The cytokinesis-block micronucleus (CBMN) assay in human populations exposed to styrene: a systematic review and meta-analysis

Styrene is a building-block of several compounds used in a wide array of materials and products. The most important human exposure to this substance occurs in industrial settings, especially among reinforced-plastics industry workers. The effect of occupational exposure to styrene on cytogenetics biomarkers has been previously reviewed with positive association observed for chromosomal aberrations, and inconclusive data for the micronucleus assay. Some limitations were noted in those studies, including inadequate exposure assessment and poor epidemiological design. Furthermore, in earlier studies micronuclei frequency was measured with protocols not as reliable as cytokinesis-block micronucleus (CBMN) assay. Aim of the present systematic review and meta-analysis is to investigate genomic instability and DNA damage as measured by the CBMN assay in lymphocytes of subjects exposed to styrene. A total of 11 studies published between 2004 and 2012 were included in the meta-analysis encompassing 479 styrene-exposed workers and 510 controls. The quality of each study was estimated by a quality scoring system which ranked studies according to the consideration of major confounders, exposure characterization, and technical parameters. An overall increase of micronuclei frequencies was found in styrene-exposure workers when compared to referents (meta-MR 1.34; 95% CI 1.18–1.52), with significant increases achieved in six individual studies. The consistency of results in individual studies, the independence of this result from major confounding factors and from the quality of the study strengthens the reliability of risk estimates and supports the use of the CBMN assay in monitoring genetic risk in styrene workers.

Effects of hypoxic culture conditions on umbilical cord-derived human mesenchymal stem cells

Following cultivation of distinct mesenchymal stem cell (MSC) populations derived from human umbilical cord under hypoxic conditions (between 1.5% to 5% oxygen (O-2)) revealed a 2- to 3-fold reduced oxygen consumption rate as compared to the same cultures at normoxic oxygen levels (21% O-2). A simultaneous measurement of dissolved oxygen within the culture media from 4 different MSC donors ranged from 15 mu mol/L at 1.5% O-2 to 196 mu mol/L at normoxic 21% O-2. The proliferative capacity of the different hypoxic MSC populations was elevated as compared to the normoxic culture. This effect was paralleled by a significantly reduced cell damage or cell death under hypoxic conditions as evaluated by the cellular release of LDH whereby the measurement of caspase 3/7 activity revealed little if any differences in apoptotic cell death between the various cultures. The MSC culture under hypoxic conditions was associated with the induction of hypoxia-inducing factor-alpha (HIF-1 alpha) and an elevated expression of energy metabolism-associated genes including GLUT-1, LDH and PDK1. Concomitantly, a significantly enhanced glucose consumption and a corresponding lactate production could be observed in the hypoxic MSC cultures suggesting an altered metabolism of these human stem cells within the hypoxic environment.

'Explicit Learning: an Effort towards Human Scheduling Algorithms'

Abstract Scheduling problems are generally NP-hard combinatorial problems, and a lot of research has been done to solve these problems heuristically. However, most of the previous approaches are problem-specific and research into the development of a general scheduling algorithm is still in its infancy. Mimicking the natural evolutionary process of the survival of the fittest, Genetic Algorithms (GAs) have attracted much attention in solving difficult scheduling problems in recent years. Some obstacles exist when using GAs: there is no canonical mechanism to deal with constraints, which are commonly met in most real-world scheduling problems, and small changes to a solution are difficult. To overcome both difficulties, indirect approaches have been presented (in [1] and [2]) for nurse scheduling and driver scheduling, where GAs are used by mapping the solution space, and separate decoding routines then build solutions to the original problem. In our previous indirect GAs, learning is implicit and is restricted to the efficient adjustment of weights for a set of rules that are used to construct schedules. The major limitation of those approaches is that they learn in a non-human way: like most existing construction algorithms, once the best weight combination is found, the rules used in the construction process are fixed at each iteration. However, normally a long sequence of moves is needed to construct a schedule and using fixed rules at each move is thus unreasonable and not coherent with human learning processes. When a human scheduler is working, he normally builds a schedule step by step following a set of rules. After much practice, the scheduler gradually masters the knowledge of which solution parts go well with others. He can identify good parts and is aware of the solution quality even if the scheduling process is not completed yet, thus having the ability to finish a schedule by using flexible, rather than fixed, rules. In this research we intend to design more human-like scheduling algorithms, by using ideas derived from Bayesian Optimization Algorithms (BOA) and Learning Classifier Systems (LCS) to implement explicit learning from past solutions. BOA can be applied to learn to identify good partial solutions and to complete them by building a Bayesian network of the joint distribution of solutions [3]. A Bayesian network is a directed acyclic graph with each node corresponding to one variable, and each variable corresponding to individual rule by which a schedule will be constructed step by step. The conditional probabilities are computed according to an initial set of promising solutions. Subsequently, each new instance for each node is generated by using the corresponding conditional probabilities, until values for all nodes have been generated. Another set of rule strings will be generated in this way, some of which will replace previous strings based on fitness selection. If stopping conditions are not met, the Bayesian network is updated again using the current set of good rule strings. The algorithm thereby tries to explicitly identify and mix promising building blocks. It should be noted that for most scheduling problems the structure of the network model is known and all the variables are fully observed. In this case, the goal of learning is to find the rule values that maximize the likelihood of the training data. Thus learning can amount to 'counting' in the case of multinomial distributions. In the LCS approach, each rule has its strength showing its current usefulness in the system, and this strength is constantly assessed [4]. To implement sophisticated learning based on previous solutions, an improved LCS-based algorithm is designed, which consists of the following three steps. The initialization step is to assign each rule at each stage a constant initial strength. Then rules are selected by using the Roulette Wheel strategy. The next step is to reinforce the strengths of the rules used in the previous solution, keeping the strength of unused rules unchanged. The selection step is to select fitter rules for the next generation. It is envisaged that the LCS part of the algorithm will be used as a hill climber to the BOA algorithm. This is exciting and ambitious research, which might provide the stepping-stone for a new class of scheduling algorithms. Data sets from nurse scheduling and mall problems will be used as test-beds. It is envisaged that once the concept has been proven successful, it will be implemented into general scheduling algorithms. It is also hoped that this research will give some preliminary answers about how to include human-like learning into scheduling algorithms and may therefore be of interest to researchers and practitioners in areas of scheduling and evolutionary computation. References 1. Aickelin, U. and Dowsland, K. (2003) 'Indirect Genetic Algorithm for a Nurse Scheduling Problem', Computer & Operational Research (in print). 2. Li, J. and Kwan, R.S.K. (2003), 'Fuzzy Genetic Algorithm for Driver Scheduling', European Journal of Operational Research 147(2): 334-344. 3. Pelikan, M., Goldberg, D. and Cantu-Paz, E. (1999) 'BOA: The Bayesian Optimization Algorithm', IlliGAL Report No 99003, University of Illinois. 4. Wilson, S. (1994) 'ZCS: A Zeroth-level Classifier System', Evolutionary Computation 2(1), pp 1-18.

Impfung gegen humane Papillomaviren (HPV) zur Prävention HPV 16/18 induzierter Zervixkarzinome und derer Vorstufen

Einleitung: Notwendige Voraussetzung für die Entstehung von Zervixkarzinomen ist eine persistierende Infektion mit humanen Papillomaviren (HPV). Die HPV-Typen 16 und 18 verursachen mit etwa 70% den überwiegenden Teil der Zervixkarzinome. Seit 2006/2007 stehen zwei Impfstoffe gegen HPV 16 und 18 zur Verfügung. Fragestellung: Wie effektiv ist die HPV-Impfung hinsichtlich der Reduktion von Zervixkarzinomen bzw. ihren Vorstufen (CIN)? Stellt die HPV-Impfung eine kosteneffektive Ergänzung zur derzeitigen Screeningpraxis dar? Gibt es Unterschiede bezüglich der Kosten-Effektivität zwischen den beiden verfügbaren Impfstoffen? Sollte aus gesundheitsökonomischer Perspektive eine Empfehlung für den Einsatz der HPV-Impfung gegeben werden? Falls ja, welche Empfehlungen bezüglich der Ausgestaltung einer Impfstrategie lassen sich ableiten? Welche ethischen, sozialen und juristischen Implikationen sind zu berücksichtigen? Methoden: Basierend auf einer systematischen Literaturrecherche werden randomisierte kontrollierte Studien zur Wirksamkeit der HPV-Impfungen für die Prävention von Zervixkarzinomen bzw. deren Vorstufen, den zervikalen intraepithelialen Neoplasien, identifiziert. Gesundheitsökonomische Modellierungen werden zur Beantwortung der ökonomischen Fragestellungen herangezogen. Die Beurteilung der Qualität der medizinischen und ökonomischen Studien erfolgt mittels anerkannter Standards zur systematischen Bewertung wissenschaftlicher Studien Ergebnisse: Bei zu Studienbeginn HPV 16/18 negativen Frauen, die alle Impfdosen erhalten haben, liegt die Wirksamkeit der Impfungen gegen HPV 16/18-induzierten CIN 2 oder höher bei 98% bis 100%. Nebenwirkungen der Impfung sind vor allem mit der Injektion assoziierte Beschwerden (Rötungen, Schwellungen, Schmerzen). Es gibt keine signifikanten Unterschiede für schwerwiegende unerwünschte Ereignisse zwischen Impf- und Placebogruppe. Die Ergebnisse der Basisfallanalysen der gesundheitsökonomischen Modellierungen reichen bei ausschließlicher Berücksichtigung direkter Kostenkomponenten von ca. 3.000 Euro bis ca. 40.000 Euro pro QALY (QALY = Qualitätskorrigiertes Lebensjahr), bzw. von ca. 9.000 Euro bis ca. 65.000 Euro pro LYG (LYG = Gewonnenes Lebensjahr). Diskussion: Nach den Ergebnissen der eingeschlossenen Studien sind die verfügbaren HPV-Impfstoffe wirksam zur Prävention gegen durch HPV 16/18 verursachte prämaligne Läsionen der Zervix. Unklar ist derzeit noch die Dauer des Impfschutzes. Hinsichtlich der Nebenwirkungen ist die Impfung als sicher einzustufen. Allerdings ist die Fallzahl der Studien nicht ausreichend groß, um das Auftreten sehr seltener Nebenwirkungen zuverlässig zu bestimmen. Inwieweit die HPV-Impfung zur Reduktion der Inzidenz und Mortalität des Zervixkarzinoms in Deutschland führen wird, hängt nicht allein von der klinischen Wirksamkeit der Impfstoffe ab, sondern wird von einer Reihe weiterer Faktoren wie der Impfquote oder den Auswirkungen der Impfungen auf die Teilnahmerate an den bestehenden Screeningprogrammen determiniert. Infolge der Heterogenität der methodischen Rahmenbedingungen und Inputparameter variieren die Ergebnisse der gesundheitsökonomischen Modellierungen erheblich. Fast alle Modellanalysen lassen jedoch den Schluss zu, dass die Einführung einer Impfung mit lebenslanger Schutzdauer bei Fortführung der derzeitigen Screeningpraxis als kosteneffektiv zu bewerten ist. Eine Gegenüberstellung der beiden verschiedenen Impfstoffe ergab, dass die Modellierung der tetravalenten Impfung bei der Berücksichtigung von QALY als Ergebnisparameter in der Regel mit einem niedrigeren (besseren) Kosten-Effektivitäts-Verhältnis einhergeht als die Modellierung der bivalenten Impfung, da auch Genitalwarzen berücksichtigt werden. In Sensitivitätsanalysen stellten sich sowohl die Schutzdauer der Impfung als auch die Höhe der Diskontierungsrate als wesentliche Einflussparameter der Kosten-Effektivität heraus. Schlussfolgerung: Die Einführung der HPV-Impfung kann zu einem verringerten Auftreten von Zervixkarzinomen bei geimpften Frauen führen. Jedoch sollten die Impfprogramme von weiteren Evaluationen begleitet werden, um die langfristige Wirksamkeit und Sicherheit beurteilen sowie die Umsetzung der Impfprogramme optimieren zu können. Von zentraler Bedeutung sind hohe Teilnahmeraten sowohl an den Impfprogrammen als auch - auch bei geimpften Frauen - an den Früherkennungsuntersuchungen. Da die Kosten-Effektivität entscheidend von der Schutzdauer, die bislang ungewiss ist, beeinflusst wird, ist eine abschließende Beurteilung der Kosten-Effektivität der HPV-Impfung nicht möglich. Eine langfristige Schutzdauer ist eine bedeutende Vorraussetzung für die Kosten-Effektivität der Impfung. Der Abschluss einer Risk-Sharing-Vereinbarung zwischen Kostenträgern und Herstellerfirmen stellt eine Option dar, um die Auswirkungen der Unsicherheit der Schutzdauer auf die Kosten-Effektivität zu begrenzen.

Report of the Working Group on Introductions and Transfers of Marine Organisms (WGITMO). 16-18 March 2016 Olbia, Italy

The 42th meeting of the ICES Working Group on Introductions and Transfers of Marine Organisms (WGITMO) was held in Olbia, Italy, 16–18 March 2016, with Anna Occhipinti-Ambrogi as host and Henn Ojaveer as chairperson. Representatives from 19 countries participated in the meeting. Attendants were from Belgium, Canada, Dennark, Estonia, Finland, France, Germany, Ireland, Israel, Italy, Lithuania, Norway, Poland, Portugal, Russia, Spain, Sweden, United Kingdom and United States. Sweden contributed by cor-respondence. The objectives of the meeting were to update information and discuss several aspects related to the introductions and transfers of non-indigenous aquatic species. Data and information management were two of the discussion topics of the meeting, with special focus on the better exploitation of the ‘Information system on aquatic non-indigenous and cryptogenic species’ (AquaNIS). The WGITMO also dedicated time for addressing the MSFD D2 issues: indicator on new non-indigenous species introduced by human activities, and opportunities and problems related to cross-regional comparison of non-indigenous species indicators. Preparation of the manuscript of the alert report on sea squirt Didemnum vexillum, which is to be published in ICES CRR series, was discussed and the steps to be taken to finalise the report were agreed. As usual, adequate time was devoted to discuss national reports, to exchange of information on the management of NIS and to review ongoing and planned research activities. The approach taken during the meeting facilitated presentations and discussions on the issues of relevance related to the Terms of References as well as on a few generic and strategically-important issues of general relevance to bioinvasions. The meeting began with a full-day joint meeting with the Working Group on Ballast and Other Ship Vectors (WGBOSV), which provided an opportunity to discuss and address issues of common interest, such as shipping and biofouling as introduction vectors. The proposed ICES demonstration advice on ‘Risk management of non-indigenous species associated with shipping in the Arctic’ was discussed, and edits were suggested for both the orientation of the demonstration advice as well as for the exact questions to be asked. Both working groups agreed that the practice of conducting back-to-back meetings with one joint day is useful and will continue in 2017. All Terms of References to be addressed for 2016 were discussed. For some Terms of Ref-erence, more detailed presentations were given, and a short overview of the information and subsequent discussion is provided herein at the end of each section. This report is structured so that each Term of Reference is dealt with in sequential order. The main body of the report contains summaries of the presentations and discussions with the more detailed documents being contained in the Annexes. WGITMO progressed each of the Terms of Reference by either completing the task or clearly identifying and agreeing on the inter-sessional activities required to still finalise the work in 2016. From 2017, WGITMO will be shifted to multi-annual management.

Bonafide, type-specific human papillomavirus persistence among HIV-positive pregnant women: predictive value for cytological abnormalities, a longitudinal cohort study

This study investigated the rate of human papillomavirus (HPV) persistence, associated risk factors, and predictors of cytological alteration outcomes in a cohort of human immunodeficiency virus-infected pregnant women over an 18-month period. HPV was typed through L1 gene sequencing in cervical smears collected during gestation and at 12 months after delivery. Outcomes were defined as nonpersistence (clearance of the HPV in the 2nd sample), re-infection (detection of different types of HPV in the 2 samples), and type-specific HPV persistence (the same HPV type found in both samples). An unfavourable cytological outcome was considered when the second exam showed progression to squamous intraepithelial lesion or high squamous intraepithelial lesion. Ninety patients were studied. HPV DNA persistence occurred in 50% of the cases composed of type-specific persistence (30%) or re-infection (20%). A low CD4+ T-cell count at entry was a risk factor for type-specific, re-infection, or HPV DNA persistence. The odds ratio (OR) was almost three times higher in the type-specific group when compared with the re-infection group (OR = 2.8; 95% confidence interval: 0.43-22.79). Our findings show that bonafide (type-specific) HPV persistence is a stronger predictor for the development of cytological abnormalities, highlighting the need for HPV typing as opposed to HPV DNA testing in the clinical setting.

Anopheles darlingi polytene chromosomes: revised maps including newly described inversions and evidence for population structure in Manaus

Salivary gland polytene chromosomes of 4th instar Anopheles darlingi Root were examined from multiple locations in the Brazilian Amazon. Minor modifications were made to existing polytene photomaps. These included changes to the breakpoint positions of several previously described paracentric inversions and descriptions of four new paracentric inversions, two on the right arm of chromosome 3 and two on the left arm of chromosome 3 that were found in multiple locations. A total of 18 inversions on the X (n = 1) chromosome, chromosome 2 (n = 7) and 3 (n = 11) were scored for 83 individuals from Manaus, Macapá and Porto Velho municipalities. The frequency of 2Ra inversion karyotypes in Manaus shows significant deficiency of heterozygotes (p < 0.0009). No significant linkage disequilibrium was found between inversions on chromosome 2 and 3. We hypothesize that at least two sympatric subpopulations exist within the An. darlingi population at Manaus based on inversion frequencies.

How relevant is the origin of human capital for immigrant wages? Evidence from Spain

The objective of this article is to analyse the role played by the different components of human capital in the wage determination of immigrants in the Spanish labour market. Using microdata from the Encuesta Nacional de Inmigrantes, we find that human capital of immigrants acquired in Spain presents higher returns than human capital obtained in home countries, reflecting the limited international transferability of the latter. This result is reinforced by the strong heterogeneity observed in wage returns to different kinds of human capital across immigrants from different origins and, in particular, by the fact that immigrants with the higher returns to human capital acquired in their home countries are those coming from other developed countries and Latin America, the two regions more similar to Spain in terms of development and/or culture.

Antitumor effect and mechanism of action of polysaccharides extracted from Polygonum perfoliatum L whole plant in human lung carcinoma A549 cell line

Purpose: To optimize the extraction conditions of polysaccharides from Polygonum perfoliatum L. (PSDP) and to evaluate their anti-tumor activities on A549 cell line. Methods: Extraction of PSDP was optimized using Box-Behnken design (BBD). Three factors of response surface methodology (RSM) including extraction time, ratio of water to raw material and number of extractions were employed to optimize the yield of PSDP. The cytotoxic effect of PSDP on human lung carcinoma A549 cell line was evaluated in vivo, while its effects on expressions of caspase3, caspase-9, Bcl-2 and Bax were determined by western blot assay. Result: BBD was significant and applicable to PSDP extraction. Based on the contour plots, response surface plots and variance analysis, it predicted that the optimum conditions for PSDP extraction were: 1.58 h (extraction time); 30.18 mL/g (ratio of water to raw material); and 2.02 (number of extractions). PSDP had significant inhibitory effect on the growth of A549 cells in a concentration- and timedependent manner (p < 0.05). After treatment with PSDP, caspase-3, caspase-9 and Bax were significantly up-regulated (p < 0.05), whereas Bcl-2 was down-regulated, all concentration-dependently. Conclusion: RSM analysis is an appropriate method to optimize PSDP extraction. The results also indicate that PSDP has significant anti-tumor effect against A549 cells, most likely via inducing mitochondria-mediated apoptosis.

Cost-effectiveness of a bivalent human papillomavirus vaccination program in Japan

Background Human papillomavirus (HPV) vaccines and their widespread adoption have the potential to relieve a large part of the burden of cervical cancer morbidity and mortality, particularly in countries that have low screening rates or, like Japan, lack a cohesive universal screening program. An economic evaluation was conducted to assess the cost-effectiveness of introducing a bivalent HPV vaccination program in Japan from a healthcare perspective. METHODS: A Markov model of the natural history of HPV infection that incorporates both vaccination and screening was developed for Japan. The modelled intervention, a bivalent HPV vaccine with a 100% lifetime vaccine efficacy and 80% vaccine coverage, given to a cohort of 12-year-old Japanese girls in conjunction with the current screening program, was compared with screening alone in terms of costs and effectiveness. A discount rate of 5% was applied to both costs and utilities where relevant. RESULTS: Vaccination alongside screening compared with screening alone is associated with an incremental cost-effectiveness ratio (ICER) of US$20315 per quality-adjusted-life-year gained if 80% coverage is assumed. The ICER at 5% coverage with the vaccine plus screening, compared with screening alone, is US$1158. CONCLUSION: The cost-effectiveness results suggest that the addition of a HPV vaccination program to Japan's cervical cancer screening program is highly likely to prove a cost-effective way to reduce the burden of cervical cancer, precancerous lesions and HPV16/18-related diseases.

Single-nucleotide polymorphism in two representative multidrug-resistant Mycobacterium bovis isolates collected from patients in a Spanish hospital harboring a human infection outbreak

Mycobacterium bovis is the etiological agent of tuberculosis in domestic and wild animals. Its involvement as a human pathogen has been highlighted again with the recent descriptions of transmission through dairy products (18), reactivation or primary infection in human immunodeficiency virus-infected patients (5), and association with meat industry workers, animal keepers, or hunters (3). Strains resistant to antituberculous drugs (M. bovis is naturally resistant to pyrazinamide) pose an additional risk (2). Several studies have demonstrated that mutations in target genes are associated with resistance to antituberculous drugs (4, 7, 10, 11, 16). However, most of them have been developed in Mycobacterium tuberculosis strains and limited data are available regarding M. bovis isolates. The aim of this study was to characterize by sequencing the main genes involved in antibiotic resistance in two multidrug-resistant (MDR) M. bovis isolates in a human outbreak detected in a hospital in Madrid that subsequently spread to several countries (5, 6, 15). The isolates were resistant to 11 drugs, but only their rpoB and katG genes have been analyzed so far (1, 14). We studied the first (93/R1) and last (95/R4) M. bovis isolates of this nosocomial outbreak, characterized by spoligotyping as SB0426 (hexacode 63-5F-5E-7F-FF-60 in the database at www.mbovis.org) (1, 13). Several genes involved in resistance to isoniazid (katG, ahpC, inhA, and the oxyR-ahpC intergenic region), rifampin (rpoB), streptomycin (rrs, rpsL), ethambutol (embB), and quinolones (gyrA) were studied. These genes, or fragments of genes, were amplified and sequenced as previously described (12). The sequence analysis revealed polymorphisms in five (ahpC, rpoB, rpsL, embB, and gyrA) out of nine analyzed genes (Table 1). Nucleotide substitutions in four genes cause a change in the encoded amino acid. Two additional synonymous mutations in ahpC and rpsL differentiated the first and last isolates from the outbreak.

Microglia as therapeutic targets in retinal degeneration: role of translocator protein (18 κDa) (TSPO) and minocycline.

Microglia are the resident immune cells of the central nervous system (CNS) and play an important role in innate immune defense as well as tissue homeostasis. Chronic microglial reactivity, microgliosis, is a general hallmark of inflammatory and degenerative diseases that affect the CNS, including the retina. There is increasing evidence that chronic microgliosis is more than just a bystander effect, but rather actively contributes to progression of degeneration through processes such as toxic nitric oxide (NO) production and even phagocytosis of stressed but viable photoreceptors. Therefore immunmodulation of microglia presents a possible therapeutic strategy for retinal degenerations. Notably, the expression of the mitochondrial translocator protein 18 (κDa) (TSPO) is highly elevated in reactive microglia as seen in several neuroinflammatory diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Therefore it is used as a gliosis biomarker in the brain. Moreover TSPO ligands show potent effects in resolving neuroinflammatory brain disorders. However, TSPO expression in the eye had not been investigated before. Further, it was unknown whether TSPO ligands’ potent immunomodulatory effects could be used to treat retinal degenerations. To fill this gap, the study aimed to analyze whether TSPO is also a potential biomarker for degenerative processes in the retina. Moreover the thesis attempted to determine whether a specific TSPO ligand, XBD173, might modulate microglial reactivity and is a potent therapeutic, to treat retinal degenerative diseases. The findings revealed that TSPO is strongly upregulated in microglial cells of retinoschisin-deficient (RS1-/y) mice, a model of inherited retinal degeneration and in a murine light damage model. A co-localization of TSPO and microglia was furthermore detectable in human retinal sections, indicating a potential role for TSPO as a biomarker for retinal degenerations. In vitro assays showed that the TSPO ligand XBD173 effectively inhibited features of microglial activation such as morphological transformation into reactive phagocytes and enhanced expression of pro-inflammatory cytokines. XBD173 also reduced microglial migration and proliferation and reduced their neurotoxic potential on photoreceptor cells. In two independent mouse models of light-induced retinal degeneration, the treatment with XBD173 reduced accumulation of amoeboid, reactive microglia in the outer retina and attenuated degenerative processes, indicated by a nearly preserved photoreceptor layer. A further question addressed in this thesis was whether minocycline, an antibiotic with additional anti-inflammatory properties is able to reduce microglial neurotoxicity and to protect the retina from degeneration. Minocycline administration dampened microglial pro-inflammatory gene expression, NO production and neurotoxicity on photoreceptors. Interestingly, in addition to its immunomodulatory effect, minocycline also increased the viability of photoreceptors in a direct manner. In the light damage model, minocycline administration counter-acted microglial activation and blocked retinal degeneration. Taken together these results identified TSPO as a biomarker for microglial reactivity and as therapeutic target in the retina. Targeting TSPO with XBD173 was able to reverse microglial reactivity and could prevent degenerative processes in the retina. In addition, the study showed that the antibiotic minocycline effectively counter-regulates microgliosis and light-induced retinal degeneration. Considering that microgliosis is a major contributing factor for retinal degenerative disorders, this thesis supports the concept of a microglia-directed therapy to treat retinal degeneration.

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.

Discharge patterns of human tensor palatini motor units during sleep onset

Study Objectives: Upper airway muscles such as genioglossus (GG) and tensor palatini (TP) reduce activity at sleep onset. In GG reduced muscle activity is primarily due to inspiratory modulated motor units becoming silent, suggesting reduced respiratory pattern generator (RPG) output. However, unlike GG, TP shows minimal respiratory modulation and presumably has few inspiratory modulated motor units and minimal input from the RPG. Thus, we investigated the mechanism by which TP reduces activity at sleep onset.

Design: The activity of TP motor units were studied during relaxed wakefulness and over the transition from wakefulness to sleep.

Setting: Sleep laboratory.

Participants: Nine young (21.4 ± 3.4 years) males were studied on a total of 11 nights.

Intervention: Sleep onset.

Measurements and Results: Two TP EMGs (thin, hooked wire electrodes), and sleep and respiratory measures were recorded. One hundred twenty-one sleep onsets were identified (13.4 ± 7.2/subject), resulting in 128 motor units (14.3 ± 13.0/subject); 29% of units were tonic, 43% inspiratory modulated (inspiratory phasic 18%, inspiratory tonic 25%), and 28% expiratory modulated (expiratory phasic 21%, expiratory tonic 7%). There was a reduction in both expiratory and inspiratory modulated units, but not tonic units, at sleep onset. Reduced TP activity was almost entirely due to de-recruitment.

Conclusions: TP showed a similar distribution of motor units as other airway muscles. However, a greater proportion of expiratory modulated motor units were active in TP and these expiratory units, along with inspiratory units, tended to become silent over sleep onset. The data suggest that both expiratory and inspiratory drive components from the RPG are reduced at sleep onset in TP.

Report on the Iowa Department of Human Services for the year ended June 30, 2015

Report on the Iowa Department of Human Services for the year ended June 30, 2015