Mutations, Clinical Findings and Survival Estimates in South American Patients with X-Linked Adrenoleukodystrophy

In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. Methods: X-ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. Results: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p. Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. Conclusions: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

Omega-3 improves glucose tolerance but increases lipid peroxidation and DNA damage in hepatocytes of fructose-fed rats

The high consumption of fructose is linked to the increase in various characteristics of the metabolic syndrome. Fish oil is beneficial for the treatment of these comorbidities, such as insulin resistance, dyslipidemia, and hepatic steatosis. The objective of this study was to evaluate the consequences of the administration of fish oil concomitant to fructose ingestion during the experiment (45 days) and during the final 15 days in high-fructose-fed rats. Male Wistar rats were divided into 5 groups: control; those receiving 10% fish oil (FO); those receiving 60% fructose (Fr); those receiving 60% fructose and 10% fish oil for 45 days (FrFO); and those receiving fructose plus soybean oil for 30 days and fish oil for the final 15 days of the study (FrFO15). There was an increase in triacylglycerol, serum total cholesterol, and hepatic volume in the Fr group. The FO and FrFO groups experienced an increase in lipid peroxidation and a decrease in serum reduced glutathione. The FrFO group suffered greater hepatic injury, with increased alanine aminotransferase levels and DNA damage. Marked n-3 incorporation occurred in the groups receiving fish oil, favoring a better response to the oral glucose tolerance test. Fructose induced comorbidities of the metabolic syndrome, and the use of fish oil promoted a better glucose tolerance, although it was accompanied by more hepatocyte damage.

Flexible and conservative features of social systems in tufted capuchin monkeys: comparing the socioecology of Sapajus libidinosus and Sapajus nigritus

Socioecological models assume that primates adapt their social behavior to ecological conditions, and predict that food availability and distribution, predation risk and risk of infanticide by males affect patterns of social organization, social structure and mating system of primates. However, adaptability and variation of social behavior may be constrained by conservative adaptations and by phylogenetic inertia. The comparative study of closely related species can help to identify the relative contribution of ecological and of genetic determinants to primate social systems. We compared ecological features and social behavior of two species of the genus Sapajus, S. nigritus in Carlos Botelho State Park, an area of Atlantic Forest in Sao Paulo state, and S. libidinosus in Fazenda Boa Vista, a semi-arid habitat in Piaui state, Brazil. S. libidinosus perceived higher predation risk and fed on clumped, high quality, and usurpable resources (fruits) all year round, whereas S. nigritus perceived lower predation risk and relied on evenly distributed, low-quality food sources (leaves) during periods of fruit shortage. As predicted by socioecology models, S. libidinosus females were philopatric and established linear and stable dominance hierarchies, coalitions, and grooming relationships. S. nigritus females competed less often, and could transfer between groups, which might explain the lack of coalitions and grooming bonds among them. Both populations presented similar group size and composition and the same polygynous mating system. The species differed from each other in accordance with differences in the characteristics of their main food sources, as predicted by socioecological models, suggesting that phylogenetic inertia does not constrain social relationships established among female Sapajus. The similarity in mating systems indicates that this element of the social system is not affected by ecological variables and thus, is a more conservative behavioral feature of the genus Sapajus. Am. J. Primatol. 74:315331, 2012. (c) 2011 Wiley Periodicals, Inc.

Relationship between body size and flying-related structures in Neotropical social wasps (Polistinae, Vespidae, Hymenoptera)

Body size influences wing shape and associated muscles in flying animals which is a conspicuous phenomenon in insects, given their wide range in body size. Despite the significance of this, to date, no detailed study has been conducted across a group of species with similar biology allowing a look at specific relationship between body size and flying structures. Neotropical social vespids are a model group to study this problem as they are strong predators that rely heavily on flight while exhibiting a wide range in body size. In this paper we describe the variation in both wing shape, as wing planform, and mesosoma muscle size along the body size gradient of the Neotropical social wasps and discuss the potential factors affecting these changes. Analyses of 56 species were conducted using geometric morphometrics for the wings and lineal morphometrics for the body; independent contrast method regressions were used to correct for the phylogenetic effect. Smaller vespid species exhibit rounded wings, veins that are more concentrated in the proximal region, larger stigmata and the mesosoma is proportionally larger than in larger species. Meanwhile, larger species have more elongated wings, more distally extended venation, smaller stigmata and a proportionally smaller mesosoma. The differences in wing shape and other traits could be related to differences in flight demands caused by smaller and larger body sizes. Species around the extremes of body size distribution may invest more in flight muscle mass than species of intermediate sizes.

Can climate shape flight activity patterns of Plebeia remota (Hymenoptera, Apidae)?

Flight activity of foragers of four colonies of Plebeia remota (Holmberg, 1903) was registered from December 1998 to December 1999, using an automated system (photocells and PLC system). The colonies originated from two different regions: Cunha, state of Sao Paulo, and Prudentopolis, state of Parana, Brazil. Flight activity was influenced by different climatic factors in each season. In the summer, the intensity of the correlations between flight activity and climatic factors was smaller than in the other seasons. During the autumn and winter, solar radiation was the factor that most influenced flight activity, while in the spring, this activity was influenced mainly by temperature. Except in the summer, the various climatic factors similarly influenced flight activity of all of the colonies. Flight activity was not affected by geographic origin of the colonies. Information concerning seasonal differences in flight activity of P. remota will be useful for prediction of geographic distribution scenarios under climatic changes.

Can climate shape flight activity patterns of Plebeia remota Hymenoptera, Apidae)?

Flight activity of foragers of four colonies of Plebeia remota (Holmberg, 1903) was registered from December 1998 to December 1999, using an automated system (photocells and PLC system). The colonies originated from two different regions: Cunha, state of São Paulo, and Prudentópolis, state of Paraná, Brazil. Flight activity was influenced by different climatic factors in each season. In the summer, the intensity of the correlations between flight activity and climatic factors was smaller than in the other seasons. During the autumn and winter, solar radiation was the factor that most influenced flight activity, while in the spring, this activity was influenced mainly by temperature. Except in the summer, the various climatic factors similarly influenced flight activity of all of the colonies. Flight activity was not affected by geographic origin of the colonies. Information concerning seasonal differences in flight activity of P. remota will be useful for prediction of geographic distribution scenarios under climatic changes.

Contributions from the systematic review of economic evaluations: the case of childhood hepatitis A vaccination in Brazil

The aim of this study was to present the contributions of the systematic review of economic evaluations to the development of a national study on childhood hepatitis A vaccination. A literature review was performed in EMBASE, MEDLINE, WOPEC, HealthSTAR, SciELO and LILACS from 1995 to 2010. Most of the studies (8 of 10) showed favorable cost-effectiveness results. Sensitivity analysis indicated that the most important parameters for the results were cost of the vaccine, hepatitis A incidence, and medical costs of the disease. Variability was observed in methodological characteristics and estimates of key variables among the 10 studies reviewed. It is not possible to generalize results or transfer epidemiological estimates of resource utilization and costs associated with hepatitis A to the local context. Systematic review of economic evaluation studies of hepatitis A vaccine demonstrated the need for a national analysis and provided input for the development of a new decision-making model for Brazil.

Genomic and proteomic approaches in pig meat quality research field

Pig meat and carcass quality is a complex concept determined by environmental and genetic factors concurring to the phenotypic variation in qualitative characteristics of meat (fat content, tenderness, juiciness, flavor,etc). This thesis shows the results of different investigations to study and to analyze pig meat and carcass quality focusing mainly on genomic; moreover proteomic approach has been also used. The aim was to analyze data from association studies between genes considered as candidate and meat and carcass quality in different pig breeds. The approach was used to detect new SNP in genes functionally associated to the studied traits and to confirm as candidate other genes already known. Five polymorphisms (one new SNP in Calponin 1 gene and four additional polymorphism already known in other genes) were considered on chromosome 2 (SSC2). Calponin 1 (CNN1) was associated to the studied traits and furthermore the results reported confirmed the data already known for Lactate dehydrogenase A (LDHA), Low density lipoprotein receptor (LDLR), Myogenic differentiation 1 (MYOD1) e Ubiquitin-like 5 (UBL5), in Italian Large White pigs. Using an in silico search it was possible to detect on SSC2 a new SNP of Deoxyhypusine synthase (DHPS) gene partially overlapping with WD repeat domain 83 (WDR83) gene and significant for the meat pH variation in Italian Large White (ILW) pigs. Perilipin 1 (PLIN1) mapping on chromosome 7 and Perilipin 2 (PLIN2) mapping on chromosome 1 were studied and the results obtained in Duroc breed have shown significant associations with carcass traits. Moreover a study of protein composition of porcine LD muscle, indicated an effect of temperature treatment of carcass, on proteins of the sarcoplasmic fraction and in particular on PGM1 phosphorylation. Future studies on pig meat quality should be based on the integration of different experimental approaches (genomics, proteomics, transcriptomics, etc).

From defined polymer architectures to structure-property relationships in vivo

Makromolekulare Wirkstoffträgersysteme sind von starkem Interesse bezüglich der klinischen Anwendung chemotherapeutischer Agenzien. Um ihr klinisches Potential zu untersuchen ist es von besonderer Bedeutung das pharmakokinetische Profil in vivo zu bestimmen. Jede Veränderung der Polymerstruktur beeinflusst die Körperverteilung des entsprechenden Makromoleküls. Aufgrund dessen benötigt man detailliertes Wissen über Struktur-Eigenschaftsbeziehungen im lebenden Organismus, um das Nanocarrier System für zukünftige Anwendungen einzustellen. In dieser Beziehung stellt das präklinische Screening mittels radioaktiver Markierung und Positronen-Emissions-Tomographie eine nützliche Methode für schnelle sowie quantitative Beobachtung von Wirkstoffträgerkandidaten dar. Insbesondere poly(HPMA) und PEG sind im Arbeitsgebiet Polymer-basierter Therapeutika stark verbreitet und von ihnen abgeleitete Strukturen könnten neue Generationen in diesem Forschungsbereich bieten.rnDie vorliegende Arbeit beschreibt die erfolgreiche Synthese verschiedener HPMA und PEG basierter Polymer-Architekturen – Homopolymere, Statistische und Block copolymere – die mittels RAFT und Reaktivesterchemie durchgeführt wurde. Des Weiteren wurden die genannten Polymere mit Fluor-18 und Iod-131 radioaktiv markiert und mit Hilfe von microPET und ex vivo Biodistributionsstudien in tumortragenden Ratten biologisch evaluiert. Die Variation in Polymer-Architektur und darauffolgende Analyse in vivo resultierte in wichtige Schlussfolgerungen. Das hydrophile / lipophile Gleichgewicht hatte einen bedeutenden Einfluss auf das pharmakokinetische Profil, mit besten in vivo Eigenschaften (geringe Aufnahme in Leber und Milz sowie verlängerte Blutzirkulationszeit) für statistische HPMA-LMA copolymere mit steigendem hydrophoben Anteil. Außerdem zeigten Langzeitstudien mit Iod-131 eine verstärkte Retention von hochmolekularen, HPMA basierten statistischen Copolymeren im Tumorgewebe. Diese Beobachtung bestätigte den bekannten EPR-Effekt. Hinzukommend stellen Überstrukturbildung und damit Polymergröße Schlüsselfaktoren für effizientes Tumor-Targeting dar, da Polymerstrukturen über 200 nm in Durchmesser schnell vom MPS erkannt und vom Blutkreislauf eliminiert werden. Aufgrund dessen wurden die hier synthetisierten HPMA Block copolymere mit PEG Seitengruppen chemisch modifiziert, um eine Verminderung in Größe sowie eine Reduktion in Blutausscheidung zu induzieren. Dieser Ansatz führte zu einer erhöhten Tumoranreicherung im Walker 256 Karzinom Modell. Generell wird die Körperverteilung von HPMA und PEG basierten Polymeren stark durch die Polymer-Architektur sowie das Molekulargewicht beeinflusst. Außerdem hängt ihre Effizienz hinsichtlich Tumorbehandlung deutlich von den individuellen Charakteristika des einzelnen Tumors ab. Aufgrund dieser Beobachtungen betont die hier vorgestellte Dissertation die Notwendigkeit einer detaillierten Polymer-Charakterisierung, kombiniert mit präklinischem Screening, um polymere Wirkstoffträgersysteme für individualisierte Patienten-Therapie in der Zukunft maßzuschneidern.rn

Rarely selected distractors in high stakes medical multiple-choice examinations and their recognition by item authors: A simulation and survey

Background Many medical exams use 5 options for multiple choice questions (MCQs), although the literature suggests that 3 options are optimal. Previous studies on this topic have often been based on non-medical examinations, so we sought to analyse rarely selected, 'non-functional' distractors (NF-D) in high stakes medical examinations, and their detection by item authors as well as psychometric changes resulting from a reduction in the number of options. Methods Based on Swiss Federal MCQ examinations from 2005-2007, the frequency of NF-D (selected by <1% or <5% of the candidates) was calculated. Distractors that were chosen the least or second least were identified and candidates who chose them were allocated to the remaining options using two extreme assumptions about their hypothetical behaviour: In case rarely selected distractors were eliminated, candidates could randomly choose another option - or purposively choose the correct answer, from which they had originally been distracted. In a second step, 37 experts were asked to mark the least plausible options. The consequences of a reduction from 4 to 3 or 2 distractors - based on item statistics or on the experts' ratings - with respect to difficulty, discrimination and reliability were modelled. Results About 70% of the 5-option-items had at least 1 NF-D selected by <1% of the candidates (97% for NF-Ds selected by <5%). Only a reduction to 2 distractors and assuming that candidates would switch to the correct answer in the absence of a 'non-functional' distractor led to relevant differences in reliability and difficulty (and to a lesser degree discrimination). The experts' ratings resulted in slightly greater changes compared to the statistical approach. Conclusions Based on item statistics and/or an expert panel's recommendation, the choice of a varying number of 3-4 (or partly 2) plausible distractors could be performed without marked deteriorations in psychometric characteristics.

Comparison of the binding and internalization properties of 12 DOTA-coupled and ¹¹¹In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607

Specific overexpression of cholecystokinin 2 (CCK2)/gastrin receptors has been demonstrated in several tumours of neuroendocrine origin. In some of these cancer types, such as medullary thyroid cancer (MTC), a sensitive diagnostic modality is still unavailable and therapeutic options for inoperable lesions are needed. Peptide receptor radionuclide therapy (PRRT) may be a viable therapeutic strategy in the management of these patients. Several CCK2R-targeted radiopharmaceuticals have been described in recent years. As part of the European Union COST Action BM0607 we studied the in vitro and in vivo characteristics of 12 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R binding peptides. In the present study, we analysed binding and internalization characteristics. Stability, biodistribution and imaging studies have been performed in parallel by other centres involved in the project.

In vivo evaluation in cynomolgus monkey brain and metabolism of [¹⁸F]fluorodeprenyl: a new MAO-B pet radioligand

In this study, we evaluated the in vivo characteristics of a new monoamine oxidase type B (MAO-B) radioligand, [¹⁸F]fluorodeprenyl, by positron emission tomography (PET) in two cynomolgus monkeys. The brain uptake of [¹⁸F]fluorodeprenyl was more than 7% (600% SUV) of the total injected radioactivity and similar to that of [¹¹C]deprenyl, an established MAO-B radioligand. The highest uptake was observed in the striatum, one of the MAO-B-rich regions, with a peak at approximately 2-3 min after injection, followed by lower uptake in the thalamus and the cortex and lowest uptake in the cerebellum. Brain uptake of [¹⁸F]fluorodeprenyl was largely inhibited by preadministration of the MAO-B inhibitor, L-deprenyl, whereas clorgyline, a MAO Type A blocker, had no significant inhibitory effect, thus demonstrating selectivity for MAO-B. [¹⁸F]Fluorodeprenyl showed relatively slow metabolism with the presence of two radiometabolite peaks with similar retention time as the labeled metabolites of [¹¹C]deprenyl. These results suggest that [¹⁸F]fluorodeprenyl is a potential PET radioligand for visualization of MAO-B activity.

[Bullet and shrapnel injuries in the face and neck regions. Current aspects of wound ballistics]

A basic understanding of the ballistic behaviour of projectiles or fragments after entering the human body is essential for the head and neck surgeon in the military environment in order to anticipate the diagnostic and therapeutic consequences of this type of injury. Although a large number of factors influence the missile in flight and after penetration of the body, the most important factor is the amount of energy transmitted to the tissue. Long guns (rifles or shotguns) have a much higher muzzle energy compared to handguns, explaining why the remote effects beyond the bullet track play a major role. While most full metal jacket bullets release their energy after 12-20 cm (depending on the calibre), soft point bullets release their energy immediately after entry into the human body. This results in a major difference in extremity wounds, but not so much in injuries with long bullet paths (e.g. diagonal shots). Shrapnel wounds are usually produced with similarly high kinetic energy to those caused by hand- and long guns. However, fragments tend to dissipate the entire amount of energy within the body, which increases the degree of tissue disruption. Of all relevant injuries in the head and neck region, soft tissue injuries make up the largest proportion (60%), while injuries to the face are seen three times more often than injuries to the neck. Concomitant intracranial or spinal injury is seen in 30% of cases. Due to high levels of wound contamination, the infection rate is approximately 15%, often associated with a complicated and/or multiresistant spectrum of germs.

Altered Behavior in Bats Affected by White-Nose Syndrome

WNS-affected bats did so over similar time frames as WNSunaffected bats. The behaviors of bats with WNS did not change as drastically as expected. Thereseems to be little to no effect on their ability to fly/forage until much later stages of the disease when they are likely near death. WNS-affected bats are grooming more which could be altering the way they use energy reserves during hibernation possibly leading tostarvation and eventually death. The decreased likelihood of arousals in response to external cues may be the result of spending more energy during previous and increasingly frequent arousals. While it is clear that WNS does result in changes in behavior whether these changes are directly in response to fungal skin infection or to some other component of the syndrome such as decreased energy availability or loss of homeostasis is unknown. bat behavior, white-nose syndrome, behavior, video surveillance, arousal patterns White-Nose Syndrome (WNS) is a disease of hibernating bats caused by the fungal pathogen Geomyces destructans. The fungus, which was first noted in 2006, invades bats wings and other exposed membranes, eventually resulting in death. Researchers have yet to understand many aspects of this disease, including basic etiology and epidemiology. There is also a lack of information on how fungal infection may change the behavior of healthy bats during hibernation or how changes in behavior may influence disease progression. Based upon the physiological changes that are known to occur in affected bats, and upon anecdotal observations of aberrant behavior in these bats, I hypothesized that WNS would significantly change the behavior of the little brown myotis (Myotis lucifugus). My research examined the behavior of hibernating bats during arousals from torpor. I compared WNS-affected and unaffected bats, in the field and incaptivity, using motion-sensitive infrared cameras. Flight maneuverability and echolocation were also tested between WNS-affected and unaffected bats during arousalsfrom hibernation to detect changes in the bats' ability to perform basic locomotion or potentially catch insect prey. Lastly, hibernating bats were artificially disturbed and theirarousal patterns were monitored to examine changes in the response to external stimuli between WNS-affected and unaffected bats.Bats with WNS groomed for longer periods of time after arousing from torpor, both in the field and in captivity. They also engaged in longer periods of any sort of activity during these arousals. There were no changes in acoustical signaling during flight tests and changes in flight maneuverability were only found in bats were seen staging" near the entrance of the mine which is itself a unique behavior exhibited by affected bats. At this point these bats were likely near death and could barely fly at all. In response toexternal stimuli bats with WNS were less likely to arouse than unaffected bats. However when they did arouse WNS-affected bats did so over similar time frames as WNSunaffected bats. The behaviors of bats with WNS did not change as drastically as expected. Thereseems to be little to no effect on their ability to fly/forage until much later stages of the disease when they are likely near death. WNS-affected bats are grooming more which could be altering the way they use energy reserves during hibernation possibly leading tostarvation and eventually death. The decreased likelihood of arousals in response to external cues may be the result of spending more energy during previous and increasingly frequent arousals. While it is clear that WNS does result in changes in behavior whetherthese changes are directly in response to fungal skin infection or to some other component of the syndrome such as decreased energy availability or loss of homeostasis is unknown."

Regional Differences in Living Standards in Eastern European Countries - Changes During the Transition

This research aimed to discover how differences in living standards between regional units changed during the period of transformation from 1990 to 1995 in Poland, the Slovak Republic, the Czech Republic and Hungary. The standard of living was measured by the so-called Living Standard Index (LSI), a composite taxonomic measure. Fixed reference points make it possible to compare the standard of living in regional administrative units and to study its dynamics. The analysis was country-specific, since the lists of variable were not fully identical for all the countries studied. The main tools used were LSI variability measures (mainly variance and standard deviation). By identifying trend patterns in the characteristics of LSIs, it was possible to compare the different countries. It was found that * differences in living standards between regional units have been decreasing during the transformation in Poland and in the Czech Republic. In the latter this process is slow and smooth, while in Poland there was a relatively sharp decline which then stopped entirely in 1994 * the only country with increasing differences between regions is Hungary and these differences are growing at a constant rate * the lowest level of regional differences in the LSI was found in Poland, followed by the Slovak Republic and the Czech Republic * the regional differences in Hungary are almost twice as high as in the Czech Republic