A brief bedside visual art intervention decreases anxiety and improves pain and mood in patients with haematologic malignancies.

Treatment of cancer-related symptoms represents a major challenge for physicians. The purpose of this pilot study was to determine whether a brief bedside visual art intervention (BVAI) facilitated by art educators improves mood, reduces pain and anxiety in patients with haematological malignancies. Thirty-one patients (21 women and 10 men) were invited to participate in a BVAI where the goal of the session was to teach art technique for ~30 min. Primary outcome measures included the change in visual analog scale, the State-Trait Anxiety Inventory and the Positive and Negative Affect Schedule scale, from baseline prior to and immediately post-BVAI. Total of 21 patients (19 women and two men) participated. A significant improvement in positive mood and pain scores (p = .003 and p = .017 respectively) as well as a decrease in negative mood and anxiety (p = .016 and p = .001 respectively) was observed. Patients perceived BVAI as overall positive (95%) and wished to participate in future art-based interventions (85%). This accessible experience, provided by artists within the community, may be considered as an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain, and future studies with balanced gender participation may support the generalisability of these findings.

Expanding the view of Clock and cycle gene evolution in Diptera.

We expanded the view of Clock (Clk) and cycle (cyc) gene evolution in Diptera by studying the fruit fly Anastrepha fraterculus (Afra), a Brachycera. Despite the high conservation of clock genes amongst insect groups, striking structural and functional differences of some clocks have appeared throughout evolution. Clk and cyc nucleotide sequences and corresponding proteins were characterized, along with their mRNA expression data, to provide an evolutionary overview in the two major groups of Diptera: Lower Diptera and Higher Brachycera. We found that AfraCYC lacks the BMAL (Brain and muscle ARNT-like) C-terminus region (BCTR) domain and is constitutively expressed, suggesting that AfraCLK has the main transactivation function, which is corroborated by the presence of poly-Q repeats and an oscillatory pattern. Our analysis suggests that the loss of BCTR in CYC is not exclusive of drosophilids, as it also occurs in other Acalyptratae flies such as tephritids and drosophilids, however, but it is also present in some Calyptratae, such as Muscidae, Calliphoridae and Sarcophagidae. This indicates that BCTR is missing from CYC of all higher-level Brachycera and that it was lost during the evolution of Lower Brachycera. Thus, we can infer that CLK protein may play the main role in the CLK\CYC transcription complex in these flies, like in its Drosophila orthologues.

Influence of smoking and alcohol during pregnancy on outcome of VLBW infants.

BACKGROUND: Nicotine and alcohol consumption have been associated with premature delivery and adverse neonatal outcome. We wanted to analyze the influence of self-reported nicotine and alcohol consumption on outcome of VLBW infants. MATERIAL AND METHODS: In an ongoing multicenter study 2475 parents of former very low birth weight (VLBW) infants born between January 2009 and December 2011 answered questionnaires about maternal smoking habits and alcohol consumption during pregnancy. 2463 (99.5%) completed questions on alcohol consumption and 2462 (99.5%) on smoking habits. These infants were stratified to reported maternal smoking and alcohol consumption during pregnancy. We compared the reasons for premature delivery, neonatal outcome and parental reports on bronchitis during the first year of life, as well as growth and development at age 2 years to pregnancy exposure. RESULTS: In nicotine exposed infants intrauterine growth restriction (31 vs. 21%, p<0.01), a birth weight below the 10th percentile (26 vs. 17%, p<0.01) and placenta abruption (9.2 vs. 5.8%, p<0.05) was seen more often. Premature rupture of membranes (24 vs. 30%, p<0.05) or HELLP syndrome (6 vs. 11%, p<0.01) was less frequent. A birth weight below the 3rd percentile was seen more frequently in mothers with reported alcohol consumption (13 vs. 6%, p<0.05). We noted an increased rate of BPD and ROP if mothers reported smoking during pregnancy (p<0.05). Growth parameters and scores on Bayley Sscales of infant development at age 2 years did not differ. CONCLUSION: Smoking during pregnancy results in a high rate of growth restricted VLBW infants. Prenatal exposition to nicotine seems to increase postnatal complications such as BPD und ROP.

Chronotype as a predictor of scholar performance in a full-time middle school.

The performance of day-to-day tasks, whether satisfactory or unsatisfactory, varies due to several environmental synchronizers, including the 24-hour light-dark cycle. For instance, human performance on physical and/or cognitive demanding activities reaches its peak during the day when the body temperature is at its circadian peak. Individual differences in the circadian peaks in temperature along with individuals' timing of sleep is referred to as chronotype. Here, we aimed to answer if (a) chronotypes affect the performance of students in a Brazilian full-time school with an early start time and if (b) there are differences in performance based on chronotype. We expected to find (a) a positive effect of the morning chronotype on the students' performance, particularly in subjects that take place in early morning; (b) while a negative effect of the evening chronotype in that same period. To address the effect of the chronotype on the students' scholar performance we build a Generalized Linear Mixed Model (GLMM). Results support the hypothesis that the students' performance is partially attributed to their chronotype. In particular, our findings shows that evening-type students are expected to have an increase of 0.038 (p ≤0.05) log counts on their performance in Portuguese classes compared to other chronotypes. Here we add evidence for the effect that individual chronotypes have on the students' performance in a Brazilian full-time middle school. Distinctive features of the studied Brazilian full-time middle school related to chronotypes are discussed.

Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network.

The German Neonatal Network (GNN) is a prospective cohort study with the focus on long term development of very-low-birth-weight infants. It was the aim of this study to determine detailed information on causes of mortality in the GNN birth cohort 2010.Major contributors to hospital mortality were recorded by the attending neonatologists for the cohort of very-low-birth-weight (VLBW) infants born in centres of the German Neonatal Network (GNN) in 2010. The data quality was approved by on-site monitoring.2 221 VLBW infants were born in GNN centres in 2010, and death occurred in 221 infants. Male infants carried a higher risk than females (58.8% males among non-survivors vs. 51.7% among survivors, p=0.047). In 11 infants, the major contributor to death was not determined by the attending neonatologist. In 25 infants born at the limit of viability, comfort palliative care was primarily initiated and 14 infants had lethal malformations. The majority of non-survivors suffered from inflammatory diseases including sepsis- or necrotizing enterocolitis (NEC)-associated death (n=56). Respiratory pathology was a major contributor to death in 65 infants including 11 infants who died from pulmonary haemorrhage.Potentially preventable complications of preterm birth such as sepsis, NEC and pulmonary haemorrhage predominate the major contributors to mortality in the GNN 2010 cohort. In order to decrease the rate of these associated deaths, future trials should focus on prophylaxis and therapy optimization strategies for these outcomes.

Estimating and Explaining the Prevalence of Tuberculosis for Asylum Seekers Upon Their Arrival in Germany.

Up until recently incidences of tuberculosis (TB) had been declining for many years in Germany. The rise in TB cases coincided with a large increase in the number of people applying for asylum. We combine data from various sources to estimate the at-entry prevalence of TB for asylum seekers from 18 countries of origin and rely on survey data to explain the varying risk of suffering from TB. Our results reveal that asylum seekers from Eastern Africa show a much higher risk of suffering from TB than asylum seekers from Afghanistan, Syria, or Iraq. The survey data suggests that asylum seekers from Africa were by far more underprivileged in their respective countries of origin and experienced a higher risk of contracting TB on their way to Germany. Information about the socio-economic situation and the circumstances of the journey to Germany may help to improve TB surveillance.

Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory.

A simple in vitro experimental system was devised to reflect the in vivo generation of a T cell anamnestic response so that T cell differentiation could be examined at the level of lymphokine gene expression. Comparison of neonatal and adult T cells revealed that both populations expressed the genes for interleukin 2 (IL-2) and its receptor, but only adult T cells were capable of transcribing mRNAs for IL-3, IL-4, IL-5, IL-6, interferon gamma, and granulocyte/macrophage colony-stimulating factor. However, neonatal T cells could be induced to undergo functional differentiation in vitro, thereby acquiring the capacity to express the lymphokine gene repertoire characteristic for adult T cells. These data suggest that the T cells generated from neonatal blood by a primary stimulation in vitro are functionally indistinguishable from the T cells in adult blood that presumably have undergone primary stimulation in vivo. Therefore, we propose that the term "memory cell" be applied to those T cells that can be identified by their differentiated state of inducible effector-lymphokine gene expression.

Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology.

The immunological basis of tuberculin-induced necrosis, known for more than a century as "Koch's phenomenon," remains poorly understood. Aerosol infection in mice with the highly virulent Mycobacterium avium strain TMC724 causes progressive pulmonary pathology strongly resembling caseating necrosis in human patients with tuberculosis. To identify the cellular and molecular mediators causing this pathology, we infected C57BL/6 mice and mice selectively deficient in recombinase activating gene (RAG)-1, alphabeta T cell receptor (TCR), gammadelta TCR, CD4, CD8, beta2-microglobulin, interferon (IFN)-gamma, interleukin (IL)-10, IL-12p35, IL-12p35/p40, or iNOS with M. avium by aerosol and compared bacterial multiplication, histopathology, and respiratory physiology in these mice. The bacterial load in the lung was similarly high in all mouse groups. Pulmonary compliance, as a surrogate marker for granulomatous infiltrations in the lung, deteriorated to a similar extent in all groups of mice, except in alphabeta TCR-knockout (KO) and IL-12-KO mice in which compliance was higher, and in IFN-gamma and inducible nitric oxide synthase-KO mice in which compliance was reduced faster. Progressive caseation of pulmonary granulomas never occurred in alphabeta TCR-KO, IL-12-KO, and IFN-gamma-KO mice and was reduced in CD4-KO mice. In summary, alphabeta TCR(+) cells and IFN-gamma are essential for the development of mycobacteria-induced pulmonary caseous necrosis. In contrast, high mycobacterial load and extensive granulomatous infiltration per se are not sufficient to cause caseation, nor is granuloma necrosis linked to the induction of nitric oxide.

The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.

Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-γ release assays or, as an alternative in individuals without a history of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and an interferon-γ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly reduces the risk of progression to TB. This TBNET consensus statement summarises current knowledge and expert opinions and provides evidence-based recommendations to reduce the TB risk among candidates for TNF antagonist therapy.

99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: lifestyle changes affecting the host-environment interface.

In industrialized nations and high-income regions of the world, the decline of infectious diseases is paralleled by an increase in allergic, autoimmune and chronic inflammatory diseases (AACID). Changes in lifestyle in westernized societies, which impact individually and collectively on intestinal microbiota, may - at least in part - account for the AACID pandemic. Many disease genes that contribute to AACID encode pattern recognition and signalling molecules in barrier-associated cells. Interactions between gene products and environmental factors depend highly upon the host's state of maturation, the composition of the skin and gut microflora, and exposure to pollutants, antibiotics and nutrients. Inflammatory stress responses, if regulated appropriately, ensure immunity, health and relative longevity; when they are dysregulated, they can no longer be terminated appropriately and thus precipitate AACID. The 99th Dahlem Conference brought together experts of various disciplines (genetics, evolution biology, molecular biology, structural biology, cell biology, immunology, microbiology, nutrition science, epidemiology and clinical medicine) to discuss the multi-faceted relationships between infection, immunity and inflammation in barrier organs and the development of AACID. In Clinical and Experimental Immunology we are presenting a compilation of background papers that formed the basis of discussions. Controversial viewpoints and gaps in current knowledge were examined and new concepts for prevention and treatment of CID were formulated.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Lazy, dynamic or minimally recrudescent? On the elusive nature and location of the mycobacterium responsible for latent tuberculosis.

In the absence of symptoms characteristic of tuberculosis (TB), a condition termed clinical latency, diagnosis is currently impossible by detection of the microorganism itself and resorts to the demonstration of an immunological memory response to antigens of Mycobacterium tuberculosis (Mtb). Whether latency is synonymous to chronic persistent infection with viable Mtb in all instances has been difficult to establish. The physical and physiological state of Mtb during latency is much disputed: are organisms mostly dormant, in a nonreplicating state of persistence, and characterized by lipid inclusions and metabolic adaptation to hypoxia, or do they continue to replicate and sometimes even escape from the fringes of granulomatous lesions or alveolar epithelial cells into adjacent airways, thereby inducing recurring immune responses? The physical nature of Mtb during latency is important as it determines which antimicrobial agents may be used to kill it, which immunomodulating strategies (including post-exposure vaccines) may be appropriate to contain it, and which diagnostic measures may be most useful to discriminate latent from reactivating infection. Two major viewpoints exist: one argues that Mtb persists mostly in a lazy state within granulomatous lesions, but periodically recrudesces, and that there is considerable heterogeneity for different sites within the lesion and within the infected lung. Throughout latency, there is a dynamic immunological interplay between Mtb and the host, necessitating continuous recruitment of cells into the granuloma, and reactivation occurs when this dynamic cellular exchange becomes dysregulated. Another view holds that dormant Mtb reside within alveolar epithelial cells in the lung apices and in adipocytes, with reactivation being associated with the upregulation of resuscitation promoting factors within Mtb and the escape of newly dividing microorganisms into alveoli and bronchi in the form of lipid pneumonia. These views need not be mutually exclusive. However, if minimal intermittent recrudescence were to take place within the alveolar space, this would contradict the very definition of latency, which implies that no access of Mtb to the airways exists during latency.

In vivo virulence of Mycobacterium tuberculosis depends on a single homologue of the LytR-CpsA-Psr proteins.

LytR-cpsA-Psr (LCP) domain containing proteins fulfil important functions in bacterial cell wall synthesis. In Mycobacterium tuberculosis complex (Mtbc) strains, the causative agents of tuberculosis (TB), the genes Rv3484 and Rv3267 encode for LCP proteins which are putatively involved in arabinogalactan transfer to peptidoglycan. To evaluate the significance of Rv3484 for Mtbc virulence, we generated a deletion mutant in the Mtbc strain H37Rv and studied its survival in mice upon aerosol infection. The deletion mutant failed to establish infection demonstrating that Rv3484 is essential for growth in mice. Following an initial phase of marginal replication in the lungs until day 21, the Rv3484 deletion mutant was almost eliminated by day 180 post-infectionem. Interestingly, the mutant also showed higher levels of resistance to meropenem/clavulanate and lysozyme, both targeting peptidoglycan structure. We conclude that Rv3484 is essential for Mtbc virulence in vivo where its loss of function cannot be compensated by Rv3267.

Solid lipid nanoparticles (SLN)--effects of lipid composition on in vitro degradation and in vivo toxicity.

Solid lipid nanoparticles (SLN) composed of two different lipid matrices were produced to assess their in vivo toxicity in mice. Matrix substances were (i) Compritol (glycerol behenate), a physiological lipid with GRAS status (generally recognized as safe [FDA]), and (ii) cetyl palmitate, a less physiological compound. Physicochemical data proved the suitability of SLN batches for intravenous administration. To assess the in vivo toxicity of produced batches, 400 microl SLN dispersion (lipid content 10% [m/m]) were administered to mice via a bolus injection for six times within a period of 20 days (high dose administration). Additionally, a multiple low dose administration was performed with Compritol-SLN as well (200 microl SLN dispersion, lipid content 2.5% [m/m]). Hepatic and splenic tissues were analysed histologically. In vivo results were dependent on the lipid matrix, as well as on the dose administered. For cetyl palmitate containing SLN no pathological results were obtained, while high dosed Compritol containing formulations led to accumulation of the lipid in liver and spleen and subsequently to pathological alterations. These alterations were found to be partially reversible within six weeks after completing intravenous administration. Liver architecture was nearly recovered. In contrast, low dosed Compritol SLN were well tolerated. Lipid accumulation and pathological alterations of high dosed Compritol SLN were attributed to the slow degradation of the Compritol matrix which could be shown by performing in vitro studies in human plasma.

Rearward Visibility Issues Related to Agricultural Tractors and Self-Propelled Machinery: Contributing Factors, Potential Solutions.

As the size, complexity, and speed of agricultural tractors and self-propelled machinery have increased, so have the visibility-related issues, placing significant importance on the visual skills, alertness, and reactive abilities of the operator. Rearward movement of large agricultural equipment has been identified in the literature as causing both fatalities and injuries to bystanders who were not visible to the operator and damage to both the machine and stationary objects. The addition of monitoring assistance, while not a new concept, has advanced significantly, offering agricultural machinery operators greater options for increasing their awareness of the area surrounding the machine. In this research, we attempt to (1) identify and describe the key contributors to agricultural machinery visibility issues, i.e., operator-related and machine-related factors, and (2) enumerate and evaluate the potential solutions being offered that address these factors. Enhanced operator safety and efficiency should result from a better understanding of the efforts to solve the visibility problems inherent in large tractors and self-propelled agricultural machinery.

Length and weight of very low birth weight infants in Germany at 2 years of age: does it matter at what age they start complementary food?

BACKGROUND/OBJECTIVES: We analysed at what age parents start complementary food in very low birth weight infants, determined risk factors for early introduction of complementary food (post-term age) and analysed whether the age at introduction of complementary food influences height or weight at 2 years of age. SUBJECTS/METHODS: Parents of premature infants born in 2009-2011 answered questionnaires regarding introduction of complementary food in the first year of life (N=2262) and were followed up at a post-term age of 2 years (N=981). Length and weight were compared with full-term infants from the KiGGs study. Logistic and linear regression analyses were conducted to study predictors for early introduction of complementary food and the influence of age at introduction of complementary food on later height and weight. RESULTS: Average age at introduction of complementary food was 3.5 months post-term age. The lower the gestational age at birth, the earlier (post-term age) vegetables and meat were introduced. Age at introduction of complementary food was influenced by intrauterine growth restriction, gestational age at birth, maternal education and a developmental delay perceived by the parents. Length and weight at a post-term age of 2 years was not negatively influenced by early introduction of complementary food. CONCLUSIONS: VLBW infants are introduced to complementary food on average before a post-term age of 4 months. There was no negative effect of early introduction of complementary food on height and weight at 2 years of age.

Insulin-mediated inhibition of tyrosinase activity and protein synthesis in melanoma cell cultures.

Insulin lowers basal levels of tyrosinase activity and inhibits the MSH-induced increase in tyrosinase in Cloudman S-91 mouse melanoma cell cultures. Insulin exerts its inhibitory effects in a typical dose-response manner, with maximal inhibition of enzyme activity occurring at 10-7 M. At maximal inhibition, tyrosinase activity is reduced to approximately 50% of the control levels. This inhibition precedes the observed inhibitory effect on cellular proliferation. Insulin not only lowers cell responsiveness to MSH, but also inhibits the tyrosinase stimulation produced by either theophylline or (Bu)2cAMP. Neither control levels nor MSH-mediated elevated cellular levels of cAMP were altered by insulin (10-7 M). These findings suggest that insulin exerts its inhibitory effects at a site distal to cAMP production. The inhibitory effect of insulin on tyrosinase activity could not be mimicked by either (Bu)2cGMP or 8-bromo-cGMP, suggesting that insulin does not exert its effects by altering cellular levels of this nucleotide. Insulin reduces the rate of incorporation of [3H]leucine into trichloroacetic acid-precipitable material by 50%, a finding which suggests that insulin may exert its inhibitory effects on tyrosinase activity and perhaps on cellular proliferation by causing a general reduction in protein synthetic rates.

Novel multi-probe RNase protection assay (RPA) sets for the detection of murine chemokine gene expression.

Chemokines play an essential role in immune and inflammatory reactions via the recruitment of leukocytes. Studying the role of chemokines in vivo is complicated by the redundancy of their action and by their promiscuous receptor usage. The simultaneous analysis of several chemokines is, therefore, advantageous in order to obtain a comprehensive view of chemokine participation in inflammatory and infectious processes. At present, no multi-probe detection systems are available for the analysis of recently described chemokines. In this study, new multi-probe RNase protection assay (RPA) template sets were developed for the analysis of murine chemokines. Chemokine cDNA fragments were generated by RT-PCR and individually subcloned into the plasmid pGEM-T providing a T7 promotor. In this way, two multi-probe template sets were constructed each containing six chemokine sequences (CXCL12/SDF-1, XCL1/lymphotactin, CCL20/exodus-1, CCL25/TECK, CX3CL1/fractalkine, CXCL1/KC, and CCL20/MDC, CXCL9/MIG, CCL9/10/MIP-1gamma, CXCL13/BLC, CCL12/MCP-5, CCL19/ELC, respectively) and templates for the two house-keeping genes L32 and GAPDH. The evaluation of these RPA template sets in various murine models demonstrated their suitability for the analysis of the above chemokines both under constitutive and infection-induced conditions. To reduce the personal radiation hazard, we found that 32P could be replaced by 33P without any loss of assay-sensitivity. These new RPA multi-probe sets provide valuable tools for the simultaneous quantitative determination of gene expression of multiple murine chemokines of both constitutive and inducible type.

Severe methanol poisoning. Application of a pharmacokinetic model for ethanol therapy and hemodialysis.

Two patients with extremely high blood methanol concentrations (260 and 282 mg/dl) were successfully treated using pharmacokinetic dosing of ethanol, hemodialysis and supportive measures. Both patients recovered completely without residual ophthalmologic deficits. Early hemodialysis and inhibition of methanol metabolism with effective ethanol concentrations were attributed to the patients' full recovery. Methanol elimination was enhanced by hemodialysis as evidenced by a decrease in half-life from eight to two and a half hours. Methanol dialysance was 98 ml/min. A dosage regimen for ethanol was devised, utilizing dose-dependent pharmacokinetic parameters and the ethanol dialysance (100 to 120 ml/min) from these two patients. An ethanol loading dose of 0.6 g/kg should be administered to an adult with an acute methanol ingestion. This dose will produce a blood ethanol concentration of approximately 100 mg/dl which can be maintained by an ethanol infusion of 66 mg/kg/hour for nondrinkers to 154 mg/kg/hour for chronic ethanol drinkers. Hemodialysis should be initiated if the blood methanol concentration is greater than 50 mg/dl. If hemodialysis is initiated, the ethanol infusion should be increased by 7.2 g/hour.