Laser-induced periodic alignment of Ag nanoparticles in soda-lime glass.
One-, two- or three-dimensional arrays of closely spaced silver nanoparticles may lead to new optical properties, due to short or long range coupling between their resonant surface plasmons, so that the spatially controlled growth of silver nanoparticles provides an efficient way to tune their optical properties. Towards this way, we present here the periodic pattern of a glass surface with silver nanoparticles by continuous ultraviolet laser exposure. The formation of the 160 nm period pattern is well described by an interference-based model which agrees with the experimental conclusions, mainly obtained by various forms of microscopy. Statistical approach based on the autocorrelation function gives quantitative description about the quality of the order in the periodic structure and about the nanoparticles averaged diameter (80 nm). We also present the optical extinction spectrum of the Laser Induced Periodic Surface Structure (LIPSS)-containing area of the glass, which unusually shows several bands in the visible range. The period of 160 nm of the periodic structure is short enough to allow coupling between nanoparticles, which makes it a possible candidate for plasmon-based optical applications.


Cerebrolysin attenuates cerebral and hepatic injury due to lipopolysaccharide in rats.
This study aimed to investigate the effect of cerebrolysin on oxidative stress in the brain and liver during systemic inflammation. Rats were intraperitoneally challenged with a single subseptic dose of lipopolysaccharide (LPS; 300 μg/kg) without or with cerebrolysin at doses of 21.5, 43 or 86 mg/kg. After 4 h, rats were euthanized and the brain and liver tissues were subjected to biochemical and histopathological analyses. Cerebrolysin revealed inhibitory effects on the elevation of lipid peroxidation and nitric oxide induced by LPS. In contrast, the decrease in reduced glutathione level and paraoxonase activity induced by LPS was attenuated by an injection of cerebrolysin in a dose-dependent manner. Moreover, cerebrolysin reduced LPS-induced activation of brain NF-κB and reversed LPS-induced decline of brain butyrylcholinesterase and acetylcholinesterase activities in a dose-dependent manner. Histopathological analyses revealed that neuronal damage and liver necrosis induced by LPS were ameliorated by cerebrolysin dose-dependently. Cerebrolysin treatment dose-dependently attenuated LPS-induced expressions in cyclooxygenase 2, inducible nitric oxide synthase, and caspase-3 in the cortex or striatum as well as the liver. These results suggest that cerebrolysin treatment might have beneficial therapeutic effects in cerebral inflammation. Cerebrolysin might also prove of value in liver disease and this possibility requires further exploration.


Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity.
Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. The aim of our study was to assess the cytokine production by sputum and blood cells from 15 refractory asthmatics (American Thoracic Society Criteria) compared to 15 mild untreated and 17 moderate treated asthmatics and 22 healthy subjects. Spontaneous production of interleukin (IL)-4, IL-6, IL-10, interferon-gamma, and tumor necrosis factor alpha was measured by immunotrapping after 24 h sputum or blood cell culture. Moderate and refractory asthmatics were both characterized by a lower production of IL-6 from their airway cells compared to healthy subjects. However, the difference was no longer significant when expressing the results per gram of sputum. No significant difference between the three groups was found regarding other cytokines. As for cytokine production from blood, the three groups of asthmatics exhibited raised production of IL-4 when compared to healthy subjects, and this was true when results were expressed per blood volume or after normalization for total leukocyte cell count. Moderate asthmatics exhibited greater production of IL-10 when compared to refractory asthmatics and healthy subjects when results were normalized for total leukocyte cell count. Sputum cells from moderate and refractory asthmatics release less IL-6. While the systemic overproduction of IL-4 was observed through the all spectrum of asthma severity, moderate asthmatics exhibited greater systemic IL-10 production compared to refractory asthmatics.


Primaquine treatment and relapse in Plasmodium vivax malaria.
The relapsing peculiarity of Plasmodium vivax is one of the prime reasons for sustained global malaria transmission. Global containment of P. vivax is more challenging and crucial compared to other species for achieving total malaria control/elimination. Primaquine (PQ) failure and P. vivax relapse is a major global public health concern. Identification and characterization of different relapse strains of P. vivax prevalent across the globe should be one of the thrust areas in malaria research. Despite renewed and rising global concern by researchers on this once 'neglected' species, research and development on the very topic of P. vivax reappearance remains inadequate. Many malaria endemic countries have not mandated routine glucose-6-phosphate dehydrogenase (G6PD) testing before initiating PQ radical cure in P. vivax malaria. This results in either no PQ prescription or thoughtless prescription and administration of PQ to P. vivax patients by healthcare providers without being concerned about patients' G6PD status and associated complications. It is imperative to ascertain the G6PD status and optimum dissemination of PQ radical cure in all cases of P. vivax malaria across the globe. There persists a compelling need to develop/validate a rapid, easy-to-perform, easy-to-interpret, quality controllable, robust, and cost-effective G6PD assay. High-dose PQ of both standard and short duration appears to be safe and more effective for preventing relapses and should be practiced among patients with normal G6PD activity. Multicentric studies involving adequately representative populations across the globe with reference PQ dose must be carried out to determine the true distribution of PQ failure. Study proving role of cytochrome P450-2D6 gene in PQ metabolism and association of CYP2D6 metabolizer phenotypes and P. vivax relapse is of prime importance and should be carried forward in multicentric systems across the globe.


Isonitrile Formation by a Non-Heme Iron(II)-Dependent Oxidase/Decarboxylase.
The electron-rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We herein provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non-heme iron(II)-dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)-3-((carboxymethyl)amino)butanoic acid to (R)-3-isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, of which several members are critical for the virulence of pathogenic mycobacteria.


The behavioral profile of children aged 1-5 years with sex chromosome trisomy (47,XXX, 47,XXY, 47,XYY).
Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early intervention. This study addressed the question of what the behavioral profile of children with SCT aged 1-5 years looks like. In total, 182 children aged 1-5 years participated in this study (NSCT =87, Nnonclinical controls = 95). Recruitment and assessment took place in the Netherlands and the United States. The SCT group was recruited through prospective follow-up (50%), information seeking parents (31%), and clinical referral (18%). Behavioral profiles were assessed with the child behavior checklist and the ages-and-stages social-emotional questionnaire. Levels of parent-rated problem behavior were higher in children with SCT. Difficulties with overall social-emotional functioning were already present in 1-year-olds, and elevated scores were persistent across the full age range. Affective and pervasive developmental behaviors were seen in late toddlerhood and prominent at preschool age. Anxiety, attention deficit, and oppositional defiant behaviors were seen in preschool-aged children. Within this cross-sectional study, the developmental trajectory of affective, pervasive developmental, and oppositional defiant behaviors seemed to be different for SCT children than nonclinical controls. Collectively, these results demonstrate the importance of behavioral screening for behavioral problems in routine clinical care for children with SCT from a young age. Social-emotional problems may require special attention, as these problems seem most prominent, showing increased risk across the full age range, and with these problems occurring regardless of the timing of diagnosis, and across all three SCT karyotypes.


Multiple model-based reinforcement learning.
We propose a modular reinforcement learning architecture for nonlinear, nonstationary control tasks, which we call multiple model-based reinforcement learning (MMRL). The basic idea is to decompose a complex task into multiple domains in space and time based on the predictability of the environmental dynamics. The system is composed of multiple modules, each of which consists of a state prediction model and a reinforcement learning controller. The "responsibility signal," which is given by the softmax function of the prediction errors, is used to weight the outputs of multiple modules, as well as to gate the learning of the prediction models and the reinforcement learning controllers. We formulate MMRL for both discrete-time, finite-state case and continuous-time, continuous-state case. The performance of MMRL was demonstrated for discrete case in a nonstationary hunting task in a grid world and for continuous case in a nonlinear, nonstationary control task of swinging up a pendulum with variable physical parameters.


Attention bias dynamics and symptom severity during and following CBT for social anxiety disorder.
Threat-related attention bias figures prominently in contemporary accounts of the maintenance of anxiety disorders, yet longitudinal intervention research relating attention bias to anxiety symptom severity is limited. Capitalizing on recent advances in the conceptualization and measurement of attention bias, we aimed to examine the relation between attention bias, indexed using trial-level bias scores (TLBSs) to quantify temporal dynamics reflecting dysregulation of attentional processing of threat (as opposed to aggregated mean bias scores) and social anxiety symptom severity over the course of cognitive-behavioral therapy (CBT) and 1-month follow-up. Adults with social anxiety disorder (N = 39) assigned to either yohimbine- or placebo-augmented CBT completed measures of attention bias and social anxiety symptom severity weekly throughout CBT (5 sessions) and at 1-week and 1-month posttreatment. TLBSs of attention bias temporal dynamics showed stronger psychometric properties than mean aggregated scores and were highly interrelated, in line with within-subject temporal variability fluctuating in time between attentional overengagement and strategic avoidance from threat. Attention bias toward threat and temporal variability in attention bias (i.e., attentional dysregulation), but not attention bias away from threat, significantly reduced over the course of CBT. Cross-lag analyses revealed no evidence of a causal relation between reductions in attentional dysregulation leading to symptom severity reduction, or vice versa. Observed relations did not vary as a function of time. We found no evidence for attentional dysregulation as a causal mechanism for symptom reduction in CBT for social anxiety disorders. Implications for future research are discussed. (PsycINFO Database Record


Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results.
Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell-depleting and interleukin-2 receptor antibodies. A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell-depleting antibody induction (36.1%) when compared with those receiving anti-interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell-depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.


Screening for oral health literacy in an urban dental clinic.
Studies show that the average person fails to understand and use health care related materials to their full potential. The goal of this study was to evaluate a health literacy instrument based on the Rapid Estimate of Adult Literacy in Medicine (REALM) that incorporates dental and medical terms into one 84-item Rapid Estimate of Adult Literacy in Medicine and Dentistry (REALM-D) measure and determine its association with patient characteristics of a culturally diverse dental clinic population. An 84-item dental/medical health literacy word list and a 48-item health beliefs and attitudes survey was provided to a sample of 200 adult patients seeking treatment for the first time at an oral diagnosis clinic located in a large urban medical center in Los Angeles, California. Of the total sample, 154 participants read all of list 1 correctly, 141 read list 2 correctly, and only 38 read list 3 correctly. Nonwhite participants had significantly lower REALM-D scores at each level of difficulty as well as the total scale score compared to white participants. Participants who reported English as not their main language had significantly lower REALM-D scores. REALM-D scores also varied significantly by level of education among participants where as level of education increased, oral health literacy increased. At a bivariate level, race, education, and English as a main language remain predictive of health literacy in a regression model. An interaction between education and English as a main language was significant. The REALM-D is an effective instrument for use by medical and dental clinicians in detecting differences among people of different backgrounds and for whom English was not their primary language.


Medication deserts: survey of neighborhood disparities in availability of prescription medications.
Only a small amount of research has focused on the relationship between socio-economic status (SES) and geographic access to prescription medications at community pharmacies in North America and Europe. To examine the relationship between a community's socio-economic context and its residents' geographic access to common medications in pharmacies, we hypothesized that differences are present in access to pharmacies across communities with different socio-economic environments, and in availability of commonly prescribed medications within pharmacies located in communities with different socio-economic status. We visited 408 pharmacies located in 168 socio-economically diverse communities to assess the availability of commonly prescribed medications. We collected the following information at each pharmacy visited: hours of operation, pharmacy type, in-store medication availability, and the cash price of the 13 most commonly prescribed medications. We calculated descriptive statistics for the sample and fitted a series of hierarchical linear models to test our hypothesis that the in-stock availability of medications differs by the socio-economic conditions of the community. This was accomplished by modeling medication availability in pharmacies on the socio-economic factors operating at the community level in a socio-economically devise urban area. Pharmacies in poor communities had significantly higher odds of medications being out of stock, OR=1.24, 95% CI [1.02, 1.52]. There was also a significant difference in density of smaller, independent pharmacies with very limited stock and hours of operation, and larger, chain pharmacies in poor communities as compared to the middle and low-poverty communities. The findings suggest that geographic access to a neighborhood pharmacy, the type of pharmacy, and availability of commonly prescribed medications varies significantly across communities. In extreme cases, entire communities could be deemed "medication deserts" because geographic access to pharmacies and the availability of the most prescribed medications within them were very poor. To our knowledge, this study is first to report on the relationship between SES and geographic access to medications using small area econometric analysis techniques. Our findings should be reasonably generalizable to other urban areas in North America and Europe and suggest that more research is required to better understand the relationship of socio-economic environments and access to medications to develop strategies to achieve equitable medication access.


Nurses under threat: a comparison of content of 28 aggression management programs.
Staff who work in the health service are now recognized as a high-risk group for assault in the workplace. Recently, professional and industrial organizations have begun to suggest appropriate curricula for training staff in aggression management. However, there is currently a plethora of aggression management training programs (AMP) available, varying both in content and in duration. In this paper, 28 programs were evaluated against 13 major content areas derived from the recommendations made from key professional and industrial organizations, and what may be today considered appropriate/ideal content areas for AMP. Information on programs available in English was sought via standard databases, the Internet, program providers, and through networking with colleagues and professional organizations. The majority of the programs reviewed covered personal safety issues for staff and patients, together with legal issues. The use of restraint, pharmacological management of aggression and seclusion were features of programs specifically addressing the needs of health care staff in mental health settings. Most programs appeared not to address the psychological and organizational costs associated with aggression in the workplace. This is surprising since the literature suggests that the effects of violence are wide and varied, including increased absenteeism and sick leave, property damage, decreased productivity, security costs, litigation, workers' compensation, reduced job satisfaction together with recruitment and retention issues. Also, few programs were based on a systematic evaluation of their outcomes. Suggestions for program development and their teaching are discussed.


Childhood obesity perceptions among African American caregivers in a rural Georgia community: a mixed methods approach.
Given the pivotal role of African American caregiver's perceptions of childhood obesity in rural areas, the inclusion of caregiver's perceptions could potentially reduce childhood obesity rates. The objective of the current study was to explore childhood obesity perceptions among African Americans in a rural Georgia community. This concurrent mixed methods study utilized two theoretical frameworks: Social Cognitive Theory and Social Ecological Model. Using a convenience sample, caregivers ages 22-65 years completed a paper-based survey (n = 135) and a face-to-face interview (n = 12) to explore perceptions of obesity risk factors, health complications, weight status, built environment features, and obesity prevention approaches. Descriptive statistics were generated and a six-step process was used for qualitative analysis. Participants commonly cited behavioral risk factors; yet, social aspects and appearance of the community were not considered contributing factors. Chronic diseases were reported as obesity health complications. Caregivers had a distorted view of their child's weight status. In addition, analysis revealed that caregivers assessed child's weight and height measurements by the child's appearance or a recent doctor visit. Environmental barriers reported by caregivers included safety concerns and insufficient physical activity venues and programs. Also, caregivers conveyed parents are an imperative component of preventing obesity. Although this study found caregivers were aware of obesity risk factors, health complications, built environment features, and prevention approaches their obesity perceptions were not incorporated into school or community prevention efforts. Findings suggest that children residing in rural areas are in need of tailored efforts that address caregiver perceptions of obesity.


Oligorotaxane Radicals under Orders.
A strategy for creating foldameric oligorotaxanes composed of only positively charged components is reported. Threadlike components-namely oligoviologens-in which different numbers of 4,4'-bipyridinium (BIPY(2+)) subunits are linked by p-xylylene bridges, are shown to be capable of being threaded by cyclobis(paraquat-p-phenylene) (CBPQT(4+)) rings following the introduction of radical-pairing interactions under reducing conditions. UV/vis/NIR spectroscopic and electrochemical investigations suggest that the reduced oligopseudorotaxanes fold into highly ordered secondary structures as a result of the formation of BIPY(•+) radical cation pairs. Furthermore, by installing bulky stoppers at each end of the oligopseudorotaxanes by means of Cu-free alkyne-azide cycloadditions, their analogous oligorotaxanes, which retain the same stoichiometries as their progenitors, can be prepared. Solution-state studies of the oligorotaxanes indicate that their mechanically interlocked structures lead to the enforced interactions between the dumbbell and ring components, allowing them to fold (contract) in their reduced states and unfold (expand) in their fully oxidized states as a result of Coulombic repulsions. This electrochemically controlled reversible folding and unfolding process, during which the oligorotaxanes experience length contractions and expansions, is reminiscent of the mechanisms of actuation associated with muscle fibers.


Obstructive sleep apnoea during REM sleep and incident non-dipping of nocturnal blood pressure: a longitudinal analysis of the Wisconsin Sleep Cohort.
Non-dipping of nocturnal blood pressure (BP) is associated with target organ damage and cardiovascular disease. Obstructive sleep apnoea (OSA) is associated with incident non-dipping. However, the relationship between disordered breathing during rapid eye movement (REM) sleep and the risk of developing non-dipping has not been examined. This study investigates whether OSA during REM sleep is associated with incident non-dipping. Our sample included 269 adults enrolled in the Wisconsin Sleep Cohort Study who completed two or more 24 h ambulatory BP studies over an average of 6.6 years of follow-up. After excluding participants with prevalent non-dipping BP or antihypertensive use at baseline, there were 199 and 215 participants available for longitudinal analysis of systolic and diastolic non-dipping, respectively. OSA in REM and non-REM sleep were defined by apnoea hypopnoea index (AHI) from baseline in-laboratory polysomnograms. Systolic and diastolic non-dipping were defined by systolic and diastolic sleep/wake BP ratios >0.9. Modified Poisson regression models estimated the relative risks for the relationship between REM AHI and incident non-dipping, adjusting for non-REM AHI and other covariates. There was a dose-response greater risk of developing systolic and diastolic non-dipping BP with greater severity of OSA in REM sleep (p-trend=0.021 for systolic and 0.024 for diastolic non-dipping). Relative to those with REM AHI<1 event/h, those with REM AHI≥15 had higher relative risk of incident systolic non-dipping (2.84, 95% CI 1.10 to 7.29) and incident diastolic non-dipping (4.27, 95% CI 1.20 to 15.13). Our findings indicate that in a population-based sample, REM OSA is independently associated with incident non-dipping of BP.


Induction of protective immunity against Schistosoma mansoni by a nonliving vaccine. IV. Fractionation and antigenic properties of a soluble adult worm immunoprophylactic activity.
An aqueous buffer-soluble, nonparticulate fraction of adult Schistosoma mansoni worms (SWAP) was separated by gel filtration on Ultragel AcA-34, and portions of the eluate were tested for their capacity to induce protective immunity against cercarial challenge when administered intradermally to mice in combination with the adjuvant BCG. All of the immunogenic activity was found in a single peak of protein excluded in the void volume of the column. This same fraction was determined by SDS-PAGE and Western immunoblotting to be unique in that it contained a component of Mr (X 10(-3) 97 (97,000) recognized monospecifically by antibodies from mice vaccinated with unseparated SWAP plus BCG. Similarly, the protective fraction was unique in possessing the capacity to elicit 24 hr delayed footpad swelling responses, as well as lymphokine production, in SWAP-BCG-immunized mice. These results suggest that the immunogenic activity of SWAP resides in a restricted population of molecules, and possibly in the 97,000 antigen detected with antibodies from vaccinated animals. Because both the protective capacity of unfractionated SWAP and the serologic reactivity of the 97,000 antigen are sensitive to digestion with protease, it is likely that the immunologic activity of these molecules is dependent on peptide-bonded structural elements.


Evidence for stabilizing selection on codon usage in chromosomal rearrangements of Drosophila pseudoobscura.
There has been a renewed interest in investigating the role of stabilizing selection acting on genome-wide traits such as codon usage bias. Codon bias, when synonymous codons are used at unequal frequencies, occurs in a wide variety of taxa. Standard evolutionary models explain the maintenance of codon bias through a balance of genetic drift, mutation and weak purifying selection. The efficacy of selection is expected to be reduced in regions of suppressed recombination. Contrary to observations in Drosophila melanogaster, some recent studies have failed to detect a relationship between the recombination rate, intensity of selection acting at synonymous sites, and the magnitude of codon bias as predicted under these standard models. Here, we examined codon bias in 2798 protein coding loci on the third chromosome of D. pseudoobscura using whole-genome sequences of 47 individuals, representing five common third chromosome gene arrangements. Fine-scale recombination maps were constructed using more than 1 million segregating sites. As expected, recombination was demonstrated to be significantly suppressed between chromosome arrangements, allowing for a direct examination of the relationship between recombination, selection, and codon bias. As with other Drosophila species, we observe a strong mutational bias away from the most frequently used codons. We find the rate of synonymous and nonsynonymous polymorphism is variable between different amino acids. However, we do not observe a reduction in codon bias or the strength of selection in regions of suppressed recombination as expected. Instead, we find that the interaction between weak stabilizing selection and mutational bias likely plays a role in shaping the composition of synonymous codons across the third chromosome in D. pseudoobscura.


Endozepines and their receptors: Structure, functions and pathophysiological significance.
The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discuss the physiopathological implications of these regulatory gliopeptides.


Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation?
Allogeneic bone marrow transplantation (BMT) is associated with a severe complication--graft-versus-host disease (GVHD). Although effectively preventing GVHD, ex vivo T-lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect. The ex vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells could allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GVHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GVHD. To obtain T cells specifically depleted by GCV, we transduced primary T cells with a retroviral vector containing the HS-tk and neomycin resistance (NeoR) genes. Gene transfer was performed by coculturing PHA +/- CD3- or alloantigen-stimulated purified T cells on an irradiated retroviral vector producer cell line or by incubating the T cells in supernatant from the producer. Subsequent culture in G418 for 1 week allowed for the selection of transduced cells. GCV treatment of interleukin-2-responding transduced and selected cells resulted in greater than 80% growth inhibition, whereas GCV treatment of control cells had no effect. Similarly, the allogeneic reactivity of HS-tk-transduced cells was specifically inhibited by GCV. Combining transduced and nontransduced T cells did not show a bystander effect, thus implying that all of the cells inhibited by GCV were indeed transduced. Lastly, studies involving the transduction of the HUT-78 (T-lymphoma) cell line suggest that stable expression of HS-tk can be maintained over 3 months in vitro in the absence of G418. In summary, we have established the feasibility of generating HS-tk-transduced T cells for subsequent in vivo transfer with hematopoietic stem cells and, if GVHD occurs, specific in vivo GCV-induced T-cell depletion in allogeneic BMT recipients.


Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity.
Astrocytes are considered the third component of the synapse, responding to neurotransmitter release from synaptic terminals and releasing gliotransmitters--including glutamate--in a Ca(2+)-dependent manner to affect neuronal synaptic activity. Many studies reporting astrocyte-driven neuronal activity have evoked astrocyte Ca(2+) increases by application of endogenous ligands that directly activate neuronal receptors, making astrocyte contribution to neuronal effect(s) difficult to determine. We have made transgenic mice that express a Gq-coupled receptor only in astrocytes to evoke astrocyte Ca(2+) increases using an agonist that does not bind endogenous receptors in brain. By recording from CA1 pyramidal cells in acute hippocampal slices from these mice, we demonstrate that widespread Ca(2+) elevations in 80%-90% of stratum radiatum astrocytes do not increase neuronal Ca(2+), produce neuronal slow inward currents, or affect excitatory synaptic activity. Our findings call into question the developing consensus that Ca(2+)-dependent glutamate release by astrocytes directly affects neuronal synaptic activity in situ.


Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers.
Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-naïve patients with SpA and to the general population. From the Swedish (Anti-Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS=5448, DANBIO=3255) patients with SpA initiating a first TNFi 2001-2011. From the Swedish National Patient and Population Registers we assembled a TNFi-naïve SpA cohort (n=28,164) and a Swedish age-matched and sex-matched general population comparator cohort (n=131 687). We identified incident cancers by linkage with the nationwide Swedish and Danish Cancer Registers 2001-2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR). Based on 1188 cancers among the TNFi-naïve patients with SpA, RR of cancer overall was 1.1 (95% CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-naïve was 0.8 (95% CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6). In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.


Immunonutrition and cancer.
The immune system is the body's primary defence against invading pathogens, non-self components and cancer cells. Inflammatory processes, including the release of pro-inflammatory cytokines and formation of reactive oxygen and nitrogen species, are an essential part of these processes. Although such actions are usually followed rapidly by anti-inflammatory effects, excessive production of pro-inflammatory cytokines, or their production in the wrong biological context may lead to situations of chronic inflammation. Whether such conditions arise as a result of exogenous chemicals, invading pathogens or disease processes, the long-term implications include an increased risk of cancer. A number of nutrients have the ability to modulate immune response and counter inflammatory processes. Zinc, epigallocatechin galate (EGCG), omega-3 polyunsaturated fatty acids and probiotics all act differently to modulate immune response, but all appear to have the potential to protect against cancer development and progression. We suggest that immunonutrition may provide a less invasive alternative to immunotherapy in protection against cancers associated with chronic inflammation.


Differential expression of granulocyte, macrophage, and hypoxia markers during early and late wound healing stages following transplantation of tissue-engineered skin substitutes of human origin.
Human pigmented tissue-engineered skin substitutes represent an advanced therapeutic option to treat skin defects. The inflammatory response is one of the major factors determining integration and long-term survival of such a graft in vivo. The aim of the present study was to investigate the spatiotemporal distribution of host-derived macrophage and granulocyte graft infiltration as well as hypoxia-inducible factor 1 alpha (HIF-1-alpha) expression in a (nu/nu) rat model. Keratinocytes, melanocytes, and fibroblasts derived from human skin biopsies were isolated, cultured, and expanded in vitro. Dermal fibroblasts were seeded into collagen type I hydrogels that were subsequently covered by keratinocytes and melanocytes in 5:1 ratio. These pigmented dermo-epidermal skin substitutes were transplanted onto full-thickness skin wounds on the back of immuno-incompetent rats and analyzed at early (1 and 3 weeks) and late (6 and 12 weeks) stages of wound healing. The expression of distinct inflammatory cell markers specific for granulocytes (HIS48) or macrophages (CD11b, CD68), as well as HIF-1-alpha were analyzed and quantified by immunofluorescence microscopy. Our data demonstrate that granulocytes infiltrate the entire graft at 1 week post-transplantation. This was followed by monocyte/macrophage recruitment to the graft at 3-12 weeks. The macrophages were initially restricted to the borders of the graft (early stages), and were then found throughout the entire graft (late stages). We observed a time-dependent decrease of macrophages. Only a few graft-infiltrating granulocytes were found between 6-12 weeks, mostly at the graft borders. A heterogeneous expression of HIF-1-alpha was observed at both early and late wound healing stages. Our findings demonstrate the spatiotemporal distribution of inflammatory cells in our transplants closely resembles the one documented for physiological wound healing.


Can pancreatic steatosis affect exocrine functions of pancreas?
Pancreatic steatosis (PS) is a generally used term to define accumulation of fat in the pancreas. In theory PS may be able to affect the exocrine function of pancreas. In this study we aimed to determine the effect of PS on exocrine pancreas function. Forty-three patients with PS determined by 3 tesla magnetic resonance imaging (MRI) and 48 patients without PS were included in this study. Patients with PS were classified as group 1 and control patients were classified as group 2. Fecal elastase-1 levels were determined. Fecal elastase-1 levels <200 μg/g were defined as exocrine pancreatic insufficiency (EPI). Patients with PS were further grouped according to severity and anatomic distribution of steatosis based on findings of 3 tesla MRI. Fecal elastase-1 levels was significantly lower in group 1 compared to group 2 (319.76±45.7 vs 549.31±69.4, respectively, p=0.003). Proportion of patients with EPI was significantly higher in group 1 than group 2 (35.5% vs 12% p=0.042). There were no significant differences in terms of severity or the anatomic distribution of PS in patients with PS with EPI based on MRI (p=0.052, p=0.198, p=0.405) Conclusion: Current study demonstrates that PS can cause EPI.


Role of apoptosis in photodynamic sensitivity of human tumour cell lines.
Photodynamic therapy (PDT) using a photosensitizer, such as haematoporphyrin derivative (HpD), in conjunction with visible light is a promising new modality to treat localized cancer. Cell death caused by PDT (through the generation of reactive oxygen species) can occur either by apoptosis (interphase death or as a secondary event following mitosis) and/or necrosis depending on the cell type, concentration and intracellular localization of the sensitizer, and the light dose. Since, apoptosis induced by PDT treatment plays an important role in determining the photodynamic efficacy, in the present work we have investigated the role of apoptotic cell death in relation to the observed differences in sensitivity to HpD-PDT between a human glioma cell line (BMG-1) carrying wild-type tumour suppressor gene p53 and a human squamous carcinoma cell line (4451) with mutated p53. HpD (photosan-3; PS-3) -PDT induced apoptosis was studied by: [A] flow-cytometric analysis of DNA content (sub G0/G1 population); [B] phosphatidylserine externalization (Annexin-V +ve cells); [C] cell size and cytoskeleton reorganization (light-scatter analysis); and [D] fluorescence microscopy (morphological features). PS-3-PDT induced a significantly higher level of apoptosis in BMG-1 cells as compared to 4451 cells. This was dependent on the concentration of PS-3 as well as post-irradiation time in both the cell lines. At 2.5 microg/ml of PS-3 the fraction of BMG-1 cells undergoing apoptosis (60%) was nearly 6 folds higher than 4451 cells (10%). In BMG-1 cells the induction of apoptosis increased with PS-3 concentration up to 5 microg/ml (>80%). However, a decrease was observed at a concentration of 10 microg/ml, possibly due to a shift in the mode of cell death from apoptosis to necrosis. In 4451 cells, on the other hand, the increase in apoptosis could be observed even up to 10 microg/ml of PS-3 (60%). Present results show that the higher sensitivity to PS-3-PDT in glioma cells arise on account of a higher level of apoptosis and suggest that induction of apoptosis is an important determinant of photodynamic sensitivity in certain cell types.


Influence of topically applied cold treatment on core temperature and cell viability in equine superficial digital flexor tendons.
To determine rate and degree of cooling for the superficial digital flexor tendon (SDFT) during a standard cryotherapy application in horses and evaluate in vitro effects of cooling on survival of tendon cells. 6 limbs of 5 adult horses and cultured cells obtained from SDFT of 3 adult horses during necropsy. In vivo data were acquired by use of a thermocouple temperature probe inserted into the SDFT of a forelimb of each standing sedated horse. After baseline temperatures were recorded, a commercial compression splint with circulating coolant was placed on each selected limb, which was then exposed to cold treatment for 60 minutes. Temperatures were recorded at 30-second intervals. Mean minimum core temperature was calculated and used to design a protocol for in vitro cold treatment of cells. Specimens were obtained from the SDFT of horses during necropsy; tendon cells were cultured in suspension and exposed to 1-hour of cold treatment that mimicked the in vivo procedure. Viability of cells after cold treatment was compared with viability of cells maintained at body temperature. After 1 hour of cold treatment, SDFT core temperature was reduced by a mean of 21.8 degrees C, reaching a mean minimum temperature of 10 degrees C. Viability did not differ significantly between cold-treated and control cells. Results indicated that topical application of cryotherapy significantly reduced core SDFT temperature in standing sedated horses. Temperatures achieved in vivo during cold treatment were not detrimental to the in vitro viability of tendon cells.


Barriers to and benefits of leisure time physical activity in the elderly: differences across cultures.
The purpose of this study was to compare ethnic differences in attitudes toward barriers and benefits of leisure-time physical activity (LTPA) in sedentary elderly Mexican (MAs) and European Americans (EAs). An in-home, cross-sectional survey was performed on 210 community-dwelling elders from 10 primary care practices in south Texas that are part of the South Texas Ambulatory Research Network, a practice-based research network. Analytical variables included ethnicity, age, sex, income, education, marital status, and LTPA. Fisher exact test was used to analyze the 100 sedentary elders (LTPA <500 kcal/wk; 63 MAs and 37 EAs). Self-consciousness and lack of self-discipline, interest, company, enjoyment, and knowledge were found to be the predominant barriers to LTPA in both groups. Both groups held similar beliefs about benefits gained from exercise, such as improved self-esteem, mood, shape, and health, but the beliefs about the positive benefits of exercise were more prevalent in MAs. These findings remained after adjusting for age, income, education, marital status, and sex. Some might think that a major barrier lies in misconception about benefits of LTPA, but in this study, both ethnic groups were accurate in their perceived benefits of LTPA. When attempting to engage elderly in LTPA, it is important not only to consider what barriers exist but also what beliefs about the benefits exist.


The design and conduct of clinical trials to limit missing data.
This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.


Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver.
IFN-alpha/beta-mediated functions promote production of MIP-1alpha (or CCL3) by mediating the recruitment of MIP-1alpha-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-gamma delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-alpha/beta and/or play intermediary roles in supporting macrophage trafficking. The chemokine MCP-1 (or CCL2) plays a distinctive role in the recruitment of macrophages by predominantly stimulating the CCR2 chemokine receptor. Here, we examine the roles of MCP-1 and CCR2 during murine CMV infection in liver. MCP-1 production preceded that of MIP-1alpha during infection and was dependent on IFN-alpha/beta effects for induction. Resident F4/80(+) liver leukocytes were identified as primary IFN-alpha/beta responders and major producers of MCP-1. Moreover, MCP-1 deficiency was associated with a dramatic reduction in the accumulation of macrophages and NK cells, as well as decreased production of MIP-1alpha and IFN-gamma in liver. These responses were also markedly impaired in mice with a targeted disruption of CCR2. Furthermore, MCP-1- and CCR2-deficient mice exhibited increased viral titers and elevated expression of the liver enzyme alanine aminotransferase in serum. These mice also had widespread virus-induced liver pathology and succumbed to infection. Collectively, these results establish MCP-1 and CCR2 interactions as factors promoting early liver inflammatory responses and define a mechanism for innate cytokines in regulation of chemokine functions critical for effective localized antiviral defenses.


Is dynamic cerebral autoregulation measurement using transcranial Doppler ultrasound reproducible in the presence of high concentration oxygen and carbon dioxide?
Reliability of cerebral blood flow velocity (CBFV) and dynamic cerebral autoregulation estimates (expressed as autoregulation index: ARI) using spontaneous fluctuations in blood pressure (BP) has been demonstrated. However, reliability during co-administration of O2 and CO2 is unknown. Bilateral CBFV (using transcranial Doppler), BP and RR interval recordings were performed in healthy volunteers (seven males, four females, age: 54 ± 10 years) on two occasions over 9 ± 4 d. Four 5 min recordings were made whilst breathing air (A), then 5%CO2 (C), 80%O2 (O) and mixed O2 + CO2 (M), in random order. CBFV was recorded; ARI was calculated using transfer function analysis. Precision was quantified as within-visit standard error of measurement (SEM) and the coefficient of variation (CV). CBFV and ARI estimates with A (SEM: 3.85 & 0.87; CV: 7.5% & 17.8%, respectively) were comparable to a previous reproducibility study. The SEM and CV with C and O were similar, though higher values were noted with M; Bland-Altman plots indicated no significant bias across all gases for CBFV and ARI (bias <0.06 cm s(-1) and <0.05, respectively). Thus, transcranial-Doppler-ultrasound-estimated CBFV and ARI during inhalation of O2 and CO2 have acceptable levels of reproducibility and can be used to study the effect of these gases on cerebral haemodynamics.


Thermodynamic inference based on coarse-grained data or noisy measurements.
Fluctuation theorems have become an important tool in single-molecule biophysics to measure free-energy differences from nonequilibrium experiments. When significant coarse-graining or noise affect the measurements, the determination of the free energies becomes challenging. In order to address this thermodynamic inference problem, we propose improved estimators of free-energy differences based on fluctuation theorems, which we test on a number of examples. The effect of the noise can be described by an effective temperature, which only depends on the signal-to-noise ratio, when the work is Gaussian distributed and uncorrelated with the error made on the work. The notion of effective temperature appears less useful for non-Gaussian work distributions or when the error is correlated with the work, but nevertheless, as we show, improved estimators can still be constructed for such cases. As an example of nontrivial correlations between the error and the work, we also consider measurements with delay, as described by linear Langevin equations.


ABCDE of prehospital ultrasonography: a narrative review.
Prehospital point-of-care ultrasound used by nonradiologists in emergency medicine is gaining ground. It is feasible on-scene and during aeromedical transport and allows health-care professionals to detect or rule out potential harmful conditions. Consequently, it impacts decision-making in prioritizing care, selecting the best treatment, and the most suitable transport mode and destination. This increasing relevance of prehospital ultrasonography is due to advancements in ultrasound devices and related technology, and to a growing number of applications. This narrative review aims to present an overview of prehospital ultrasonography literature. The focus is on civilian emergency (trauma and non-trauma) setting. Current and potential future applications are discussed, structured according to the airway, breathing, circulation, disability, and environment/exposure (ABCDE) approach. Aside from diagnostic implementation and specific protocols, procedural guidance, therapeutic ultrasound, and challenges are reviewed.


Protein imaging. Single-protein spin resonance spectroscopy under ambient conditions.
Magnetic resonance is essential in revealing the structure and dynamics of biomolecules. However, measuring the magnetic resonance spectrum of single biomolecules has remained an elusive goal. We demonstrate the detection of the electron spin resonance signal from a single spin-labeled protein under ambient conditions. As a sensor, we use a single nitrogen vacancy center in bulk diamond in close proximity to the protein. We measure the orientation of the spin label at the protein and detect the impact of protein motion on the spin label dynamics. In addition, we coherently drive the spin at the protein, which is a prerequisite for studies involving polarization of nuclear spins of the protein or detailed structure analysis of the protein itself.


Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro.
Cannabinoids have analgesic, immunomodulatory and anti-inflammatory properties and attenuate joint damage in animal models of arthritis. In this study the mechanisms of action of the synthetic cannabinoid agonists, HU-210 and Win-55,212-2, were studied to determine if they affected interleukin-1 alpha (IL-1alpha)-induced proteoglycan and collagen degradation in bovine nasal cartilage explant cultures and prostaglandin E2 (PGE2) production in primary cultures of bovine articular chondrocytes. The effects of the inactive enantiomer, Win-55,212-3, were compared with those of the active enantiomer, Win-55,212-2, to determine if the effects were cannabinoid (CB)-receptor mediated. The chondrocytes and explants were stimulated by IL-1alpha (100 U mL(-1) identical with 0.06 nM and 500 U mL(-1) identical with 0.3 nM, respectively). Proteoglycan breakdown was determined as sulfated glycosaminoglycan (sGAG) release using the dimethylmethylene blue assay. Collagen degradation was determined as hydroxyproline in the conditioned culture media and cartilage digests. PGE2 was determined by ELISA. Expression of cannabinoid receptors, CB1 and CB2; cyclooxygenase-1 and -2 (COX-1 and COX-2); inducible nitric oxide synthase (iNOS); as well as activation of nuclear factor-kappa B (NF-kappaB) in chondrocytes were studied using immunoblotting techniques and immunofluorescence. The results showed that HU-210 and Win-55,212-2 (5-15 microM) significantly inhibited IL-1-alpha stimulated proteoglycan (P < 0.001) and collagen degradation (P < 0.001). Win-55,212-2 (5-10 microM) also significantly inhibited PGE2 production (P < 0.01). At 5 microM, Win-55,212-2 inhibited the expression of iNOS and COX-2 and activation of NF-kappaB. Chondrocytes appeared to constitutively express cannabinoid receptors CB1 and CB2. It is concluded that biologically stable synthetic cannabinoids protect cartilage matrix from degradation induced by cytokines and this effect is possibly CB-receptor mediated and involves effects on prostaglandin and nitric oxide metabolism. Cannabinoids could also be producing these effects via inhibition of NF-kappaB activation.


Chronic temporal lobe epilepsy is associated with enhanced Alzheimer-like neuropathology in 3×Tg-AD mice.
The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Senile plaques and tauopathy are found in epileptic human temporal lobe structures, and individuals with AD have an increased incidence of spontaneous seizures. However, why and how epilepsy is associated with enhanced AD-like pathology remains unknown. We have recently shown β-secretase-1 (BACE1) elevation associated with aberrant limbic axonal sprouting in epileptic CD1 mice. Here we sought to explore whether BACE1 upregulation affected the development of Alzheimer-type neuropathology in mice expressing mutant human APP, presenilin and tau proteins, the triple transgenic model of AD (3×Tg-AD). 3×Tg-AD mice were treated with pilocarpine or saline (i.p.) at 6-8 months of age. Immunoreactivity (IR) for BACE1, β-amyloid (Aβ) and phosphorylated tau (p-tau) was subsequently examined at 9, 11 or 14 months of age. Recurrent convulsive seizures, as well as mossy fiber sprouting and neuronal death in the hippocampus and limbic cortex, were observed in all epileptic mice. Neuritic plaques composed of BACE1-labeled swollen/sprouting axons and extracellular AβIR were seen in the hippocampal formation, amygdala and piriform cortices of 9 month-old epileptic, but not control, 3×Tg-AD mice. Densities of plaque-associated BACE1 and AβIR were elevated in epileptic versus control mice at 11 and 14 months of age. p-Tau IR was increased in dentate granule cells and mossy fibers in epileptic mice relative to controls at all time points examined. Thus, pilocarpine-induced chronic epilepsy was associated with accelerated and enhanced neuritic plaque formation and altered intraneuronal p-tau expression in temporal lobe structures in 3×Tg-AD mice, with these pathologies occurring in regions showing neuronal death and axonal dystrophy.


Chaotic scattering in solitary wave interactions: a singular iterated-map description.
We derive a family of singular iterated maps--closely related to Poincare maps--that describe chaotic interactions between colliding solitary waves. The chaotic behavior of such solitary-wave collisions depends on the transfer of energy to a secondary mode of oscillation, often an internal mode of the pulse. This map allows us to go beyond previous analyses and to understand the interactions in the case when this mode is excited prior to the first collision. The map is derived using Melnikov integrals and matched asymptotic expansions and generalizes a "multipulse" Melnikov integral. It allows one to find not only multipulse heteroclinic orbits, but exotic periodic orbits. The maps exhibit singular behavior, including regions of infinite winding. These maps are shown to be singular versions of the conservative Ikeda map from laser physics and connections are made with problems from celestial mechanics and fluid mechanics.


The Translation and Cultural Adaptation of Patient-reported Outcome Measures for a Clinical Study Involving Traditional Health Providers and Bio-medically Trained Practitioners.
This study reports on the cultural and language translation of measures for use with Zulu speakers in South Africa. The translation process was purposefully used to integrate our diverse 14 person study team by employing Community Based Participatory Research (CBPR) strategies. Measures included: the Medical Outcomes Study HIV Health Survey (MOS-HIV), Center for Epidemiologic Studies Depression Scale (CES-D), and Perceived Stress Scale (PSS). The translation was made complex by the variation in Zulu dialects across regions and even between two cities only forty-five minutes apart. Carefully conceived translations can simultaneously produce good translationsand deepen team members' understanding of each-other.


Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.


The tumor microenvironment and immune responses in prostate cancer patients.
The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.


Interferon-gamma inhibits seminal plasma induction of colony-stimulating factor 2 in mouse and human reproductive tract epithelial cells.
Seminal fluid interacts with the female reproductive tract to initiate a permissive immune response that facilitates embryo implantation and pregnancy success. The immune-regulatory cytokine interferon-γ (IFNG), which can be elevated in seminal plasma, is associated with reduced fertility. Here, we investigated how IFNG influences the female immune response to seminal fluid. In human Ect1 cervical epithelial cells, IFNG added at physiologically relevant concentrations substantially impaired seminal plasma-induced synthesis of key cytokines colony-stimulating factor 2 (CSF2) and interleukin-6 (IL6). Seminal fluid-induced CSF2 synthesis was also suppressed in the uterus of mice in vivo, when IFNG was delivered transcervically 12 h after mating. Transforming growth factor B1 (TGFB1) is the major seminal fluid signaling factor which elicits CSF2 induction, and IFNG exhibited potent dose-dependent suppression of CSF2 synthesis induced by TGFB1 in murine uterine epithelial cells in vitro. Similarly, IFNG suppressed TGFB1-mediated CSF2 induction in Ect1 cells and human primary cervical epithelial cells; however, IL6 regulation by IFNG was independent of TGFB1. Quantitative PCR confirmed that CSF2 regulation by IFNG in Ect1 cells occurs at the gene transcription level, secondary to IFNG suppression of TGFBR2 encoding TGFB receptor 2. Conversely, TGFB1 suppressed IFNG receptor 1 and 2 genes IFNGR1 and IFNGR2. These data identify IFNG as a potent inhibitor of the TGFB-mediated seminal fluid interaction with relevant reproductive tract epithelia in mice and human. These findings raise the prospect that IFNG in the male partner's seminal fluid impairs immune adaptation for pregnancy following coitus in women.


Automatic scoring of dicentric chromosomes as a tool in large scale radiation accidents.
Mass casualty scenarios of radiation exposure require high throughput biological dosimetry techniques for population triage in order to rapidly identify individuals who require clinical treatment. The manual dicentric assay is a highly suitable technique, but it is also very time consuming and requires well trained scorers. In the framework of the MULTIBIODOSE EU FP7 project, semi-automated dicentric scoring has been established in six European biodosimetry laboratories. Whole blood was irradiated with a Co-60 gamma source resulting in 8 different doses between 0 and 4.5Gy and then shipped to the six participating laboratories. To investigate two different scoring strategies, cell cultures were set up with short term (2-3h) or long term (24h) colcemid treatment. Three classifiers for automatic dicentric detection were applied, two of which were developed specifically for these two different culture techniques. The automation procedure included metaphase finding, capture of cells at high resolution and detection of dicentric candidates. The automatically detected dicentric candidates were then evaluated by a trained human scorer, which led to the term 'semi-automated' being applied to the analysis. The six participating laboratories established at least one semi-automated calibration curve each, using the appropriate classifier for their colcemid treatment time. There was no significant difference between the calibration curves established, regardless of the classifier used. The ratio of false positive to true positive dicentric candidates was dose dependent. The total staff effort required for analysing 150 metaphases using the semi-automated approach was 2 min as opposed to 60 min for manual scoring of 50 metaphases. Semi-automated dicentric scoring is a useful tool in a large scale radiation accident as it enables high throughput screening of samples for fast triage of potentially exposed individuals. Furthermore, the results from the participating laboratories were comparable which supports networking between laboratories for this assay.


The risk of asbestos exposure in South African diamond mine workers.
Asbestos is associated with South African diamond mines due to the nature of kimberlite and the location of the diamond mines in relation to asbestos deposits. Very little is known about the health risks in the diamond mining industry. The objective of this study was to explore the possibility of asbestos exposure during the process of diamond mining. Scanning electron microscopy and energy-dispersive X-ray spectroscopy analysis were used to identify asbestos fibres in the lungs of diamond mine workers who had an autopsy for compensation purposes and in the tailings and soils from three South African diamond mines located close to asbestos deposits. The asbestos lung fibre burdens were calculated. We also documented asbestos-related pathological findings in diamond mine workers at autopsy. Tremolite-actinolite asbestos fibres were identified in the lungs of five men working on diamond mines. Tremolite-actinolite and/or chrysotile asbestos were present in the mine tailings of all three mines. Mesothelioma, asbestosis, and/or pleural plaques were diagnosed in six diamond mine workers at autopsy. These findings indicate that diamond mine workers are at risk of asbestos exposure and, thus, of developing asbestos-related diseases. South Africa is a mineral-rich country and, when mining one commodity, it is likely that other minerals, including asbestos, will be accidentally mined. Even at low concentrations, asbestos has the potential to cause disease, and mining companies should be aware of the health risk of accidentally mining it. Recording of comprehensive work histories should be mandatory to enable the risk to be quantified in future studies.


Poly(ethylene oxide)-b-poly(3-sulfopropyl methacrylate) block copolymers for calcium phosphate mineralization and biofilm inhibition.
Poly(ethylene oxide) (PEO) has long been used as an additive in toothpaste, partly because it reduces biofilm formation on teeth. It does not, however, reduce the formation of dental calculus or support the remineralization of dental enamel or dentine. The present article describes the synthesis of new block copolymers on the basis of PEO and poly(3-sulfopropyl methacrylate) blocks using atom transfer radical polymerization. The polymers have very large molecular weights (over 10(6) g/mol) and are highly water-soluble. They delay the precipitation of calcium phosphate from aqueous solution but, upon precipitation, lead to relatively monodisperse hydroxyapatite (HAP) spheres. Moreover, the polymers inhibit the bacterial colonization of human enamel by Streptococcus gordonii, a pioneer bacterium in oral biofilm formation, in vitro. The formation of well-defined HAP spheres suggests that a polymer-induced liquid precursor phase could be involved in the precipitation process. Moreover, the inhibition of bacterial adhesion suggests that the polymers could be utilized in caries prevention.


Topical Coenzyme Q10 Eye Drops as an Adjuvant Treatment in Challenging Refractory Corneal Ulcers: A Case Series and Literature Review.
The management of nonhealing corneal ulcers, particularly in patients with neurotrophic corneas, remains a challenging problem today. Some patients may fail to respond to conventional therapy, making new alternative agents necessary to treat these resistant cases. In this article, we aim to present six challenging cases of refractory corneal ulcers that revealed healing response to the adjuvant treatment with coenzyme Q10 (CoQ10) eye drops and to review the literature examining of new therapeutic agents. Our study was designed as a descriptive case series demonstrating the use of novel coenzyme Q10 eye drops in refractory corneal ulcers. In our case series, CoQ10 eye drops were added to the existing therapies as an adjuvant agent in six cases: three cases with neurotrophic corneal ulcers, two cases with postinfectious corneal ulcers (one unknown etiology+one Acanthamoeba keratitis), and 1 case with Stevens-Johnson syndrome. All cases were monitored regularly and corneal images were taken at all visits. All nonhealing corneas with conventional therapy revealed recovery after the addition of CoQ10 eye drops. Except for two cases that responded to the CoQ10 eye drops more rapidly (within 1 to 2 weeks), complete corneal healing was observed in four cases between weeks 4 and 8. No adverse events were reported in these cases throughout the follow-up period. Coenzyme Q10 eye drops can be considered as an important adjuvant therapeutic agent promoting corneal epithelial wound healing in challenging cases.


Panoptic Feature Fusion Net: A Novel Instance Segmentation Paradigm for Biomedical and Biological Images.
Instance segmentation is an important task for biomedical and biological image analysis. Due to the complicated background components, the high variability of object appearances, numerous overlapping objects, and ambiguous object boundaries, this task still remains challenging. Recently, deep learning based methods have been widely employed to solve these problems and can be categorized into proposal-free and proposal-based methods. However, both proposal-free and proposal-based methods suffer from information loss, as they focus on either global-level semantic or local-level instance features. To tackle this issue, we present a Panoptic Feature Fusion Net (PFFNet) that unifies the semantic and instance features in this work. Specifically, our proposed PFFNet contains a residual attention feature fusion mechanism to incorporate the instance prediction with the semantic features, in order to facilitate the semantic contextual information learning in the instance branch. Then, a mask quality sub-branch is designed to align the confidence score of each object with the quality of the mask prediction. Furthermore, a consistency regularization mechanism is designed between the semantic segmentation tasks in the semantic and instance branches, for the robust learning of both tasks. Extensive experiments demonstrate the effectiveness of our proposed PFFNet, which outperforms several state-of-the-art methods on various biomedical and biological datasets.


The INFIR Cohort Study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India.
The aim of this study was to find predictors of neuropathy and reactions, determine the most sensitive methods for detecting peripheral neuropathy, study the pathogenesis of neuropathy and reactions and create a bank of specimen, backed up by detailed clinical documentation. A multi-centre cohort study of 303 multibacillary leprosy patients in Northern India was followed for 2 years. All newly registered MB patients requiring a full course of MDT, who were smear positive and/or had six or more skin lesions and/or had two or more nerve trunks involved, were eligible. A detailed history was taken and physical and neurological examinations were performed. Nerve function was assessed at each visit with nerve conduction testing, warm and cold detection thresholds, vibrometry, dynamometry, monofilaments and voluntary muscle testing. Because the latter two are widely used in leprosy clinics, they were used as 'gold standard' for sensory and motor impairment. Other outcome events were type 1 and 2 reactions and neuritis. All subjects had a skin biopsy at registration, repeated at the time of an outcome event, along with a nerve biopsy. These were examined using a variety of immunohistological techniques. Blood sampling for serological testing was done at every 4-weekly clinic visit. At diagnosis, 115 patients had an outcome event of recent onset. Many people had skin lesions overlying a major nerve trunk, which were shown to be significantly associated with an increased of sensory or motor impairment. The most important adjusted odds ratios for motor impairment were, facial 4.5 (1.3-16) and ulnar 3.5 (1.0-8.5); for sensory impairment they were, ulnar 2.9 (1.3-6.5), median 3.6 (1.1-12) and posterior tibial 4.0 (1.8-8.7). Nerve enlargement was found in 94% of patients, while only 24% and 3% had paraesthesia and nerve tenderness on palpation, respectively. These increased the risk of reactions only marginally. Seven subjects had abnormal tendon reflexes and seven abnormal joint position sense. In all but one case, these impairments were accompanied by abnormalities in two or more other nerve function tests and thus seemed to indicate more severe neuropathy. At diagnosis, 38% of a cohort of newly diagnosed MB leprosy patients had recent or new reactions or nerve damage at the time of intake into the study. The main risk factor for neuropathy found in this baseline analysis was the presence of skin lesions overlying nerve trunks. They increased the risk of sensory or motor impairment in the concerned nerve by 3-4 times. For some nerves, reactional signs in the lesions further increased this risk to 6-8 times the risk of those without such lesions. Patients with skin lesions overlying peripheral nerve trunks should be carefully monitored for development of sensory or motor impairment.


Plasmonic Fano resonances in nanohole quadrumers for ultra-sensitive refractive index sensing.
Plasmonic Fano resonances arising from electromagnetic interactions in metallic nanostructures exhibit spectral characteristics analogous to those from the electron waves in oligomer molecules. Though a great deal of research interest has been attracted to study the optical properties and explore the associated applications of metallic nanoparticle oligomers, the plasmonic response of their complementary structures--nanohole clusters--remains largely unexplored. Here we show numerically by a full-wave finite element method that a nanohole quadrumer can sustain two Fano resonances when the incident electric field is oriented along the long-axis of the quadrumer system. The underlying physical mechanisms responsible for the Fano resonance formation are revealed explicitly by spectrally deconstructing the Fano lineshape, spatially decomposing the structure configuration and mapping the electric field profile and charge distribution, which collectively demonstrate a strong mode coupling between either two antiparallel dipolar modes or dipole-quadruple modes in the nanohole quadrumer. We further show that the spectral profile of the Fano resonance including the resonance linewidth and spectral contrast can be engineered flexibly by adjusting the geometrical parameters of the nanohole cluster, including the nanohole diameter, film thickness and interhole distance. With an optimized and realistic geometrical configuration, the nanohole quadrumer system exhibits an overall sensing figure of merit up to 14.25, far surpassing the value reported for conventional nanoparticle oligomers.


What do you mean, "epigenetic"?
Interest in the field of epigenetics has increased rapidly over the last decade, with the term becoming more identifiable in biomedical research, scientific fields outside of the molecular sciences, such as ecology and physiology, and even mainstream culture. It has become increasingly clear, however, that different investigators ascribe different definitions to the term. Some employ epigenetics to explain changes in gene expression, others use it to refer to transgenerational effects and/or inherited expression states. This disagreement on a clear definition has made communication difficult, synthesis of epigenetic research across fields nearly impossible, and has in many ways biased methodologies and interpretations. This article discusses the history behind the multitude of definitions that have been employed since the conception of epigenetics, analyzes the components of these definitions, and offers solutions for clarifying the field and mitigating the problems that have arisen due to these definitional ambiguities.


Increased paediatric hospitalizations for empyema in Australia after introduction of the 7-valent pneumococcal conjugate vaccine.
To examine rates of paediatric hospitalization for empyema and pneumonia in Australia before and after the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7). Rates of paediatric hospitalization for empyema and pneumonia (bacterial, viral and all types) were calculated following the codes of the International Classification of Diseases, tenth revision (ICD-10) as a principal diagnosis. The expected number of hospitalizations after the PCV7 was introduced was estimated on the basis of the observed number of hospitalizations before the introduction of the PCV7. Incidence rate differences (IRDs) and incidence rate ratios (IRRs) were calculated. Hospitalization incidence in each study period was expressed as the number of hospitalizations per million (10(6)) person-years. The population of children aged 0-19 years in Australia from 1998 to 2004 and from 2005 to 2010, as reported by the Australian Bureau of Statistics, was used to calculate the number of person-years in each period. In the 5 years following the introduction of the PCV7, hospitalizations for pneumonia were fewer than expected (15 304 fewer; 95% confidence interval, CI: 14 646-15 960; IRD: -552 per 10(6) person-years; 95% CI: -576 to -529 per 10(6) person-years; IRR: 0.78; 95% CI: 0.77-0.78). Hospitalizations for empyema, on the other hand, were more than expected (83 more; 95% CI: 37-128; IRD: 3 per 10(6) person-years; 95% CI: 1-5 per 10(6) person-years; IRR: 1.35; 95% CI: 1.14-1.59). Reductions in hospitalizations were observed for all ICD-10 pneumonia codes across all age groups. The increase in empyema hospitalizations was only significant among children aged 1 to 4 years. The introduction of the PCV7 in Australia was associated with a substantial decrease in hospitalizations for childhood pneumonia and a small increase in hospitalizations for empyema.


Management of common sleep disorders.
Sleep disorders are common and affect sleep quality and quantity, leading to increased morbidity. Patients with sleep disorders can be categorized as those who cannot sleep, those who will not sleep, those with excessive daytime sleepiness, and those with increased movements during sleep. Insomnia, defined as difficulty initiating or maintaining sleep that results in daytime impairment, is diagnosed using history findings and treated with cognitive behavior therapy, with or without sleep hypnotics. Restless legs syndrome is characterized by an urge to move the legs that worsens with rest, is relieved by movement, and often occurs in the evening or at night. Restless legs syndrome is treated based on the frequency of symptoms. Narcolepsy is characterized by excessive sleepiness, cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis. It is diagnosed using a sleep log or actigraphy, followed by overnight polysomnography and a multiple sleep latency test. Narcolepsy is treated with stimulants, such as modafinil; selective serotonin reuptake inhibitors; or gamma hydroxybutyric acid (sodium oxybate). Patients with snoring and witnessed apneas may have obstructive sleep apnea, which is diagnosed using overnight polysomnography. Continuous positive airway pressure is the most common and effective treatment for obstructive sleep apnea. Rapid eye movement sleep behavior disorder is characterized by increased muscle tone during rapid eye movement sleep, resulting in the patient acting out dreams with possible harmful consequences. It is diagnosed based on history and polysomnography findings, and treated with environmental safety measures and melatonin or clonazepam.


Reproducibility of histological assessment of carotid plaque: implications for studies of carotid imaging.
Thromboembolism from carotid plaque is an important cause of stroke. Identification of unstable plaque would therefore be clinically useful. Unfortunately, studies of carotid plaque imaging have shown poor agreement with histology. However, this may be due to inconsistent methods and the variability of assessments of carotid plaque histology, rather than inadequate imaging. We assessed the reproducibility of histological assessment in 60 plaques, and section-to-section variability along the length of 26 plaques. Kappa values ranged from 0.35 to 0.89 and from 0.44 to 0.68, respectively, for intra- and inter-observer reproducibility. There was considerable section-to-section variability within plaques. The accuracy of imaging of carotid plaque morphology will be underestimated unless variability in the histology assessment is taken into account.


Structural and functional assessment of the brain in European Americans with mild-to-moderate kidney disease: Diabetes Heart Study-MIND.
Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs). A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2) and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education. Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m(2) and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): -72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: -1.0, P = 0.03) and UACR and normalized TWMLV (β: -0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing. In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs.


Upper and Lower Limb Movement Kinematics in Aging FMR1 Gene Premutation Carriers.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the FMR1 gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating individuals with FXTAS and asymptomatic premutation carriers. This study aimed to clarify the extent to which quantitative measures of gait and upper limb kinematics may serve as biobehavioral markers of FXTAS degeneration. Nineteen premutation carriers (aged 46-77 years), including 9 with possible, probable, or definite FXTAS and 16 sex- and IQ-matched healthy controls, completed tests of non-constrained walking and reaching while both standing (static reaching) and walking (dynamic reaching) to quantify gait and upper limb control, respectively. For the non-constrained walking task, participants wore reflective markers and walked at their preferred speed on a walkway. During the static reaching task, participants reached and lifted boxes of different sizes while standing. During the dynamic reaching task, participants walked to reach and lift the boxes. Movement kinematics were examined in relation to clinical ratings of neuromotor impairments and CGG repeat length. During non-constrained walking, individuals with FXTAS showed decreased stride lengths and stride velocities, increased percentages of double support time, and increased variabilities of cadence and center of mass relative to both asymptomatic premutation carriers and controls. While individuals with FXTAS did not show any static reaching differences relative to the other two groups, they showed multiple differences during dynamic reaching trials, including reduced maximum reaching velocity, prolonged acceleration time, and jerkier movement of the shoulder, elbow, and hand. Gait differences during non-constrained walking were associated with more severe clinically rated posture and gait symptoms. Reduced maximum reaching velocity and increased jerkiness during dynamic reaching were each related to more severe clinically rated kinetic dysfunction and overall neuromotor symptoms in FMR1 premutation carriers. Our findings suggest kinematic alterations consistent with gait ataxia and upper limb bradykinesia are each selectively present in individuals with FXTAS, but not asymptomatic aging premutation carriers. Consistent with neuropathological and magnetic resonance imaging (MRI) studies of FXTAS, these findings implicate cerebellar and basal ganglia degeneration associated with neuromotor decline. Our results showing associations between quantitative kinematic differences in FXTAS and clinical ratings suggest that objective assessments of gait and reaching behaviors may serve as critical and reliable targets for detecting FXTAS risk and monitoring progression.


Coronary artery calcium determined by electron beam computed tomography for predicting angiographic coronary artery disease in moderate- to high-risk Chinese patients.
The aim of this study was to evaluate the prevalence of coronary calcification among moderate- to high-risk Chinese patients and to evaluate the ability of the coronary calcium score determined by electron beam computed tomography (EBCT) to predict angiographic coronary artery disease in this population. We enrolled 163 consecutive patients and analyzed their cardiovascular risk factors, coronary calcium scores and coronary angiogram results. One hundred and twenty-five patients (76.7%) had a positive EBCT scan result (coronary calcium score >0). The prevalence of calcification and the calcium scores showed a graded relation to the number of cardiovascular risk factors and age (p < 0.001 for trend). Coronary calcium scores showed statistically significant differences between patients with angiographic evidence of coronary artery disease and patients with normal coronary angiography (p < 0.05), but could not differentiate between patients with significant and insignificant coronary artery disease. Receiver operating characteristic curve analysis showed that a coronary calcium score >5 predicted angiographic coronary artery disease with 93% sensitivity and 86% specificity (area under the curve 0.95 +/- 0.019). Multivariate analysis showed a coronary calcium score >5 to be the strongest independent predictor of angiographic coronary artery disease (odds ratio 120.7, 95% confidence interval 21.7-671.4; p < 0.001). Coronary calcium score determined by EBCT appears to have a similar predictive value in Chinese patients as it does in other ethnic populations that have been reported to date.


Serial neuropsychological assessment and magnetic resonance imaging analysis in multiple sclerosis.
To assess the correlation between cognitive dysfunction and disease burden in multiple sclerosis (MS) during a 1-year period. The Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis was performed at entrance and 1 year. Patients underwent at least 20 proton density (range, 20-24) and T2-weighted axial magnetic resonance imaging (MRI) brain scans except for stable patients who were scanned monthly. Magnetic resonance imaging was evaluated using computer-automated, 3-dimensional volumetric analysis. A research clinic of a university hospital. Forty-four patients with MS of the following disease categories: relapsing-remitting (14), relapsing-remitting progressive (12), chronic progressive (13), and stable (5). The relationships between scores on the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis and 2 MRI measures (total lesion volume and brain to intracranial cavity volume ratio) were assessed using linear regression. These MRI measures were also compared with cognitive status at 1 year using analysis of variance. Overall, there was no decline in mean cognitive test performance during 1 year. Significant correlations were found between baseline neuropsychological test scores of nonverbal memory, information-processing speed, and attention and both MRI measures. Patients with chronic progressive MS demonstrated the strongest correlations. At 1 year, change in information-processing speed and attention correlated with change in total lesion volume. The mean increase in total lesion volume was 5.7 mL for 4 patients whose cognitive status worsened compared with 0.4 mL for 19 patients who improved and 0.5 mL for 21 patients who remained stable. During a 1-year period mean cognitive performance did not worsen. Automated volumetric MRI measures of total lesion volume and brain to intracranial cavity volume ratio correlated with neuropsychological performance, especially in patients with chronic progressive MS. Worsening MRI lesion burden correlated with cognitive decline.


The Meaning of the Lived Experience of Lifestyle Changes for People with Severe Mental Illness.
The aim of this study was to elucidate the meaning of the lived experience of lifestyle changes as perceived by people with severe mental illness (SMI). People with SMI who have experience in managing lifestyle changes were interviewed (n = 10). The interviews were analyzed with a phenomenological hermeneutic approach. The findings reveal three themes: (1) struggling with inner and outer limitations, (2) on one's own but together with others and (3) longing for living a life in harmony. The meaning of lifestyle changes can be understood as a person's internal and external endeavors to make well-considered decisions about lifestyle changes. Support should focus on strengthening the person's self-efficacy and should be based on the person's experiences.


Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation.
Transplanting stem cells before birth offers an unparalleled opportunity to initiate corrective treatment for numerous childhood diseases with minimal or no host conditioning. Although long-term engraftment has been demonstrated following in utero hematopoietic cellular transplantation during immune quiescence, it is unclear if prenatal tolerance becomes unstable with immune activation such as during a viral syndrome. Using a murine model of in utero hematopoietic cellular transplantation, the impact of an infection with lymphocytic choriomeningitis virus on prenatal allospecific tolerance was examined. The findings in this report illustrate that established mechanisms of donor-specific tolerance are strained during potent immune activation. Specifically, a transient reversal in the anergy of alloreactive lymphocytes is seen in parallel with the global immune response toward the virus. However, these changes return to baseline following resolution of the infection. Importantly, prenatal engraftment remains stable during and after immune activation. Collectively, these findings illustrate the robust nature of allospecific tolerance in prenatal mixed chimerism compared with models of postnatal chimerism and provides additional support for the prenatal approach to the treatment of congenital benign cellular disease.


Analysis and Outcomes of Cataract Surgery in Patients with Acquired Immunodeficiency Syndrome.
To investigate the surgical outcomes, complications and postoperative progression in HIV patients undergoing cataract surgery in a teaching hospital. A retrospective cohort study of patients with HIV/AIDS who had cataract surgery from January 2000 until December 2011 at a tertiary referral multidisciplinary hospital in Singapore. We identified 44 eyes from 29 patients. Preoperatively, 41.3% had no ophthalmic manifestations of HIV/AIDS, while 16 eyes had quiescent cytomegalovirus retinitis (CMVR). Postoperatively, 1 eye developed new CMVR, while 1 eye had reactivation of previous CMVR. Of eyes with new or previous CMVR, 1 eye developed rhegmatogenous retinal detachment (RD) postoperatively. Only 3 eyes had prolonged postoperative inflammation. There were no cases of endophthalmitis or cystoid macular edema. Postoperative improvement of at least two Snellen lines was achieved in 86.6% of eyes. Cataract surgery in HIV patients is generally safe, regardless of CD4 count, but their general and ocular health should be optimized preoperatively.