Classical and nonclassical effects in surface hopping methodology for simulating coupled electronic-nuclear dynamics.
In this paper, we analyze the detailed quantum-classical behavior of two alternative approaches to simulating molecular dynamics with electronic transitions: the popular fewest switches surface hopping (FSSH) method, introduced by Tully in 1990 [Tully, J. Chem. Phys., 1990, 93, 1061] and our recently developed quantum trajectory surface hopping (QTSH) method [Martens, J. Phys. Chem. A, 2019, 123, 1110]. Both approaches employ an independent ensemble of trajectories that undergo stochastic transitions between electronic surfaces. The methods differ in their treatment of energy conservation, with FSSH imposing conservation of the classical kinetic plus potential energy by rescaling the classical momentum when a surface hop occurs while QTSH incorporates a quantum force throughout the dynamics which leads naturally to the conservation of the full quantum-classical energy. We investigate the population transfer and energy budget of the surface hopping methods for several simple model systems and compare with exact quantum results. In addition, the detailed dynamics of the trajectory ensembles in phase space are compared with the quantum evolution in the Wigner representation. Conclusions are drawn.


Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe haemophilia A.
Severe haemophilia A is a lifelong condition that requires treatment with exogenous clotting factor. While primary prophylaxis is the clinically preferred method of delivering treatment, its provision is costly. A 2002 evaluation of primary prophylaxis suggested an incremental cost-effectiveness of approximately 50,000 pounds per additional quality-adjusted life-year (QALY). However, since this time, preferable evaluative methods have been developed and means of assessing the value of future research also now exist. Thus, the primary aims of this study were to update a previously published cost-effectiveness analysis of primary prophylaxis vs. treating on-demand in terms of methods and to estimate the value of undertaking further primary research. The base case incremental cost-effectiveness ratio was shown to be approximately 37,000 pounds, 10,000 pounds lower than the value published in 2002. The main reason for this difference was the use of different structural assumptions and methods to fit the various model parameters. At a willingness to pay per additional QALY threshold of 30,000 pounds, the probability prophylaxis is cost-effective was 13%. However, this increased to over 90% when alternative structural assumptions were employed, such as the rate at which future QALYs are discounted. The value of further research to increase the precision of this newly calculated cost-effectiveness estimate was high at a threshold willingness to pay values of 30,000- 40,000 pounds per QALY, particularly for the utilities associated with the health states. Thus, there is considerable value in conducting further primary research related to economic aspects of primary prophylaxis.


The impact of infant crying on the parent-infant relationship.
Infant crying is distressing for parents, evoking a range of difficult feelings. Infants who cry often maybe perceived as difficult by their parents, with negative effects on bonding and attachment. Infant crying as a stimulus for child-abuse is also highlighted, as parents' feelings of frustration may provoke harmful responses towards the child. A non-exhaustive literature review was conducted, exploring the impact of infant crying on parents, using CASP tools to support the analysis of twenty qualitative and quantitative studies, published between 2003 and 2013. This paper reports the findings of the review, with a specific focus on the effects of infant crying on the parent-infant relationship. The findings suggest parents may experience anxiety, depression, helplessness, anger and frustration in response to infant crying. Negative effects on bonding and parental perception of the baby are identified. Parents may also experience thoughts of harming their baby, and subsequent feelings of guilt and shame. Universal interventions to help parents prepare for parenthood, and to respond positively to crying are strongly recommended. Opportunities for parents to discuss their feelings towards their infant should be maximised, reducing the impact of infant crying on bonding and attachment. Parents should be empowered to develop strategies and sources of support to help them cope. Early identification of parents experiencing difficulties in coping with infant crying is essential, and risk in relation to potential abuse must be assessed. Health visitors have a key role in providing such support.


Economic study on the impact of side effects in patients taking oxycodone controlled-release for noncancer pain.
Chronic pain is a prevalent condition in the United States. Musculoskeletal pain, including joint and back pain, is the most common type of chronic pain, and many patients with back pain have a neuropathic component. Pain has direct economic consequences. While oxycodone controlled-release (CR) is one of the most widely used oral long-acting opioids for pain, including pain with a neuropathic component, it is often associated with bothersome side effects, resulting in additional medical resource use (MRU) and costs. To examine the impact on MRU and costs to payers of side effects in patients taking oxycodone CR alone or in combination with other pain medications for noncancer pain (including those with neuropathic pain symptoms). A nationwide convenience sample of adults in the United States, who participated in a survey research panel and reported current use of oxycodone CR for noncancer pain, completed an online survey between November 2, 2010, and December 13, 2010. Respondents were excluded if they reported current use of other extended-release or long-acting opioid prescription medications. The survey consisted of questions on demographics, clinical characteristics, pain characteristics, experience with pain medication, and MRU associated with side effects. Payer costs were calculated based on the MRU reported by the respondents multiplied by Medicare reimbursement rates for hospitalizations and outpatient visits and average wholesale price (AWP) minus 20% for medications. A subgroup of patients who reported neuropathic pain symptoms also was examined. After applying the exclusion criteria, 432 respondents completed the survey. Approximately half of the respondents (n = 219; 50.7%) reported neuropathic pain symptoms. The majority of respondents were Caucasian (88.4%) and female (63.7%) with an average age of 41.8 years (14.89). Respondents most frequently reported low back pain (41.2%), followed by osteoarthritis/rheumatoid arthritis (20.4%), neuropathic pain (10.6%), and fibromyalgia (9.0%). Respondents reported having their pain condition for an average of 5.4 (7.42) years. On days when taken, respondents reported a mean oxycodone CR daily dose of 83.3 mg (126.93) taken in an average of 2 doses. Most respondents (82.4%) reported experiencing at least 1 side effect with 77.5% being bothered by at least 1 side effect. The most frequently reported side effects ( greater than 25%) were drowsiness (41.4%), constipation (37.0%), fatigue or daytime sleepiness (36.6%), and dizziness (27.1%). Among respondents who reported being bothered by one or more side effects in the previous month, MRU associated with side effects was reported by 39.1% of respondents and significantly increased as the level of side-effect bother increased from 19.8% among those "A little bit bothered" to 38.4% among those "Bothered" to 61.0% among those "Extremely bothered" (P less than 0.001). Additionally, total average payer costs (in 2010 dollars) per respondent in the previous month associated with side effects were $238 ($1,159) and also significantly increased as the level of side-effect bother increased from $61 ($512) among those "A little bit bothered" to $238 ($1,160) among those "Bothered" to $425 ($1,561) among those "Extremely bothered" (P less than 0.001). Results reported in the neuropathic pain subgroup were similar to results reported in the total study sample. Among adults taking oxycodone CR for chronic noncancer pain (with or without a neuropathic pain component), over three-fourths reported being bothered by side effects. Respondents who reported higher levels of side-effect bother also reported greater MRU, resulting in increased payer costs. The results of this study provide further support of the econo-mic burden to payers associated with opioid-related side effects in patients with chronic noncancer pain, with and without neuropathic pain.


Importance of thiopurine S-Methyltransferase gene polymorphisms for prediction of azathioprine toxicity.
Our study aims to find the relationship between metabolic enzyme thiopurine S-methyltransferase (TPMT) gene polymorphisms and clinical output of the therapy with azathioprine. We focused on patients who experienced leucopenia caused by high blood levels of active azathioprine metabolites. Our group consists of 87 patients who have been treated by azathioprine. 21 individuals experienced leucopenia during treatment with standard dose of azathioprine. We have used PCR-REA and "real-time" PCR methods for genotype detection G238C, G460G and A719G substitutions in TPMT gene. We have found statistical association between the presence of non-standard TPMT alleles and adverse event associated with azathioprine treatment - leucopenia (p=0.0033). Our results confirm that TPMT genotyping prior to the treatment with azathioprine could predict patients with genetic predisposition for serious leucopenia and seems to be a useful genetic marker for individualisation of the therapy.


Tenotomy of the middle ear muscles : An unknown surgical approach in Meniere's disease.
Tenotomy of the tendon of the stapedius and tensor tympani muscles is a relatively unknown therapeutic procedure in Menière's disease. Widespread approaches include medicinal treatment with betahistine or diuretics as well as interventional procedures, such as intratympanic gentamicin or glucocorticoid injection, vestibular neurectomy, labyrinthectomy or endolymphatic sac surgery. The exact pathomechanism of this approach is not fully known. It is assumed that by cutting the tendons of both middle ear muscles in cases of endolymphatic hydrops the stapes is not additionally actively pushed against the oval window but can deviate laterally and thereby does not augment the inner ear pressure even further. Studies have shown that this method does not only improve vestibular symptoms but also, in contrast to most other strategies, increases the hearing level. The formation of scar tissue and the resulting reduction of ossicular chain mobility, especially due to postoperative infections, may limit the success of tenotomy and should be considered as a possible factor in cases of limited postoperative vertigo control.


[Elongation of the axoneme and dynamics of intraflagellar transport].
Cilia and flagella are essential organelles in most eukaryotes including human beings. In this review, we will discuss the mode of assembly of these complex organelles that depends on a dynamic process called intraflagellar transport or IFT. IFT delivers structural elements at the distal end of the cilium where assembly takes place, thereby allowing the growth of the organelle. We next discuss the different models for control of cilium length and their alterations in ciliopathies, genetic diseases associated to ciliary defects.


Preclinical biosafety evaluation of cell-based therapies: emerging global paradigms.
Cell-based therapies have the potential to treat a diversity of disease conditions, many representing significant and long-standing unmet medical needs. Certain properties of cell-based therapies, such as differentiation potential and proliferative potential, present safety concerns uniquely distinct from those of small molecule drugs and other macromolecule biologics. These cellular products carry risks associated with localized host tissue response, long-term persistence, ectopic tissue formation, differentiation to undesirable cell and tissue types, uncontrollable biodistribution, tumorigenicity, and immunogenicity. Such risks are generally evaluated in preclinical animal model studies as part of a comprehensive safety program prior to administration in humans. However, safety assessment for these products can be challenging because of inconsistent approaches to product characterization, inadequately defined product parameters that anticipate adverse events, and the lack of standardized approaches in evaluating in vivo host responses. In this symposium, we introduced cell-based therapies as an emerging product class to the Society of Toxicologic Pathology (STP) and highlighted key challenges for consideration during product biosafety evaluation.


Long-term stress levels are synchronized in dogs and their owners.
This study reveals, for the first time, an interspecific synchronization in long-term stress levels. Previously, acute stress, has been shown to be highly contagious both among humans and between individuals of other species. Here, long-term stress synchronization in dogs and their owners was investigated. We studied 58 dog-human dyads and analyzed their hair cortisol concentrations (HCC) at two separate occasions, reflecting levels during previous summer and winter months. The personality traits of both dogs and their owners were determined through owner-completed Dog Personality Questionnaire (DPQ) and human Big Five Inventory (BFI) surveys. In addition, the dogs' activity levels were continuously monitored with a remote cloud-based activity collar for one week. Shetland sheepdogs (N = 33) and border collies (N = 25), balanced for sex, participated, and both pet dogs and actively competing dogs (agility and obedience) were included to represent different lifestyles. The results showed significant interspecies correlations in long-term stress where human HCC from both summer and winter samplings correlated strongly with dog HCC (summer: N = 57, χ2 = 23.697, P < 0.001, β = 0.235; winter: N = 55, χ2 = 13.796, P < 0.001, β = 0.027). Interestingly, the dogs' activity levels did not affect HCC, nor did the amount of training sessions per week, showing that the HCC levels were not related to general physical activity. Additionally, there was a seasonal effect in HCC. However, although dogs' personalities had little effects on their HCC, the human personality traits neuroticism, conscientiousness, and openness significantly affected dog HCC. Hence, we suggest that dogs, to a great extent, mirror the stress level of their owners.


Transrectal ultrasound biopsy of the prostate: does it still have a role in prostate cancer diagnosis?
Transrectal ultrasound (TRUS) guided biopsy of the prostate has been a standard diagnostic approach for prostate cancer over the past thirty years. Today, the role of TRUS biopsy is being challenged by transperineal (TP) prostate biopsy due to concerns over the safety and diagnostic yield of TRUS biopsy. TRUS biopsy still offers a convenient, reliable and accessible tool for diagnosing prostate cancer in the majority of patients. It continues to play a role in prostate cancer diagnosis, especially where hospital resource allocation is limited, including the public sector. TRUS biopsy has low rates of severe complications, although there remains room for improvement in current practice to improve the tolerability and reduce the incidence of post-biopsy infection.


Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.
Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.


Local signaling with molecular diffusion as a decoder of Ca2+ signals in synaptic plasticity.
Synaptic plasticity is induced by the influx of calcium ions (Ca2+) through N-methyl-D-aspartate receptors (NMDARs), and the direction and strength of the response depend on the frequency of the synaptic inputs. Recent studies have shown that the direction of synaptic plasticity is also governed by two distinct NMDAR subtypes (NR1/NR2A, NR1/NR2B). How are the different types of regulation (frequency-dependent and receptor-specific) processed simultaneously? To clarify the molecular basis of this dual dependence of synaptic plasticity, we have developed a mathematical model of spatial Ca2+ signaling in a dendritic spine. Our simulations revealed that calmodulin (CaM) activation in the vicinity of NMDARs is strongly affected by the diffusion coefficient of CaM itself, and that this 'local CaM diffusion system' works as a dual decoder of both the frequency of Ca2+ influxes and their postsynaptic current shapes, generated by two NMDAR subtypes, implying that spatial factors may underlie the complicated regulation scheme of synaptic plasticity.


A new pathogen transmission mechanism in the ocean: the case of sea otter exposure to the land-parasite Toxoplasma gondii.
Toxoplasma gondii is a land-derived parasite that infects humans and marine mammals. Infections are a significant cause of mortality for endangered southern sea otters (Enhydra lutris nereis), but the transmission mechanism is poorly understood. Otter exposure to T. gondii has been linked to the consumption of marine turban snails in kelp (Macrocystis pyrifera) forests. It is unknown how turban snails acquire oocysts, as snails scrape food particles attached to surfaces, whereas T. gondii oocysts enter kelp beds as suspended particles via runoff. We hypothesized that waterborne T. gondii oocysts attach to kelp surfaces when encountering exopolymer substances (EPS) forming the sticky matrix of biofilms on kelp, and thus become available to snails. Results of a dietary composition analysis of field-collected snails and of kelp biofilm indicate that snails graze the dense kelp-biofilm assemblage composed of pennate diatoms and bacteria inserted within the EPS gel-like matrix. To test whether oocysts attach to kelp blades via EPS, we designed a laboratory experiment simulating the kelp forest canopy in tanks spiked with T. gondii surrogate microspheres and controlled for EPS and transparent exopolymer particles (TEP - the particulate form of EPS). On average, 19% and 31% of surrogates were detected attached to kelp surfaces covered with EPS in unfiltered and filtered seawater treatments, respectively. The presence of TEP in the seawater did not increase surrogate attachment. These findings support a novel transport mechanism of T. gondii oocysts: as oocysts enter the kelp forest canopy, a portion adheres to the sticky kelp biofilms. Snails grazing this biofilm encounter oocysts as 'bycatch' and thereby deliver the parasite to sea otters that prey upon snails. This novel mechanism can have health implications beyond T. gondii and otters, as a similar route of pathogen transmission may be implicated with other waterborne pathogens to marine wildlife and humans consuming biofilm-feeding invertebrates.


The 3 R's for Platelet-Rich Fibrin: A "Super" Tri-Dimensional Biomaterial for Contemporary Naturally-Guided Oro-Maxillo-Facial Soft and Hard Tissue Repair, Reconstruction and Regeneration.
Platelet-Rich fibrin (PRF) is a three-dimensional (3-D) autogenous biomaterial obtained via simple and rapid centrifugation from the patient's whole blood samples, without including anti-coagulants, bovine thrombin, additives, or any gelifying agents. At the moment, it is safe to say that in oral and maxillofacial surgery, PRFs (particularly, the pure platelet-rich fibrin or P-PRF and leukocyte and platelet-rich fibrin or L-PRF sub-families) are receiving the most attention, essentially because of their simplicity, cost-effectiveness, and user-friendliness/malleability; they are a fairly new "revolutionary" step in second-generation therapies based on platelet concentration, indeed. Yet, the clinical effectiveness of such surgical adjuvants or regenerative platelet concentrate-based preparations continues to be highly debatable, primarily as a result of preparation protocol variability, limited evidence-based clinical literature, and/or poor understanding of bio-components and clinico-mechanical properties. To provide a practical update on the application of PRFs during oral surgery procedures, this critical review focuses on evidence obtained from human randomized and controlled clinical trials only. The aim is to serve the reader with current information on the clinical potential, limitations, challenges, and prospects of PRFs. Accordingly, reports often associate autologous PRFs with early bone formation and maturation; accelerated soft-tissue healing; and reduced post-surgical edema, pain, and discomfort. An advanced and original tool in regenerative dentistry, PRFs present a strong alternative and presumably cost-effective biomaterial for oro-maxillo-facial tissue (soft and hard) repair and regeneration. Yet, preparation protocols continue to be a source of confusion, thereby requiring revision and standardization. Moreover, to increase the validity, comprehension, and therapeutic potential of the reported findings or observations, a decent analysis of the mechanico-rheological properties, bio-components, and their bioactive function is eagerly needed and awaited; afterwards, the field can progress toward a brand-new era of "super" oro-dental biomaterials and bioscaffolds for use in oral and maxillofacial tissue repair and regeneration, and beyond.


Who is responsible for providing care? Investigating the role of care tasks and past experiences in a cross-sectional survey in the Netherlands.
Many countries face substitution from formal to informal care. It is essential that a sufficient number of caregivers, such as family, friends or neighbors, are willing and able to lend care to address the needs of ill or elderly persons. We investigated whether the general public, who might become caregivers in the future, and current informal caregivers align with the shift to more informal caregiving. We studied the views on the responsibility for care of the general public versus the government, and whether these views differed among groups with diverse past experiences with care in terms of own health problems or previous caregiving activities. Data (n = 1097) was collected among the Dutch Health Care Consumer Panel with a survey in October 2015. Multivariate analyses of the views on responsibility for care in general and for different types of care were performed using (i) health, (ii) informal care, and (iii) general background characteristics, among a sample of the general public and among a subgroup of current caregivers. The majority (67%) of the respondents would be willing to provide informal care in the future, when necessary. Respondents were more willing to provide support tasks than personal or nursing care activities. Among current caregivers, views on responsibility for care were associated with their past experience. Experiencing less burden of caregiving was associated with perceiving the general public as more responsible for personal or nursing care. The results of this study show that substitution from formal to informal care is more in line with public views when support activities are concerned than personal or nursing care. In addition, burdened caregivers also consider the government more responsible for personal or nursing care. When handing over care tasks to the public domain a critical view is needed on which care tasks are most appropriate for this.


The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases.
Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the 'bright side' of e cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework. Areas covered: We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson's disease and Huntington disease. Expert commentary: Despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.


Glycine inhibition of asparaginase.
Administration of either Escherichia coli asparaginase or guinea pig serum to C3H/HE mice with the 6C3HED lymphosarcoma is followed by depression of glycine in the tumor. This decrease in cellular glycine concentration does not occur in a tumor resistant to asparaginase. The inhibition of the lymphosarcoma by asparaginase can be reversed by intraperitoneal injection of asparagine or glycine. This reversal appears to be specific because lysine, threonine, serine, and aspartic acid were ineffective. Loss of cellular glycine may be more important than loss of asparagine because of the requirement for glycine in purine synthesis.


Bilingual and monolingual brains compared: a functional magnetic resonance imaging investigation of syntactic processing and a possible "neural signature" of bilingualism.
Abstract Does the brain of a bilingual process language differently from that of a monolingual? We compared how bilinguals and monolinguals recruit classic language brain areas in response to a language task and asked whether there is a "neural signature" of bilingualism. Highly proficient and early-exposed adult Spanish-English bilinguals and English monolinguals participated. During functional magnetic resonance imaging (fMRI), participants completed a syntactic "sentence judgment task" [Caplan, D., Alpert, N., & Waters, G. Effects of syntactic structure and propositional number on patterns of regional cerebral blood flow. Journal of Cognitive Neuroscience, 10, 541-552, 1998]. The sentences exploited differences between Spanish and English linguistic properties, allowing us to explore similarities and differences in behavioral and neural responses between bilinguals and monolinguals, and between a bilingual's two languages. If bilinguals' neural processing differs across their two languages, then differential behavioral and neural patterns should be observed in Spanish and English. Results show that behaviorally, in English, bilinguals and monolinguals had the same speed and accuracy, yet, as predicted from the Spanish-English structural differences, bilinguals had a different pattern of performance in Spanish. fMRI analyses revealed that both monolinguals (in one language) and bilinguals (in each language) showed predicted increases in activation in classic language areas (e.g., left inferior frontal cortex, LIFC), with any neural differences between the bilingual's two languages being principled and predictable based on the morphosyntactic differences between Spanish and English. However, an important difference was that bilinguals had a significantly greater increase in the blood oxygenation level-dependent signal in the LIFC (BA 45) when processing English than the English monolinguals. The results provide insight into the decades-old question about the degree of separation of bilinguals' dual-language representation. The differential activation for bilinguals and monolinguals opens the question as to whether there may possibly be a "neural signature" of bilingualism. Differential activation may further provide a fascinating window into the language processing potential not recruited in monolingual brains and reveal the biological extent of the neural architecture underlying all human language.


Does cognitive behaviour therapy for insomnia reduce clinical levels of fatigue, anxiety and depression in cancer patients?
This secondary analysis of data from a randomised controlled trial explores associations between common symptom clusters and evaluates pre-treatment to post-treatment changes in clinical levels of these symptoms following cognitive behaviour therapy for insomnia (CBT-I). Baseline data from 113 participants with insomnia were explored to establish rates of and associations between clinical levels of fatigue, anxiety and depression across the sample. Effects of CBT-I on this symptom cluster were also explored by examining changes in pre-treatment to post-treatment levels of fatigue, anxiety and depression. At baseline, the most common symptom presentation was insomnia + fatigue, and 30% of the sample reported at least three co-morbid symptoms. Post-CBT, the number of those experiencing clinical insomnia and clinical fatigue decreased. There were no changes in anxiety rates from baseline to post-treatment in the CBT group and modest reductions in rates of those with clinical depression. Seven individuals (9.6%) from the CBT group were completely symptom free at post-treatment compared with 0% from the treatment as usual condition. Chi-square analysis revealed a significant relationship between group allocation and changes in symptoms of insomnia and fatigue. No such relationship was found between group allocation and mood variables. These findings confirm the high rate of symptom co-morbidities among cancer patients and highlight strong associations between sleep and fatigue. CBT-I appears to offer generalised benefit to the symptom cluster as a whole and, specifically, is effective in reducing fatigue, which exceeded clinical cut-offs prior to implementation of the intervention. This has implications for the diagnosis/management of common symptoms in cancer patients.


The association of educational achievement and school dropout with risk of alcoholism: a twenty-five-year prospective study of inner-city children.
This prospective study is focused on the characteristics leading to alcohol use disorders in early adulthood among a cohort of black children. The principal aim of this work is to examine the impact of educational attainment, school dropout and early school adaptation on the development of alcohol abuse and dependence in adulthood. From a population that consisted of 1,242 first graders in 1966-67, a total of 953 were interviewed at age 32-33 about their current alcohol and drug use, educational attainment, employment and family situation. Diagnoses of alcohol abuse and dependence were defined according to DSM-III-R criteria resulting in identification of 13.5% as having a lifetime alcohol use disorder. Early predictions of an alcohol use disorder in adulthood included early reports of underachievement in first grade by the child's teacher, dropping out of high school, whether the family set definite rules about school during adolescence, and how often the adolescent worked on homework with his/her family. The results suggest that educational achievement and some early adaptive behaviors in school are associated with risk for alcohol use disorders. The public health importance of the findings are discussed.


Generation of Recombinant Antibodies against the beta-(1,6)-Branched beta-(1,3)-D-Glucan Schizophyllan from Immunized Mice via Phage Display.
beta-(1,6)-Branched beta-(1,3)-D-glucans like schizophyllan from the basidiomycete Schizophyllum commune excite various immunostimulatory effects and have been clinically tested as adjuvants. Some of the glucans are also applicable in food or petrol industry due to their viscosity and temperature stability in aqueous solution. Antibodies against these glucans could be used as tool for analysis of glucan preparations or for further research of its bioactivity. Therefore, an immune phage display library was constructed from mice immunized with schizophyllan. Three recombinant monoclonal antibodies were isolated from this library by affinity selection (panning) on schizophyllan. The half-maximal effective concentration (EC50) values for those antibodies varied between 16.4 ng mL-1 and 21.3 ng mL-1. The clones showed binding specificity not only for schizophyllan but also for other beta-(1,6)-branched beta-(1,3)-D-glucans of similar macromolecular structure. Denaturation of the secondary structure led to a reduced antibody binding, indicating an epitope requiring the correct conformation of the triple helical structure of the glucans.


Fidelity to and comparative results across behavioral interventions evaluated through the RE-AIM framework: a systematic review.
The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework was developed to determine potential public health impact of interventions (i.e., programs, policy, and practice). The purpose of this systematic review was to determine (1) comparative results across accurately reported RE-AIM indicators, (2) relevant information when there remains under-reporting or misclassification of data across each dimension, (3) the degree to which authors intervened to improve outcomes related to each dimension, and (4) the number of articles reporting RE-AIM dimensions for a given study. In April 2013, a systematic search of the RE-AIM framework was completed in PubMed, PSYCHInfo, EbscoHost, Web of Science, and Scopus. Evidence was analyzed until January 2015. Eighty-two interventions that included empirical data related to at least one of the RE-AIM dimensions were included in the review. Across these interventions, they reached a median sample size of 320 participants (M = 4894 ± 28,256). Summarizing the effectiveness indicators, we found that: the average participation rate was 45 % (±28 %), 89 % of the interventions reported positive changes in the primary outcome and 11 interventions reported broader outcomes (e.g., quality of life). As for individual-level maintenance, 11 % of studies showed effects ≥6 months post-program. Average setting and staff adoption rates were 75 % (±32 %) and 79 % (±28 %), respectively. Interventions reported being delivered as intended (82 % (±16 %)) and 22 % intervention reported adaptations to delivery. There were insufficient data to determine average maintenance at the organizational level. Data on costs associated with each dimension were infrequent and disparate: four studies reported costs of recruitment, two reported intervention costs per participant, and two reported adoption costs. The RE-AIM framework has been employed in a variety of populations and settings for the planning, delivery, and evaluation of behavioral interventions. This review highlights inconsistencies in the degree to which authors reported each dimension in its entirety as well as inaccuracies in reporting indicators within each dimension. Further, there are few interventions that aim to improve outcomes related to reach, adoption, implementation, and maintenance.


Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia.
The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedow's disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM) and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum.In this case, we postulated that the infiltration of inflammatory cells was not found because the patient's condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases.


Evaluating serratus anterior muscle function in neck pain using muscle functional magnetic resonance imaging.
Muscle functional magnetic resonance imaging (mfMRI) quantifies exercise-induced alterations in soft-aqueous skeletal muscle as a surrogate measure of muscle activity. Because of its excellent spatiotemporal resolution, mfMRI can be used as a noninvasive evaluation of the function of muscles that are challenging to evaluate, such as the serratus anterior (SA) muscle. The purpose of this preliminary study was to investigate the feasibility of evaluating SA muscle function in individuals with neck pain compared with healthy controls using mfMRI. Muscle functional magnetic resonance imaging scans of the SA muscle were obtained before and immediately after an isometric upper limb exercise in 10 subjects with chronic ipsilateral mechanical neck pain and scapular dysfunction (scan on symptomatic side) and in 10 age- and sex-matched healthy subjects. Scans were recorded at 4 intervertebral levels (T6-7, T7-8, T8-9, and T9-10). Differences in water relaxation values (T2 relaxation) quantified from scans before and after exercise were calculated (T2 shift) as a measure of SA muscle activity at each level and compared between groups. There were significant effects for level (P = .03) and significant group × level interactions (P = .04) but no significant main effect for group (P = .59). Post hoc tests revealed that significant differences in T2 shift values between levels were only evident in the healthy control group. This study demonstrated that despite some inherent challenges associated with imaging the SA muscle, mfMRI appears to have adequate spatiotemporal resolution to effectively evaluate SA muscle activity and function in healthy and clinical populations.


NEDE: an open-source scripting suite for developing experiments in 3D virtual environments.
As neuroscientists endeavor to understand the brain's response to ecologically valid scenarios, many are leaving behind hyper-controlled paradigms in favor of more realistic ones. This movement has made the use of 3D rendering software an increasingly compelling option. However, mastering such software and scripting rigorous experiments requires a daunting amount of time and effort. To reduce these startup costs and make virtual environment studies more accessible to researchers, we demonstrate a naturalistic experimental design environment (NEDE) that allows experimenters to present realistic virtual stimuli while still providing tight control over the subject's experience. NEDE is a suite of open-source scripts built on the widely used Unity3D game development software, giving experimenters access to powerful rendering tools while interfacing with eye tracking and EEG, randomizing stimuli, and providing custom task prompts. Researchers using NEDE can present a dynamic 3D virtual environment in which randomized stimulus objects can be placed, allowing subjects to explore in search of these objects. NEDE interfaces with a research-grade eye tracker in real-time to maintain precise timing records and sync with EEG or other recording modalities. Python offers an alternative for experienced programmers who feel comfortable mastering and integrating the various toolboxes available. NEDE combines many of these capabilities with an easy-to-use interface and, through Unity's extensive user base, a much more substantial body of assets and tutorials. Our flexible, open-source experimental design system lowers the barrier to entry for neuroscientists interested in developing experiments in realistic virtual environments.


Spatiotemporal Modeling of the Key Migratory Events During the Initiation of Adaptive Immunity.
Initiation of adaptive immunity involves distinct migratory cell populations coming together in a highly dynamic and spatially organized process. However, we lack a detailed spatiotemporal map of these events due to our inability to track the fate of cells between anatomically distinct locations or functionally identify cell populations as migratory. We used photo-convertible transgenic mice (Kaede) to spatiotemporally track the fate and composition of the cell populations that leave the site of priming and enter the draining lymph node to initiate immunity. We show that following skin priming, the lymph node migratory population is principally composed of cells recruited to the site of priming, with a minor contribution from tissue resident cells. In combination with the YAe/Eα system, we also show that the majority of cells presenting antigen are CD103+CD11b+ dendritic cells that were recruited to the site of priming during the inflammatory response. This population has previously only been described in relation to mucosal tissues. Comprehensive phenotypic profiling of the cells migrating from the skin to the draining lymph node by mass cytometry revealed that in addition to dendritic cells, the migratory population also included CD4+ and CD8+ T cells, B cells, and neutrophils. Taking our complex spatiotemporal data set, we then generated a model of cell migration that quantifies and describes the dynamics of arrival, departure, and residence times of cells at the site of priming and in the draining lymph node throughout the time-course of the initiation of adaptive immunity. In addition, we have identified the mean migration time of migratory dendritic cells as they travel from the site of priming to the draining lymph node. These findings represent an unprecedented, detailed and quantitative map of cell dynamics and phenotypes during immunization, identifying where, when and which cells to target for immunomodulation in autoimmunity and vaccination strategies.


A Modified Glycosaminoglycan, GM-0111, Inhibits Molecular Signaling Involved in Periodontitis.
Periodontitis is characterized by microbial infection, inflammation, tissue breakdown, and accelerated loss of alveolar bone matrix. Treatment targeting these multiple stages of the disease provides ways to treat or prevent periodontitis. Certain glycosaminoglycans (GAGs) block multiple inflammatory mediators as well as suppress bacterial growth, suggesting that these GAGs may be exploited as a therapeutic for periodontitis. We investigated the effects of a synthetic GAG, GM-0111, on various molecular events associated with periodontitis: growth of Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) pathogenic bacteria associated with periodontitis; activation of pro-inflammatory signaling through TLR2 and TLR4 in mouse macrophage RAW 264.7 cells and heterologously expressed HEK 293 cells; osteoclast formation and bone matrix resorption in cultured mouse pre-osteoclasts. (1) GM-0111 suppressed the growth of P. gingivalis and A. actinomycetemcomitans even at 1% (w/v) solution. The antibacterial effects of GM-0111 were stronger than hyaluronic acid (HA) or xylitol in P. gingivalis at all concentrations and comparable to xylitol in A. actinomycetemcomitans at ≥2% (w/v) solution. We also observed that GM-0111 suppressed biofilm formation of P. gingivalis and these effects were much stronger than HA. (2) GM-0111 inhibited TLR-mediated pro-inflammatory cellular signaling both in macrophage and HEK 293 cells with higher selectivity for TLR2 than TLR4 (IC50 of 1-10 ng/mL vs. > 100 μg/mL, respectively). (3) GM-0111 blocked RANKL-induced osteoclast formation (as low as 300 ng/mL) and bone matrix resorption. While GM-0111 showed high affinity binding to RANKL, it did not interfere with RANKL/RANK/NF-κB signaling, suggesting that GM-0111 inhibits osteoclast formation by a RANKL-RANK-independent mechanism. We report that GM-0111 inhibits multiple molecular events involved in periodontitis, spanning from the early pro-inflammatory TLR signaling, to pathways activated at the later stage component of bone loss.


Alteration of p53 damage response by tamoxifen treatment.
Hormone therapy is often used in association with chemotherapy in the treatment of estrogen-responsive breast cancers. By using breast adenocarcinoma cell lines, we show that antiestrogen treatment leads to a dramatic decrease of p53 protein levels. This effect leads to a loss of wild-type p53 response to genotoxic treatment. This inhibition is assessed by the lack of p53 protein accumulation and the loss of the p53-dependent induction of p21(WAF1/CIP1) expression. Given that the effects of several anticancer agents are mediated through DNA damage, these observations suggest that antiestrogen treatment could modulate cellular response to chemotherapeutic agents.


Electrophoretic deposition and characterization of nanocomposites and nanoparticles on magnesium substrates.
This study introduces a triphasic design of biodegradable materials composed of nanophase hydroxyapatite (nHA), poly(lactic-co-glycolic acid) (PLGA), and magnesium (Mg) substrates for musculoskeletal implant applications. Specifically, nHA_PLGA composites and nHA nanoparticles were synthesized, deposited on three-dimensional Mg substrates using electrophoretic deposition (EPD), and characterized. The three components involved, that is, nHA, PLGA, and Mg are all biodegradable in the human body, thus promising for biodegradable implant and device applications. Mg and its alloys are attractive for musculoskeletal implant applications due to their comparable modulus and strength to cortical bone. Controlling the interface of Mg with the biological environment, however, is the key challenge that currently limits this biodegradable metal for broad applications in medical implants. This article particularly focuses on creating nanostructured interface between the biodegradable Mg and surrounding tissue for the dual purposes of (1) mediating the degradation of the Mg-based substrates and (2) potentially enhancing osteointegration. Nanophase hydroxyapatite (nHA) is an excellent candidate as a coating material due to its osteoconductivity, while the polymer phase promotes interfacial adhesion between the nHA and Mg. Moreover, the degradation products of PLGA and Mg neutralize each other. Surface characterization showed successful deposition of nHA_PLGA composite microspheres and nHA nanoparticles on Mg substrates using EPD. Mg substrates coated with nHA_PLGA composites showed greater adhesion strength when compared with nHA coating, and slower corrosion rate than nHA coated Mg and non-coated Mg. The triphasic composites of nHA, PLGA and Mg are promising as the next-generation biodegradable materials for medical applications.


DNA polymerase activity as an index of lymphocyte stimulation: studies in Down's syndrome.
The ability of peripheral blood lymphocytes to respond to phytohemagglutinin (PHA) in vitro was studied in patients with Down's syndrome. The response was measured by the increase in DNA polymerase activity and the rate of incorporation of tritiated thymidine by the cultured lymphocytes. These activities were significantly lower in PHA-stimulated lymphocytes from patients with Down's syndrome compared with age- and sex-matched, mentally retarded patients without Down's syndrome from the same institution and the normal healthy volunteers. The impairment in response to PHA does not seem to be related to the presence of Australia antigen in patients with Down's syndrome or to institutionalization itself. In contrast to DNA polymerase activity and thymidine-(3)H uptake, there was no significant difference in the percentage of blast transformation in the three groups studied. The poor response of the lymphocytes from patients with Down's syndrome to a mitogenic stimulus could reflect an impairment of cellular immune functions in these patients which may be one of the factors contributing to the vulnerability of these patients to repeated or persistent infections.


Calcium Sensing Receptor as a Novel Mediator of Adipose Tissue Dysfunction: Mechanisms and Potential Clinical Implications.
Obesity is currently a serious worldwide public health problem, reaching pandemic levels. For decades, dietary and behavioral approaches have failed to prevent this disease from expanding, and health authorities are challenged by the elevated prevalence of co-morbid conditions. Understanding how obesity-associated diseases develop from a basic science approach is recognized as an urgent task to face this growing problem. White adipose tissue (WAT) is an active endocrine organ, with a crucial influence on whole-body homeostasis. WAT dysfunction plays a key role linking obesity with its associated diseases such as type 2 diabetes mellitus, cardiovascular disease, and some cancers. Among the regulators of WAT physiology, the calcium-sensing receptor (CaSR) has arisen as a potential mediator of WAT dysfunction. Expression of the receptor has been described in human preadipocytes, adipocytes, and the human adipose cell lines LS14 and SW872. The evidence suggests that CaSR activation in the visceral (i.e., unhealthy) WAT is associated with an increased proliferation of adipose progenitor cells and elevated adipocyte differentiation. In addition, exposure of adipose cells to CaSR activators in vitro elevates proinflammatory cytokine expression and secretion. An increased proinflammatory environment in WAT plays a key role in the development of WAT dysfunction that leads to peripheral organ fat deposition and insulin resistance, among other consequences. We propose that CaSR may be one relevant therapeutic target in the struggle to confront the health consequences of the current worldwide obesity pandemic.


A prospective examination of Axis I psychiatric disorders in the first 5 years following moderate to severe traumatic brain injury.
Psychiatric disorders commonly emerge during the first year following traumatic brain injury (TBI). However, it is not clear whether these disorders soon remit or persist for long periods post-injury. This study aimed to examine, prospectively: (1) the frequency, (2) patterns of co-morbidity, (3) trajectory, and (4) risk factors for psychiatric disorders during the first 5 years following TBI. Participants were 161 individuals (78.3% male) with moderate (31.2%) or severe (68.8%) TBI. Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV, administered soon after injury and 3, 6 and 12 months, and 2, 3, 4 and 5 years post-injury. Disorder frequencies and generalized estimating equations were used to identify temporal relationships and risk factors. In the first 5 years post-injury, 75.2% received a psychiatric diagnosis, commonly emerging within the first year (77.7%). Anxiety, mood and substance-use disorders were the most common diagnostic classes, often presenting co-morbidly. Many (56.5%) experienced a novel diagnostic class not present prior to injury. Disorder frequency ranged between 61.8 and 35.6% over time, decreasing by 27% [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.65-0.83] with each year post-injury. Anxiety disorders declined significantly over time (OR 0.73, 95% CI 0.63-0.84), whilst mood and substance-use disorder rates remained stable. The strongest predictors of post-injury disorder were pre-injury disorder (OR 2.44, 95% CI 1.41-4.25) and accident-related limb injury (OR 1.78, 95% CI 1.03-3.07). Findings suggest the first year post-injury is a critical period for the emergence of psychiatric disorders. Disorder frequency declines thereafter, with anxiety disorders showing greater resolution than mood and substance-use disorders.


Chemotherapeutic strategies for reducing transmission of Plasmodium vivax malaria.
Effective use of anti-malarial drugs is key to reducing the transmission potential of Plasmodium vivax. In patients presenting with symptomatic disease, treatment with potent and relatively slowly eliminated blood schizontocidal regimens administered concurrently with a supervised course of 7 mg/kg primaquine over 7-14 days has potential to exert the greatest transmission-blocking benefit. Given the spread of chloroquine-resistant P. vivax strains, the artemisinin combination therapies dihydroartemisinin + piperaquine and artesunate + mefloquine are currently the most assured means of preventing P. vivax recrudescence. Preliminary evidence suggests that, like chloroquine, these combinations potentiate the hypnozoitocidal effect of primaquine, but further supportive evidence is required. In view of the high rate of P. vivax relapse following falciparum infections in co-endemic regions, there is a strong argument for broadening current radical cure policy to include the administration of hypnozoitocidal doses of primaquine to patients with Plasmodium falciparum malaria. The most important reservoir for P. vivax transmission is likely to be very low-density, asymptomatic infections, the majority of which will arise from liver-stage relapses. Therefore, judicious mass administration of hypnozoitocidal therapy will reduce transmission of P. vivax to a greater extent than strategies focused on treatment of symptomatic patients. An efficacious hypnozoitocidal agent with a short curative treatment course would be particularly useful in mass drug administration campaigns.


Cortical Excitations, Cortisol Excretion and Estimation of Tolerable Nightly Over-Flights.
Noise induces cortisol excretion even below the awakening threshold. This is based upon the existence of very close subcortical central nervous connections between parts of the auditory system (e. g. amygdala) showing typical plasticity effects and the hypothalmic-pituitary-adrenal (HPA)-axis. Repeated noise events (e.g. over-flights during nigh-time) will lead to accumulation of the cortisol concentration in blood. This happens because its time constant of exponential decrease is about 50 to 10 times larger than that one for adrenaline and noradrenaline. A twofold attempt has been made to calculate the cortisol accumulation using an initial value of noise induced small cortisol increase (rounded value 14 ng/ml) at the nightly threshold of beginning vegetative overreaction around 53 dB(A). A mean time-constant of 64 min has been applied based upon experimental studies. Using in a first step the range of minimal and maximal normal cortisol values as border line and taking into account a relation between peak sound pressure level and cortical excitation given by a power function (exponent 0.32, based on evoked potential studies in man) results in a formula to estimate tolerable events during night-time periods (over-flights in a given time range). Examples of results for 8 hours in the night are for instance values of 11 events with 55 dB(A) indoor peak level or 5 events with 75 dB(A) indoor peak level respectively. Those values of tolerable nightly noise events estimated on the basis of physiological processes and peak levels cannot be recalculated as or compared with equivalent sound levels.


Distinct signaling cascades of TREM-1, TLR and NLR in neutrophils and monocytic cells.
Triggering receptor expressed on myeloid cells 1 (TREM-1) is an important mediator of innate inflammatory responses in microbial infections and sepsis. TREM-1 ligation on neutrophils (PMN) or monocytes results in the production of proinflammatory cytokines. Engagement of TREM-1 induces the activation of MAP kinases as well as rapid Ca(2+) mobilization. However, a detailed understanding of TREM-1 signaling pathways is currently lacking. We evaluated the TREM-1 signaling hierarchy in monocytic cells and found that the acute myeloid leukemia cell line MUTZ-3 expresses TREM-1 in a natural and functional manner. We compared essential signaling molecules of the TREM-1, TLR and NLR cascade in MUTZ-3 cells as well as primary monocytes or PMN by Western blot analysis. These studies confirmed the essential role of phosphatidyl inositide 3-kinase (PI3K) and p38MAPK in the TREM-1 as well as the TLR or NLR cascade of monocytic cells. Importantly, PI3K and p38MAPK signals in monocytic cells both control Ca(2+) mobilization and are directly connected in the TREM-1 signaling hierarchy, which contrasts previous results obtained in PMN. Taken together, our results indicate cell type-specific differences in the TREM-1 signaling cascade and contribute to an enhanced understanding of the regulation of innate inflammatory responses.


Trans-10, cis-12 conjugated linoleic acid activates the integrated stress response pathway in adipocytes.
Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) causes fat loss in mouse white adipose tissue (WAT) and adipocytes in culture. The early transcriptome changes in treated WAT and 3T3-L1 adipocytes were analyzed using high-density microarrays to better characterize the signaling pathways responding to t10c12 CLA. Gene expression responses between 4 and 24 h after treatment showed a common set of early gene expression changes indicative of an integrated stress response (ISR). The responses of 3T3-L1 preadipocytes treated with t10c12 CLA or adipocytes treated with the cis-9, trans-11 isomer of CLA did not show the ISR, indicating the effect is specific to adipocytes responding to t10c12 CLA. Western blot analysis found increased phosphorylation of eIF2 alpha and increased production of ATF4 confirming at least part of the response to t10c12 CLA is mediated through the ISR pathway. Immunofluorescence microscopy found that the cell type expressing ATF3, an indicator of the ISR, was early stage adipocytes containing oil droplets but lacking the abundant levels of fatty acid binding protein-4 (FABP4) (AP2) found in mature adipocytes. Our data suggests that the ISR precedes and is possibly the cause of the later induction of proinflammatory cytokines observed in t10c12 CLA treated adipocytes. The release of proinflammatory cytokines may explain how the ISR in early stage adipocytes causes lipid loss in mature adipocytes.


Using videos to assess preference for novel stimuli in children with autism.
A primary effort of preference assessment research has been to develop strategies to identify potential reinforcers for educational, social, and behavioral programming for individuals with disabilities, including children with autism. However, little attention has been paid to the identification of preferred stimuli children with autism may not have previous experience with. The purpose of this study was to evaluate the extent to which a video-based preference assessment may accurately identify preference for novel stimuli. We compared the results of the video-based preference assessment with no access to novel stimuli to the results of a preference assessment conducted in a tangible format with access. We then conducted the same video-based preference assessment a second time to evaluate the extent to which exposure to stimuli affected assessment results. The results provide preliminary support that a video-based preference assessment may accurately identify preference for novel stimuli. Implications and future directions are discussed.


Airborne Ns (NO2 and NH3) in the Rijeka Bay area (Croatia), 1980-1995.
The determination of ambient levels of nitrogen dioxide (NO2) and ammonia (NH3) in the Rijeka Bay area started in 1980, as a part of the air quality monitoring programme. The results of 15 years of surveying (1980/81-1994/95) on ambient levels of these pollutants at two sampling sites are given in this work. Site 1 is located in the city, opposite the old petroleum refinery facilities, while Site 2 is located in the settlement 25 km from the city, opposite the eastern industrial zone. Annual means of NO2 varied between 34 and 60 g/m3 at Site 1 and between 14 and 26 g/m3 at Site 2, but do not follow the 40% reduction in industrial emissions of this pollutant, probably due to the dominant impact of other minor sources, like traffic. Yearly averages of NH3 were in the range of 13 to 26 g/m 3 at Site 1 and 7 to 16 g/m3 at Site 2, and are practically constant during the period studied.


Genetic framework for flowering-time regulation by ambient temperature-responsive miRNAs in Arabidopsis.
Flowering is the primary trait affected by ambient temperature changes. Plant microRNAs (miRNAs) are small non-coding RNAs playing an important regulatory role in plant development. In this study, to elucidate the mechanism of flowering-time regulation by small RNAs, we identified six ambient temperature-responsive miRNAs (miR156, miR163, miR169, miR172, miR398 and miR399) in Arabidopsis via miRNA microarray and northern hybridization analyses. We also determined the expression profile of 120 unique miRNA loci in response to ambient temperature changes by miRNA northern hybridization analysis. The expression of the ambient temperature-responsive miRNAs and their target genes was largely anticorrelated at two different temperatures (16 and 23 degrees C). Interestingly, a lesion in short vegetative phase (SVP), a key regulator within the thermosensory pathway, caused alteration in the expression of miR172 and a subset of its target genes, providing a link between a thermosensory pathway gene and miR172. The miR172-overexpressing plants showed a temperature-independent early flowering phenotype, suggesting that modulation of miR172 expression leads to temperature insensitivity. Taken together, our results suggest a genetic framework for flowering-time regulation by ambient temperature-responsive miRNAs under non-stress temperature conditions.


Nonawake vs Awake Placement of Spinal Cord Stimulators: A Prospective, Multicenter Study Comparing Safety and Efficacy.
Spinal cord stimulation (SCS) is a common intervention for managing intractable pain. Generally, leads are implanted in a minimally invasive procedure with verbal feedback regarding the location and nature of generated paresthesias by active stimulation; in this way their optimal location can be confirmed. However, lead placement under general anesthesia can have additional benefits. To investigate the outcomes of awake vs asleep lead placement procedures. In this prospective multicenter open label trial, subjects were assigned to undergo asleep (n = 19) or awake (n = 11) SCS implantations in a nonrandomized fashion. Subjects received paddle leads following laminotomy. The process for intraoperative programming differed between the groups: awake subjects participated by verbally reporting on pain-paresthesia overlap, while for asleep subjects, paresthesia location was inferred based on electromyographic monitoring. Operative time was shorter for the asleep group compared to the awake group (88.9 ± 51.2 min vs 125.2 ± 37.9, respectively; P = .018), as well as 27% less total time spent in the operating room (95.4 ± 48.6 min vs 130.6 ± 39.9; P = .014). At 6 wk postimplant, subjects in the asleep group had better pain-paresthesia overlap than the awake group (83.5% ± 19.8 coverage vs 46.6% ± 44.5, respectively; P = .05) and fewer extraneous paresthesia (16.7% ± 23.1 vs 71.2% ± 30.3; P < .001). Both groups had equivalent levels of pain relief (more than 50%) after 6 and 24 wk of treatment. There were 2 adverse events in the asleep group compared to 6 in the awake group. Electrophysiological monitoring during asleep SCS implantation is a robust tool becoming more frequently used. This comparative prospective series demonstrates that asleep placement allows for shorter procedure and operating room times with superior paresthesia coverage profiles, while maintaining lower adverse events and equal clinical outcomes for pain relief.


Oxidative α,ω-diyne coupling as an approach towards novel peptidic macrocycles.
The Glaser-Hay diyne coupling proved to be an efficient cyclisation approach towards diyne containing peptidic macrocycles. A variety of tetrapeptide-based macrocyclic 1,3-diynes were obtained from O-propargylated serine or tyrosine residues using Cu(OAc)2·H2O and NiCl2 under an O2-atmosphere. The effect of the linear 1,3-diyne on peptide conformations was studied by NMR and compared with a macrocycle bearing a saturated linker.


CYP3A5 mRNA degradation by nonsense-mediated mRNA decay.
The total CYP3A5 mRNA level is significantly greater in carriers of the CYP3A5*1 allele than in CYP3A5*3 homozygotes. Most of the CYP3A5*3 mRNA includes an intronic sequence (exon 3B) containing premature termination codons (PTCs) between exons 3 and 4. Two models were used to investigate the degradation of CYP3A5 mRNA: a CYP3A5 minigene consisting of CYP3A5 exons and introns 3 to 6 transfected into MCF7 cells, and the endogenous CYP3A5 gene expressed in HepG2 cells. The 3'-untranslated region g.31611C>T mutation has no effect on CYP3A5 mRNA decay. Splice variants containing exon 3B were more unstable than wild-type (wt) CYP3A5 mRNA. Cycloheximide prevents the recognition of PTCs by ribosomes: in transfected MCF7 and HepG2 cells, cycloheximide slowed down the degradation of exon 3B-containing splice variants, suggesting the participation of nonsense-mediated decay (NMD). When PTCs were removed from pseudoexon 3B or when UPF1 small interfering RNA was used to impair the NMD mechanism, the decay of the splice variant was reduced, confirming the involvement of NMD in the degradation of CYP3A5 splice variants. Induction could represent a source of variability for CYP3A5 expression and could modify the proportion of splice variants. The extent of CYP3A5 induction was investigated after exposure to barbiturates or steroids: CYP3A4 was markedly induced in a pediatric population compared with untreated neonates. However, no effect could be detected in either the total CYP3A5 RNA, the proportion of splice variant RNA, or the protein level. Therefore, in these carriers, induction is unlikely to switch on the phenotypic CYP3A5 expression in carriers of CYP3A5*3/*3.


Increased hydrogen peroxide and thiobarbituric acid-reactive products in expired breath condensate of asthmatic patients.
Symptoms of bronchial asthma are a manifestation of airway inflammation. Circulatory leucocytes (predominantly eosinophils, mast cells and neutrophils), release inflammatory mediators, including reactive oxygen species, i.e. superoxide anion which is dismutated to hydrogen peroxide (H2O2). Neutrophils from asthmatics generate greater amounts of these species than those of healthy subjects. Some of the H2O2 and thiobarbituric acid-reactive products (TBARs) can evaporate from alveolar lining fluid, and could be expired from the airways of asthmatics. In this study, therefore, we determined whether asthmatic patients exhale more H2O2 and TBARs than healthy subjects. We examined 10 healthy subjects as a control group and 21 asthmatic subjects. In asthmatic subjects, forced expiratory volume in one second (FEV1), was 68+/-9% of predicted value, peak expiratory flow rate (PEFR) was 65+/-8% pred, and bronchial reversibility was 34+/-5% of prebronchodilated FEV1. The mean H2O2 level measured spectrofluorimetrically in the expired breath condensate of asthmatic subjects was 26 fold higher than that in healthy controls (0.26+/-0.29 vs 0.01+/-0.03 nM; p<0.05). The concentration of TBARs in breath condensate was also higher in asthmatic patients compared with nonasthmatics (0.073+/-0.071 vs 0.004+/-0.009 nM; p<0.05). There was a significant correlation between H2O2 level and concentration of TBARs in asthmatic patients (r=0.74; p<0.01). There was also a strong inverse correlation between H2O2 content of all asthmatics and FEV1% pred (r=-0.63; p<0.005) and PEFR% pred (r=-0.52; p<0.05). We conclude that there are elevated levels of hydrogen peroxide and thiobarbituric acid-reactive products in expired breath condensate of asthmatic patients, and that measurement of these substances in the expired breath condensate could be a simple, noninvasive method that could be used as a biochemical marker of airway inflammation.


Verbal episodic memory along the course of schizophrenia and bipolar disorder: a new perspective.
Impairment on episodic memory (EM) has been strongly correlated with psychiatric disorders, including schizophrenia (SZ) and bipolar disorder (BD). Morevover, the effects of course and progression of the illness on cognitive functioning have not been well established. The aim of the present study is to assess performance of episodic memory in BD and SZ according to their clinical stages. Subjects who met DSM-IV criteria for bipolar disorder (n=43) and schizophrenia (31), on euthymia or clinical remission, were recruited from the outpatients facilities at Hospital de Clínicas de Porto Alegre (Brazil). They were classified into two clinical stages (early or late for BD, and recent onset or chronic for SZ) and compared to 54 healthy controls. Episodic memory performance was assessed by means the Hopkins Verbal Learning Test-Revised (HVLT-R) that measures verbal learning and episodic memory in both disorders. Our results showed that patients in early stage of BD (EBD) performed better performance on the total immediate free recall (p<0.0001, F=12.060) as well as in delayed free recall (p<0.0001, F=13.914) compared to late stage (LBD) and SZ groups. In the ability to retain words learned, LBD and chronic (CSZ) were more impaired than other groups. Furthermore, the variation of learning (i.e, learning effects) along the 3 trials of immediate free recall was similar between groups. In conclusion, we found a cognitive decline alongside with the progression of BD whereas such impairment was evident in the early of SZ. Despite this, both groups (BD and SZ) seem to maintain the ability to learn. It emphasizes the relevance of studying new therapeutic strategies, in particular, cognitive rehabilitation/remediation techniques as promissory treatment for psychiatric patients, even in those with moderate disabilities.


First Report of Agrobacterium vitis as Causal Agent of Crown Gall Disease of Grapevine in Tunisia.
Since October 2011, a serious outbreak of crown gall disease was observed on 1- and 2-year-old grapevines (Vitis vinifera L.) cv. Superior Seedless in several vineyards located in the region of Regueb in the center of Tunisia. Fifty isolates of Agrobacterium were isolated on a tartrate medium from galls of affected plants. To prepare template DNA, cell suspensions were lysed in 0.25% sodium-azide (NaN3) buffer prepared in 1% Triton X-100 by heating the samples at 95°C for 10 to 15 min (1). The strains were differentiated using a multiplex PCR assay with a combination of VIRFF1/VIRFR2 and VIRD2S4F716/VIRD2S4R1036 primers (2), which detect regions of virF and virD2 genes, respectively, in A. vitis strains carrying octopine or nopaline Ti plasmids and A. vitis vitopine strains. In order to differentiate A. vitis strains from A. tumefaciens strains, PGF/PGR (4), a polygalacturonase specific primer set, was added to the mixture in multiplex PCR. The isolates segregated into three main groups. The first group carries octopine type Ti plasmids, the second carries vitopine type Ti plasmids, and the third group carries both octopine and vitopine type Ti plasmids. The polygalacturonase gene sequence from 10 isolates showed 94 to 97% identity to the sequences of A. vitis previously deposited in the NCBI GenBank database (Accession No. CP000633.1gb). The biochemical test results corresponded to the results of genetic analysis. The ability to aerobically convert lactose to 3-ketolactose was tested by spotting bacteria onto medium containing lactose and flooding plates with a layer of Benedict's reagents after incubation at 28°C for 48 h. Acid production from glucose was tested by spotting bacterial strains onto potato dextrose agar (PDA) medium supplemented with CaCO3. Alkali production from L-tartrate was tested by streaking bacteria on AB minimal medium supplemented with L-tartrate and growth in salt medium was tested by streaking on nutrient broth supplemented with 2% NaCl. All isolates except one were negative in 3-ketolactose. They were negative in acid clearing on PDA-CaCO3, grew in 2% NaCl, and produced alkali from tartarate. Pathogenicity of all 50 strains was tested on 1-month-old tomato plants (Lycopersicum esculentum cv. Riograndi). Plants were inoculated on the stem by pricking one to three times through a drop of inoculum (108 CFU/ml) at three inoculation sites. Sterile distilled water was used as control treatment. Plants were grown for 4 weeks at 23 ± 3°C and symptoms were recorded. Typical tumors developed at the inoculation sites and no symptoms were observed on the control plants. In Tunisia, crown gall disease was observed only on stone fruit trees and only A. tumefaciens Biovar 1 have been reported and assigned to four genomic species G4, G6 G7, and G8 basically on the recA sequencing (3). To our knowledge, this is the first report of A. vitis determined as the causal agent of grapevine crown gall in Tunisia. References: (1) A. Abolmaaty et al. Microbios 101:181, 2000. (2) F. Bini et al. Vitis 47:181, 2008. (3) D. Costechareyre et al. Microb. Ecol. 60:862, 2010. (4) E. Szegedi and S. Bottka. Vitis 41:37, 2002.


Cost feasibility of a pre-checking medical tourism system for U.S. patients undertaking joint replacement surgery in Taiwan.
Medical tourism is a relatively recent global economic and political phenomenon that has assumed increasing importance for developing countries, particularly in Asia. In fact, Taiwan possesses a niche for developing medical tourism because many hospitals provide state-of-the-art medicine in all disciplines and many doctors are trained in the United States (US). Among the most common medical procedures outsourced, joint replacements such as total knee replacement (TKR) and total hip replacement (THR) are two surgeries offered to US patients at a lower cost and shorter waiting time than in the US. This paper proposed a pre-checking medical tourism system (PCMTS) and evaluated the cost feasibility of recruiting American clients traveling to Taiwan for joint replacement surgery. Cost analysis was used to estimate the prime costs for each stage in the proposed PCMTS. Sensitivity analysis was implemented to examine how different pricings for medical checking and a surgical operation (MC&SO) and recovery, can influence the surplus per patient considering the PCMTS. Finally, the break-even method was adopted to test the tradeoff between the sunk costs of investment in the PCMTS and the annual surplus for participating hospitals. A novel business plan was built showing that pre-checking stations in medical tourism can provide post-operative care and recovery follow-up. Adjustable pricing for hospital administrators engaged in the PCMTS consisted of two main costs: US$3,700 for MC&SO and US$120 for the hospital stay. Guidelines for pricing were provided to maximize the annual surplus from this plan with different number of patients participating in PCMTS. The maximal profit margin from each American patient undertaking joint surgery is about US$24,315. Using cost analysis, this article might be the first to evaluate the feasibility of PCMTS for joint replacement surgeries. The research framework in this article is applicable when hospital administrators evaluate the feasibility of outsourced medical procedures other than TKR and THR.


Synergistic effect of ATP for RuvA-RuvB-Holliday junction DNA complex formation.
The Escherichia coli RuvB hexameric ring motor proteins, together with RuvAs, promote branch migration of Holliday junction DNA. Zero mode waveguides (ZMWs) constitute of nanosized holes and enable the visualization of a single fluorescent molecule under micromolar order of the molecules, which is applicable to characterize the formation of RuvA-RuvB-Holliday junction DNA complex. In this study, we used ZMWs and counted the number of RuvBs binding to RuvA-Holliday junction DNA complex. Our data demonstrated that different nucleotide analogs increased the amount of Cy5-RuvBs binding to RuvA-Holliday junction DNA complex in the following order: no nucleotide, ADP, ATPγS, and mixture of ADP and ATPγS. These results suggest that not only ATP binding to RuvB but also ATP hydrolysis by RuvB facilitates a stable RuvA-RuvB-Holliday junction DNA complex formation.


Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.
The purpose of this study was to examine whether ingesting a pre-workout dietary supplement (PWS) with and without synephrine (S) during training affects training responses in resistance-trained males. Resistance-trained males (N = 80) were randomly assigned to supplement their diet in a double-blind manner with either a flavored placebo (PLA); a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg); or, the PWS supplement with Citrus aurantium extract containing 20 mg of synephrine (PWS + S) once per day for 8-weeks during training. Participants donated a fasting blood sample and had body composition (DXA), resting heart rate and blood pressure, cognitive function (Stroop Test), readiness to perform, bench and leg press 1 RM, and Wingate anaerobic capacity assessments determined a 0, 4, and 8-weeks of standardized training. Data were analyzed by MANOVA with repeated measures. Performance and cognitive function data were analyzed using baseline values as covariates as well as mean changes from baseline with 95% confidence intervals (CI). Blood chemistry data were also analyzed using Chi-square analysis. Although significant time effects were seen, no statistically significant overall MANOVA Wilks' Lambda interactions were observed among groups for body composition, resting heart and blood pressure, readiness to perform questions, 1RM strength, anaerobic sprint capacity, or blood chemistry panels. MANOVA univariate analysis and analysis of changes from baseline with 95% CI revealed some evidence that cognitive function and 1RM strength were increased to a greater degree in the PWS and/or PWS + S groups after 4- and/or 8-weeks compared to PLA responses. However, there was no evidence that PWS + S promoted greater overall training adaptations compared to the PWS group. Dietary supplementation of PWS and PWS + S did not increase the incidence of reported side effects or significantly affect the number of blood values above clinical norms compared to PLA. Results provide some evidence that 4-weeks of PWS and/or PWS + S supplementation can improve some indices of cognitive function and exercise performance during resistance-training without significant side effects in apparently health males. However, these effects were similar to PLA responses after 8-weeks of supplementation and inclusion of synephrine did not promote additive benefits. This trial (NCT02999581) was retrospectively registered on December 16th 2016.


CdS quantum dots as fluorescence probes for the sensitive and selective detection of highly reactive HSe- ions in aqueous solution.
Water-soluble cadmium sulfide (CdS) quantum dots (QDs) capped by mercaptoacetic acid were synthesized by aqueous-phase arrested precipitation, and characterized by transmission electron microscopy, spectrofluorometry, and UV-Vis spectrophotometry. The prepared luminescent water-soluble CdS QDs were evaluated as fluorescence probes for the detection of highly reactive hydrogen selenide ions (HSe(-) ions). The quenching of the fluorescence emission of CdS QDs with the addition of HSe(-) ions is due to the elimination of the S(2-) vacancies which are luminescence centers. Quantitative analysis based on chemical interaction between HSe(-) ions and the surface of CdS QDs is very simple, easy to develop, and has demonstrated very high sensitivity and selectivity features. The effect of foreign ions (common anions and biologically relevant cations) on the fluorescence of the CdS QDs was examined to evaluate the selectivity. Only Cu(2+) and S(2-) ions exhibit significant effects on the fluorescence of CdS QDs. With the developed method, we are able to determine the concentration of HSe(-) ions in the range from 0.10 to 4.80 micromol L(-1), and the limit of detection is 0.087 micromol L(-1). The proposed method was successfully applied to monitor the obtained HSe(-) ions from the reaction of glutathione with selenite. To the best of our knowledge, this is the first report on fluorescence analysis of HSe(-) ions in aqueous solution.


eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2.
Macrophages represent one of the first lines of defense during infections and are essential for resolution of inflammation following pathogen clearance. Rapid activation or suppression of protein synthesis via changes in translational efficiency allows cells of the immune system, including macrophages, to quickly respond to external triggers or cues without de novo mRNA synthesis. The translational repressors eIF4E-binding proteins 4E-BP1 and 4E-BP2 (4E-BP1/2) are central regulators of proinflammatory cytokine synthesis during viral and parasitic infections. However, it remains to be established whether 4E-BP1/2 play a role in translational control of anti-inflammatory responses. By comparing translational efficiencies of immune-related transcripts in macrophages from wild-type and 4E-BP1/2 double-knockout mice, we found that translation of mRNAs encoding two major regulators of inflammation, IL-10 and PG-endoperoxide synthase 2/cyclooxygenase-2, is controlled by 4E-BP1/2. Genetic deletion of 4E-BP1/2 in macrophages increased endogenous IL-10 and PGE2 protein synthesis in response to TLR4 stimulation and reduced their bactericidal capacity. The molecular mechanism involves enhanced anti-inflammatory gene expression (sIl1ra, Nfil3, Arg1, Serpinb2) owing to upregulation of IL-10-STAT3 and PGE2-C/EBPβ signaling. These data provide evidence that 4E-BP1/2 limit anti-inflammatory responses in macrophages and suggest that dysregulated activity of 4E-BP1/2 might be involved in reprogramming of the translational and downstream transcriptional landscape of macrophages during pathological conditions, such as infections and cancer.


Investigation of the effects of orally administered trazodone on intraocular pressure, pupil diameter, physical examination variables, and sedation level in healthy equids.
To investigate the effects of orally administered trazodone on intraocular pressure (IOP), pupil diameter measured in the vertical plane (ie, vertical pupil diameter [VPD]), selected physical examination variables, and sedation level in healthy equids. 7 horses and 1 pony. Food was withheld for 12 hours prior to drug administration. After baseline (time 0) sedation scoring, physical examination, and measurement of IOP and VPD, equids received 1 dose (approx 6 mg/kg) of trazodone orally. Examination and measurement procedures were repeated 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Blood samples were collected at each time point for analysis of plasma trazodone concentrations. Repeated-measures analysis was used to compare examination results between downstream time points and baseline. 7 of 8 equids had mild sedation from 0.5 to 8 hours after treatment; compared with baseline values, mean IOP was significantly lower from 0.5 hours to 8 hours, mean VPD was significantly smaller at 0.5 hours, and mean rectal temperature was significantly lower from 1 to 8 hours after drug administration. Adverse effects (signs of excitement in 1 equid and sweating in 4) were self-limiting and considered minor. Mean maximum plasma concentration of trazodone was 1,493 ng/mL 0.75 hours after administration, and terminal half-life of the drug was 9.96 hours. The described oral dose of trazadone elicited sedation with a few self-limiting adverse effects in the study sample. Drug effects on IOP and VPD may alter ocular examination findings. Further investigation is warranted prior to use of trazodone for sedation in equids, particularly those with ophthalmic conditions.


The effect of spinal cord stimulation on pain medication reduction in intractable spine and limb pain: a systematic review of randomized controlled trials and meta-analysis.
Objective: To synthesize the evidence regarding the effect of spinal cord stimulation (SCS) on opioid and pain medication reduction in patients with intractable spine or limb pain. Methods: A comprehensive literature search was conducted to identify RCTs of patients with chronic back and/or limb pain of greater than one year duration. Only comparative studies were included (ie, conventional SCS vs medical therapy, conventional SCS vs high-frequency SCS) and were required to have a minimum follow-up period of 3 months. Random effect meta-an alysis was used to compare the three interventions. Results were expressed as odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CI). Results: We identified five trials enrolling 489 patients. Three of the trials reported the results as a number of patients who were able to reduce or eliminate opioid consumption in the SCS vs medical therapy group. The odds of reducing opioid consumption were significantly increased in the SCS group compared to medical therapy (OR 8.60, CI {1.93-38.30}). Two of the trials reported the results as mean medication dose reduction as measured by the Medication Quantification Scale (MQS) in the SCS group vs medical therapy group. MQS score significantly decreased in the SCS group and not in the medical group (WMD -1.97, 95% CI {-3.67, -0.27}). One trial reported a number of patients in high-frequency SCS who were able to reduce opioids vs number of patients in conventional SCS group who were able to reduce opioids. Thirty-four percent of the patients in the high-frequency group and 26% of the patients in the conventional SCS group were able to reduce opioid consumption; however, there was not a significant difference between groups (OR 1.43, 95% CI {0.74, 2.78}). This trial also quantified the opioid reduction in morphine equivalent dosage (MED). In the high-frequency SCS group, average MED decreased by 24.8 mg vs average MED decrease of 7.3 mg in the conventional SCS group. Again, the difference between groups did not reach statistical significance (-17.50, CI {-66.27, 31.27}). Conclusions: In patients with intractable spine/limb pain, SCS was associated with increased odds of reducing pain medication consumption. However, results should be treated with caution as available data were limited, and clinical significance of these findings requires further study.


Multiple linear regression modeling of disinfection by-products formation in Istanbul drinking water reservoirs.
Oxidation of raw water with chlorine results in formation of trihalomethanes (THM) and haloacetic acids (HAA). Factors affecting their concentrations have been found to be organic matter type and concentration, pH, temperature, chlorine dose, contact time and bromide concentration, but the mechanisms of their formation are still under investigation. Within this scope, chlorination experiments have been conducted with water reservoirs from Terkos, Buyukcekmece and Omerli lakes, Istanbul, with different water quality regarding bromide concentration and organic matter content. The factors studied were pH, contact time, chlorine dose, and specific ultraviolet absorbance (SUVA). The determination of disinfection by-products (DBP) was carried out by gas chromatography techniques. Statistical analysis of the results was focused on the development of multiple regression models for predicting the concentrations of total THM and total HAA based on the use of pH, contact time, chlorine dose, and SUVA. The developed models provided satisfactory estimations of the concentrations of the DBP and the model regression coefficients of THM and HAA are 0.88 and 0.61, respectively. Further, the Durbin-Watson values confirm the reliability of the two models. The results indicate that under these experimental conditions which indicate the variations of pH, chlorine dosages, contact time, and SUVA values, the formation of THM and HAA in water can be described by the multiple linear regression technique.


E-vapor aerosols do not compromise bone integrity relative to cigarette smoke after 6-month inhalation in an ApoE-/- mouse model.
Cigarette smoke (CS) exposure is one of the leading risk factors for human health. Nicotine-containing inhalable products, such as e-cigarettes, can effectively support tobacco harm reduction approaches. However, there are limited comparative data on the effects of the aerosols generated from electronic vapor products (e-vapor) and CS on bone. Here, we report the effects of e-vapor aerosols and CS on bone morphology, structure, and strength in a 6-month inhalation study. Eight-week-old ApoE-/- mice were exposed to aerosols from three different e-vapor formulations-CARRIER (propylene glycol and vegetable glycerol), BASE (CARRIER and nicotine), TEST (BASE and flavor)-to CS from 3R4F reference cigarettes at matched nicotine concentrations (35 µg/L) or to fresh air (Sham) (N = 10 per group). Tibiae were analyzed for bone morphology by µCT imaging, biomechanics by three-point bending, and by histological analysis. CS inhalation caused a significant decrease in cortical and total bone volume fraction and bone density relative to e-vapor aerosols. Additionally, CS exposure caused a decrease in ultimate load and stiffness. In contrast, bone structural and biomechanical parameters were not significantly affected by e-vapor aerosol or Sham exposure. At the dissection time point, there was no significant difference in body weight or tibia bone weight or length among the groups. Histological findings revealed microcracks in cortical bone areas among all exposed groups compared to Sham control. In conclusion, because of the bone-preserving effect of e-vapor aerosols relative to CS exposure, e-vapor products could potentially constitute less harmful alternatives to cigarettes in situations in which bone health is of importance.


Changes in hospitalizations for chronic respiratory diseases after two successive smoking bans in Spain.
Existing evidence on the effects of smoke-free policies on respiratory diseases is scarce and inconclusive. Spain enacted two consecutive smoke-free regulations: a partial ban in 2006 and a comprehensive ban in 2011. We estimated their impact on hospital admissions via emergency departments for chronic obstructive pulmonary disease (COPD) and asthma. Data for COPD (ICD-9 490-492, 494-496) came from 2003-2012 hospital admission records from the fourteen largest provinces of Spain and from five provinces for asthma (ICD-9 493). We estimated changes in hospital admission rates within provinces using Poisson additive models adjusted for long-term linear trends and seasonality, day of the week, temperature, influenza, acute respiratory infections, and pollen counts (asthma models). We estimated immediate and gradual effects through segmented-linear models. The coefficients within each province were combined through random-effects multivariate meta-analytic models. The partial ban was associated with a strong significant pooled immediate decline in COPD-related admission rates (14.7%, 95%CI: 5.0, 23.4), sustained over time with a one-year decrease of 13.6% (95%CI: 2.9, 23.1). The association was consistent across age and sex groups but stronger in less economically developed Spanish provinces. Asthma-related admission rates decreased by 7.4% (95%CI: 0.2, 14.2) immediately after the comprehensive ban was implemented, although the one-year decrease was sustained only among men (9.9%, 95%CI: 3.9, 15.6). The partial ban was associated with an immediate and sustained strong decline in COPD-related admissions, especially in less economically developed provinces. The comprehensive ban was related to an immediate decrease in asthma, sustained for the medium-term only among men.


The effect of travel loss on evolutionarily stable distributions of populations in space.
A key assumption of the ideal free distribution (IFD) is that there are no costs in moving between habitat patches. However, because many populations exhibit more or less continuous population movement between patches and traveling cost is a frequent factor, it is important to determine the effects of costs on expected population movement patterns and spatial distributions. We consider a food chain (tritrophic or bitrophic) in which one species moves between patches, with energy cost or mortality risk in movement. In the two-patch case, assuming forced movement in one direction, an evolutionarily stable strategy requires bidirectional movement, even if costs during movement are high. In the N-patch case, assuming that at least one patch is linked bidirectionally to all other patches, optimal movement rates can lead to source-sink dynamics where patches with negative growth rates are maintained by other patches with positive growth rates. As well, dispersal between patches is not balanced (even in the two-patch case), leading to a deviation from the IFD. Our results indicate that cost-associated forced movement can have important consequences for spatial metapopulation dynamics. Relevance to marine reserve design and the study of stream communities subject to drift is discussed.


Health effects of inhaled gasoline engine emissions.
Despite their prevalence in the environment, and the myriad studies that have shown associations between morbidity or mortality with proximity to roadways (proxy for motor vehicle exposures), relatively little is known about the toxicity of gasoline engine emissions (GEE). We review the studies conducted on GEE to date, and summarize the findings from each of these studies. While there have been several studies, most of the studies were conducted prior to 1980 and thus were not conducted with contemporary engines, fuels, and driving cycles. In addition, many of the biological assays conducted during those studies did not include many of the assays that are conducted on contemporary inhalation exposures to air pollutants, including cardiovascular responses and others. None of the exposures from these earlier studies were characterized at the level of detail that would be considered adequate today. A recent GEE study was conducted as part of the National Environmental Respiratory Center (www.nercenter.org). In this study several in-use mid-mileage General Motors (Chevrolet S-10) vehicles were purchased and utilized for inhalation exposures. An exposure protocol was developed where engines were operated with a repeating California Unified Driving Cycle with one cold start per day. Two separate engines were used to provide two cold starts over a 6-h inhalation period. The exposure atmospheres were characterized in detail, including detailed chemical and physical analysis of the gas, vapor, and particle phase. Multiple rodent biological models were studied, including general toxicity and inflammation (e.g., serum chemistry, lung lavage cell counts/differentials, cytokine/chemokine analysis, histopathology), asthma (adult and in utero exposures with pulmonary function and biochemical analysis), cardiovascular effects (biochemical and electrocardiograph changes in susceptible rodent models), and susceptibility to infection (Pseudomonas bacteria challenge). GEE resulted in significant biological effects for upregulation of MIP-2, clearance of Pseudomonas bacteria, development of allergic response after in utero exposure, and cardiovascular indicators of vasoconstriction, oxidant stress, and damage.