Impact of Nanomorphology on Surface Doping of Organic Semiconductors: The Pentacene-C60F48 Interface.
Establishing the rather complex correlation between the structure and the charge transfer in organic-organic heterostructures is of utmost importance for organic electronics and requires spatially resolved structural, chemical, and electronic details. Insight into this issue is provided here by combining atomic force microscopy, Kelvin probe force microscopy, photoemission electron microscopy, and low-energy electron microscopy for investigating a case study. We select the interface formed by pentacene (PEN), benchmark among the donor organic semiconductors, and a p-type dopant from the family of fluorinated fullerenes. As for Buckminsterfullerene (C60), the growth of its fluorinated derivative C60F48 is influenced by the thickness and crystallinity of the PEN buffer layer, but the behavior is markedly different. We provide a microscopic description of the C60F48/PEN interface formation and analyze the consequences in the electronic properties of the final heterostructure. For just one single layer of PEN, a laterally complete but noncompact C60F48/PEN interface is created, importantly affecting the surface work function. Nonetheless, from the very beginning of the second layer formation, the presence of epitaxial and nonepitaxial PEN domains dramatically influences the growth dynamics and extremely well packed two-dimensional C60F48 islands develop. Insightful elemental maps of the C60F48/PEN surface spatially resolve the nonuniform distribution of the dopant molecules, which leads to a heterogeneous work function landscape.


Inhibition and termination of physiological responses by GTPase activating proteins.
Physiological processes are strictly organized in space and time. However, in cell physiology research, more attention is given to the question of space rather than to time. To function as a signal, environmental changes must be restricted in time; they need not only be initiated but also terminated. In this review, we concentrate on the role of one specific protein family involved in biological signal termination. GTPase activating proteins (GAPs) accelerate the endogenously low GTP hydrolysis rate of monomeric guanine nucleotide-binding proteins (GNBPs), limiting thereby their prevalence in the active, GTP-bound form. We discuss cases where defective or excessive GAP activity of specific proteins causes significant alteration in the function of the nervous, endocrine, and hemopoietic systems, or contributes to development of infections and tumors. Biochemical and genetic data as well as observations from human pathology support the notion that GAPs represent vital elements in the spatiotemporal fine tuning of physiological processes.


Enhanced expression of Organic Cation Transporters in bronchial epithelial cell layers following insults associated with asthma - Impact on salbutamol transport.
Increasing evidence suggests Organic Cation Transporters (OCT) might facilitate the absorption of inhaled bronchodilators, including salbutamol, across the lung epithelium. This is essentially scarred and inflamed in asthma. Accordingly, the impact of epithelial insults relevant to asthma on OCT expression and salbutamol transport was evaluated in air-liquid interfaced layers of the human broncho-epithelial cell line Calu-3. These were physically injured and allowed to recover for 48h or exposed to the pro-inflammatory stimulant lipopolysaccharide (LPS) for 48h and the aeroallergen house dust mite (HDM) for 8h twice over 48h. Increases in transporter expression were measured following each treatment, with the protein levels of the OCTN2 subtype consistently raised by at least 50%. Interestingly, OCT upregulation upon LPS and HDM challenges were dependent on an inflammatory event occurring in the cell layers. Salbutamol permeability was higher in LPS exposed layers than in their untreated counterparts and in both cases, was sensitive to the OCT inhibitor tetraethylammonium. This study is the first to show epithelial injury, inflammation and allergen abuse upregulate OCT in bronchial epithelial cells, which might have an impact on the absorption of their substrates in diseased lungs.


Astroglial activation and altered amyloid metabolism in human repetitive concussion.
To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood-brain barrier (BBB) impairment. A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25-12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). The main outcome measures were CSF concentrations of astroglial activation markers (glial fibrillary acidic protein [GFAP] and YKL-40), markers reflecting amyloid precursor protein metabolism (Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ), and BBB function (CSF:serum albumin ratio). Nine of the 28 athletes returned to play within a year, while 19 had persistent PCS >1 year. Athletes with PCS >1 year had higher RPQ scores and number of concussions than athletes with PCS <1 year. Median concentrations of GFAP and YKL-40 were higher in athletes with PCS >1 year compared with controls, although with an overlap between the groups. YKL-40 correlated with RPQ score and the lifetime number of concussions. Athletes with rcTBI had lower concentrations of Aβ40 and Aβ42 than controls. The CSF:serum albumin ratio was unaltered. This study suggests that PCS may be associated with biomarker evidence of astroglial activation and β-amyloid (Aβ) dysmetabolism in the brain. There was no clear evidence of Aβ deposition as Aβ40 and Aβ42 were reduced in parallel. The CSF:serum albumin ratio was unaltered, suggesting that the BBB is largely intact in PCS.


Dogs fail to recognize a human pointing gesture in two-dimensional depictions of motion cues.
Few studies have investigated biological motion perception in dogs and it remains unknown whether dogs recognise the biological identity of two-dimensional animations of human motion cues. To test this, we assessed the dogs' (N = 32) responses to point-light displays of a human performing a pointing gesture towards one of two pots. At the start of the experiment the demonstrator was a real-life person, but over the course of the test dogs were presented with two-dimensional figurative representations of pointing gestures in which visual information was progressively removed until only the isolated motion cues remained. Dogs' accuracy was above chance level only with real-life and black-and-white videos, but not with the silhouette or the point-light figure. Dogs' accuracy during these conditions was significantly lower than in the real-life condition. This result could not be explained by trial order since dogs' performance was still not higher than chance when only the point-light figure condition was presented after the initial demonstration. The results imply that dogs are unable to recognise humans in two-dimensional depictions of human motion cues only. In spite of extensive exposure to human movement, dogs need more perceptual cues to detect equivalence between human two-dimensional animations and the represented living entity.


The role of p53 in hypoxia-induced apoptosis.
Hypoxia represents one of the most physiologically relevant stresses, having significant roles in both normal development and malignant progression. Exposure to severe hypoxia leads to the accumulation of p53 which can in turn lead to rapid apoptosis. In contrast to the response to DNA-damaging agents, hypoxia-induced p53 has little or no transcriptional transactivation capabilities and instead seems to function primarily as a transrepressor in order to induce apoptosis.


Transcript levels of the soluble sperm factor protein phospholipase C zeta 1 (PLCζ1) increase through induced spermatogenesis in European eel.
Activation at fertilization of the vertebrate egg is triggered by Ca(2+) waves. Recent studies suggest the phospholipase C zeta (PLCζ), a sperm-specific protein, triggers egg activation by an IP3-mediated Ca(2+) release and allow Ca(2+) waves at fertilization. In the present study we cloned, characterized, and phylogenetically positioned the European eel PLCζ (PLCζ1). It is 1521 bp long, with 10 exons encoding an open reading frame of 506 amino acids. The amino acid sequence contains an EF-hand domain, X and Y catalytic domains, and a carboxy-terminal C2 domain, all typical of other PLCζ orthologous. The tissue distribution was studied, and the gene expression was determined in testis during induced sexual maturation at three different thermal regimes. Also, brain and pituitary expression was studied through sex maturation at constant temperature. plcζ1 was expressed in brain of male and female, in testis but not in ovaries. By first time in vertebrates, it is reported plcζ1 expression in the pituitary gland. Testis plcζ1 expression increased through spermatogenesis under all the thermal regimes, but being significantly elevated at lower temperatures. It was very low when testis contained only spermatogonia or spermatocytes, while maximum expression was found during spermiogenesis. These results support the hypothesis for an eel sperm-specific PLCζ1 inducing egg activation, similarly to mammals and some teleosts, but different from some other teleost species, which express this protein in ovaries, but not in testes.


Addiction Treatment in America: After Money or Aftercare?
There are approximately 14,500 clinics and programs in America that provide treatment for all types of addictive behaviors we call "Reward Deficiency Syndrome (RDS)". While most of these have good intentions to provide needed help to the victims of RDS, we propose herein that most of their efforts, especially during periods of aftercare, are not based on the existing scientific evidence. We use "aftercare" to refer to any form of program or therapy following primary treatment including 12-Step programs. Very few programs actually provide any evidenced-based treatment approaches during this most vulnerable period in recovery. In this trieste we are suggesting that a hypodopaminergic trait (genetic) and/or state (epigenetic) is critical in terms of continued motivation to use/abuse of alcohol or other drugs and can lead to relapse. While there is evidence for the approved FDA drugs to treat drug addiction (e.g. alcohol, opiates, nicotine) these drugs favor a short-term benefit by blocking dopamine. We argue instead for the utilization of long-term benefits that induce "dopamine homeostasis", or in simpler terms "normalcy". We suggest that this could be accomplished through a number of holistic modalities including, but not limited to, dopamine-boosting diets, hyper-oxygenation, heavy metal detoxification, exercise, meditation, yoga, and most importantly, brain neurotransmitter balancing with nutraceuticals such as KB220 variants. We embrace 12-step programs and fellowships but not as a stand-alone modality, especially during aftercare. We also provide some scientific basis for why resting state functional connectivity (rsfMRI) is so important and may be the cornerstone in terms of how to treat RDS. We postulate that since drugs, food, smoking, gambling, and even compulsive sexual behavior could reduce rsfMRI then modalities (following required research), that can restore this impaired cross talk between various brain regions (e.g. Nucleus accumbens, cingulate gyrus, hippocampus etc.) should be incorporated into the aftercare plan in all treatment programs in America. Anything less will ultimately lead to the so called "revolving door" for as many as 90% of treatment participants.


Oxidative dehalogenation and denitration by a flavin-dependent monooxygenase is controlled by substrate deprotonation.
Enzymes that are capable of detoxifying halogenated phenols (HPs) and nitrophenols (NPs) are valuable for bioremediation and waste biorefining. HadA monooxygenase was found to perform dual functions of oxidative dehalogenation (hydroxylation plus halide elimination) and denitration (hydroxylation plus nitro elimination). Rate constants associated with individual steps of HadA reactions with phenol, halogenated phenols and nitrophenols were measured using combined transient kinetic approaches of stopped-flow absorbance/fluorescence and rapid-quench flow techniques. Density functional theory was used to calculate the thermodynamic and electronic parameters associated with hydroxylation and group elimination steps. These parameters were correlated with the rate constants of hydroxylation, group elimination, and overall product formation to identify factors controlling individual steps. The results indicated that the hydroxylation rate constant is higher when the pK a of the phenolic group is lower, i.e. it is more easily deprotonated, but not higher when the energy gap between the E LUMO of the C4a-hydroperoxy-FAD intermediate and the E HOMO of the phenolate substrate is lower. These data suggest that the substrate deprotonation has a higher energy barrier than the -OH transfer, and thus controls the hydroxylation step. For the group elimination, the process is controlled by the ability of the C-X bond to break. For the overall product formation (hydroxylation and group elimination combined), this analysis showed that the rate constant of product formation is dependent on the pK a value of the substrate, indicating that the overall reaction is controlled by substrate deprotonation. This step also likely has the highest energy barrier and thus controls the overall process of oxidative dehalogenation and denitration by HadA. This report is the first to identify a key mechanistic factor controlling the enzymatic processes of oxidative dehalogenation and denitration.


Hormone and metabolite changes associated with extended breeding fasts in male northern elephant seals (Mirounga angustirostris).
We measured metabolic hormones and several key metabolites in breeding adult male northern elephant seals to examine the regulation of fuel metabolism during extended natural fasts of over 3 months associated with high levels of energy expenditure. Males were sampled twice, early and late in the fast, losing an average of 23% of body mass and 47% of adipose stores between measurements. Males exhibited metabolic homeostasis over the breeding fast with no changes in glucose, non-esterified fatty acids, or blood urea nitrogen. Ketoacids increased over the fast but were very low when compared to other fasting species. Changes within individuals in total triiodothyronine (tT(3)) were positively related to daily energy expenditure (DEE) and protein catabolism. Differences in levels of thyroid hormones relative to that observed in weaned pups and females suggest a greater deiodination of T(4) to support the high DEE of breeding males. Relative levels of leptin and ghrelin were consistent with the suppression of appetite but a significant reduction in growth hormone across the fast was contrary to expectation in fasting mammals. The lack of the increase in cortisol during fasting found in conspecific weaned pups and lactating females may contribute to the ability of breeding males to spare protein despite high levels of energy expenditure. Together these findings reveal significant differences with conspecifics under varying nutrient demands, suggesting metabolic adaptation to extended high energy fasts.


Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant.
Methylmalonic acidemia (MMA) is an inherited organic acidemia usually present with recurrent episodes of acute illness. A typical episode is ushered in with ketonuria and vomiting, followed by acidosis, dehydration, and lethargy, leading, in the absence of aggressive treatment, to coma and death. We report an infant with MMA presented with diabetes symptoms. A 13-month-old girl complained of polydipsia, diuresis, and loss of weight. She had clinical signs of diabetic ketoacidosis such as dehydration, deep sighing respiration, smell of ketones, lethargy, and vomiting. Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion. Two days after her discharge, after having a meal rich in protein, she was brought unconscious with hepatomegaly, severe acidosis, ketonuria, and mild hyperammonemia. The absence of hyperglycemia and the presence of neurologic findings suggested organic acidemia. MMA was diagnosed because of methylmalonic aciduria and elevated C3 carnitine esters. Cranial magnetic resonance imaging (MRI) showed increased uptake of radiocontrast material in the basal ganglia bilaterally. A homozygous mutation in exon 4 of the MMAA gene was found in mutation analysis and confirmed the diagnosis of cblA-deficient MMA. Neurologic regression was improved with treatment of low-protein diet, vitamin B12, and l-carnitine. In patients born to consanguineous parents who admit during infancy with severe acidosis refractory to treatment, organic acidemias should be kept in mind, even they have high blood glucose. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the sequelae.


Influence of Post-disaster Evacuation on Incidence of Metabolic Syndrome.
After the Great East Japan Earthquake, over 160,000 residents near the Fukushima Daiichi Nuclear Power Plant were forced to evacuate due to a nuclear accident. Health problems in these evacuees have since become major issues. We examined the association between evacuation and incidence of metabolic syndrome (METS) among residents in Fukushima. We conducted a cohort study among residents aged 40-74 years without METS at the time of the disaster in Fukushima. Among 20,269 residents who met the inclusion criteria before the disaster, 8,547 residents (3,697 men and 4,850 women; follow-up proportion: 42.2%) remained available for follow-up examinations after the disaster by the end of March 2013. The main outcome was incidence of METS, defined by guidelines from the Japanese committee, using data from the Comprehensive Health Check before and after the disaster. We divided participants by evacuation status and compared outcomes between groups. Using a logistic regression model, we estimated the odds ratio for incidence of METS, adjusting for potential confounders, age, gender, waist circumference, exercise habit, and alcohol consumption. Incidence of METS was higher in evacuees (men 19.2%, women 6.6%) than in non-evacuees (men 11.0%, women 4.6%). Evacuees had higher body mass index, waist circumference, triglycerides, and fasting plasma glucose after the disaster than non-evacuees. We found a significant association between evacuation and incidence of METS (adjusted odds ratio 1.72, 95% confidence interval; 1.46-2.02). This is the first study to demonstrate that evacuation after a disaster is associated with increased incidence of METS.


Radon: a likely carcinogen at all exposures.
Radon is a well-established lung carcinogen that has been extensively studied. Very high concentrations can occur in some underground mines. Concentrations also tend to build up in homes. Epidemiological studies of radon-exposed miners and of residential radon and lung cancer are reviewed. Quantitative estimates of the risk of lung cancer, based on the experience of the miners, are applied to residential radon exposures in the United Kingdom. Strategies for the prevention of lung cancer induced by residential radon are discussed. Estimates are uncertain, but residential radon is probably responsible for about 2000 lung cancer deaths per year in the United Kingdom, or around 6% of the total, making it the second biggest cause after smoking. Over 80% of the deaths are estimated to occur at ages less than 75 and over 80% in smokers or ex-smokers. Around 90% of radoninduced deaths in the United Kingdom probably occur as a result of exposures to radon concentrations below the currently recommended action level of 200 Bq m(-3). Further work is needed to obtain more reliable estimates of the risk of lung cancer associated with residential radon and on the cost-effectiveness of various intervention strategies before the most appropriate policies can be developed for managing exposure to this natural carcinogen.


Multidisciplinary Development and Initial Validation of a Clinical Knowledge Base on Chronic Respiratory Diseases for mHealth Decision Support Systems.
Most mobile health (mHealth) decision support systems currently available for chronic obstructive respiratory diseases (CORDs) are not supported by clinical evidence or lack clinical validation. The development of the knowledge base that will feed the clinical decision support system is a crucial step that involves the collection and systematization of clinical knowledge from relevant scientific sources and its representation in a human-understandable and computer-interpretable way. This work describes the development and initial validation of a clinical knowledge base that can be integrated into mHealth decision support systems developed for patients with CORDs. A multidisciplinary team of health care professionals with clinical experience in respiratory diseases, together with data science and IT professionals, defined a new framework that can be used in other evidence-based systems. The knowledge base development began with a thorough review of the relevant scientific sources (eg, disease guidelines) to identify the recommendations to be implemented in the decision support system based on a consensus process. Recommendations were selected according to predefined inclusion criteria: (1) applicable to individuals with CORDs or to prevent CORDs, (2) directed toward patient self-management, (3) targeting adults, and (4) within the scope of the knowledge domains and subdomains defined. Then, the selected recommendations were prioritized according to (1) a harmonized level of evidence (reconciled from different sources); (2) the scope of the source document (international was preferred); (3) the entity that issued the source document; (4) the operability of the recommendation; and (5) health care professionals' perceptions of the relevance, potential impact, and reach of the recommendation. A total of 358 recommendations were selected. Next, the variables required to trigger those recommendations were defined (n=116) and operationalized into logical rules using Boolean logical operators (n=405). Finally, the knowledge base was implemented in an intelligent individualized coaching component and pretested with an asthma use case. Initial validation of the knowledge base was conducted internally using data from a population-based observational study of individuals with or without asthma or rhinitis. External validation of the appropriateness of the recommendations with the highest priority level was conducted independently by 4 physicians. In addition, a strategy for knowledge base updates, including an easy-to-use rules editor, was defined. Using this process, based on consensus and iterative improvement, we developed and conducted preliminary validation of a clinical knowledge base for CORDs that translates disease guidelines into personalized patient recommendations. The knowledge base can be used as part of mHealth decision support systems. This process could be replicated in other clinical areas.


Contrast enhanced magnetic resonance imaging of the terminal ileum in children with Crohn's disease.
Recently, magnetic resonance imaging (MRI) has been introduced in the diagnosis of patients with inflammatory bowel disease (IBD). However, it is still rarely reported in paediatric IBD. We studied the diagnostic value of gadolinium enhanced MRI in revealing inflammation of the distal ileum in children with Crohn's disease (CD) and in differentiating them from patients with other inflammatory diseases of the gut. MRI was performed using a polyethylene glycol (PEG) solution as oral contrast agent to distend the small bowel (CE-PEG-MRI). Seventy five consecutive patients (median age 13.6 years, range 8-17) with suspected CD underwent ileocolonoscopy with biopsy and CE-PEG-MRI. CD activity was measured by the paediatric Crohn's disease activity index (PCDAI). CE-PEG-MRI was evaluated with an overall score calculated, taking into account both wall thickness and contrast enhancement. Active CD with distal ileitis was diagnosed in 26 cases, active ulcerative colitis (UC) in 18, and spondyloarthropathy and indeterminate ileocolitis in 11; 20 children served as controls. In all CD patients, CE-PEG-MRI revealed a marked ileal involvement with increased wall thickness and parietal contrast enhancement and showed a high concordance with endoscopy and histology, whereas the test was negative in all controls. Of the 18 UC patients, CE-PEG-MRI was negative in 15 and showed a mild parietal contrast enhancement of the terminal ileum in only three of seven patients with backwash ileitis. Among the group of spondyloarthropathy patients, six had mucosal erosions and five mild superficial ileitis: CE-PEG-MRI was negative in four and revealed only mild parietal contrast enhancement of the ileal wall in seven. CE-PEG-MRI did not show an increase in wall thickness of the distal ileum in any of the UC or spondyloarthropathy patients. The sensitivity and specificity of CE-PEG-MRI related to the presence of erosive ileitis, as documented by endoscopy, were 84% and 100%, respectively. In addition, the test correlated markedly with endoscopy and histology in the entire population (r=0.94; r=0.95, respectively) as well as with the PCDAI in CD patients (r=0.91). In children with active CD, CE-PEG-MRI is a very sensitive and specific test for the detection of distal ileitis and for differentiation from other inflammatory diseases of the gut. The test could also be useful for the firstline diagnostic approach in children with suspected CD. The high correlation of CE-PEG-MRI with ileal endoscopy and histology as well as with PCDAI makes this test of great interest for future studies as a tool for monitoring the clinical course and the effect of therapy in CD patients.


Delivery of VEGF using collagen-coated polycaprolactone scaffolds stimulates angiogenesis.
Establishing sufficient vascularization in scaffold remains a challenge for tissue-engineering. To improve angiogenesis, we incorporated vascular endothelial growth factor (VEGF) in collagen-coating over the porous polycaprolactone (PCL) scaffolds. The release kinetics of loaded VEGF from collagen-coated PCL (col-PCL) scaffolds was same as from scaffolds without the collagen. The bioactivity of VEGF delivered by the col-PCL scaffolds was confirmed by human umbilical vein endothelial cell (HUVEC) proliferation and chorioallantoic membrane (CAM) assay. The col-PCL scaffolds were implanted subcutaneously in mice for 7 and 14 days. At day 7, vascularization within scaffolds loaded with VEGF was superior to that in the scaffolds without VEGF. However, the vessel connectivity to host circulatory system was incomplete and restricted to the scaffold edges. At day 14, blood vessels in scaffolds reached density similar to the subcutaneous tissue and were perfusable throughout the implant thickness. Prewashing the scaffolds with saline to remove the unbound growth factor decreased the initial burst release and sustained the VEGF-mediated angiogenesis in vivo. In conclusion, our study demonstrates that physically adsorbed VEGF stimulated angiogenesis in collagen-coated PCL scaffolds.


Indirect effects of large herbivores on snakes in an African savanna.
Many large mammal species are declining in African savannas, yet we understand relatively little about how these declines influence other species. Previous studies have shown that the removal of large herbivorous mammals from large-scale, replicated experimental plots results in a dramatic increase in the density of small mammals, an increase that has been attributed to the relaxation of competition between rodents and large herbivores for food resources. To assess whether the removal of large herbivores also influenced a predator of small mammals, we measured the abundance of the locally common olive hissing snake, Psammophis mossambicus, over a 19-mo period in plots with and without large herbivores. Psammophis mossambicus was significantly more abundant in plots where large herbivores were removed and rodent numbers were high. Based on results from raptor surveys and measurements of vegetative cover, differences in snake density do not appear to be driven by differences in rates of predation on snakes. Instead, snakes appear to be responding numerically to greater abundances of small-mammal prey in areas from which large herbivores have been excluded. This is the first empirical demonstration of the indirect effects of large herbivores on snake abundance and presents an interesting example of how the influence of dominant and keystone species can move through a food web.


Physical activity for antenatal and postnatal depression in women attempting to quit smoking: randomised controlled trial.
Antenatal depression is associated with harmful consequences for both the mother and child. One intervention that might be effective is participation in regular physical activity although data on this question in pregnant smokers is currently lacking. Women were randomised to six-weekly sessions of smoking cessation behavioural-support, or to the same support plus 14 sessions combining treadmill exercise and physical activity consultations. Among 784 participants (mean gestation 16-weeks), EPDS was significantly higher in the physical activity group versus usual care at end-of-pregnancy (mean group difference (95% confidence intervals (CIs)): 0.95 (0.08 to 1.83). There was no significant difference at six-months postpartum. A pragmatic intervention to increase physical activity in pregnant smokers did not prevent depression at end-of-pregnancy or at six-months postpartum. More effective physical activity interventions are needed in this population. Current Controlled Trials ISRCTN48600346 . The trial was prospectively registered on 21/07/2008.


Beyond expectation: a case for nonpersonal contextual factors in a more comprehensive approach to the placebo effect and the contribution of environmental psychology.
Creating an optimized health care environment to maximize the probability and magnitude of placebo effects draws on a number of well-researched mechanisms such as the patient's positive expectation toward treatment outcome. Patient-centered communication styles influence expectations and can thus be considered as a form of supplemental treatment. Unconsciously processed contextual triggering and facilitating placebo effects are omnipresent in clinical settings as well as in all other social and physical environments. Contextual cues in both the social and physical domain exert influences on the recipient's emotional state and recreational experiences. While the majority of research focuses on improving the patients' expectations, classical conditioning effects of nonsocial contextual factors have been largely neglected in discussions on practical implementation of placebo-enhancing environments. Built on the empirically well-supported argument that conditioning processes act as a powerful tool to mobilize self-healing resources just as verbally induced expectations do, we argue for a stronger consideration of the effects of permanent, nonsocial and nonverbal environmental contexts. Environmental psychology is a new field of research within the psychological domain and offers a toolbox of opportunities for medical psychological research and health care practitioners to improve the treatment outcomes and benefits of health care environments.


Nutrient conditions are primary drivers of bacterial capsule maintenance in Klebsiella.
The fitness cost associated with the production of bacterial capsules is considered to be offset by the protection provided by these extracellular structures against biotic aggressions or abiotic stress. However, it is unknown if the capsule contributes to fitness in the absence of these. Here, we explored conditions favouring the maintenance of the capsule in Klebsiella pneumoniae, where the capsule is known to be a major virulence factor. Using short-term experimental evolution on different Klebsiella strains, we showed that small environmental variations have a strong impact on the maintenance of the capsule. Capsule inactivation is frequent in nutrient-rich, but scarce in nutrient-poor media. Competitions between wild-type and capsule mutants in nine different strains confirmed that the capsule is costly in nutrient-rich media. Surprisingly, these results also showed that the presence of a capsule provides a clear fitness advantage in nutrient-poor conditions by increasing both growth rates and population yields. The comparative analyses of the wild-type and capsule mutants reveal complex interactions between the environment, genetic background and serotype even in relation to traits known to be relevant during pathogenesis. In conclusion, our data suggest there are novel roles for bacterial capsules yet to be discovered and further supports the notion that the capsule's role in virulence may be a by-product of its contribution to bacterial adaptation outside the host.


Lectin capture strategies combined with mass spectrometry for the discovery of serum glycoprotein biomarkers.
The application of mass spectrometry to identify disease biomarkers in clinical fluids like serum using high throughput protein expression profiling continues to evolve as technology development, clinical study design, and bioinformatics improve. Previous protein expression profiling studies have offered needed insight into issues of technical reproducibility, instrument calibration, sample preparation, study design, and supervised bioinformatic data analysis. In this overview, new strategies to increase the utility of protein expression profiling for clinical biomarker assay development are discussed with an emphasis on utilizing differential lectin-based glycoprotein capture and targeted immunoassays. The carbohydrate binding specificities of different lectins offer a biological affinity approach that complements existing mass spectrometer capabilities and retains automated throughput options. Specific examples using serum samples from prostate cancer and hepatocellular carcinoma subjects are provided along with suggested experimental strategies for integration of lectin-based methods into clinical fluid expression profiling strategies. Our example workflow incorporates the necessity of early validation in biomarker discovery using an immunoaffinity-based targeted analytical approach that integrates well with upstream discovery technologies.


Loop-mediated isothermal PCR (LAMP) for the diagnosis of falciparum malaria.
A recently described loop-mediated isothermal polymerase chain reaction (LAMP) for molecular detection of Plasmodium falciparum was compared with microscopy, PfHRP2-based rapid diagnostic test (RDT), and nested polymerase chain reaction (PCR) as the "gold standard" in 115 Bangladeshi in-patients with fever. DNA extraction for LAMP was conducted by conventional methods or simple heating of the sample; test results were either assessed visually or by gel electrophoresis. Conventional DNA extraction followed by gel electrophoresis had the highest agreement with the reference method (81.7%, kappa = 0.64), with a sensitivity (95% CI) of 76.1% (68.3-83.9%), comparable to RDT and microscopy, but a specificity of 89.6% (84.0-95.2%) compared with 100% for RDT and microscopy. DNA extraction by heat treatment deteriorated specificity to unacceptable levels. LAMP enables molecular diagnosis of falciparum malaria in settings with limited technical resources but will need further optimization. The results are in contrast with a higher accuracy reported in an earlier study comparing LAMP with a non-validated PCR method.


Effect of management of patients with Anorexia and Bulimia nervosa on symptoms and impulsive behavior.
The aim of the study was to provide further and up to date information on the evaluation of the management of Anorexia and Bulimia nervosa at the Eating Disorders Unit (EDU) of the Ljubljana Psychiatric Clinic, based upon detailed assessment of the eating disorders specific and non specific symptoms of impulsive behaviors, highly correlated with these entities. 34 female patients with anorexia (restrictive or purgative type) and 38 female patients with Bulimia nervosa (purgative or non-purgative type) undergoing hospital treatment at the EDU were evaluated upon admission, as well as upon discharge and three and six months after discharge, using the Eating Disorder Questionnaire. Upon discharge a marked decrease in the overall symptoms was noted. The differences in symptoms incidences between the two groups were significantly specific for the individual form of eating disorder, especially upon admission, and were more pronounced in anorexia group. In later measurements, performed during the period of three and six months after discharge, a mild trend of increase in the disorder specific symptoms was detected in both groups, but was not statistically significant. In addition to binging on food, striking, quarreling and spending sprees are characteristics of patients with eating disorders, which in particular apply to the Bulimia nervosa group. Apart from the disorder specific symptoms, impulsive behavior was also reduced during study period, while the difference in its occurrence between the two groups gradually became non-significant. The management of patients with eating disorders at the EDU was successful in both groups, confirmed by an intense reduction of the disorder specific symptoms, impulsive behavior and increased stability recorded three and six months after discharge. The study strongly suggests that the effect of treatment regime for eating disorders can be predicted by careful assessment of the relevant symptoms and impulsive behavioral patterns.


Differing patterns of temporal atrophy in Alzheimer's disease and semantic dementia.
To characterize and quantify the patterns of temporal lobe atrophy in AD vs semantic dementia and to relate the findings to the cognitive profiles. Medial temporal lobe atrophy is well described in AD. In temporal variant frontotemporal dementia (semantic dementia), clinical studies suggest polar and inferolateral temporal atrophy with hippocampal sparing, but quantification is largely lacking. A volumetric method for quantifying multiple temporal structures was applied to 26 patients with probable AD, 18 patients with semantic dementia, and 21 matched control subjects. The authors confirmed the expected bilateral hippocampal atrophy in AD relative to controls, with involvement of the amygdala bilaterally and the right parahippocampal gyrus. Contrary to expectations, patients with semantic dementia had asymmetric hippocampal atrophy, more extensive than AD on the left. As predicted, the semantic dementia group showed more severe involvement of the temporal pole bilaterally and the left amygdala, parahippocampal gyrus (including the entorhinal cortex), fusiform gyrus, and the inferior and middle temporal gyri. Performance on semantic association tasks correlated with the size of the left fusiform gyrus, whereas naming appeared to depend upon a wider left temporal network. Episodic memory measures, with the exception of recognition memory for faces, did not correlate with temporal measures. Hippocampal atrophy is not specific for AD but is also seen in semantic dementia. Distinguishing the patients with semantic dementia was the severe global but asymmetric (left > right) atrophy of the amygdala, temporal pole, and fusiform and inferolateral temporal gyri. These findings have implications for diagnosis and understanding of the cognitive deficits in AD and semantic dementia.


Enhancing HIV Treatment Access and Outcomes Amongst HIV Infected Children and Adolescents in Resource Limited Settings.
Introduction Increasing access to HIV-related care and treatment for children aged 0-18 years in resource-limited settings is an urgent global priority. In 2011-2012 the percentage increase in children accessing antiretroviral therapy was approximately half that of adults (11 vs. 21 %). We propose a model for increasing access to, and retention in, paediatric HIV care and treatment in resource-limited settings. Methods Following a rapid appraisal of recent literature seven main challenges in paediatric HIV-related care and treatment were identified: (1) lack of regular, integrated, ongoing HIV-related diagnosis; (2) weak facility-based systems for tracking and retention in care; (3) interrupted availability of dried blood spot cards (expiration/stock outs); (4) poor quality control of rapid HIV testing; (5) supply-related gaps at health facility-laboratory interface; (6) poor uptake of HIV testing, possibly relating to a fatalistic belief about HIV infection; (7) community-associated reasons e.g. non-disclosure and weak systems for social support, resulting in poor retention in care. Results To increase sustained access to paediatric HIV-related care and treatment, regular updating of Policies, review of inter-sectoral Plans (at facility and community levels) and evaluation of Programme implementation and impact (at national, subnational, facility and community levels) are non-negotiable critical elements. Additionally we recommend the intensified implementation of seven main interventions: (1) update or refresher messaging for health care staff and simple messaging for key staff at early childhood development centres and schools; (2) contact tracing, disclosure and retention monitoring; (3) paying particular attention to infant dried blood spot (DBS) stock control; (4) regular quality assurance of rapid HIV testing procedures; (5) workshops/meetings/dialogues between health facilities and laboratories to resolve transport-related gaps and to facilitate return of results to facilities; (6) community leader and health worker advocacy at creches, schools, religious centres to increase uptake of HIV testing and dispel fatalistic beliefs about HIV; (7) use of mobile communication technology (m-health) and peer/community supporters to maintain contact with patients. Discussion and Conclusion We propose that this package of facility, community and family-orientated interventions are needed to change the trajectory of the paediatric HIV epidemic and its associated patterns of morbidity and mortality, thus achieving the double dividend of improving HIV-free survival.


Physiological and digestive effects of Neotyphodium coenophialum-infected tall fescue fed to lambs.
The digestive responses and degradation of ergovaline and production of lysergic acid in the rumen of sheep offered Neotyphodium coenophialum-infected tall fescue straw at 2 ergovaline levels were investigated. Six crossbred wethers (56 +/- 3.0 kg of BW) were used in a randomized crossover design involving 2 treatments, for a total of 6 observations per treatment. The experiment consisted of two 28-d feeding periods with a 14-d washout period between them. The treatments were 1) tall fescue straw containing <0.010 mg of ergovaline/kg (E-), and 2) tall fescue straw containing 0.610 mg of ergovaline/kg (E+). Feed, orts, and feces were measured and analyzed for DM, ADF, and CP, and used to determine digestibilities. Feed and water intake were monitored throughout the feeding periods. Body weight and serum prolactin levels were measured at the beginning and end of each feeding period. Ruminal fluid was sampled 3 times (d 0, 3, and 28) during each 28-d feeding period for determination of ergovaline, lysergic acid, ammonia, and pH. Samples were collected before feeding (0 h) and at 6 and 12 h after feeding. Total fecal and urine collection commenced on d 21 and continued until d 25 of each feeding period. Ruminal ammonia, ruminal pH, and rectal temperature were not influenced by ergovaline concentration (P > 0.10). Digestion of DM, ADF, and CP was not different between treatments (P > 0.10). Daily water intake was less for the E+ diet (2.95 vs. 2.77 L/d; P < 0.05) as was serum prolactin (22.9 vs. 6.4 ng/mL; P < 0.05). Ergovaline concentration in ruminal fluid increased over sampling days at each sampling time (P < 0.05). Lysergic acid concentration in ruminal fluid increased over time from d 0 to 3 (P < 0.05) but was not different between d 3 and 28 (P > 0.10). In the E+ treatment, ergovaline was not detectable in the urine, whereas the concentration in the feces was 0.480 mg/kg. Lysergic acid was detected in the diet of the E+ treatment at 0.041 g/kg, lysergic acid in the urine was 0.067 mg/kg and in the feces was 0.102 mg/kg. The apparent digestibility of the alkaloids was 64.2% for ergovaline and -12.5% for lysergic acid. Approximately 35% of dietary ergovaline and 248% of dietary lysergic acid were recovered in the feces and urine. The appearance of lysergic acid in the feces, urine, and ruminal fluid is likely due to microbial degradation of ergovaline in the rumen and further breakdown in the lower digestive tract.


Derivation of Two Critical Appraisal Scores for Trainees to Evaluate Online Educational Resources: A METRIQ Study.
Online education resources (OERs), like blogs and podcasts, increasingly augment or replace traditional medical education resources such as textbooks and lectures. Trainees' ability to evaluate these resources is poor, and few quality assessment aids have been developed to assist them. This study aimed to derive a quality evaluation instrument for this purpose. We used a three-phase methodology. In Phase 1, a previously derived list of 151 OER quality indicators was reduced to 13 items using data from published consensus-building studies (of medical educators, expert podcasters, and expert bloggers) and subsequent evaluation by our team. In Phase 2, these 13 items were converted to seven-point Likert scales used by trainee raters (n=40) to evaluate 39 OERs. The reliability and usability of these 13 rating items was determined using responses from trainee raters, and top items were used to create two OER quality evaluation instruments. In Phase 3, these instruments were compared to an external certification process (the ALiEM AIR certification) and the gestalt evaluation of the same 39 blog posts by 20 faculty educators. Two quality-evaluation instruments were derived with fair inter-rater reliability: the METRIQ-8 Score (Inter class correlation coefficient [ICC]=0.30, p<0.001) and the METRIQ-5 Score (ICC=0.22, p<0.001). Both scores, when calculated using the derivation data, correlated with educator gestalt (Pearson's r=0.35, p=0.03 and r=0.41, p<0.01, respectively) and were related to increased odds of receiving an ALiEM AIR certification (odds ratio=1.28, p=0.03; OR=1.5, p=0.004, respectively). Two novel scoring instruments with adequate psychometric properties were derived to assist trainees in evaluating OER quality and correlated favourably with gestalt ratings of online educational resources by faculty educators. Further testing is needed to ensure these instruments are accurate when applied by trainees.


Optical cuff for optogenetic control of the peripheral nervous system.
Nerves in the peripheral nervous system (PNS) contain axons with specific motor, somatosensory and autonomic functions. Optogenetics offers an efficient approach to selectively activate axons within the nerve. However, the heterogeneous nature of nerves and their tortuous route through the body create a challenging environment to reliably implant a light delivery interface. Here, we propose an optical peripheral nerve interface-an optocuff-, so that optogenetic modulation of peripheral nerves become possible in freely behaving mice. Using this optocuff, we demonstrate orderly recruitment of motor units with epineural optical stimulation of genetically targeted sciatic nerve axons, both in anaesthetized and in awake, freely behaving animals. Behavioural experiments and histology show the optocuff does not damage the nerve thus is suitable for long-term experiments. These results suggest that the soft optocuff might be a straightforward and efficient tool to support more extensive study of the PNS using optogenetics.


Sensibility testing in peripheral-nerve compression syndromes. An experimental study in humans.
Sensibility testing in peripheral-nerve compression syndromes was investigated in an experimental study in humans. Twelve volunteer subjects had controlled external compression of the median nerve at the carpal tunnel at a level of forty, fifty, sixty, and seventy millimeters of mercury. The subjects were then monitored for thirty to 240 minutes with four sensory tests: two-point discrimination, moving two-point discrimination, Semmes-Weinstein pressure monofilaments, and vibration. Sensory and motor conduction, subjective sensations, and motor strength were also continuously tested. The threshold tests (vibration and Semmes-Weinstein monofilaments testing) consistently reflected gradual decreases in nerve function in both subjective sensation and electrical testing, while the innervation density tests (two-point discrimination and moving two-point discrimination) remained normal until nearly all sensory conduction had ceased. Decreased muscle strength occurred late, and not until changes had already occurred in each of the sensory tests. Threshold tests of sensibility correlated accurately with symptoms of nerve compression and electrodiagnostic studies, and are being evaluated for clinical use in a variety of peripheral-nerve compression syndromes.


Juvenile Parkinsonism: clinical and metabolic characteristics.
Twenty one patients with idiopathic Parkinsonism beginning before the age of 40 years were investigated. The mean duration of the disease was 19 years. There was a good and sustained response to levodopa. Only four patients reached stages IV and V (Hoehn and Yahr). Intolerance to levodopa was observed in the more advanced stages of the disease. In the series the familial incidence of Parkinsonism (2 cases) and essential tremor (3 cases) was very low. Thyroid disorder, diabetes mellitus or macrocytic anaemia was not found in any of the cases.


Proliferation, hyperplasia, neogenesis, and neoplasia in the islets of Langerhans.
Pancreatic disease is responsible for significant morbidity and mortality as a result of pancreatic carcinoma and diabetes mellitus. Regulation of endocrine cell mass is thought to have a central role in the pathogenesis of both these diseases. Islet cell proliferation, hypertrophy, neogenesis, and apoptosis are the main determinants of endocrine cell mass in the pancreas, and their understanding has been improved by new clues of their genetic and molecular basis. Beta cells have attracted most research interest because of potential implications in the treatment of diabetes mellitus and hypoglycemic disorders. The processes that operate during pancreatic adaptation to a changing hormonal milieu are important in pancreatic carcinogenesis. There is evidence that somatostatin and its receptors are fundamental regulators of endocrine cell mass and are involved in islet tumorigenesis.


Superbroad near to mid infrared luminescence from closo-deltahedral Bi5(3+) cluster in Bi5(GaCl4)3.
Closo-deltahedral Bi(5)(3+) cluster in Bi(5)(GaCl(4))(3), which can be synthesized in benzene by oxidizing bismuth metal either with BiCl(3) or GaCl(3), respectively, can absorb ultraviolet, visible and infrared lights, and luminesce superbroadly in near to mid infrared (NMIR) spectral range from 1 to 3μm at room temperature. Slight geometry change of the cluster can lead to the redshift of emission peak. These observations may initialize the development of Bi-based NMIR light sources with superbroad emission spectrum, where Bi(5)(3+) or similar polycationic species act as activators. Disputable crystal structure of Bi(5)(GaCl(4))(3) was redefined by classic Rietveld refining analysis. Consistent with crystallographic data, excitation, emission, temporal decay and time-resolved infrared emission spectra all reveal only one type of luminescent centers, viz. Bi(5)(3+), in the compound. And a new absorption of Bi(5)(3+) was found at ~1100nm.


Induction of an antigen cascade by diversified subcutaneous/intratumoral vaccination is associated with antitumor responses.
Cancer vaccines targeting tumor-associated antigens are being investigated for the therapy of tumors. Numerous strategies, including the direct intratumoral (i.t.) vaccination route, have been examined. For tumors expressing carcinoembryonic antigen (CEA) as a model tumor-associated antigen, we previously designed poxviral vectors that contain the transgenes for CEA and a triad of T-cell costimulatory molecules, B7-1, intercellular adhesion molecule-1, (ICAM-1), and leukocyte function associated antigen-3 (LFA-3) (CEA/TRICOM). Two types of poxvirus vectors were developed: replication-competent recombinant vaccinia and replication-defective recombinant fowlpox. We have shown previously that a vaccine regimen composed of priming mice s.c. with recombinant vaccinia-CEA/TRICOM and boosting i.t. with recombinant fowlpox-CEA/TRICOM was superior to priming and boosting vaccinations using the conventional s.c. route in inducing T-cell responses specific for CEA. These studies also showed that CEA was needed to be present both in the vaccine and in the tumor for therapeutic effects. To determine specific immune responses associated with vaccination-mediated tumor regression, CEA-transgenic mice bearing CEA(+) tumors were vaccinated with the CEA/TRICOM s.c./i.t. regimen, and T-cell immune responses were assessed. In CEA(+) tumor-bearing mice vaccinated with the CEA/TRICOM s.c./i.t. regimen, T-cell responses could be detected not only to CEA encoded in vaccine vectors but also to other antigens expressed on the tumor itself: wild-type p53 and an endogenous retroviral epitope of gp70. Moreover, the magnitude of CD8(+) T-cell immune responses to gp70 was far greater than that induced to CEA or p53. Finally, the predominant T-cell population infiltrating the regressing CEA(+) tumor after therapy was specific for gp70. These studies show that the breadth and magnitude of antitumor immune cascades to multiple antigens could be critical in the therapy of established tumors.


Predictability of helminth parasite host range using information on geography, host traits and parasite community structure.
Host-parasite associations are complex interactions dependent on aspects of hosts (e.g. traits, phylogeny or coevolutionary history), parasites (e.g. traits and parasite interactions) and geography (e.g. latitude). Predicting the permissive host set or the subset of the host community that a parasite can infect is a central goal of parasite ecology. Here we develop models that accurately predict the permissive host set of 562 helminth parasites in five different parasite taxonomic groups. We developed predictive models using host traits, host taxonomy, geographic covariates, and parasite community composition, finding that models trained on parasite community variables were more accurate than any other covariate group, even though parasite community covariates only captured a quarter of the variance in parasite community composition. This suggests that it is possible to predict the permissive host set for a given parasite, and that parasite community structure is an important predictor, potentially because parasite communities are interacting non-random assemblages.


Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada.
Smith-Lemli-Opitz syndrome (OMIM 270400) (SLOS) is caused by inherited enzymatic deficiency of 3beta-hydroxysterol-Delta7-reductase (7-dehydrocholesterol-Delta7-reductase, DHCR7). SLOS is diagnosed clinically by the demonstration of elevated levels of 7-dehydrocholesterol (7DHC) in body fluids or tissues. SLOS is associated with mental retardation of variable degree and severe behavior abnormalities. The physical abnormalities range from minor facial anomalies to lethal malformations of the central nervous system, heart, kidneys, and other organs. The exact incidence of SLOS is not known. Although there exist estimates of the incidence of SLOS ranging from 1 in 20,000 to 1 in 60,000, no prospective studies of the incidence of SLOS, based on the clinical data and biochemical diagnosis of SLOS, have been performed. Five unrelated cases of SLOS were diagnosed in Ontario during a 12-month period. The diagnoses were made based on the demonstration of elevated 7DHC in plasma or amniotic fluid. The birth rate for Ontario for that period was 132,000 births. The incidence of SLOS in Ontario was at least 1 in 26,500 pregnancies in 1999-2000. Given that 86% of the population of Ontario is of European origin, the incidence of SLOS in the Ontario population of European origin was at least 1 in 22,700. As infants with mild forms of SLOS born during this period may remain undiagnosed, these numbers likely are underestimates. This observation has implications for prenatal and newborn screening for this potentially treatable inherited disorder.


No difference in cross-modal attention or sensory discrimination thresholds in autism and matched controls.
Autism has been associated with abnormalities in sensory and attentional processing. Here, we assessed these processes independently in the visual and auditory domains using a visual contrast-discrimination task and an auditory modulation-depth discrimination task. To evaluate changes in sensory function by attention, we measured behavioral performance (discrimination accuracy) when subjects were cued to attend and respond to the same stimulus (frequent valid cue) or cued to attend to one stimulus and respond to the non-cued stimulus (infrequent invalid cue). The stimuli were presented at threshold to ensure equal difficulty across participants and groups. Results from fifteen high-functioning adult individuals with autism and fifteen matched controls revealed no significant differences in visual or auditory discrimination thresholds across groups. Furthermore, attention robustly modulated performance accuracy (performance was better for valid than invalid cues) in both sensory modalities and to an equivalent extent in both groups. In conclusion, when using this well-controlled method, we found no evidence of atypical sensory function or atypical attentional modulation in a group of high functioning individuals with clear autism symptomatology.


The kinetics of spontaneous calcium oscillations and arrhythmogenesis in the in vivo heart during ischemia/reperfusion.
The correlation between spontaneous calcium oscillations (S-CaOs) and arrhythmogenesis has been investigated in a number of theoretical and experimental in vitro models. There is an obvious lack of studies that directly investigate how the kinetics of S-CaOs correlates with a specific arrhythmia in the in vivo heart. The purpose of the study is to investigate the correlation between the kinetics of S-CaOs and arrhythmogenesis in the intact heart using an experimental model of ischemia/reperfusion (I/R). Perfused Langendorff guinea pig (GP) hearts were subjected to global I/R (10-15 minutes/10-15 minutes). The heart was stained with a voltage-sensitive dye (RH237) and loaded with a Ca2+ indicator (Rhod-2 AM). Membrane voltage (Vm) and intracellular calcium transient (Ca(i)T) were simultaneously recorded with an optical mapping system of two 16 x 16 photodiode arrays. S-CaOs were considered to arise from a localized focal site within the mapped surface when these preceded the associated membrane depolarizations by 2-15 ms. In 135 episodes of ventricular arrhythmias from 28 different GP experiments, 23 were linked to S-CaOs that were considered to arise from or close to the mapped epicardial window. Self-limited or sustained S-CaOs had a cycle length of 130-430 ms and could trigger propagated ventricular depolarizations. Self-limited S-CaOs that followed the basic beat action potential (AP)/Ca(i)T closely resembled phase 3 early afterdepolarizations. Fast S-CaOs could remain confined to a localized site (concealed) or exhibit varying conduction patterns. This could manifest as (1) an isolated premature beat (PB), bigeminal, or trigeminal rhythm; (2) ventricular tachycardia (VT) when a regular 2:1 conduction from the focal site develops; or (3) ventricular fibrillation (VF) when a complex conduction pattern results in wave break and reentrant excitation. The study examined, for the first time in the intact heart, the correlation between the kinetics of focal S-CaOs during I/R and arrhythmogenesis. S-CaOs may remain concealed or manifest as PBs, VT, or VF. A "benign looking" PB during I/R may represent "the tip of the iceberg" of an underlying potentially serious arrhythmic mechanism.


Quantitative analysis of formal caregivers' use of communication strategies while assisting individuals with moderate and severe Alzheimer's disease during oral care.
This cross-sectional observational study examined formal caregivers' use of task-focused and social communication strategies while assisting individuals with moderate and severe Alzheimer's disease residing in a long-term care facility during a basic activity of daily living: toothbrushing. Thirteen formal caregiver-resident dyads were observed during a total of 78 separate toothbrushing sessions. All caregiver utterances occurring during the task were transcribed and coded for type of communication strategy utilizing a multidimensional observational coding scheme, which was developed a priori. Overall, the majority of residents, irrespective of disease severity, successfully completed toothbrushing with the support of caregiver assistance. Caregivers assisting residents with moderate and severe AD were found to use a variety of communication strategies, with task-focused strategies accounting for the majority of use. For the most part, the communicative strategies employed did not differ across disease severity. However, some differences were identified including the use of one proposition, paraphrased repetition, using the resident's name, and provision of full assistance, with these strategies being used more often when assisting individuals with severe AD. This study adds to the emerging literature supporting the use of specific communication strategies while assisting residents with AD during the completion of daily tasks. From reviewing this study, readers will be able to identify a variety of communication strategies, both task-focused and relational, that formal caregivers utilize while assisting residents with moderate and severe Alzheimer's disease (AD) during a basic activity of daily living. Furthermore, the reader will be able to distinguish between communication strategies that are optimal when assisting individuals with moderate AD as compared to assisting individuals with severe AD.


RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites.
In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8-dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8- and RNF168-deficient cells to form 53BP1 foci. We propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites.


The pancreas in human type 1 diabetes: providing new answers to age-old questions.
Although studies of pancreata from type 1 diabetes (T1D) patients largely fell dormant for a period of decades, research efforts have recently been 'rekindled' in this area to address, using modern techniques, many unanswered questions related to the pathogenesis of this disease. As historically noted, a pancreatic infiltrate commonly referred to as 'insulitis' is present at the symptomatic onset of T1D. Recent studies have further characterized this infiltrate both in terms of its cellular composition as well as the mechanisms that likely underlie beta cell death in T1D. In addition, the notion that the pancreas from T1D patients is completely devoid of insulin producing cells years after the onset of disease has been challenged, whereas the concepts of whether beta cell regeneration or replication are present have also been subject to much debate. Novel concepts regarding the rate and degree of beta cell loss throughout the natural history of the disease have also been put forward to aid in explaining the disorder's pathogenesis. Although answers to many long-standing questions in T1D have recently been addressed, perhaps the main finding has been one supporting a disease of remarkable heterogeneity. However, additional lessons remain to be learned from the pancreas in T1D. Hence, attempts aimed at organizing the scientific community to address these issues are ongoing, particularly those from collaborative efforts, including the Belgium Organ Donor Consortium and the Network for Pancreatic Organ Donors with Diabetes (nPOD).


Selective recovery of Pd(II) from extremely acidic solution using ion-imprinted chitosan fiber: Adsorption performance and mechanisms.
A novel, selective and acid-resisting chitosan fiber adsorbent was prepared by the ion-imprinting technique using Pd(II) and epichlorohydrin as the template and two-step crosslinking agent, respectively. The resulting ion-imprinted chitosan fibers (IIF) were used to selectively adsorb Pd(II) under extremely acidic synthetic metal solutions. The adsorption and selectivity performances of IIF including kinetics, isotherms, pH effects, and regeneration were investigated. Pd(II) rapidly adsorbed on the IIF within 100 min, achieving the adsorption equilibrium. The isotherm results showed that the maximum Pd(II) uptake on the IIF was maintained as 324.6-326.4 mg g(-1) in solutions containing single and multiple metals, whereas the Pd(II) uptake on non-imprinted fibers (NIF) decreased from 313.7 to 235.3 mg g(-1) in solution containing multiple metals. Higher selectivity coefficients values were obtained from the adsorption on the IIF, indicating a better Pd(II) selectivity. The amine group, supposedly the predominant adsorption site for Pd(II), was confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The pH value played a significant role on the mechanism of the selective adsorption in the extremely acidic conditions. Furthermore, the stabilized performance for three cycles of sorption/desorption shows a potential for further large-scale applications.


Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia.
Although previous studies have examined the efficacy of pitavastatin, its tolerability and effects on lipid concentrations have not been compared with those of atorvastatin in a multicenter, randomized study. This trial compared the efficacy and tolerability of pitavastatin and atorvastatin in hypercholesterolemic Korean adults. This 8-week, multicenter, randomized, open-label, dose-titration study was conducted at 18 clinical centers in Korea between May 2005 and February 2006. After a 4-week dietary lead-in period, patients with hypercholesterolemia were randomized to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d. Patients who had not reached the low-density lipoprotein cholesterol (LDL-C) goal by week 4 received a double dose of the assigned medication for an additional 4 weeks. Efficacy was evaluated in terms of achievement of the National Cholesterol Education Program Adult Treatment Panel III LDL-C goals and changes from baseline in other lipids and high-sensitivity C-reactive protein (hs-CRP). The tolerability profile was assessed by physical and electro-cardiographic examinations, laboratory tests, and recording adverse reactions at all visits. A total of 268 patients were randomized to treatment, and 222 (82.8%) completed the study (149 women, 73 men; mean age, 59 years; mean weight, 63.5 kg). At the end of the study, there was no significant difference between the pitavastatin and atorvastatin groups in the proportion of patients achieving the LDL-C goal (92.7% [102/110] vs 92.0% [103/112], respectively). In addition, there were no significant differences between groups in terms of the percent changes from baseline in LDL-C, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), or hs-CRP. Twenty-six of 136 patients (19.1%) taking pitavastatin reported 35 treatment-emergent adverse reactions; 33 of 132 patients (25.0%) taking atorvastatin reported 39 treatment-emergent adverse reactions. Elevations in creatine kinase were observed in 6 patients (4.4%) in the pitavastatin group and 7 patients (5.3%) in the atorvastatin group. There were no serious adverse drug reactions in either group. In these adult Korean patients with hypercholesterolemia, pitavastatin and atorvastatin did not differ significantly in terms of the proportions of patients achieving the LDL-C goal; reductions in LDL-C, total cholesterol, and triglycerides; or increases in HDL-C. Both drugs were well tolerated.


Hydrodynamical Fingerprint of a Neighbour in a Fish Lateral Line.
For fish, swimming in group may be favorable to individuals. Several works reported that in a fish school, individuals sense and adjust their relative position to prevent collisions and maintain the group formation. Also, from a hydrodynamic perspective, relative-position and kinematic synchronisation between adjacent fish may considerably influence their swimming performance. Fish may sense the relative-position and tail-beat phase difference with their neighbors using both vision and the lateral-line system, however, when swimming in dark or turbid environments, visual information may become unavailable. To understand how lateral-line sensing can enable fish to judge the relative-position and phase-difference with their neighbors, in this study, based on a verified three-dimensional computational fluid dynamics approach, we simulated two fish swimming adjacently with various configurations. The lateral-line signal was obtained by sampling the surface hydrodynamic stress. The sensed signal was processed by Fast Fourier Transform (FFT), which is robust to turbulence and environmental flow. By examining the lateral-line pressure and shear-stress signals in the frequency domain, various states of the neighboring fish were parametrically identified. Our results reveal that the FFT-processed lateral-line signals in one fish may potentially reflect the relative-position, phase-differences, and the tail-beat frequency of its neighbor. Our results shed light on the fluid dynamical aspects of the lateral-line sensing mechanism used by fish. Furthermore, the presented approach based on FFT is especially suitable for applications in bioinspired swimming robotics. We provide suggestions for the design of artificial systems consisting of multiple stress sensors for robotic fish to improve their performance in collective operation.


Aldose reductase inhibition protects diabetic and nondiabetic rat hearts from ischemic injury.
Diabetes increases the incidence of cardiovascular disease as well as the complications of myocardial infarction. Studies using animal models of diabetes have demonstrated that the metabolic alterations occurring at the myocyte level may contribute to the severity of ischemic injury in diabetic hearts. Of the several mechanisms being investigated to understand the pathogenesis of diabetic complications, the increased metabolism of glucose via the polyol pathway has received considerable attention. Deviant metabolic regulation due to increased flux through aldose reductase in diabetic hearts may influence the ability of the myocardium to withstand ischemia insult. To determine if aldose reductase inhibition improves tolerance to ischemia, hearts from acute type I diabetic and nondiabetic control rats were isolated and retrograde perfused. Each group was exposed to 1 micromol/l zopolrestat, a specific inhibitor of aldose reductase, for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion in the absence of zopolrestat. Zopolrestat reduced sorbitol levels before ischemia in diabetic hearts. The cytosolic redox state (NADH/NAD+), as measured by lactate-to-pyruvate ratios, was significantly lowered under baseline, ischemic, and reperfusion conditions in diabetic hearts perfused with zopolrestat. In these diabetic hearts, ATP was significantly higher in zopolrestat hearts during ischemia, as were phosphocreatine and left ventricular-developed pressure on reperfusion. Zopolrestat provided similar metabolic and functional benefits in nondiabetic hearts. Creatine kinase release was reduced by approximately 50% in both nondiabetic and diabetic hearts treated with zopolrestat. These data indicate that inhibition of aldose reductase activity preserves high-energy phosphates, maintains a lower cytosolic NADH/NAD+ ratio, and markedly protects both diabetic and nondiabetic hearts during ischemia and reperfusion.


Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.
BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.


Trans-anal rectal injuries.
The diagnosis of trans-anal rectal injuries is usually delayed because of the patient's denial. Some of these injuries are self-inflicted or caused by criminal assault, leading to delayed presentation. We aimed to study the causes, clinical presentation, management and clinical outcome of transanal rectal injuries. The records of 12 patients (nine males) with a median age of 36.5 (range 20-64) years, had trans-anal rectal injury and were treated between 1993 and 2006 at Al-Ain Hospital, were reviewed. Injury was caused by a fall on a sharp object in five patients, by a rectal foreign body in two patients, by a compressed air hose in two patients, by sexual assault in two patients, and by rectal cleansing enema in one patient. Seven patients presented two hours after the injury, four patients within 8-24 hours, and one sexually-assaulted patient presented after seven days. Injuries were in the anterior rectal wall in seven, in the rectosigmoid junction in three, and in the anorectal region in two patients. Ten patients presented with peritonitis, four were in shock, seven had bleeding per rectum, and two had a weak sphincter. The complication rate was significantly higher in the colostomy patients compared with primary repair (5/6 compared with 0/6, p-value is less than 0.02, Fisher's exact test). All patients survived. The median (range) hospital stay was ten (9-72) days. Diagnosis of trans-anal rectal injuries is usually delayed because of late presentation. Sexual assault should be suspected following rectal injuries. Colostomy is not always mandatory.


Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study.
To investigate the role of "behavioral inhibition to the unfamiliar" as an early temperamental characteristic of children at risk for adult panic disorder and agoraphobia (PDAG), we compared children of parents with PDAG with those from psychiatric comparison groups. Fifty-six children aged 2 to 7 years, matched for age, socioeconomic status, ethnic background, and ordinal position, were blindly evaluated at the Harvard Infant Study laboratory, Cambridge, Mass. The rates of behavioral inhibition in children of probands with PDAG, with or without comorbid major depressive disorder (MDD), were significantly higher than for our comparison group without PDAG. Further, the data suggest a progression of increasing rates of inhibition from the comparison group without MDD (15.4%), to MDD (50.0%), and to comorbid PDAG and MDD (70%) and PDAG (84.6%). In contrast, the rate of behavioral inhibition in children of probands with MDD did not meaningfully differ from the comparison group without MDD. Behavioral inhibition to the unfamiliar, as defined and measured in the previous work of the Harvard Infant Study program, is highly prevalent in the offspring of adults in treatment for PDAG. These children appear to be at risk for distress and disability in childhood and also perhaps for development of psychiatric disorder in later childhood and aulthood.


The role of distal S6 hydrophobic residues in the voltage-dependent gating of CaV2.3 channels.
The hydrophobic locus VAVIM is conserved in the S6 transmembrane segment of domain IV (IVS6) in Ca(V)1 and Ca(V)2 families. Herein we show that glycine substitution of the VAVIM motif in Ca(V)2.3 produced whole cell currents with inactivation kinetics that were either slower (A1719G approximately V1720G), similar (V1718G), or faster (I1721G approximately M1722G) than the wild-type channel. The fast kinetics of I1721G were observed with a approximately +10 mV shift in its voltage dependence of activation (E(0.5,act)). In contrast, the slow kinetics of A1719G and V1720G were accompanied by a significant shift of approximately -20 mV in their E(0.5,act) indicating that the relative stability of the channel closed state was decreased in these mutants. Glycine scan performed with Val (349) in IS6, Ile(701) in IIS6, and Leu(1420) in IIIS6 at positions predicted to face Val(1720) in IVS6 also produced slow inactivating currents with hyperpolarizing shifts in the activation and inactivation potentials, again pointing out a decrease in the stability of the channel closed state. Mutations to other hydrophobic residues at these positions nearly restored the channel gating. Altogether these data indicate that residues at positions equivalent to 1720 exert a critical control upon the relative stability of the channel closed and open states and more specifically, that hydrophobic residues at these positions promote the channel closed state. We discuss a three-dimensional homology model of Ca(V)2.3 based upon Kv1.2 where hydrophobic residues at positions facing Val(1720) in IS6, IIS6, and IIIS6 play a critical role in stabilizing the closed state in Ca(V)2.3.


Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most?
Radiation therapy (RT) improves control of Hodgkin lymphoma (HL), but patients who undergo RT are at risk for late effects, including cardiovascular disease and second cancers, because of radiation doses to organs at risk (OARs). Proton therapy (PT) can reduce OAR doses compared with conventional photon RT. However, access to PT is currently limited, so referrals must be appropriately selective. We aimed to identify subgroups of patients with HL who could benefit the most dosimetrically from RT with PT based on the prechemotherapy disease characteristics. Normal tissue radiation doses were calculated for 21 patients with HL who were treated with deep-inspiration breath-hold pencil-beam scanning (PBS) PT and compared with doses from 3-dimensional conformal (3D-CRT) and partial arc volumetric modulated (PartArc) photon RT. Prechemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared with photon RT were identified. Treatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the seventh thoracic level and for female patients with axillary disease. In addition, an increasing dosimetric benefit for some OARs was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord, and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS, but some high-dose measures and hot spots were increased with PBS compared with partial arc volumetric modulated photon RT. PBS gives good target coverage and local control while providing reductions in radiation dose to OARs for individuals who receive RT for HL compared with advanced photon RT. Our findings highlight groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT.


Dopamine Transporter and Reward Anticipation in a Dimensional Perspective: A Multimodal Brain Imaging Study.
Dopamine function and reward processing are highly interrelated and involve common brain regions afferent to the nucleus accumbens, within the mesolimbic pathway. Although dopamine function and reward system neural activity are impaired in most psychiatric disorders, it is unknown whether alterations in the dopamine system underlie variations in reward processing across a continuum encompassing health and these disorders. We explored the relationship between dopamine function and neural activity during reward anticipation in 27 participants including healthy volunteers and psychiatric patients with schizophrenia, depression, or cocaine addiction, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) multimodal imaging with a voxel-based statistical approach. Dopamine transporter (DAT) availability was assessed with PET and [11C]PE2I as a marker of presynaptic dopamine function, and reward-related neural response was assessed using fMRI with a modified Monetary Incentive Delay task. Across all the participants, DAT availability in the midbrain correlated positively with the neural response to anticipation of reward in the nucleus accumbens. Moreover, this relationship was conserved in each clinical subgroup, despite the heterogeneity of mental illnesses examined. For the first time, a direct link between DAT availability and reward anticipation was detected within the mesolimbic pathway in healthy and psychiatric participants, and suggests that dopaminergic dysfunction is a common mechanism underlying the alterations of reward processing observed in patients across diagnostic categories. The findings support the use of a dimensional approach in psychiatry, as promoted by the Research Domain Criteria project to identify neurobiological signatures of core dysfunctions underling mental illnesses.


Internet-based stress management for distressed managers: results from a randomised controlled trial.
The aim of this randomised controlled trial (RCT) was to evaluate the efficacy of a guided internet-based stress management intervention (iSMI) among distressed managers compared with a attention control group (AC) with full access to treatment-as-usual. A total sample of 117 distressed managers, mainly employed in the healthcare, IT, communication and educational sector, were randomised to either iSMI (n=59) or an AC group (n=58). The iSMI consisted of eight modules including cognitive behavioural stress management and positive management techniques. Participants received a minimal and weekly guidance from a psychologist or master-level psychology student focusing on support, feedback and adherence to the intervention. Self-report data were assessed at pre, post and 6 months after the intervention. The primary outcome was perceived stress (Perceived Stress Scale-14). The secondary outcomes included mental and work-related health outcomes. Participants in the iSMI intervention reported significantly less symptoms of perceived stress (d=0.74, 95% CI 0.30 to 1.19) and burnout (d=0.95, 95% CI 0.53 to 1.37) compared with controls, at postassessment. Significant medium-to-large effect sizes were also found for depression, insomnia and job satisfaction. Long-term effects (6 months) were seen on the mental health outcomes. This is one of the first studies showing that iSMIs can be an effective, accessible and potentially time-effective approach of reducing stress and other mental-related and work-related health symptoms among distressed managers. Future studies are needed addressing distressed managers and the potential of indirect effects on employee stress and satisfaction at work.


TLR3 deficiency in patients with herpes simplex encephalitis.
Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.


Quantitative measures of the palate using enhanced electropalatography.
Electropalatography (EPG) is a useful tool for investigating tongue dynamics in experimental phonetic research and speech therapy. However, data provided by EPG are a two-dimensional representation in which all absolute positional information is lost. This paper presents an enhanced EPG (eEPG) system which uses digitised palate shape data to display the tongue-palate contact pattern in three dimensions. The palate shapes are obtained using a colour-encoded structured light three-dimensional digitisation system. The three-dimensional palate shape is displayed on a Silicon Graphics workstation as a surface made up of polygons represented by a quadrilateral mesh. EPG contact patterns are superimposed on to the three-dimensional palate shape by displaying the relevant polygons in a different colour. By using this system, differences in shape between individual palates, apparent on visual inspection of the actual palates, are also apparent in the image on screen. Further, methods have been devised for computing absolute distances along paths lying on the palate surface. Combining this with calibrated palate shape data allows accurate measurements to be made between contact locations on the palate. These have been validated with manual measurements. In addition, vocal tract areas in the oral cavity have been estimated by using the absolute measurements on the palate for a given contact pattern, and assuming a flat tongue profile in the uncontacted area.


Lenalidomide Induced Late-Onset Acute Respiratory Distress Syndrome.
A 77-year-old man with multiple myeloma (MM) presented with shortness of breath to the emergency department. He also had history of chronic obstructive pulmonary disease, chronic pulmonary embolism and nephrectomy due to malignancy 10 years ago. He had been treated for 9 months with lenalidomide because of MM. He diagnosed with adult respiratory distress syndrome due to lenalidomide. We aimed to demonstrate late onset and destructive effects of lenalidomide on the lungs.


The conserved NDR kinase Orb6 controls polarized cell growth by spatial regulation of the small GTPase Cdc42.
The conserved NDR kinase regulates cell morphogenesis and polarized cell growth in different eukaryotic cells ranging from yeast to neurons. Although studies have unraveled the mechanism of regulation of NDR kinase activity, the mechanism of morphology control by NDR and the effectors that mediate NDR function are unknown. Via a chemical genetic approach, we show that the fission yeast NDR homolog, Orb6 kinase, maintains polarized cell growth at the cell tips by spatially regulating the localization of Cdc42 GTPase, a key morphology regulator. Loss of Orb6 kinase activity leads to the recruitment of Cdc42 GTPase and the Cdc42-dependent formin For3, normally found only at the cell tips, to the cell sides. Furthermore, we show that loss of Orb6 kinase activity leads to ectopic lateral localization of the Cdc42 guanine nucleotide exchange factor (GEF) Gef1, but not of the other Cdc42 GEF, Scd1. Consistent with these observations, gef1 deletion suppresses the increased cell diameter phenotype of orb6 mutants. In contrast, the microtubule cytoskeleton and the localization of the microtubule-dependent polarity markers Tea1 and Tea4 are not altered by loss of Orb6 kinase activity. Our findings indicate that the conserved NDR kinase Orb6 regulates cell polarity by spatially restricting the localization and activity of Cdc42 GTPase.


An intestinal Candida albicans model for monomicrobial and polymicrobial biofilms and effects of hydrolases and the Bgl2 ligand.
Candida albicans is the most prevalent human fungal pathogen. In biofilms, C. albicans becomes more resistant to antifungal agents because of the production of an extracellular matrix (ECM) that protects the yeast cells. This study aimed to determine the effects of hydrolase enzymes and the Bgl2 ligand on monomicrobial and polymicrobial biofilms. Biofilm induction in rats was carried out using streptomycin (25 mg/kg) and gentamicin (7.5 mg/kg) administered orally once per day for 5 days. Rats were injected subcutaneously with cortisone acetate (225 mg/kg) as an immunosuppressant on day 5. In addition, rats were orally administered C. albicans for the single microbial model and a combination of C. albicans with Escherichia coli for the polymicrobial model. Following the biofilm production, the groups were treated with glucosamine (8.57 mg/kg body weight) and Achatina fulica hydrolases (1.5 mL) orally for 2 weeks. The reduction of the biofilm was measured using confocal laser scanning microscopy (CLSM). Data were analyzed using a t-test, with a significance value of 95%. CLSM images revealed a strong association between C. albicans and E. coli in the polymicrobial biofilm. On the contrary, the combination treatment using glucosamine and A. fulica hydrolases reduced the ECM of the single microbial biofilm (53.58%). However, treatment effectiveness against the matrix (19.17%) was reduced in the polymicrobial model. There is a strong association between C. albicans and E. coli in the formation of polymicrobial biofilms. The combination of glucosamine and the A. fulica enzyme can reduce the single microbial biofilm ECM; however, it is ineffective in the polymicrobial model.


Alpha-melanocyte stimulating hormone and its analogue Nle4DPhe7 alpha-MSH affect morphology, tyrosinase activity and melanogenesis in cultured human melanocytes.
Although melanocyte stimulating hormone (MSH) peptides are known to stimulate pigmentation in man, previous reports suggest that human melanocytes are relatively unresponsive to these peptides in vitro. This may be related to the conditions under which the melanocytes were cultured. Thus, we have re-investigated the in vitro effects of MSH peptides using human melanocytes cultured in the absence of artificial mitogens. Human melanocytes were incubated with alpha-MSH or its potent analogue Nle4Dphe7 alpha-MSH for 3 days. After 18 hours, melanocyte morphology had evolved from mainly bipolar to dendritic in approximately 66% of cultures. Nle4DPhe7 alpha-MSH produced dose-related increases in both tyrosinase activity and melanin content although the degree of response was variable and tyrosinase activity was the relatively more responsive to the peptide. Similar results were obtained with alpha-MSH, but, although the effect on melanin content was similar to that of Nle4DPhe7 alpha-MSH, the effect on tyrosinase activity was less marked. The preliminary EC50 values for the actions of the MSH peptides suggest that they may be equipotent in their actions on human melanocytes. In addition, we have demonstrated that the common melanocyte mitogens 12-O-tetradecanoyl phorbol-13-acetate (TPA) and cholera toxin affect basal melanogenesis and modulate the effects of the MSH peptides. However, not all melanocyte cultures showed melanogenic responses to the MSH peptides. Ability to respond was unrelated to basal levels of tyrosinase activity or melanin content. In at least some cultures, morphological and melanogenic responses appear to be independent of one another.(ABSTRACT TRUNCATED AT 250 WORDS)


Smokable ("ice", "crystal meth") and non smokable amphetamine-type stimulants: clinical pharmacological and epidemiological issues, with special reference to the UK.
"Ice", "crystal meth", is the smokable form of methamphetamine hydrochloride. This paper will comment on the pharmacological, epidemiological, clinical and social issues related to smoking the drug as opposed to either its injection or ingestion. Furthermore, some data related to amphetamines/methamphetamines consumption, request for treatment, seizures, related offences and deaths in the UK (1990-2002) will be offered here. Peak rates, for most indicators, were reached at the end of the '90s, to fall down in the following years. The only indicator which seemed not to show any declining rates is number of deaths, but this may be related to a more general increase in stimulant death rates recently observed in the UK. It is argued that methamphetamines, and particularly "crystal meth", could reach the same prevalence levels of use in the UK as it is already in the US but recent reclassification of the drug to Class A in the UK could help to better control this emerging issue.


The relationship between early childhood head injury and later life criminal behaviour: a longitudinal cohort study.
Childhood head injury has been associated with the development of behavioural and psychological problems. This study examined the relationship between head injury in young childhood and subsequent criminal behaviour. Data were from the Providence cohort of the Collaborative Perinatal Project, a multicentre longitudinal study aimed at identifying the role of perinatal and prenatal factors on child health. History of head injury between ages 0 and 7 years was ascertained from health records of 2893 children. In total, 120 (4%) of children had a head injury. Propensity score matching was used to match each head injury case to five controls. Negative binomial regression was used to estimate the relationship between head injury and number of arrests, and log binomial regression was used to estimate risk of conduct problems. Those who suffered any head injury from ages 0 to 7 years had approximately 1.5 times the rate of arrests and risk of conduct problems compared with uninjured controls, though results did not meet the p<0.05 threshold for statistical significance. Severe head injury was associated with a twofold increased rate of juvenile arrests (incident rate ratio=2.44, 95% CI 0.93 to 6.46) and risk of conduct problems (risk ratio=2.47, 95% CI 0.90 to 6.74) that approached statistical significance. Head injury in childhood was associated with increased criminality and conduct problems. Future work should identify mechanisms of this association in order to develop interventions to prevent criminal behaviour resulting from head injury.