 month. A rare case of intractable hiccups due to an uncommon location of cavernous hemangioma in the dorsal medulla is illustrated. With respect to the management, surgical excision was performed, and postsurgical complete recovery was witnessed, which has been reported only in six cases worldwide to date. A mechanism of the hiccups reflex arc is discussed in detail with special reference to the need for equal emphasis on evaluating central nervous system causes and peripheral etiologies for pertinent hiccups.


Comparing the Neuropsychiatric Profile of Patients with Alzheimer Disease Who Present Spared versus Impaired Executive Functioning.
Background. A "dysexecutive" group of patients with Alzheimer disease (AD) has been previously identified, and these patients have been found to present higher frequency of psychiatric symptoms and more pronounced functional impact. This study aimed at evaluating the frequency of neuropsychiatric symptoms in patients with early AD who present with impaired executive functioning. Methods. Thirty patients with early AD diagnosis were divided into a spared (SEF) and an impaired (IEF) executive functioning group according to their performance scores on neuropsychological tests. Their closest relatives or caregivers completed the Cambridge behavioral inventory (CBI), which assesses behavioral symptoms grouped into 13 categories. Results. A significant difference was exclusively found between SEF and IEF in terms of the frequency of stereotypies and repetitive motor behavior (U = 60.5, P = .024). Conclusions. The presence of stereotypies could be associated with a dysexecutive profile in AD patients. These results shed light on the role of frontal circuitry in the expression of motor symptoms in AD and prompt for further research that will contribute to the differential diagnosis both of different subtypes of AD and other types of dementia.


'Say no': a feasibility trial of a brief intervention to reduce instances of indulgent energy-intake episodes.
The aim of this study is to examine the feasibility of a brief intervention to reduce instances of indulgent energy intake. Forty-five participants with a body mass index (BMI) ≥25 kg m-2 were randomized to one of three groups for 8 weeks. The control group was asked to complete a questionnaire every 4 days, the self-monitoring group was given the same instructions but also asked to 'say no' to indulgences. The self-monitoring and feedback group was asked to do the same but in addition to send a photograph or description of that to which they had 'said no' and were then provided with feedback. All participants reported on indulgences for 7 days prospectively at baseline and 8-week follow-up. The follow-up rate was 80%; completion of questionnaires was 63% and 87 text messages were sent. The control group reduced their indulgences by 4.1 (SD 10.0), the self-monitoring group by 13.8 (SD 16.8) and self-monitoring and feedback group by 9.0 (SD 11.7) per week. All bar one, feasibility progression criteria were met and this was the return of the indulgence diaries during the intervention period. The study demonstrates the feasibility of a brief intervention to reduce the number of indulgences people ate. The progression criteria were met and areas of improvement are highlighted.


Effects of a cognitive behavioural treatment in patients with type 2 diabetes when added to managed care; a randomised controlled trial.
Effects of a cognitive behavioural treatment (CBT) in type 2 diabetes patients were studied in a randomised controlled trial. Patients were recruited from a diabetes care system (DCS). The intervention group (n = 76) received managed care from the DCS and CBT. The control group (n = 78) received managed care only. Effects on risk of developing coronary heart disease (CHD), clinical characteristics, lifestyle, determinants of behaviour change, quality of life, and depression were assessed after 6 and 12 months. The intervention did not result in a significant reduction of CHD risk (difference between intervention and control group was -0.32 % (95 % CI: -2.27; 1.63). The amount of heavy physical activity increased significantly in the intervention group at 6 months [intervention versus control group was 20.14 min/day (95 % CI: 4.6; 35.70)]. Quality of life and level of depression improved as well. All effects disappeared after 6 months. No effects were found on clinical characteristics.


Incorporating a virtual curriculum into ophthalmology education in the coronavirus disease-2019 era.
The purpose of this review is to describe the transition of ophthalmology education to a virtual curriculum during the COVID-19 pandemic. We highlight innovative solutions ophthalmic educators implemented for medical students, residents, and fellows. Clinical and surgical ophthalmology volume abruptly decreased in March 2020 as a result of the COVID-19 public health crisis. All didactics, grand rounds, and journal clubs shifted to an online format. Ophthalmic educators collaborated with other institutions in the United States and abroad on shared virtual curricula and seminars, and simulation-based training tools were better emphasized for surgical skill acquisition. We share the latest literature written by ophthalmic educators on successful adaptation of these new instructional strategies. The COVID-19 pandemic transformed ophthalmology education overnight and accelerated the adoption of innovative e-virtual learning resources for trainees. These changes will undoubtedly remain part of the new paradigm of medical education in the post-COVID era.


The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.
Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.


Efficient antioxidant defence systems of spring barley in response to stress induced jointly by the cyst nematode parasitism and cadmium exposure.
This research aimed to establish how Hordeum vulgare responds to abiotic and biotic stress affecting in tandem. Plants were inoculated with Heterodera filipjevi and treated with cadmium (Cd) concentration (5 μM) that can occur in the cultivated soil. To verify the hypothesis about participation of increased antioxidative defence in H. vulgare under stress, biochemical and microscopic methods were implemented. The amount of superoxide anions and hydrogen peroxide was diminished in plants that were both nematode-inoculated and cadmium-treated. Superoxide anions were rendered harmless by increased activity of superoxide dismutase, and H2O2 was scavenged via Foyer-Halliwell-Asada pathway. The unique enhanced antioxidant capacity of double stressed plants was also linked with the accumulation of S-nitrosoglutathione as nitrosoglutathione reductase activity was inhibited. Furthermore, stimulated activity of arginase in these plants could promote polyamine synthesis and indirectly enhance non-enzymatic antioxidant mechanism. Results indicate that different antioxidants operating together significantly restricted oxidation of lipids and proteins, thus the integrity of cell membranes and protein functions were maintained. The ROS deactivation machinery in barley leaves showed an unusual response during stress induced by H. filipjevi infection and cadmium treatment. Plants could induce a multi-component model of stress response, to detoxify Cd ions and efficiently repair stress damage.


Black magnetic spherule fallout in the eastern gulf of Mexico.
Large numbers of black metallic spherules ranging in diameter from a few micrometers to over 800 micrometers are raining into the eastern Gulf of Mexico and adjacent areas of western Florida. The composition of the flux, its association with glass spherules and coky particles, and its magnitude point to industrial pollution, probably coal- and coke-burning facilities around the perimeter of the gulf, as the source. Since metallic particles represent only a small fraction of most fly ash, such an influx of large numbers of black magnetic spherules must be symptomatic of a much higher rate of sedimentation of fly ash. The internal microstructures and the general appearance of spherules derived from industrial processes are similar to those of particles derived from cosmic sources. Because of the high potential for contamination in micrometeorite studies, a complete compositional verification of each "cosmic" particle may be necessary.


Reflections on key methodological decisions in national burden of disease assessments.
Summary measures of population health are increasingly used in different public health reporting systems for setting priorities for health care and social service delivery and planning. Disability-adjusted life years (DALYs) are one of the most commonly used health gap summary measures in the field of public health and have become the key metric for quantifying burden of disease (BoD). BoD methodology is, however, complex and highly data demanding, requiring a substantial capacity to apply, which has led to major disparities across researchers and nations in their resources to perform themselves BoD studies and interpret the soundness of available estimates produced by the Global Burden of Disease Study. BoD researchers from the COST Action European Burden of Disease network reflect on the most important methodological choices to be made when estimating DALYs. The paper provides an overview of eleven methodological decisions and challenges drawing on the experiences of countries working with BoD methodology in their own national studies. Each of these steps are briefly described and, where appropriate, some examples are provided from different BoD studies across the world. In this review article we have identified some of the key methodological choices and challenges that are important to understand when calculating BoD metrics. We have provided examples from different BoD studies that have developed their own strategies in data usage and implementation of statistical methods in the production of BoD estimates. With the increase in national BoD studies developing their own strategies in data usage and implementation of statistical methods in the production of BoD estimates, there is a pressing need for equitable capacity building on the one hand, and harmonization of methods on the other hand. In response to these issues, several BoD networks have emerged in the European region that bring together expertise across different domains and professional backgrounds. An intensive exchange in the experience of the researchers in the different countries will enable the understanding of the methods and the interpretation of the results from the local authorities who can effectively integrate the BoD estimates in public health policies, intervention and prevention programs.


Three-Dimensional Accuracy of Digital Implant Impressions: Effects of Different Scanners and Implant Level.
To compare the three-dimensional (3D) accuracy of conventional direct implant impressions with digital implant impressions from three intraoral scanners, as well as different implant levels-bone level (BL) and tissue level (TL). Two-implant master models were used to simulate a threeunit implant-supported fixed dental prosthesis. Conventional test models were made with direct impression copings and polyether impressions. Scan bodies were hand-tightened onto master models and scanned with the three scanners. This was done for the TL and BL test groups, for a total of eight test groups (n = 5 each). A coordinate measuring machine measured linear distortions (dx, dy, dz), global linear distortion (dR), angular distortions (dθy, dθx), and absolute angular distortions (Absdθy, Absdθx) between the master models, test models, and .stl files of the digital scans. The mean dR ranged from 35 to 66 μm; mean dθy angular distortions ranged from -0.186 to 0.315 degrees; and mean dθx angular distortions ranged from -0.206 to 0.164 degrees. Two-way analysis of variance showed that the impression type had a significant effect on dx, dz, and Absdθy, and the implant level had a significant effect on dx and Absdθx (P < .05). Among the BL groups, the mean dR of the conventional group was lower than and significantly different from the digital test groups (P = .010), while among the TL groups, there was no statistically significant difference (P = .572). The 3D accuracy of implant impressions varied according to the impression technique and implant level. For BL test groups, the conventional impression group had significantly lower distortion than the digital impression groups. Among the digital test groups, the TR system had comparable mean linear and absolute angular distortions to the other two systems but exhibited the smallest standard deviations.


Morus alba L. Stem Extract Attenuates Pain and Articular Cartilage Damage in the Anterior Cruciate Ligament Transection-Induced Rat Model of Osteoarthritis.
This study was designed to investigate the anti-nociceptive effect of Morus alba stem extract as well as its cartilage protective effect in the anterior cruciate ligament transection (ACLT)-induced rat model of osteoarthritis (OA). The anti-nociceptive effect of this plant extract was determined by measuring hind limb weight bearing, while the severity of cartilage damage to the knee joints was evaluated using the modified Mankin grading system. Oral administration of M. alba stem extract (56 and 560 mg/kg) significantly attenuated joint pain as indicated by a significant (p < 0.05) increase in the values of percent weight borne on the operated hind limb for the OA-induced groups that received M. alba stem extract at 56 and 560 mg/kg when compared to those of the vehicle-treated OA-induced group. In addition, a significant improvement in the Mankin score was also observed in rats treated with 560 mg/kg M. alba stem extract, which was in agreement with its pain-relieving effect. The results showed that M. alba stem extract exhibited an anti-nociceptive effect as well as cartilage protection in the ACLT-induced rat model of OA, supporting its potential use as a therapeutic treatment for OA.


Narrating survival and change in Guatemala and South Africa: the politics of representation and a liberatory community psychology.
Peace accords and international interventions have contributed to the suspension of armed conflict and the censuring of repressive regimes in many parts of the world. Some governments and their opposition parties have agreed to the establishment of commissions or other bodies designed to create historical records of the violations of human rights and foster conditions that facilitate reparatory and reconciliatory processes. This paper explores selected roles that community psychologists have played in this process of remembering the past and constructing new identities towards creating a more just future. With reference to two community groups (in Guatemala and South Africa) we show how efforts to "speak out" about one's own experiences of political and military repression involve complex representational politics that go beyond the simple binary opposition of silencing versus giving voice. The Guatemalan group consisted of Mayan Ixil women who, together with the first author, used participatory action research and the PhotoVoice technique to produce a book about their past and present struggles. The South African group, working within the ambit of the Truth and Reconciliation Commission and in collaboration with the third author and others, explored ways of speaking about their roles in apartheid and post-apartheid society. Although both these initiatives can be seen as moments in on-going struggles to overcome externally-imposed repressive practices that censor the voices of marginalized communities, they also serve to dispel overly romanticized notions of "univocal" communities now liberated to express themselves in an unmediated and unequivocal fashion. The paper discusses how each group of women instead entered into subtly nuanced relationships with community psychologists involving a continual interplay between the authenticity of their self-representational accounts and the requirements of the discursive technologies into which they were being inducted and the material conditions within their sites of struggle. In both cases the group's agenda also evolved over time, so that what emerged was not so much a particular account of themselves, or even the development of a particular "voice" for speaking about themselves, but an unfolding process--for the groups and for the community psychologists who accompanied them--of becoming active players in the postmodern, mediated world of self-representational politics and social struggle.


ARA and EADV criteria for classification of systemic lupus erythematosus in patients with cutaneous lupus erythematosus.
To verify (1) how many patients with cutaneous lupus erythematosus (CLE) fulfill 4 or more American Rheumatism Association (ARA) and European Academy of Dermatology and Venereology (EADV) criteria for classification of systemic lupus erythematosus (SLE); (2) which criteria are mostly fulfilled; (3) the severity of the disease in patients fulfilling criteria; (4) how many patients with systemic involvement fail to fulfill 4 ARA and EADV criteria. We studied 207 patients with chronic and subacute CLE, classified according to ARA and EADV criteria. Twenty-four patients with localized discoid (L-DLE; 21.8%), 22 with disseminated discoid (D-DLE; 30.5%) and 7 with subacute CLE (SCLE; 28%) had 4 or more ARA criteria. With EADV criteria, these figures fell to 7 (6.4%), 7 (9.7%) and 6 (24%), respectively. Only 3 L-DLE (2.7%), 5 D-DLE (6.9%) and 3 SCLE cases (12%) defined as SLE by ARA criteria and 1, 3 and 3, respectively, by EADV criteria had a renal or neurological disorder, hemolytic anemia and/or thrombocytopenia, vasculitis or serositis. ARA criteria did not classify 7 patients with a similar visceral involvement, while EADV criteria failed in 11 patients. In our patients, ARA criteria showed a sensitivity of 88%, a specificity of 79%, a positive predictive value of 56% and a negative predictive value of 96%. EADV criteria showed a sensitivity of only 64%, but a specificity of 93%, a positive predictive value of 61% and a negative predictive value of 94%. ARA criteria should not be used in CLE patients as they are too sensitive, poorly specific and altogether misleading. EADV criteria are more specific, but less sensitive.


Cigarette dependence among males and females aged 50+ living in Izmir, Turkey.
Smoking, the most important preventable cause of death overall, is also the leading cause of cancer-related mortality. Tobacco consumption has a direct or indirect relationship with most types of cancer. In Turkey, the second leading cause of death is cancer, with lung cancer the most prevalent. The aim of this study was to determine the level of cigarette dependence among men and women aged 50+, living in Izmir. This research is a descriptive and cross-sectional field study, carried out with the participation of a total of 2,497 subjects. It was found that 48.8% of the participants used to be smokers, and 95.5% of the smoking participants had been smoking for at least 11 years at the time of study. 36.1% of the participants were being exposed to secondhand smoke at home, and almost one third of the smokers (29%) had a moderate level of dependence. Continuing education may help high-risk groups develop good habits for a healthier lifestyle such as smoking less and quitting smoking, thereby reducing the level of morbidity and mortality of most common types of cancer.


New insights in molecular mechanisms involved in chronic kidney disease using high-resolution plasma proteome analysis.
The reduced glomerular filtration rate in the advanced stages of chronic kidney disease (CKD) leads to plasma accumulation of uraemic retention solutes including proteins. It has been hypothesized that these changes may, at least in part, be responsible for CKD-associated morbidity and mortality. However, most studies focused on the role of individual proteins, while a holistic, large-scale, integrative approach may generate significant additional insight. In a discovery study, we analysed the plasma proteome of patients with stage 2-3 CKD (n = 14) and stage 5 CKD with haemodialysis (HD) (n = 15), using high-resolution LC-MS/MS analysis. Selected results were validated in a cohort of 40 patients with different CKD stages with or without HD, using ELISA. Of a total of 2054 detected proteins, 127 displayed lower, while 206 displayed higher abundance in the plasma of patients on HD. Molecular pathway analysis confirmed the modification of known processes involved in CKD complications, including decreased haemostasis and increased inflammation, complement activation and vascular damage. In addition, we identified the plasma increase during CKD progression of lysozyme C and leucine-rich alpha-2 glycoprotein, two proteins related to vascular damage and heart failure. High level of leucine-rich alpha-2 glycoprotein was associated with higher mortality in stage 5 CKD patients on HD. This study provides for the first time a comprehensive assessment of CKD plasma proteome, contributing to new knowledge and potential markers of CKD. These results will serve as a basis for future studies investigating the relevance of these molecules in CKD associated morbidity and mortality.


Real-Time Motor Cortex Mapping for the Safe Resection of Glioma: An Intraoperative Resting-State fMRI Study.
Resting-state functional MR imaging has been used for motor mapping in presurgical planning but never used intraoperatively. This study aimed to investigate the feasibility of applying intraoperative resting-state functional MR imaging for the safe resection of gliomas using real-time motor cortex mapping during an operation. Using interventional MR imaging, we conducted preoperative and intraoperative resting-state intrinsic functional connectivity analyses of the motor cortex in 30 patients with brain tumors. Factors that may influence intraoperative imaging quality, including anesthesia type (general or awake anesthesia) and tumor cavity (filled with normal saline or not), were studied to investigate image quality. Additionally, direct cortical stimulation was used to validate the accuracy of intraoperative resting-state fMRI in mapping the motor cortex. Preoperative and intraoperative resting-state fMRI scans were acquired for all patients. Fourteen patients who successfully completed both sufficient intraoperative resting-state fMRI and direct cortical stimulation were used for further analysis of sensitivity and specificity. Compared with those subjected to direct cortical stimulation, the sensitivity and specificity of intraoperative resting-state fMRI in localizing the motor area were 61.7% and 93.7%, respectively. The image quality of intraoperative resting-state fMRI was better when the tumor cavity was filled with normal saline (P = .049). However, no significant difference between the anesthesia types was observed (P = .102). This study demonstrates the feasibility of using intraoperative resting-state fMRI for real-time localization of functional areas during a neurologic operation. The findings suggest that using intraoperative resting-state fMRI can avoid the risk of intraoperative seizures due to direct cortical stimulation and may provide neurosurgeons with valuable information to facilitate the safe resection of gliomas.


Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling.
The overall neurobiological mechanisms by which lithium and valproate stabilize mood in bipolar disorder patients have yet to be fully defined. The therapeutic efficacy and dissimilar chemical structures of these medications suggest that they perturb both shared and disparate cellular processes. To investigate key pathways and functional clusters involved in the global action of lithium and valproate, we generated interaction networks formed by well-supported drug targets. Striking functional similarities emerged. Intersecting nodes in lithium and valproate networks highlighted a strong enrichment of apoptosis clusters and neurotrophin signaling. Other enriched pathways included MAPK, ErbB, insulin, VEGF, Wnt and long-term potentiation indicating a widespread effect of both drugs on diverse signaling systems. MAPK1/3 and AKT1/2 were the most preponderant nodes across pathways suggesting a central role in mediating pathway interactions. The convergence of biological responses unveils a functional signature for lithium and valproate that could be key modulators of their therapeutic efficacy.


Dermal absorption of isopropyl alcohol from a commercial hand rub: implications for its use in hand decontamination.
Isopropyl alcohol-containing hand rubs are widely used in healthcare for hand decontamination. Ten healthy adult volunteers applied a commercially available isopropyl alcohol-containing hand rub to their hands every 10 min over a 4 h period. Blood isopropyl alcohol levels were measured at the beginning and end of the study. At the end of the study, measurable blood isopropyl alcohol levels (range 0.5-1.8 mg/l) were recorded in nine subjects. We confirmed that isopropyl alcohol could be absorbed through the intact skin of adult humans. The social and medical implications are discussed.


A longitudinal study of recipients' views and experiences of intra-family egg donation.
For the past 10 years, we have been carrying out a longitudinal investigation of egg donation families in the UK; a subsample of recipients in these families had a child by egg donation from a sister or sister-in-law. In response to the current debate over the practice of intra-family donation, together with the general lack of available data on the consequences of donation between family members, we examined recipients' experiences of donation between sisters and sisters-in-law. We analysed data from a subsample of recipient mothers who were taking part in a larger investigation of gamete donation families. Mothers were visited at home and interviewed when their child was aged 1, 3, 7 and 10 years. Data from nine recipient mothers whose egg donor was either their sister or sister-in-law were examined to assess the nature of mothers', fathers' and the child's relationship with the donor, and whether mothers had disclosed the nature of their child's conception to others, including the child. The majority of recipient mothers reported positive relationships between the donor and members of their family (themselves, their partner and their children). Most mothers were happy with the donor's level of involvement with the child and reported that they and the donor maintained their social roles within the family, i.e. as mother and aunt, respectively. By age 10, two children had been told that they had been conceived using egg donation, both of whom had been told the identity of the donor. Although the sample was small, this study provides the first longitudinal data on the experiences of families created using donated gametes from a family member. Intra-family donation between sisters or sisters-in-law can be a positive experience for recipients during the first 10 years following the child's birth. Studies that are specifically designed to look at donation between family members are needed to better evaluate the practice.


Think Hard or Think Smart: Network Reconfigurations After Divergent Thinking Associate With Creativity Performance.
Evidence suggests divergent thinking is the cognitive basis of creative thoughts. Neuroimaging literature using resting-state functional connectivity (RSFC) has revealed network reorganizations during divergent thinking. Recent studies have revealed the changes of network organizations when performing creativity tasks, but such brain reconfigurations may be prolonged after task and be modulated by the trait of creativity. To investigate the dynamic reconfiguration, 40 young participants were recruited to perform consecutive Alternative Uses Tasks (AUTs) for divergent thinking and two resting-state scans (before and after AUT) were used for mapping the brain reorganizations after AUT. We split participants into high- and low-creative groups based on creative achievement questionnaire (CAQ) and targeted on reconfigurations of the two brain networks: (1) default-mode network (DMN) and (2) the network seeded at the left inferior frontal gyrus (IFG) because the between-group difference of AUT-induced brain activation located at the left IFG. The changes of post-AUT RSFCs (DMN and IFGN) indicated the prolonged effect of divergent thinking. More specifically, the alterations of RSFCIFG-AG and RSFCIFG-IPL (AG: angular gyrus, IPG: inferior parietal lobule) in the high-creative group had positive relationship with their AUT performances (originality and fluency), but not found in the low-creative group. Furthermore, the RSFC changes of DMN did not present significant relationships with AUT performances. The findings not only confirmed the possibility of brain dynamic reconfiguration following divergent thinking, but also suggested the distinct IFGN reconfiguration between individuals with different creativity levels.


Stereomotion suppression and the perception of speed: accuracy and precision as a function of 3D trajectory.
The precision and accuracy of speed discrimination performance for stereomotion stimuli were assessed for several receding 3D trajectories confined to the horizontal meridian. It has previously been demonstrated in a variety of tasks that detection thresholds are substantially higher when subjects observe a stereomotion stimulus than when simply viewing one of its component monocular half-images--a phenomenon known as stereomotion suppression (C. W. Tyler, 1971). Using monocularly visible motion in depth targets, we found mean speed discrimination thresholds to be higher for stereomotion, compared with monocular lateral speed discrimination thresholds for equivalent stimuli, demonstrating a disadvantage for binocular viewing in the case of speed discrimination as well. Furthermore, speed discrimination thresholds for motion in depth were not systematically affected by trajectory angle; hence, the disadvantage of binocular viewing persists even when there are concurrent changes in binocular visual direction. Lastly, there was a tendency for oblique trajectories of stereomotion to be perceived as faster than equally rapid motion receding directly away from the subject along the midline. Our data, in addition to earlier stereomotion suppression observations, are consistent with a stereomotion system that takes a noisy, weighted difference of the stimulus velocities in the two eyes to compute motion in depth.


Wing kinematics in a hovering dronefly minimize power expenditure.
When an insect hovers or performs constant-speed flight, its wings flap at certain amplitude, frequency, angle of attack, etc., and the flight is balanced (vertical force equals to the weight, and horizontal force and pitch moment are zero). It is possible that when some other sets of values of wing kinematical parameters are used, the force and moment balance conditions can still be satisfied. Does the wing kinematics used by a constant-speed flying insect minimize the power expenditure? In this study, whether the wing kinematics used by a freely hovering dronefly minimizes its energy expenditure was investigated. First, the power consumption using the set of values of wing kinematical parameters that was actually employed by the insect was computed. Then, the kinematical parameters were changed while keeping the equilibrium flight conditions satisfied, and the power consumption was recalculated. It was found that wing kinematical parameters used by the freely hovering dronefly are very close to that minimize its energy consumption, and they can ensure the margin of controllability from hovering to maneuvers. That is, slight change of wing kinematical parameters did not cause significant change of the specific power (maintained a relatively small value).


Precision and accuracy of single-molecule FRET measurements-a multi-laboratory benchmark study.
Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods.


Preventability of drug-related harms - part II: proposed criteria, based on frameworks that classify adverse drug reactions.
'Preventability' is a crucial concept in the literature on adverse drug effects. However, a systematic review of the definitions of preventability of adverse drug effects has suggested that none fits all circumstances. Furthermore, when the reliability of these definitions has been examined they have been found to be imperfect. To propose and outline a method for determining the theoretical preventability of an adverse drug effect, based on frameworks for classifying adverse drug reactions - the EIDOS and DoTS methods. EIDOS is based on the mechanism of action of the drug. It observes that a drug (an Extrinsic species) causes an adverse effect by interacting with an Intrinsic species that is its target when the two are Distributed together, and that the resulting pathophysiological Outcome (the adverse effect) causes the Sequela (the adverse reaction). DoTS observes that the Dose-relatedness of the adverse effect compared with the beneficial effect is relevant (determining toxic, collateral, or hypersusceptibility effects), that adverse effects have Time-courses (varying from immediate to delayed), and that there are individual Susceptibility factors. We have elicited many published examples that show that each of these factors in the causation of an adverse drug effect can be adduced to assess its preventability. We have constructed a flowchart that illustrates how the processes can be logically analysed. This approach suggests methods for devising prospective preventive strategies and for deciding retrospectively whether an adverse reaction in an individual should have been prevented.


Implementation of High-Quality Warm-White Light-Emitting Diodes by a Model-Experimental Feedback Approach Using Quantum Dot-Salt Mixed Crystals.
In this work, a model-experimental feedback approach is developed and applied to fabricate high-quality, warm-white light-emitting diodes based on quantum dots (QDs) as color-conversion materials. Owing to their unique chemical and physical properties, QDs offer huge potential for lighting applications. Nevertheless, both emission stability and processability of the QDs are limited upon usage from solution. Incorporating them into a solid ionic matrix overcomes both of these drawbacks, while preserving the initial optical properties. Here borax (Na2B4O7·10H2O) is used as a host matrix because of its lower solubility and thereby reduced ionic strength in water in comparison with NaCl. This guarantees the stability of high-quality CdSe/ZnS QDs in the aqueous phase during crystallization and results in a 3.4 times higher loading amount of QDs within the borax crystals compared to NaCl. All steps from the synthesis via mixed crystal preparation to the warm-white LED preparation are verified by applying the model-experimental feedback, in which experimental data and numerical results provide feedback to each other recursively. These measures are taken to ensure a high luminous efficacy of optical radiation (LER) and a high color rendering index (CRI) of the final device as well as a correlated color temperature (CCT) comparable to an incandescent bulb. By doing so, a warm-white LED with a LER of 341 lm/Wopt, a CCT of 2720 K and a CRI of 91.1 is produced. Finally, we show that the emission stability of the QDs within the borax crystals on LEDs driven at high currents is significantly improved. These findings indicate that the proposed warm-white light-emitting diodes based on QDs-in-borax hold great promise for quality lighting.


Tactical lighting in special operations medicine: survey of current preferences.
Success in Special Operations Forces medicine (SOFMED) is dependent on maximizing visual capability without compromising the provider or casualty position when under fire. There is no single ideal light source suitable for varied SOFMED environments. We present the results of an online survey of Special Operations Medical Operators in an attempt to determine strengths and weaknesses of current systems. There was no consensus ideal hue for tactical illumination. Most Operators own three or more lights, and most lights were not night vision compatible. Most importantly, nearly 25% of respondents reported that lighting issues contributed to a poor casualty outcome; conversely, a majority (50 of 74) stated their system helped prevent a poor outcome. Based on the results of this initial survey, we can affirm that the design and choice of lighting is critical to SOFMED success. We are conducting ongoing studies to further define ideal systems for tactical applications including field, aviation, and marine settings.


Visual rehabilitation in end-stage inflammatory ocular surface disease with the osteo-odonto-keratoprosthesis: results from the UK.
To report the long-term results of osteo-odonto-keratoprosthesis (OOKP) surgery in the visual rehabilitation of patients with corneal blindness from end-stage inflammatory ocular surface disease. A non-comparative retrospective case series of 36 consecutive patients treated at the National OOKP referral centre in Brighton, UK, between November 1996 and March 2006. A total of 36 patients, with age ranging from 19 to 87 years (mean 51 (SD 19) years), were included in the analysis. The main preoperative diagnoses were Stevens-Johnson syndrome (n = 16, or 44%), severe thermal or chemical burns (n = 6, or 17%), and mucous membrane pemphigoid (n = 5, or 14%). The remainder of the cases comprised miscellaneous causes of dry eye (n = 9, or 25%), which included one each of graft versus host disease, ectodermal dysplasia, ionising radiation damage, cicatrising conjunctivitis from topical medication, trachoma, congenital trigeminal nerve hypoplasia, linear IgA disease, Sjögren syndrome and nutritional deficiency. Follow-up ranged from 6 months to 9 years (mean 3.9 (SD 2.5) years). Anatomical retention during the entirety of the follow-up period was seen in 72% of patients. The main factor resulting in anatomical failure was resorption of the OOKP lamina, which occurred in seven cases (or 19%). Predicted resorption in three cases resulted in successful planned exchange of the lamina, but two cases underwent emergency removal of the OOKP, and two cases developed endophthalmitis. Human leucocyte antigen-matched allografts suffered a higher rate of laminar resorption. Out of the entire cohort, 30 patients (or 83%) had some improvement in vision, 28 (or 78%) achieved vision of 6/60 or better, and 19 (or 53%) achieved 6/12 or better. The best-achieved vision was retained throughout the follow-up period in 61% of cases. Survival analysis suggested that the probability of retaining vision >6/60 5 years after surgery was 53 (10)%. Vision-threatening complications occurred in nine cases (or 25%) and included endophthalmitis, retinal detachment and glaucoma. De novo glaucoma occurred in six patients (or 24%) but was seen overall in 17 patients (or 47%), 10 of whom required surgical treatment. OOKP surgery can restore useful and lasting vision in patients suffering from end-stage ocular surface disease, for whom conventional corneal surgery is not possible. The main problems seen in this study were laminar resorption, particularly in allografts, and glaucoma.


Immunological effects of recombinant feline interferon-omega (KT-80) administration in the dog.
The immunological effects of recombinant feline interferon-omega (rFeIFN-omega ; KT-80, Toray) were examined on administration to healthy dogs. The activities of whole blood cells, macrophages, and natural killer cells were enhanced. Moreover, the whole blood activity was examined when KT-80 was administered to dogs which had been diagnosed as having natural canine parvovirus (CPV) infection. Only some cases in which the activity increased until 3 hr post-administration survived. These results suggest that rFeIFN-omega (KT-80) treatment enhanced the cellular immunity of normal dogs, and could exert significant therapeutic effects on only natural CPV infected dogs with induced continuous immunoenhancement.


Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial.
Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. clinicaltrials.gov Identifier: NCT00658073.


Structures of β-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.


Prospective study of factors influencing conditional discharge from a forensic hospital: the DUNDRUM-3 programme completion and DUNDRUM-4 recovery structured professional judgement instruments and risk.
We set out to examine whether structured professional judgement instruments DUNDRUM-3 programme completion (D-3) and DUNDRUM-4 recovery (D-4) scales along with measures of risk, mental state and global function could distinguish between those forensic patients detained in a secure forensic hospital (not guilty by reason of insanity or unfit to stand trial) who were subsequently discharged by a mental health review board. We also examined the interaction between these measures and risk, need for therapeutic security and eventual conditional discharge. A naturalistic observational cohort study was carried out for 56 patients newly eligible for conditional discharge. Patients were rated using the D-3, D-4 and other scales including HCR-20, S-RAMM, START, SAPROF, PANSS and GAF and then observed over a period of twenty three months during which they were considered for conditional discharge by an independent Mental Health Review Board. The D-3 distinguished which patients were subsequently discharged by the Mental Health Review board (AUC = 0.902, p < 0.001) as did the D-4 (AUC = 0.848, p < 0.001). Item to outcome analysis showed each item of the D-3 and D-4 scales performed significantly better than random. The HCR-20 also distinguished those later discharged (AUC = 0.838, p < 0.001) as did the S-RAMM, START, SAPROF, PANSS and GAF. The D-3 and D-4 scores remained significantly lower (better) for those discharged even when corrected for the HCR-20 total score. Item to outcome analyses and logistic regression analysis showed that the strongest antecedents of discharge were the GAF and the DUNDRUM-3 programme completion scores. Structured professional judgement instruments should improve the quality, consistency and transparency of clinical recommendations and decision making at mental health review boards. Further research is required to determine whether the DUNDRUM-3 programme completion and DUNDRUM-4 recovery instruments predict those who are or are not recalled or re-offend after conditional discharge.


The Human Brain Traverses a Common Activation-Pattern State Space Across Task and Rest.
Much of our lives are spent in unconstrained rest states, yet cognitive brain processes are primarily investigated using task-constrained states. It may be possible to utilize the insights gained from experimental control of task processes as reference points for investigating unconstrained rest. To facilitate comparison of rest and task functional magnetic resonance imaging data, we focused on activation amplitude patterns, commonly used for task but not rest analyses. During rest, we identified spontaneous changes in temporally extended whole-brain activation-pattern states. This revealed a hierarchical organization of rest states. The top consisted of two competing states consistent with previously identified "task-positive" and "task-negative" activation patterns. These states were composed of more specific states that repeated over time and across individuals. Contrasting with the view that rest consists of only task-negative states, task-positive states occurred 40% of the time while individuals "rested," suggesting task-focused activity may occur during rest. Together our results suggest that brain activation dynamics form a general hierarchy across task and rest, with a small number of dominant general states reflecting basic functional modes and a variety of specific states potentially reflecting a wide variety of cognitive processes.


Gender-related differences in acute aortic dissection.
Few data exist on gender-related differences in clinical presentation, diagnostic findings, management, and outcomes in acute aortic dissection (AAD). Accordingly, we evaluated 1078 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) to assess differences in clinical features, management, and in-hospital outcomes between men and women. Of the patients enrolled in IRAD (32.1%) with AAD, 346 were women. Although less frequently affected by AAD (32.1% of AAD), women were significantly older and had more often presented later than men (P=0.008); symptoms of coma/altered mental status were more common, whereas pulse deficit was less common. Diagnostic imaging suggestive of rupture, ie, periaortic hematoma, and pleural or pericardial effusion were more commonly observed in women. In-hospital complications of hypotension and tamponade occurred with greater frequency in women, resulting in higher in-hospital mortality compared with men. After adjustment for age and hypertension, women with aortic dissection die more frequently than men (OR, 1.4, P=0.04), predominantly in the 66- to 75-year age group. Moreover, surgical outcome was worse in women than men (P=0.013); type A dissection in women was associated with a higher surgical mortality of 32% versus 22% in men despite similar delay, surgical technique, and hemodynamics. Our analysis provides insights into gender-related differences in AAD with regard to clinical characteristics, management, and outcomes; important diagnostic and therapeutic implications may help shed light on aortic dissection in women to improve their outcomes.


Mechanistic evidence for tracking the seasonality of photosynthesis with solar-induced fluorescence.
Northern hemisphere evergreen forests assimilate a significant fraction of global atmospheric CO2 but monitoring large-scale changes in gross primary production (GPP) in these systems is challenging. Recent advances in remote sensing allow the detection of solar-induced chlorophyll fluorescence (SIF) emission from vegetation, which has been empirically linked to GPP at large spatial scales. This is particularly important in evergreen forests, where traditional remote-sensing techniques and terrestrial biosphere models fail to reproduce the seasonality of GPP. Here, we examined the mechanistic relationship between SIF retrieved from a canopy spectrometer system and GPP at a winter-dormant conifer forest, which has little seasonal variation in canopy structure, needle chlorophyll content, and absorbed light. Both SIF and GPP track each other in a consistent, dynamic fashion in response to environmental conditions. SIF and GPP are well correlated (R2 = 0.62-0.92) with an invariant slope over hourly to weekly timescales. Large seasonal variations in SIF yield capture changes in photoprotective pigments and photosystem II operating efficiency associated with winter acclimation, highlighting its unique ability to precisely track the seasonality of photosynthesis. Our results underscore the potential of new satellite-based SIF products (TROPOMI, OCO-2) as proxies for the timing and magnitude of GPP in evergreen forests at an unprecedented spatiotemporal resolution.


Effects of endotracheal tube suctioning on arterial oxygen tension and heart rate variability.
The purpose of this study was to examine the autonomic mechanisms underlying changes in heart rate (HR) and systolic blood pressure (SBP) responses to endotracheal tube (ETT) suctioning and to compare the open versus closed methods of ETT suctioning on these measures and on arterial oxygen tension. Eighteen orally intubated participants, 33 to 82 years of age (M = 60 years), were randomized for the order of suctioning method. Arterial oxygen tension (PaO2) was measured before suctioning and 30 s and 5 min following suctioning. Beat-to-beat HR and arterial blood pressure data were collected for 10-min periods before and after suctioning. HR and SBP measures were analyzed before suctioning and 1 min and 5 min following suctioning. Although there were no significant effects of ETT suctioning on the autonomic mechanisms of HR modulation and no significant differences between the two methods of suctioning, ETT suctioning resulted in an increase in HR, SBP, and PaO2. However, there was a decrease in the parasympathetic nervous system indicator of HR variability (HRV) following open suctioning. All patients in this study maintained a PaO2 level 80 mm Hg, which may account for our lack of significant autonomic changes. This suggests that hyperoxygenation with 100% oxygen for a minimum of 1 min (or 20 breaths), as delivered by preoxygenation modes available on most microprocessor ventilators, should be the method of choice for all hyperoxygenation procedures to avoid a decrease in PaO2 following suctioning.


Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline.
Merkel cell carcinoma (MCC) is a rare tumour of the skin of neuro-endocrine origin probably developing from neuronal mechanoreceptors. A collaborative group of multidisciplinary experts form the European Dermatology Forum (EDF), The European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on MCC diagnosis and management, based on a critical review of the literature, existing guidelines and expert's experience. Clinical features of the cutaneous/subcutaneous nodules hardly contribute to the diagnosis of MCC. The diagnosis is made by histopathology, and an incisional or excisional biopsy is mandatory. Immunohistochemical staining contributes to clarification of the diagnosis. Initial work-up comprises ultrasound of the loco-regional lymph nodes and total body scanning examinations. The primary tumour should be excised with 1-2cm margins. In patients without clinical evidence of regional lymph node involvement, sentinel node biopsy is recommended, if possible, and will be taken into account in a new version of the AJCC classification. In patients with regional lymph node involvement radical lymphadenectomy is recommended. Adjuvant radiotherapy might be considered in patients with multiple affected lymph nodes of extracapsular extension. In unresectable metastatic MCC mono- or poly-chemotherapy achieve high remission rates. However, responses are usually short lived. Treatment within clinical trials is regarded as a standard of care in disseminated MCC.


Kinetics of retrovirus mediated gene transfer: the importance of intracellular half-life of retroviruses.
Gene therapy is a new therapeutic modality that holds vast potential for the treatment of genetic disorders. Retroviruses are used as a vehicle for the transfer of genes into mammalian cells. The process of gene transfer has been shown to depend on the cell cycle status of target cells. We constructed a mathematical model that integrates the kinetics of gene transfer with cell cycle kinetics. We define three cell populations: uninfected cells, cells with the virus in their cytoplasm, but not integrated, and infected cells, in which the viral DNA has integrated in their genome. Our model predicts that the stability of the viral particles after internalization in the cellular cytoplasm, limits the process of gene transfer. Intracellular viral half-life also limits the usefulness of synchronization experiments, used to detect cell cycle dependence of the gene transfer process. We use the predictions of our model to propose a new experimental method for the detection of cell cycle dependence of retrovirus mediated gene transfer. It is based on the maturity distributions of the infected cells, and it is independent of viral intracellular stability. Despite the importance of the viral intracellular half-life this quantity still remains unknown. An extended version of the model is used to simulate a novel experimental method that measures the intracellular retroviral half-life. Analytical solutions of a simplified model confirm our numerical results and reveal the key dimensionless groups that characterize the process of gene transfer. Knowledge of the intracellular half-life of retroviral vectors is of particular importance for the design of new vectors, especially for slowly growing target cells, such as the stem cells of the hematopoietic system.


Evolution in pancreas transplantation techniques: simultaneous kidney-pancreas transplantation using portal-enteric drainage without antilymphocyte induction.
To report initial experience with the combination of a novel technique of portal-enteric pancreas transplantation with newer immunosuppressive strategies that eliminate antilymphocyte induction therapy. A new surgical technique of pancreas transplantation has been developed with portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric). The introduction of potent immunosuppressive agents may allow simultaneous kidney and pancreas transplants (SKPT) to be performed without antilymphocyte induction. From September 1996 to November 1998, the authors performed 28 primary SKPTs with portal-enteric drainage and no antilymphocyte induction. All patients received triple immunosuppression with tacrolimus, mycophenolate mofetil, and steroids. The study group had a mean age of 38 years and a mean preoperative duration of diabetes of 25 years. Four patients (14%) had prior kidney transplants. All patients had immediate renal allograft function. Actual patient, kidney, and pancreas graft survival rates were 86%, 82%, and 82%, respectively, after a mean follow-up of 12 months. Four patients died, three as a result of cardiac events unrelated to SKPT. Five kidney and five pancreas grafts were lost, including five deaths with function and three cases of chronic rejection. The mean length of stay and total charges for the initial hospital stay were 12.5 days and $99,517. The mean number of readmissions was 2.9, and 10 patients (36%) had no readmissions. Six patients (21 %) developed acute rejection, with five (18%) receiving antilymphocyte therapy. Seven patients (25%) underwent relaparotomy, including two (7%) for intraabdominal infection. Nine patients (32%) had major infections, including three (11%) with cytomegaloviral infection. Of the 24 surviving patients, 22 (92%) are both dialysis- and insulin-free. These preliminary results suggest that SKPT with portal-enteric drainage without antilymphocyte induction can be performed with excellent outcomes.


Alpha tonoplast intrinsic protein is specifically associated with vacuole membrane involved in an autophagic process.
Autophagy in plant cells is induced by nutrient starvation. Initially, double membrane-bound organelles, termed autophagosomes, enclose a portion of cytoplasm, and then fuse with a vacuole or lysosome to give an autolysosome. Autolysosomes can be visualized by incubating cells in the presence of a membrane-permeable cysteine protease inhibitor. The inhibitor presumably decreases proteolytic degradation of the autolysosome contents that are composed of portions of cytoplasm enclosed by the membrane originating from the inner membrane of autophagosomes, and allows them to accumulate. The origin of membranes that give rise to autophagosomes and autolysosomes is unknown. Here we use an acidotropic fluorescent dye, LysoTracker Red, to label autolysosomes specifically. We demonstrate that autolysosome membranes are marked by the presence of alpha-tonoplast intrinsic protein (alpha-TIP) but not by gamma-TIP or delta-TIP. The identification of a TIP specifically associated with membranes derived from an autophagic process may help our understanding of how plant cells generate and maintain functionally distinct types of vacuoles.


Semaxinib (SU5416) as a therapeutic agent targeting oncogenic Kit mutants resistant to imatinib mesylate.
Activating mutations in the Kit receptor are frequently observed in various malignancies, pointing Kit as a molecule of interest for drug inhibition. When mutated on Asp 816 (corresponding to Asp 814 in the mouse), as preferentially found in human mastocytosis and acute myeloid leukemia, Kit became non-sensitive to imatinib mesylate (Gleevec). Erythroleukemic cells isolated from Spi-1/PU.1 transgenic mice express Kit mutated at codon 814 (Kit(D814Y) or Kit(D814V)) or codon 818 (Kit(D818Y)). Using these cells in vitro, we demonstrate that the tyrosine kinase inhibitor SU5416 (Semaxinib) induces growth arrest and apoptosis independent of the mutation type by inhibiting the functions of Kit, including Kit autophosphorylation and activation of Akt, Erk1/Erk2 and Stat3 downstream signaling pathways. These findings indicate that SU5416 may be a promising tool to kill cancer cells driven by Kit oncogenic mutations that are resistant to treatment with imatinib mesylate.