Impact of selection for residual feed intake on production traits and behavior of mule ducks.
A divergent selection experiment of Muscovy sires based on the residual feed intake (RFI) of their male mule progeny was initiated in 2009. Using electronic feeders, the aim of this study was to establish whether 3 generations of selection for RFI had an impact on feeding behavior traits and general behavior, and to examine its effect on liver and meat quality. Eighty mule ducks, issued from 8 Muscovy drakes per line with extreme RFI, were tested in a pen equipped with 4 electronic feeders. Feeding behaviors were recorded from 3 to 7 wk after hatching under ad libitum feeding conditions. Then animals were prepared for overfeeding with a 3-week period of restricted feeding, and overfed during 12 d before slaughter. The RFI was significantly lower in the low RFI line than in the high RFI line (-5.4 g/d, P = 0.0005) and daily feed intake was reduced both over the entire test period (-5 g/d, P = 0.049) and on a weekly basis (P = 0.006). Weekly and total feed conversion ratios were also significantly lower (-0.08, P = 0.03 and -0.06, P = 0.01, respectively). Low RFI ducks had more frequent meals, spent as much time eating as high RFI ducks, and their feeding rate was lower when analyzed at the wk level only. Additionally no significant correlation between feed efficiency and feeding behavior traits was evidenced, indicating only limited relationships between RFI and feeding patterns. Some differences in behavioral responses to stressors (open field test combined with a test measuring the response to human presence) suggested that a lower RFI is associated with less fearfulness. Selection for RFI had no effect on liver weight and quality and a slightly deleterious impact on meat quality (decreased drip loss and L*). Finally, low RFI animals had higher body weights after restricted feeding from wk 10 to wk 12 and after overfeeding than high RFI ducks. This suggests that selection for reduced RFI until 7 wk of age increases the feed efficiency up to slaughter.


Public health information in crisis-affected populations: a review of methods and their use for advocacy and action.
Valid and timely information about various domains of public health underpins the effectiveness of humanitarian public health interventions in crises. However, obstacles including insecurity, insufficient resources and skills for data collection and analysis, and absence of validated methods combine to hamper the quantity and quality of public health information available to humanitarian responders. This paper, the second in a Series of four papers, reviews available methods to collect public health data pertaining to different domains of health and health services in crisis settings, including population size and composition, exposure to armed attacks, sexual and gender-based violence, food security and feeding practices, nutritional status, physical and mental health outcomes, public health service availability, coverage and effectiveness, and mortality. The paper also quantifies the availability of a minimal essential set of information in large armed conflict and natural disaster crises since 2010: we show that information was available and timely only in a small minority of cases. On the basis of this observation, we propose an agenda for methodological research and steps required to improve on the current use of available methods. This proposition includes setting up a dedicated interagency service for public health information and epidemiology in crises.


Cough: occupational and environmental considerations: ACCP evidence-based clinical practice guidelines.
This section of the guideline aims to review the role of occupational and environmental factors in causing and contributing to cough. It also aims to indicate when such causes should be considered in a clinical setting, and a general approach to assessment and management. A review was performed of published data between 1985 and 2004 using PubMed. The search terms used included "air pollution," "sick building syndrome," "occupational asthma," "occupational lung disease," "hypersensitivity pneumonitis" (HP), "cigarette smoke," and "asthma." Selected articles were chosen when meeting the objectives, but the extent of articles available and the limited space for this section does not permit a fully comprehensive review of all of these areas, for which the reader is referred to other sections of this clinical practice guideline, the published literature, textbooks of occupational lung disease, or more specific review articles. Almost any patient presenting with cough may have an occupational or environmental cause of or contribution to their cough. The importance of this is that recognition and intervention may result in full or partial improvement of the cough, may limit the need for medication/symptomatic treatment, and may improve the long-term prognosis. Nonoccupational environmental contributing factors for upper and lower airway causes of cough include indoor irritant and allergenic agents such as cigarette smoke, cooking fumes, animals, dust mites, fungi, and cockroaches. Causes of HP indoors include birds and fungal antigens. Outdoor pollutants and allergens also contribute to upper and lower airway causes of cough. Occupational exposures can cause hypersensitivity responses leading to rhinitis and upper airway cough syndrome, previously referred to as postnasal drip syndrome, as well as asthma, HP, chronic beryllium disease, and hard metal disease, as well as irritant or toxic responses. The diagnosis is only reached by initially considering possible occupational and environmental factors, and by obtaining an appropriate medical history to determine relevant exposures, followed by objective investigations. This may require referral to a center of expertise.


Subtraction-based approach for enhancing the depth sensitivity of time-resolved NIRS.
The aim of this study was to evaluate enhancing of the depth sensitivity of time-resolved near-infrared spectroscopy with a subtraction-based approach. Due to the complexity of light propagation in a heterogeneous media, and to prove the validity of the proposed method in a heterogeneous turbid media we conducted a broad analysis taking into account a number of parameters related to the method as well as various parameters of this media. The results of these experiments confirm that the depth sensitivity of the subtraction-based approach is better than classical approaches using continuous-wave or time-resolved methods. Furthermore, the results showed that the subtraction-based approach has a unique, selective sensitivity to a layer at a specific depth. In vivo application of the proposed method resulted in a greater magnitude of the hemodynamic changes during functional activation than with the standard approach.


Disseminated phaeohyphomycosis: review of an emerging mycosis.
Disseminated phaeohyphomycosis is an uncommon infection caused by dematiaceous fungi, although the number of case reports about this infection has been increasing in recent years. A total of 72 cases are reviewed. Scedosporium prolificans is by far the most common cause. The presence of melanin in their cell walls may be a virulence factor for these fungi. The primary risk factor is decreased host immunity, although cases in apparently immunocompetent patients have been reported. Eosinophilia was seen in 11% of cases. Endocarditis is mostly reported on bioprosthetic valves, particularly those of porcine origin. The outcome of antifungal therapy remains poor, with an overall mortality rate of 79%. Special precautions taken for immunocompromised patients may help prevent exposure to fungi during the patients' period of greatest risk. The development of newer antifungal agents and combination therapy may hold promise in improving the management of these devastating infections in the future.


Macrophages are required for adult salamander limb regeneration.
The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.


Do neuromuscular adaptations occur in endurance-trained boys and men?
Most research on the effects of endurance training has focused on endurance training's health-related benefits and metabolic effects in both children and adults. The purpose of this study was to examine the neuromuscular effects of endurance training and to investigate whether they differ in children (9.0-12.9 years) and adults (18.4-35.6 years). Maximal isometric torque, rate of torque development (RTD), rate of muscle activation (Q30), electromechanical delay (EMD), and time to peak torque and peak RTD were determined by isokinetic dynamometry and surface electromyography (EMG) in elbow and knee flexion and extension. The subjects were 12 endurance-trained and 16 untrained boys, and 15 endurance-trained and 20 untrained men. The adults displayed consistently higher peak torque, RTD, and Q30, in both absolute and normalized values, whereas the boys had longer EMD (64.7+/-17.1 vs. 56.6+/-15.4 ms) and time to peak RTD (98.5+/-32.1 vs. 80.4+/-15.0 ms for boys and men, respectively). Q30, normalized for peak EMG amplitude, was the only observed training effect (1.95+/-1.16 vs. 1.10+/-0.67 ms for trained and untrained men, respectively). This effect could not be shown in the boys. The findings show normalized muscle strength and rate of activation to be lower in children compared with adults, regardless of training status. Because the observed higher Q30 values were not matched by corresponding higher performance measures in the trained men, the functional and discriminatory significance of Q30 remains unclear. Endurance training does not appear to affect muscle strength or rate of force development in either men or boys.


A CD57+ CTL Degranulation Assay Effectively Identifies Familial Hemophagocytic Lymphohistiocytosis Type 3 Patients.
Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.


Gene duplication and multiplicity of collagenases in Clostridium histolyticum.
Clostridium histolyticum collagenase contains a number of different active components. Previously we have shown that colH encodes a 116-kDa collagenase (ColH) and a 98-kDa gelatinase. We purified a different 116-kDa collagenase (ColG) from the culture supernatant and sequenced its gene (colG). We also identified four other gelatinases (105, 82, 78, and 67 kDa) and determined their N-terminal amino acid sequences, all of which coincided with that of either ColG or ColH. Hybridization experiments showed that each gene is present in a single copy and each gene is transcribed into a single mRNA. These results suggest that all the gelatinases are produced from the respective full-length collagenase by the proteolytic removal of C-terminal fragments. The substrate specificities of the enzymes suggest that colG and colH encode class I and class II enzymes, respectively. Analysis of their DNA locations by pulsed-field gel electrophoresis and nucleotide sequencing of their surrounding regions revealed that the two genes are located in different sites on the chromosome. C. histolyticum colG is more similar to C. perfringens colA than to colH in terms of domain structure. Both colG and colA have a homologous gene, mscL, at their 3' ends. These results suggest that gene duplication and segment duplication have occurred in an ancestor cell common to C. histolyticum and C. perfringens and that further divergence of the parent gene produced colG and colA.


Genotype distribution of cervical human papillomavirus DNA in women with cervical lesions in Bioko, Equatorial Guinea.
The HVP vaccine is a useful tool for preventing cervical cancer. The purpose of this study is to determine the most frequent HPV genotypes in Equatorial Guinea in order to develop future vaccination strategies to apply in this country. A campaign against cervical cancer was carried out in the area on a total of 1,680 women. 26 of the women, following cytological screening, were treated surgically with a loop electrosurgical excision procedure (LEEP). Cases were studied histologically and were genotyped from paraffin blocks by applying a commercial kit that recognized 35 HPV types. Cytological diagnoses included 17 HSIL, 1 LSIL, 5 ASC-H and 3 AGUS. Histological diagnosis resulted in 3 cases of microinvasive squamous cell carcinoma stage IA of FIGO, 9 CIN-3, 8 CIN-2, 2 CIN-1, 3 flat condylomas and mild dysplasia of the endocervical epithelium. Fifteen of twenty-five cases genotyped were positive for HPV (60%). HPV 16 and 33 were identified in four cases each, HPV 58 in two other cases, and HPV 18, 31, 52, and 82 in one case, with one HPV 16 and 58 coinfection. The frequency of HPV types in the African area varies in comparison to other regions, particularly in Europe and USA. Vaccination against the five most common HPV types (16, 33, 58, 18, and 31) should be considered in the geographic region of West Africa and specifically in Equatorial Guinea.


Association of dietary factors with presence and severity of tinnitus in a middle-aged UK population.
The impact of dietary factors on tinnitus has received limited research attention, despite being a considerable concern among people with tinnitus and clinicians. The objective was to examine the link between dietary factors and presence and severity of tinnitus. This study used the UK Biobank resource, a large cross-sectional study of adults aged 40-69. 171,722 eligible participants were asked questions specific to tinnitus (defined as noises such as ringing or buzzing in the head or ears). Dietary factors included portions of fruit and vegetables per day, weekly fish consumption (oily and non-oily), bread type, cups of caffeinated coffee per day, and avoidance of dairy, eggs, wheat and sugar. We controlled for lifestyle, noise exposure, hearing, personality and comorbidity factors. Persistent tinnitus, defined as present at least a lot of the time, was elevated with increased: (i) fruit/vegetable intake (OR = 1.01 per portion/day), (ii) bread (wholemeal/wholegrain, OR = 1.07; other bread, 1.20) and (iii) dairy avoidance (OR = 1.27). Persistent tinnitus was reduced with: (i) fish consumption (non-oily, OR = 0.91; oily, 0.95), (ii) egg avoidance (OR = 0.87) and (iii) caffeinated coffee consumption (OR = 0.99 per cup/day). Reports of "bothersome" tinnitus (moderate-severe handicap) reduced with wholemeal/wholegrain bread intake (OR = 0.86) [corrected].Reports of less frequent transient tinnitus increased with dairy avoidance (OR = 1.18) and decreased with caffeinated coffee (OR = 0.98 per cup/day) and brown bread (OR = 0.94). This is the first population study to report the association between dietary factors and tinnitus. Although individually dietary associations are mostly modest, particular changes in diet, such as switching between foodstuffs, may result in stronger associations. These findings offer insights into possible dietary associations with tinnitus, and this may be useful when discussing management options in combination with other lifestyle changes and therapies.


Susceptibility to addictive behaviour in online and traditional poker playing environments.
With the growing number of virtual sites and easy access to them, as well as increasing popularity of the game, online poker could foster addiction. The aim of the current inquiry was to gauge susceptibility to behavioural addiction in online and traditional poker players. Ninety-six online poker players and 35 traditional players were tested on the basis of the "Components model" for addiction (Griffiths, 2005). Using a Likert scale, ratings on six components were examined: salience, conflict, mood modification, withdrawal symptoms, tolerance, and relapse. The traditional players scored higher than online players on measures of conflict, mood modification, and relapse. While none of the traditional players were at risk, the majority of them (94.7%) were symptomatic. Two online players were at risk, 67.7% symptomatic and 30.2% asymptomatic. No significant correlations have emerged between the amount and history of poker playing and the addiction scores. The current findings suggest that most traditional players are prone to behavioural addiction while the majority of the online players are also symptomatic.


Short term effects of air pollution on health: a European approach using epidemiologic time series data: the APHEA protocol.
Results from several studies over the past five years have shown that the current levels of pollutants in Europe and North America have adverse short term effects on health. The APHEA project aims to quantifying these in Europe, using standardised methodology. The project protocol and analytical methodology are presented here. Daily time series data were gathered for several air pollutants (sulphur dioxide; particulate matter, measured as total particles or as the particle fraction with an aerodynamic diameter smaller than a certain cut off, or as black smoke; nitrogen dioxide; and ozone) and health outcomes (the total and cause specific number of deaths and emergency hospital admissions). The data included fulfilled the quality criteria set by the APHEA protocol. Fifteen European cities from 10 different countries with a total population over 25 million. The APHEA collaborative group decided on a specific methodological procedure to control for confounding effects and evaluate the hypothesis. At the same time there was sufficient flexibility to allow local characteristics to be taken into account. The procedure included modelling of all potential confounding factors (that is, seasonal and long term patterns, meteorological factors, day of the week, holidays, and other unusual events), choosing the "best" air pollution models, and applying diagnostic tools to check the adequacy of the models. The final analysis used autoregressive Poisson models allowing for overdispersion. Effects were reported as relative risks contrasting defined increases in the corresponding pollutant levels. Each participating group applied the analyses to their own data. This methodology enabled results from many different European settings to be considered collectively. It represented the best available compromise between feasibility, comparability, and local adaptibility when using aggregated time series data not originally collected for the purpose of epidemiological studies.


Mapping of tyrosine hydroxylase in the diencephalon of alpaca (Lama pacos) and co-distribution with somatostatin-28 (1-12).
Based on previous work describing the distribution of somatostatin-28 (1-12) in the male alpaca (Lama pacos) diencephalon, and owing to the well known interactions between this peptide and the catecholaminergic system, the aims of this work are (1) to describe the distribution of putative catecholaminergic cell groups in the alpaca diencephalon and (2) to study the possible morphological basis of the interactions between these substances in the diencephalon of the alpaca by using double immunohistochemistry methods. Thus, the distribution of catecholaminergic cell groups in the alpaca diencephalon agrees with that previously described in the diencephalon of other mammalian species of the same order: the A11, A12, A13, A14 and A15d cell groups have been identified; however, we have observed an additional hitherto undescribed cell group containing tyrosine hydroxylase in the medial habenula. In addition, double-labelling procedures did not reveal neurons containing tyrosine hydroxylase and somatostatin, suggesting that the hypothalamic interactions between catecholamines and somatostatin at intra-cellular level must be carried out by a somatostatin molecule other than fragment (1-12). Otherwise, the overlapping distribution patterns of these substances would suggest some interconnections between groups of chemospecific neurons. These results could be the starting point for future studies on hypothalamic functions in alpacas, for example those concerning reproductive control, since other physiological studies have suggested that this species could have different regulatory mechanisms from other mammalian species. Our results support the Manger hypothesis that the same nuclear complement of neural systems exists in the brain of species of the same order.


Substance flow analysis: a case study of fluoride exposure through food and beverages in young children living in Ethiopia.
Dental and skeletal fluorosis is endemic in the Ethiopian Rift Valley. Children are especially vulnerable to excessive fluoride intake because their permanent teeth are still being formed. Strategies to reduce the total fluoride intake by children are thus warranted. By combining the results of field studies in Ethiopia, the relevant pathways for fluoride intake have been identified in 28 children 2-5 years of age living in two villages on the Wonji Shoa Sugar Estate in the Ethiopian Rift Valley. The focus of the present study was to simulate the fluoride intake of the children using the methods of material flow analysis (MFA) and substance flow analysis. With a model based on MFA, we quantified the potential reduction in total fluoride intake given different scenarios-for example, by reducing the fluoride intake from drinking water and cooking water. The results show clearly that only by removing fluoride completely from both drinking and cooking water does the probability of remaining below the daily tolerable upper intake level exceed 50%. Both prepared food and food ingredients must be taken into consideration when assessing the total fluoride intake by children living in high-fluoride areas. This knowledge will help health personnel, the government, and the food authorities to give scientifically based advice on strategies for reducing the total fluoride intake by children living in high-fluoride areas in the Ethiopian Rift Valley.


Probing silicon quantum dots by single-dot techniques.
Silicon nanocrystals represent an important class of non-toxic, heavy-metal free quantum dots, where the high natural abundance of silicon is an additional advantage. Successful development in mass-fabrication, starting from porous silicon to recent advances in chemical and plasma synthesis, opens up new possibilities for applications in optoelectronics, bio-imaging, photovoltaics, and sensitizing areas. In this review basic physical properties of silicon nanocrystals revealed by photoluminescence spectroscopy, lifetime, intensity trace and electrical measurements on individual nanoparticles are summarized. The fabrication methods developed for accessing single Si nanocrystals are also reviewed. It is concluded that silicon nanocrystals share many of the properties of direct bandgap nanocrystals exhibiting sharp emission lines at low temperatures, on/off blinking, spectral diffusion etc. An analysis of reported results is provided in comparison with theory and with direct bandgap material quantum dots. In addition, the role of passivation and inherent interface/matrix defects is discussed.


Effect of iodine, selenium and cobalt rumen boluses given to dry dairy cows on the immunoglobulin and thyroid hormone status of calves.
The objective was to determine the effect of rumen boluses containing 6800 mg iodine, 1000 mg selenium and 1000 mg cobalt given to dry dairy cows on the efficiency of colostral immunoglobulin G (IgG) absorption in calves. Thirteen cows received the bolus approximately 58 days before calving. A further 12 cows received no bolus and were used as controls. The cows were housed as one group. Calves were prevented from suckling for the first 24 h of life, and were given three feeds of a fixed quantity of colostrum. At 24 h, the average plasma concentrations of IgG in the calves were 15.5 and 13.4 g/L for the control and bolus groups, respectively; these were not significantly different (P = 0.212). Bolus treatment was associated with higher levels of free and total tri-iodothyronine (T3) and thyroxine (T4) in the dams (all P < 0.001), although it had no effect on thyroid hormone levels in the calves. There were nevertheless positive and negative relationships between the efficiency with which colostral IgG was absorbed at 24 h and, respectively, total T3 at 24 h (P < 0.05) and total T4 at 1 h of age (P < 0.05). The underlying basis for these relationships remains to be established.


A bibliometric review of oncolytic virus research as a novel approach for cancer therapy.
In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research. A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software. In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters. The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.


Multiscale study of mononuclear CoII SMMs based on curcuminoid ligands.
This work introduces a novel family of CoII species having a curcuminoid (CCMoid) ligand, 9Accm, attached, namely [Co(9Accm)2(py)2] (1) and [Co(9Accm)2(2,2'-bpy)] (2), achieved in high yields by the use of a microwave reactor, and exhibiting two different arrangements for the 9Accm ligands, described as "cis"(2) and "trans"(1). The study of the similarities/differences of the magnetic, luminescent and surface behaviors of the two new species, 1 and 2, is the main objective of the present work. The determined single-crystal structures of both compounds are the only CoII-CCMoid structures described in the literature so far. Both compounds exhibit large positive D values, that of 1 (D = +74 cm-1) being three times larger than that of 2 (D = +24 cm-1), and behave as mononuclear Single-Molecule Magnets (SMMs) in the presence of an external magnetic field. Their similar structures but different anisotropy and SMM characteristics provide, for the first time, deep insight on the spin-orbital effects thanks to the use of CASSCF/NEVPT2 calculations implementing such contributions. Further magnetic studies were performed in solution by means of paramagnetic 1H NMR, where both compounds (1 and 2) are stable in CDCl3 and display high symmetry. Paramagnetic NMR appears to be a useful diagnostic tool for the identification of such molecules in solution, where the resonance values found for the methine group (-CH-) of 9Accm vary significantly depending on the cis or trans disposition of the ligands. Fluorescence studies show that both systems display chelation enhancement of quenching (CHEQ) with regard to the free ligand, while 1 and 2 display similar quantum yields. Deposition of 1-2 on HOPG and Si(100) surfaces using spin-coating was studied using AFM; UV photoemission experiments under the same conditions display 2 as the most robust system. The measured occupied density of states of 2 with UV photoemission is in excellent agreement with theoretical DFT calculations.


Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease.
It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (beta-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of beta-amyloid plaques and an increase in the number of beta-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.


Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients.
Patients with suspected stroke first assessed by ambulance paramedics require early recognition to facilitate appropriate triage and early treatment. We determined paramedic's accuracy in detecting acute stroke signs by comparing agreement between neurological signs recorded in the Face Arm Speech Test (FAST), a stroke recognition instrument, by paramedics on the scene and by stroke physicians after admission. Suspected stroke patients admitted by ambulance paramedics directly to an acute stroke unit through a rapid ambulance protocol were examined by a trainee stroke neurologist or admitting stroke physician over a 1-year period. Recorded neurological signs (facial weakness, arm weakness, speech disturbance) in confirmed acute stroke/transient ischemic attack (TIA) cases were compared between paramedics and the stroke neurologist/physician. Ambulance crews referred 278 suspected stroke patients of whom 217 (78%) had confirmed stroke (n=189) or TIA (n=28); 95% were examined by the stroke neurologist (median 18 hours after paramedic assessment). Recorded signs and agreement between paramedics and stroke physicians in confirmed stroke group were: facial weakness, 68% versus 70% (kappa=0.49; 95% CI: 0.36 to 0.62); arm weakness, 96% versus 95% (kappa=0.77; 95% CI: 0.55 to 0.99); and speech disturbance, 79% versus 77% (kappa=0.69; 95% CI: 0.56 to 0.82). Interrater agreement was complete for arm weakness in 98% cases. Recognition of neurological deficits by ambulance paramedics using FAST shows good agreement with physician assessment, even allowing for temporal evolution of deficits. The high prevalence and good agreement for arm weakness suggest that this sign may have the greatest usefulness for prehospital ambulance triage and paramedic-based neuroprotective trials.


Hospitals' efficiency in Iran: A systematic review and meta-analysis.
Given that the need to pay attention to measuring efficiency is considered as one of the main pillars of improving the level of efficiency in hospitals, so this study was carried out aimed to determine the mean technical efficiency (The technical efficiency is bound by zero and one and a score of less than one means that the theatre is inefficient as it could) score in terms of type and activity of the hospital, input-oriented and output-oriented attitude, returns to scale (In economics, returns to scale and economies of scale are related but different concepts that describe what happens as the scale of production increases in the long run, when all input levels including physical capital usage are variable (chosen by the firm). The concept of returns to scale arises in the context of a firm's production function. It explains the behavior of the rate of increase) in hospitals of Iran using data envelopment analysis (DEA) (DEA is a nonparametric method in operations' research and economics for the estimation of production frontiers. It is used to empirically measure productive efficiency of decision-making units) and stochastic frontier analysis (SFA) (SFA is a method of economic modeling. It has its starting point in the stochastic production frontier models simultaneously introduced by Aigner, Lovell and Schmidt[1977] and Meeusen and Van den Broeck[1977]. The present study was carried out with a systematic review of all studies conducted on measuring efficiency of hospitals in Iran from March 21, 2001 to December 21, 2017 using DEA and SFA. Eleven databases were searched using appropriate keywords and 470 articles were found and evaluated using a checklist, and finally, 24 articles were entered into the meta-analysis process. Meta-analysis was performed using random effect model and fixed-effect model, and study heterogeneity was investigated using Q-Cochran test and I 2 index. Furthermore, the main reasons of study heterogeneity were identified due to meta-regression. The average technical efficiency score of hospitals using DEA and SFA method was obtained equal to 0.885 and 0.809, respectively. Furthermore, with regard to the DEA method, 0.885, 0.891.0.952 and 0.913 was obtained for input-oriented and output-oriented, general and specialized care hospitals and constant returns respectively. With regard to SFA method, 0.733, 0.664, 0.641, 0.802, was obtained, and the inputs and outputs affect measuring the efficiency. In contrast, the DEA method can investigate several input and output simultaneously and is used as an effective and flexible tool in order to measure the efficiency of the hospital. DEA can be easily used for calculating efficiency scores based on the proper selection of input and output indicators. The data envelopment analysis method and different input and output variables have been used in most studies conducted in Iran, and Stochastic Frontier Analysis has been less considered. In the present study, the DEA method in governmental educational hospitals showed a higher efficiency than SFA method in the hospitals under study. But in general, due to lack of optimal efficiency level in the hospital, it is suggested that policymakers determine the hospital efficiency indices in order to evaluate their efficiency from different dimensions. The average technical efficiency score of hospitals using DEA and SFA method was obtained equal to 0.885 and 0.809, respectively. Also, the mean technical efficiency score in terms of input-oriented and output-oriented, general and specialized care hospitals and constant returns to scale using the DEA method was obtained equal to 0.885, 0.891.0.952 and 0.913 and using the SFA method, respectively, it was equal to 0.733, 0.664, 0.641, 0.802, and the inputs and outputs affecting measuring the efficiency. There is no significant difference between the mean efficiency score between the two methods, but the data envelopment analysis method is used more. It is suggested that the hospitals efficiency indicators to be determined in order to more accurately evaluate the hospitals efficiency.


Morphological features of TMPRSS2-ERG gene fusion prostate cancer.
The TMPRSS2-ETS fusion prostate cancers comprise 50-70% of the prostate-specific antigen (PSA)-screened hospital-based prostate cancers examined to date, making it perhaps the most common genetic rearrangement in human cancer. The most common variant involves androgen-regulated TMPRSS2 and ERG, both located on chromosome 21. Emerging data from our group and others suggests that TMPRSS2-ERG fusion prostate cancer is associated with higher tumour stage and prostate cancer-specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphological phenotype. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. Statistical analysis was performed to look for significant associations between morphological features and TMPRSS2-ERG fusion status. Five morphological features were associated with TMPRSS2-ERG fusion prostate cancer: blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumour spread, and signet-ring cell features, all with p-values < 0.05. Only 24% (n=30/125) of tumours without any of these features displayed the TMPRSS2-ERG fusion. By comparison, 55% (n=38/69) of cases with one feature (RR=3.88), 86% (n=38/44) of cases with two features (RR=20.06), and 93% (n=14/15) of cases with three or more features (RR=44.33) were fusion positive (p<0.001). To our knowledge, this is the first study that demonstrates a significant link between a molecular alteration in prostate cancer and distinct phenotypic features. The strength of these findings is similar to microsatellite unstable colon cancer and breast cancer involving BRCA1 and BRCA2 mutations. The biological effect of TMPRSS2-ERG overexpression may drive pathways that favour these common morphological features that pathologists observe daily. These features may also be helpful in diagnosing TMPRSS2-ERG fusion prostate cancer, which may have both prognostic and therapeutic implications.


ICD Coding from Clinical Text Using Multi-Filter Residual Convolutional Neural Network.
Automated ICD coding, which assigns the International Classification of Disease codes to patient visits, has attracted much research attention since it can save time and labor for billing. The previous state-of-the-art model utilized one convolutional layer to build document representations for predicting ICD codes. However, the lengths and grammar of text fragments, which are closely related to ICD coding, vary a lot in different documents. Therefore, a flat and fixed-length convolutional architecture may not be capable of learning good document representations. In this paper, we proposed a Multi-Filter Residual Convolutional Neural Network (MultiResCNN) for ICD coding. The innovations of our model are two-folds: it utilizes a multi-filter convolutional layer to capture various text patterns with different lengths and a residual convolutional layer to enlarge the receptive field. We evaluated the effectiveness of our model on the widely-used MIMIC dataset. On the full code set of MIMIC-III, our model outperformed the state-of-the-art model in 4 out of 6 evaluation metrics. On the top-50 code set of MIMIC-III and the full code set of MIMIC-II, our model outperformed all the existing and state-of-the-art models in all evaluation metrics. The code is available at https://github.com/foxlf823/Multi-Filter-Residual-Convolutional-Neural-Network.


Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression.
The adrenal steroid dehydroepiandrosterone (DHEA) may improve vascular function, but the mechanism is unclear. In the present study, we show that DHEA significantly increased cell viability, reduced caspase-3 activity, and protected both bovine and human vascular endothelial cells against serum deprivation-induced apoptosis. This effect was dose dependent and maximal at physiological concentrations (0.1-10 nM). DHEA stimulation of bovine aortic endothelial cells resulted in rapid and dose-dependent phosphorylation of Akt, which was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), the upstream kinase of Akt. Accordingly, inhibition of PI3K or transfection of the cells with dominant-negative Akt ablated the antiapoptotic effect of DHEA. The induced Akt phosphorylation and subsequent cytoprotective effect of DHEA were dependent on activation of Galphai proteins, but were estrogen receptor independent, because these effects were blocked by pertussis toxin but not by the estrogen receptor inhibitor ICI182,780 or the aromatase inhibitor aminoglutethimide. Finally, DHEA enhanced antiapoptotic Bcl-2 protein expression, its promoter activity, and gene transcription attributable to the activation of the PI3K/Akt pathway. Neutralization of Bcl-2 by antibody transfection significantly decreased the antiapoptotic effect of DHEA. These findings provide the first evidence that DHEA acts as a survival factor for endothelial cells by triggering the Galphai-PI3K/Akt-Bcl-2 pathway to protect cells against apoptosis. This may represent an important mechanism underlying the vascular protective effect of DHEA.


Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability.
Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. We identify putative causal variants, enhancers, genes, and cell types for 30-60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.


Production and dose determination of the Infection and Treatment Method (ITM) Muguga cocktail vaccine used to control East Coast fever in cattle.
The Infection and Treatment Method (ITM) of vaccination against the apicomplexan parasite Theileria parva has been used since the early 1970s and is still the only commercially available vaccine to combat the fatal bovine disease, East Coast fever (ECF). The disease is tick-transmitted and results in annual economic losses of at least $300 million per year. While this vaccine technology has been available for over 40 years, few attempts have been made to standardize the production process and characterize the vaccine. The latest batch was produced in early 2008 at the International Livestock Research Institute (ILRI). The vaccine production involves the use of cattle free from parasites routinely monitored throughout the production process, and a pathogen-free tick colony. This paper describes the protocol used in the recent production, and the process improvements, including improved quality control tools, that had not been employed in previous ITM productions. The paper also describes the processes involved in determining the appropriate field dose, which involved a three-step in vivo study with various dilutions of the vaccine stabilate. The vaccine was shown to be safe and viable after production, and a suitable field dose was identified as 1 ml of a 1:100 dilution.


A Biased View of μ-Opioid Receptors?
The field of biased agonism has grown substantially in recent years and the μ-opioid receptor has been one of the most intensively studied receptor targets for developing biased agonists. Yet, despite extensive research efforts, the development of analgesics with reduced adverse effects remains a significant challenge. In this review we discuss the evidence to support the prevailing hypothesis that a G protein-biased agonist at the μ-opioid receptor would be an effective analgesic without the accompanying adverse effects associated with conventional μ-opioid agonists. We also assess the current status of established and novel μ-opioid-receptor ligands that are proposed to be biased ligands. SIGNIFICANCE STATEMENT: The idea that biased agonists at the μ-opioid receptor might provide a therapeutic advantage in terms of producing effective analgesia with fewer adverse effects has driven the design of novel G protein-biased agonists. However, is the desirability of G protein-biased agonists at μ-opioid receptor substantiated by what we know of the physiology and pharmacology of the receptor? Also, do any of the novel biased agonists live up to their initial promise? Here we address these issues by critically examining the evidence that G protein bias really is desirable and also by discussing whether the ligands so far developed are clearly biased in vitro and whether this produces responses in vivo that might be commensurate with such bias.


Differential-Mobility Spectrometry of 1-Deoxysphingosine Isomers: New Insights into the Gas Phase Structures of Ionized Lipids.
Separation and structural identification of lipids remain a major challenge for contemporary lipidomics. Regioisomeric lipids differing only in position(s) of unsaturation are often not differentiated by conventional liquid chromatography-mass spectrometry approaches leading to the incomplete, or sometimes incorrect, assignation of molecular structure. Here we describe an investigation of the gas phase separations by differential-mobility spectrometry (DMS) of a series of synthetic analogues of the recently described 1-deoxysphingosine. The dependence of the DMS behavior on the position of the carbon-carbon double bond within the ionized lipid is systematically explored and compared to trends from complementary investigations, including collision cross-sections measured by drift tube ion mobility, reaction efficiency with ozone, and molecular dynamics simulations. Consistent trends across these modes of interrogation point to the importance of direct, through-space interactions between the charge site and the carbon-carbon double bond. Differences in the geometry and energetics of this intramolecular interaction underpin DMS separations and influence reactivity trends between regioisomers. Importantly, the disruption and reformation of these intramolecular solvation interactions during DMS are proposed to be the causative factor in the observed separations of ionized lipids which are shown to have otherwise identical collision cross-sections. These findings provide key insights into the strengths and limitations of current ion-mobility technologies for lipid isomer separations and can thus guide a more systematic approach to improved analytical separations in lipidomics.


Hemorrhagic and necrotizing hepatitis associated with administration of a modified live canine adenovirus-2 vaccine in a maned wolf (Chrysocyon brachyurus).
A 15-yr-old, female, maned wolf (Chrysocyon brachyurus) was euthanized after presenting semicomatose with severe, uncontrolled frank hemorrhage from her rectum 6 days following a routine physical examination and vaccination. Histopathology indicated severe hemorrhagic and necrotizing hepatitis with intranuclear basophilic inclusion bodies in the liver that were thought to be consistent with adenoviral infection. Further classification by polymerase chain reaction, immunohistochemical staining, virus isolation, and electron microscopy confirmed the etiologic agent to be canine adenovirus-2. A representative sample of the vaccine that had been used was submitted and sequenced along with the virus isolated from the maned wolf. The sequencing of the etiologic agent that had been isolated from the maned wolf was determined to be the same as the strain of virus used in the production of the modified live vaccine that had been administered 6 days prior to death. From this information, the diagnosis of vaccine-induced adenoviral hepatitis was made. This is the first confirmed case of vaccine-induced canine adenoviral hepatitis in a maned wolf.


A Secure and Efficient Data Sharing and Searching Scheme in Wireless Sensor Networks.
Wireless sensor networks (WSN) generally utilize cloud computing to store and process sensing data in real time, namely, cloud-assisted WSN. However, the cloud-assisted WSN faces new security challenges, particularly outsourced data confidentiality. Data Encryption is a fundamental approach but it limits target data retrieval in massive encrypted data. Public key encryption with keyword search (PEKS) enables a data receiver to retrieve encrypted data containing some specific keyword in cloud-assisted WSN. However, the traditional PEKS schemes suffer from an inherent problem, namely, the keyword guessing attack (KGA). KGA includes off-line KGA and on-line KGA. To date, the existing literature on PEKS cannot simultaneously resist both off-line KGA and on-line KGA performed by an external adversary and an internal adversary. In this work, we propose a secure and efficient data sharing and searching scheme to address the aforementioned problem such that our scheme is secure against both off-line KGA and on-line KGA performed by external and internal adversaries. We would like to stress that our scheme simultaneously achieves document encryption/decryption and keyword search functions. We also prove our scheme achieves keyword security and document security. Furthermore, our scheme is more efficient than previous schemes by eliminating the pairing computation.


Activation of visual pigments by light and heat.
Vision begins with photoisomerization of visual pigments. Thermal energy can complement photon energy to drive photoisomerization, but it also triggers spontaneous pigment activation as noise that interferes with light detection. For half a century, the mechanism underlying this dark noise has remained controversial. We report here a quantitative relation between a pigment's photoactivation energy and its peak-absorption wavelength, λ(max). Using this relation and assuming that pigment activations by light and heat go through the same ground-state isomerization energy barrier, we can predict the relative noise of diverse pigments with multi-vibrational-mode thermal statistics. The agreement between predictions and our measurements strongly suggests that pigment noise arises from canonical isomerization. The predicted high noise for pigments with λ(max) in the infrared presumably explains why they apparently do not exist in nature.


Frequency and impact of regional musculoskeletal disorders
Regional musculoskeletal disorders are a major cause of morbidity both in the community and in the workplace. They comprise a heterogeneous group of conditions that are, for the most part, poorly characterized. Consequently, agreed diagnostic criteria have not existed for many of these disorders, and epidemiological investigations have used varied or ill-defined approaches to case definition. This chapter describes our current understanding of the epidemiology of regional pain disorders and details the strengths and weaknesses of the available data. Pain syndromes can be divided anatomically into those which cause generalized pain, such as fibromyalgia syndrome and myofascial pain syndromes, and those which are confined to one regional anatomical area. The latter group comprise those of the neck, shoulder, elbow, wrist/hand, hip, knee and ankle/foot. Current information is considered on the known risk factors for disorders at these sites, in addition to their impact upon both the individual and society.


Volatile organic compounds in Arctic snow: concentrations and implications for atmospheric processes.
The role of volatile organic compounds (VOC) in the snowpack for atmospheric oxidation, gas-particle transfer and aerosol formation remains poorly understood, partly due to a lack of methodology and unavailable data. We deployed solid phase micro-extraction (SPME) gas chromatography with flame ionization detection for measurement of halogenated, aromatic and oxygenated VOC in the snow pack in Alert, NU, Canada, a High Arctic site. Maximum concentrations in snow were 39 ± 6 μg L(-1) (styrene), indicating a potential VOC contribution to atmospheric oxidation and aerosol formation. Concurrently sampled air had concentrations of up to 1.0 ± 0.3 ng L(-1) (trichloroethene). Back trajectory data showed a change of air mass source region during a depletion event of several VOC in snow (e.g., trichloroethene and benzene). Snow profiles showed an enrichment of most compounds close to the surface. During a second study in Barrow, AK, USA VOC were quantified in snow and frost flowers in the Montreal lab. In Barrow work was carried out as part of the extensive OASIS (Ocean-Atmosphere-Sea Ice-Snowpack) field campaign. Maximum VOC concentrations were up to 1.3 ± 0.1 μg L(-1) (acetophenone). Bromoform in frost flowers averaged 0.19 ± 0.04 μg L(-1), indicating the potential to contribute to bromine generation through photolysis.


Partial plasma cell differentiation as a mechanism of lost major histocompatibility complex class II expression in diffuse large B-cell lymphoma.
Loss of major histocompatibility complex class II (MHC II) expression is associated with poor patient outcome in diffuse large B-cell lymphoma (DLBCL). As MHC II molecules are lost with plasmacytic differentiation in normal cells, we asked whether MHC II loss in DLBCL is associated with an altered differentiation state. We used gene expression profiling, quantum dots, and immunohistochemistry to study the relationship between MHC II and plasma cell markers in DLBCL and plasmablastic lymphoma (PBL). Results demonstrate that MHC II(-) DLBCL immunophenotypically overlap with PBL and demonstrate an inverse correlation between MHC II and plasma cell markers MUM1, PRDM1/Blimp1, and XBP1s. In addition, MHC II expression is significantly higher in germinal center-DLBCL than activated B cell-DLBCL. A minor subset of cases with an unusual pattern of mislocalized punctate MHC II staining and intermediate levels of mRNA is also described. Finally, we show that PBL is negative for MHC II. The results imply a spectrum of MHC II expression that is more frequently diminished in tumors derived from B cells at the later stages of differentiation (with complete loss in PBL). Our observations provide a possible unifying concept that may contribute to the poor outcome reported in all MHC II(-) B-cell tumors.


Imported typhoid fever in Switzerland, 1993 to 2004.
In industrialized countries, typhoid fever occurs mainly in returned travelers. To determine the need for preventive strategies, eg, for vaccination, continuous monitoring is needed to assess where the risk for travelers is highest. To investigate where the risk for travelers to acquire typhoid fever is highest, 208 patients with typhoid fever and recent travel were matched with travelers' statistics collected by the Swiss Federal Office of Statistics. At the beginning of the study period, up to 30 infections with Salmonella typhi were recorded per year in Switzerland. Since 2001, less than 15 confirmed cases per year occurred. A majority of the 208 (88.5%) typhoid cases were associated with recent travel. Countries with highest risk were Pakistan (24 per 100,000), Cambodia (20 per 100,000), Nepal (14 per 100,000), India (12 per 100,000), and Sri Lanka (9 per 100,000). We found that over a 12-year period (1993-2004), the travel-associated risk of typhoid fever is highest for destinations in the Indian subcontinent. All other regions showed a decline, most markedly in southern Europe. Our results suggest that typhoid fever vaccination should be recommended for all travelers to countries in South Asia. Otherwise, vaccination of tourists to frequently visited low- and intermediate-risk areas is not necessary, unless there are behavioral risk factors.


Lipid-mediated DNA and siRNA Transfection Efficiency Depends on Peptide Headgroup.
A series of amphiphiles with differing cationic tri- and di- peptide headgroups, designed and synthesized based on lysine (K), ornithine (O), arginine (R), and glycine (G), have been characterized and evaluated for DNA and siRNA delivery. DNA-lipoplexes formed from the tri- and di- lipopeptides possessed lipid:nucleic acid charge ratios of 7:1 to 10:1, diameters of ~200 nm to 375 nm, zeta potentials of 23 mV to 41 mV, melting temperatures of 12 °C to 46 °C, and lamellar repeat periods of 6 nm to 8 nm. These lipid-DNA complexes formed supramolecular structures in which DNA is entrapped at the surface between multilamellar liposomal vesicles. Compared to their DNA counterparts, siRNA-lipoplexes formed slightly larger complexes (348 nm to 424 nm) and required higher charge ratios to form stable structures. Additionally, it was observed that lipids with multivalent, tripeptide headgroups (i.e., KGG, OGG, and RGG) were successful at transfecting DNA in vitro, whereas DNA transfection with the dipeptide lipids proved ineffective. Cellular uptake of DNA was more effective with the KGG compared to the KG lipopeptide. In siRNA knockdown experiments, both tri- and di- peptide lipids (i.e., RGG, GGG, KG, OG, RG, GG) showed some efficacy, but total cellular uptake of siRNA complexes was not indicative of knockdown outcomes and suggested that the intracellular fate of lipoplexes may be a factor. Overall, this lipopeptide study expands the library of efficient DNA transfection vectors available for use, introduces new vectors for siRNA delivery, and begins to address the structure-activity relationships which influence delivery and transfection efficacy.


Childhood cancer survivor cohorts in Europe.
With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.


Sequential addition of H2O, CH3OH, and NH3 to Al3O3-: a theoretical study.
Photoelectron spectra of two species, Al3O3(H2O)2- and Al3O3(CH3OH)2-, that are produced by the addition of two water or methanol molecules to Al3O3- are interpreted with density-functional geometry optimizations and electron propagator calculations of vertical electron detachment energies. In both cases, there is only one isomer that is responsible for the observed spectral features. A high barrier to the addition of a second molecule may impede the formation of Al3O3N2H6- clusters in an analogous experiment with NH3.


Sex-specific differential survival of extra-pair and within-pair offspring in song sparrows, Melospiza melodia.
It is widely hypothesized that the evolution of female extra-pair reproduction in socially monogamous species reflects indirect genetic benefits to females. However, a critical prediction of this hypothesis, that extra-pair young (EPY) are fitter than within-pair young (WPY), has rarely been rigorously tested. We used 18 years of data from free-living song sparrows, Melospiza melodia, to test whether survival through major life-history stages differed between EPY and WPY maternal half-siblings. On average, survival of hatched chicks to independence from parental care and recruitment, and their total lifespan, did not differ significantly between EPY and WPY. However, EPY consistently tended to be less likely to survive, and recruited EPY survived for significantly fewer years than recruited WPY. Furthermore, the survival difference between EPY and WPY was sex-specific; female EPY were less likely to survive to independence and recruitment and lived fewer years than female WPY, whereas male EPY were similarly or slightly more likely to survive and to live more years than male WPY. These data indicate that extra-pair paternity may impose an indirect cost on females via their female offspring and that sex-specific genetic, environmental or maternal effects may shape extra-pair reproduction.


A randomized trial of atropine regimens for treatment of moderate amblyopia in children.
To compare daily atropine to weekend atropine as prescribed treatments for moderate amblyopia in children younger than 7 years. Prospective, randomized multicenter clinical trial (30 sites). One hundred sixty-eight children younger than 7 years with amblyopia in the range of 20/40 to 20/80 associated with strabismus, anisometropia, or both. Randomization either to daily atropine or to weekend atropine for 4 months. Partial responders were continued on the randomized treatment until no further improvement was noted. Visual acuity (VA) in the amblyopic eye after 4 months. The improvement in VA of the amblyopic eye from baseline to 4 months averaged 2.3 lines in each group. The VA of the amblyopic eye at study completion was either (1) at least 20/25 or (2) better than or equal to that of the sound eye in 39 children (47%) in the daily group and 45 children (53%) in the weekend group. The VA of the sound eye at the end of follow-up was reduced by 2 lines in one patient in each group. Stereoacuity outcomes were similar in the 2 groups. Weekend atropine provides an improvement in VA of a magnitude similar to that of the improvement provided by daily atropine in treating moderate amblyopia in children 3 to 7 years old. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.


Fibrillins 1 and 2 perform partially overlapping functions during aortic development.
Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Fbn1-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. Analysis of the neonatal Fbn1-/- aorta documented a disorganized and poorly developed medial layer but normal levels of elastin cross-links. Transcriptional profiling revealed that aneurysm progression in Fbn1 null mice is accompanied by unproductive up-regulation of gene products normally involved in tissue repair and vascular integrity, such as plasminogen activator inhibitor-1, activin A, and cysteine-rich angiogenic protein 61. In contrast to Fbn1-/- mice, Fbn2 null mice had a well developed and morphologically normal aortic wall. However, virtually all Fbn1-/-;Fbn2-/- embryos and about half of the Fbn1+/-;Fbn2-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1-/- mice. Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures. Collectively, these data demonstrate that involvement of fibrillin-2 in the initial assembly of the aortic matrix overlaps in part with fibrillin-1 and that continued fibrillin-1 deposition is absolutely required for the maturation and function of the vessel during neonatal life.


Near-infrared light-triggered drug release from UV-responsive diblock copolymer-coated upconversion nanoparticles with high monodispersity.
The preparation of a new near-infrared (NIR) light-responsive nanocarrier for controlled drug release is demonstrated. Upconversion nanoparticles (UCNPs) were coated with an amphiphilic diblock copolymer through surface-initiated atom transfer radical polymerization, in which the inner block is hydrophobic, ultraviolet (UV)-sensitive poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) (PNB), and the outer block is hydrophilic poly(methoxy polyethylene glycol monomethacrylate) (POEG). The resulting polymer/UCNP nanocarrier is thermally stable in water over a wide temperature range (5-70 °C) and is uniform in size (120 nm hydrodynamic diameter, polydispersity index <0.1). The diblock copolymer self-assembly on the surface of each UCNP occurs in aqueous solution, which allows encapsulation of antitumor drugs like doxorubicin (DOX) by the hydrophobic "micelle-like" core of PNB surrounding the NIR-sensitive UCNP. Under 980 nm laser exposure, the UV light emitted by the single UCNP is absorbed by the PNB inner layer, which results in cleavage of o-nitrobenzyl groups and formation of carboxylic acid groups. The increasing hydrophilicity of the diblock copolymer resulting from the NIR light-triggered photochemical reaction can thus disrupt the nanocarrier and leads to the release of DOX molecules. This diblock copolymer self-assembly-based approach to constructing NIR light-responsive nanocarriers of well-defined structures is general and offers possibilities for photocontrolled drug delivery.


The impact of oral pain on quality of life during pregnancy in low-income Brazilian women.
To assess the effects of oral pain on oral health-related quality of life during pregnancy and document measures taken by pregnant women seeking relief for oral pain. Their experience of other types of pain were also investigated. A sample of pregnant women who were admitted to a public hospital to give birth were invited to participate in this cross-sectional study. Those who agreed were asked if they had experienced any pain due to problems with their mouth, teeth, or dentures during the 6 months prior to the interviews. Interviewees who answered affirmatively were questioned about the effects of this pain on their normal activities with the Oral Impacts on Daily Performances (OIDP) tool. The study population consisted of 504 subjects (83% of the eligible individuals). A high prevalence of untreated dental caries was found. The prevalences of oral pain, headaches, back pain, and pelvic pain were 39.1%, 61.5%, 59.3%, and 60.9%, respectively. Of those reporting pain, 168 (33.3%) reported having had difficulty doing at least one of the activities included in the OIDP due to oral pain. The most frequently mentioned effects were difficulty in maintaining emotional balance (23.6%), difficulty eating (22.8%), and difficulty cleaning teeth (20%). The mean and median OIDP scores were 13.9% and 8.0%, respectively. Oral pain during pregnancy was an important problem for this group of women and had a negative effect on their quality of life.


Consensus on the clinical management, screening-to-treat, and surveillance of Helicobacter pylori infection to improve gastric cancer control on a nationwide scale.
Previous international consensus statements provided general policies for the management of Helicobacter pylori infection. However, there are geographic differences in the prevalence and antimicrobial resistance of H. pylori, and in the availability of medications and endoscopy. Thus, nationwide or regional consensus statements are needed to improve control of H. pylori infection and gastric cancer. This consensus statement for management of H. pylori in Taiwan has three major sections: (1) optimal diagnosis and indications; (2) current treatment strategies; and (3) screening-to-treat and surveillance for control of gastric cancer. The literature review emphasized recent data for development of draft statements and determination of levels of evidence. Twenty-five Taiwan experts conducted a consensus conference, by a modified Delphi process, to modify the draft statements. Consensus, defined as an agreement of least 80% of the experts, and recommendation grade were determined by anonymous voting. There were 24 consensus statements. Section 1 has seven statements on recommendations for the diagnosis and indications for treatment of H. pylori infection. Section 2 has 10 statements that provide an updated treatment algorithm for first-line, second-line, and third-line regimens. Section 3 has seven statements regarding H. pylori eradication for reducing the risk of gastric cancer, with a cost-benefit analysis. After H. pylori eradication, the consensus highlights the use of endoscopic surveillance and/or chemoprevention to further reduce the burden of gastric cancer. This consensus statement has updated recommendations for improving the clinical management of H. pylori infection in areas such as Taiwan, which have high prevalence of H. pylori infection and gastric cancer.


A report of vitamin and mineral supplement use among university athletes in a division I institution.
The influences of gender, ethnicity, and sport of varsity athletes on their vitamin/mineral supplementation habits were examined. Subjects included 145 females and 266 males from 22 varsity teams; 80% were Caucasian; 12% African American; and 8% Combined-Other. Over half of the subjects took supplements. Males were more likely than females to give "too expensive" as a reason for not taking supplements, and "improve athletic performance" and "build muscle" as reasons for taking supplements. The most common supplement was multivitamins plus minerals. Females were more likely to take calcium and iron, and males vitamins B12 and A. African Americans were the most likely to take vitamin A. Males were more likely to get supplement information from nutritionists/dietitians and self, and females from family members or friends and physicians or pharmacists. Football players were more likely to get supplement information from nutritionists/dietitians, and males in other sports from coaches/trainers. There were some differences in vitamin/mineral supplement habits of the athletes by gender, ethnicity, and sport.


Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens.
We report the identification of two novel minor histocompatibility antigens (mHAgs), encoded by two separate single nucleotide polymorphisms on a single gene, BCL2A1, and restricted by human histocompatibility leukocyte antigen (HLA)-A*2402 (the most common HLA-A allele in Japanese) and B*4403, respectively. Two cytotoxic T lymphocyte (CTL) clones specific for these mHAgs were first isolated from two distinct recipients after hematopoietic cell transplantation. Both clones lyse only normal and malignant cells within the hematopoietic lineage. To localize the gene encoding the mHAgs, two-point linkage analysis was performed on the CTL lytic patterns of restricting HLA-transfected B lymphoblastoid cell lines obtained from Centre d'Etude du Polymorphisme Humain. Both CTL clones showed a completely identical lytic pattern for 4 pedigrees and the gene was localized within a 3.6-cM interval of 15q24.3-25.1 region that encodes at least 46 genes. Of those, only BCL2A1 has been reported to be expressed in hematopoietic cells and possess three nonsynonymous nucleotide changes. Minigene transfection and epitope reconstitution assays with synthetic peptides identified both HLA-A*2402- and B*4403-restricted mHAg epitopes to be encoded by distinct polymorphisms within BCL2A1.


Action sentences activate sensory motor regions in the brain independently of their status of reality.
Some studies have reported that understanding concrete action-related words and sentences elicits activations of motor areas in the brain. The present fMRI study goes one step further by testing whether this is also the case for comprehension of nonfactual statements. Three linguistic structures were used (factuals, counterfactuals, and negations), referring either to actions or, as a control condition, to visual events. The results showed that action sentences elicited stronger activations than visual sentences in the SMA, extending to the primary motor area, as well as in regions generally associated with the planning and understanding of actions (left superior temporal gyrus, left and right supramarginal gyri). Also, we found stronger activations for action sentences than for visual sentences in the extrastriate body area, a region involved in the visual processing of human body movements. These action-related effects occurred not only in factuals but also in negations and counterfactuals, suggesting that brain regions involved in action understanding and planning are activated by default even when the actions are described as hypothetical or as not happening. Moreover, some of these regions overlapped with those activated during the observation of action videos, indicating that the act of understanding action language and that of observing real actions share neural networks. These results support the claim that embodied representations of linguistic meaning are important even in abstract linguistic contexts.


Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo.
Growth factor receptors provide unique opportunities for development of targeted anticancer therapy. Members of the type I receptor tyrosine kinase family, including epidermal growth factor (EGF) receptor (EGFR) and ErbB-2/neu, are often overexpressed in various human cancer cells, including breast. Recently, it has been shown that both ErbB-3 and ErbB-4 are receptors for heregulin (HRG)/Neu differentiation factor. Eight chimeric toxins composed of the extracellular and EGF-like domains of four different HRG isoforms and truncated Pseudomonas exotoxin (PE38KDEL) were constructed. The fusion proteins exhibited activity similar to the native HRG in inducing ErbB receptors phosphorylation. The EGF-like domain of HRG13 and HRGbeta2 fused to PE38KDEL showed the highest cytotoxic activity, with a IC50 of < or = 0.001 ng/ml. The alpha isoforms that were fused to PE38KDEL were 100-fold less active than the beta isoforms. The HRG-Pseudomonas exotoxin (PE) toxins show extremely high activity against cells expressing ErbB-4 receptor, alone or together with other members of the ErbB receptor family. Cells that do not express ErbB-4 but express ErbB-3 receptor, together with the ErbB-2 or EGFR, exhibited moderate sensitivity to HRG-PE toxins. HRG-PE toxins have little or no activity against cells expressing EGFR, ErbB-2, or ErbB-3 alone. More than an 80% tumor regression was achieved by intratumor injection of 1 microg of fusion proteins per day for 5 days. Continuous i.p. administration of EGF-like domain of HRGbeta1-PE38KDEL for 7 days via a miniosmotic pump at a dose of 40 microg/kg/day inhibited the growth of ErbB-4 receptor positive but not ErbB-4 receptor negative cell lines in athymic nude mice. We conclude that there is therapeutic potential of HRG-PE toxins in the therapy of cancers overexpressing the ErbB-4 or ErbB-2 plus ErbB-3 receptors.


Panton-Valentine Leukocidin-positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis.
Panton-Valentine Leukocidin-expressing (PVL+) methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen worldwide causing fatal necrotizing pneumonias in otherwise healthy individuals but has not been described in patients with cystic fibrosis (CF). Following two cases of patients with CF admitted with lung abscesses in association with PVL+ MRSA, we examined the incidence and the clinical characteristics of MRSA acquisition in our CF patient population. Newly acquired MRSA isolates from patients with CF followed up at St. Louis Children's Hospital were analyzed for the presence of Panton-Valentine leukocidin coding region, clindamycin susceptibility, staphylococcal cassette chromosome (SCC) mec type, and multilocus sequence type. Medical records and pulmonary function studies at the time of MRSA isolation were reviewed. MRSA isolates from 40 CF patients were available for analysis. Six children (15%) had PVL+ MRSA infection. All PVL+ organisms were clindamycin susceptible. Patients who acquired a PVL+ organism were more likely to have a focal pulmonary infiltrate on chest radiograph, including cavitary lung lesions in two patients (p = 0.04), a markedly greater decline in FEV1 at the time of MRSA detection (p = 0.01), and a significantly higher WBC count (p = 0.04) and absolute neutrophil count (p = 0.04). These patients were more likely to be admitted for IV antibiotic therapy for respiratory illnesses (p < 0.01). We describe the emergence of PVL+ MRSA in our CF population in association with development of invasive lung infections including lung abscesses. Early identification and treatment of CF patients with newly acquired PVL+ MRSA may be crucial.


Electric and magnetic polarization singularities of first-order Laguerre-Gaussian beams diffracted at a half-plane screen.
Based on the vector Fresnel diffraction integrals, analytical expressions for the electric and magnetic components of first-order Laguerre-Gaussian beams diffracted at a half-plane screen are derived and used to study the electric and magnetic polarization singularities in the diffraction field for both two- and three-dimensional (2D and 3D) cases. It is shown that there exist 2D and 3D electric and magnetic polarization singularities in the diffraction field, which do not coincide each other in general. By suitably varying the waist width ratio, off-axis displacement parameter, amplitude ratio, or propagation distance, the motion, pair-creation, and annihilation of circular polarization singularities, and the motion of linear polarization singularities take place in 2D and 3D electric and magnetic fields. The V point, at which two circular polarization singularities with the same topological charge but opposite handedness collide, appears in the 2D electric field under certain conditions in the diffraction field and free-space propagation. A comparison with the free-space propagation is also made.


Association of erectile dysfunction and urolithiasis.
In recent years, it has been shown that there is association between metabolic syndrome and urinary stone disease. Stone disease and erectile dysfunction (ED) are considered as systemic diseases which are associated with hormonal and metabolic disorders. Therefore we investigated the relationship between ED and urinary tract calculi. 98 male patients with urolithiasis and 59 randomly selected male patients without stone disease were included in the study. Serum testosterone (T) levels were measured and International Index of Erectile Function (IIEF)-15 questionnaire forms were used to assess ED. The prevalence of ED was found 29% (29 patients) in the urolithiasis group. Sixty-nine patients (71%) had no ED; 16 (16.3%) had mild, 5 (5.1%) had moderate and 8 (8.2%) had severe ED. None of the patients in the control group had severe or modarete ED, six patients (10.2%) had mild ED. Serum T levels were detected at the level of biochemical hypogonadism on 13 patients with stones (13.3%) and T levels were detected at the lower limit in 18 (18.3%) patients. In our study we have shown that ED and low T levels are significantly associated with urolithiasis. We propose that the patients with urolitiasis should be evaluated for ED and hypogonadism.


Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins.
A variety of polyamine spider and wasp toxins are known to block N-methyl-D-aspartate receptor channels and recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that lack the edited glutamate receptor (GluR)2 subunit. Recently, inward rectification of GluR2-lacking AMPA receptors was shown to be caused by voltage-dependent block by intracellular spermine. Here we demonstrate that, when applied extracellularly, the endogenous polyamines spermine and spermidine, as well as monoacylated spermine analogs and the polyamine toxins ageltoxin-489 and philanthotoxin-433, exerted a use-dependent and weakly voltage-dependent block of AMPA receptors that lack the edited GluR2 subunit, when the recombinant receptors were expressed in Xenopus oocytes. External spermine and polyamine toxins were also effective blockers of AMPA receptor mutants that did not not show inwardly rectifying kainate responses but had high calcium permeability. The polyamines and polyamine toxins also markedly reduced inwardly rectifying currents of native AMPA receptors expressed by a class of hippocampal interneurons in rat CA3 stratum radiatum that appear not to express the GluR2 subunit. In contrast, polyamines had little or no effect on the linear or outwardly rectifying kainate responses of other interneurons or CA3 pyramidal cells in which GluR2 mRNA was routinely detected. Together with previous reports, these data suggest that endogenous polyamines may bind to GluR2-lacking AMPA receptors at two or more distinct sites, one near the cytoplasmic side of the pore and the other nearer the outer side of the pore.


Digital Breast Tomosynthesis Versus Additional Diagnostic Mammographic Views for the Evaluation of Asymmetric Mammographic Densities.
Introduction Many young females present with an advanced stage of breast cancer, which has a negative effect on the prognosis. Digital breast tomosynthesis is a new emerging imaging technique that aids in improving the specificity of mammography with subsequent early detection of breast cancer, especially in women with radiographically dense breasts. Tomosynthesis is subjectively preferred to conventional mammography and may offer superior diagnostic accuracy for the evaluation of breast lesions. Method Two breast radiologists retrospectively reviewed asymmetric densities using protocols that were institutional review board-approved in 185 patients aged 18 - 70 years (mean: 48 years) who underwent diagnostic mammography and tomosynthesis. Each asymmetric density was interpreted once with tomosynthesis and once with supplemental mammographic views; both modes included the mediolateral oblique and craniocaudal views in a fully crossed and balanced design by using a five-category Breast Imaging Reporting and Data System (BI-RADS) assessment and a probability-of-malignancy score. If the abnormality persisted and appeared benign or completely disappeared on both modalities, the agreement between additional views and tomosynthesis was determined by calculating Kappa value. If there was a discrepancy between additional views and tomosynthesis, the abnormality was subjected to ultrasound. In our study, 89 asymmetric densities were subjected to ultrasound. Results In a total of 182 cases, 84 (46.15%) were categorized as BIRADS-0; 97 (53.30 %) as BIRADS-I, and one (0.55 %) as BIRADS-II on an additional view. Among the asymmetric densities categorized as BIRADS-0 on additional mammography views, digital breast tomosynthesis categorized 72, six, five, and one patient as BIRADS-0, BIRADS-I, BIRADS-II, and BIRADS-IV, respectively. For densities categorized as BIRADS-I (97) on additional view, digital breast tomosynthesis categorized 10 and 87 densities as BIRADS-0 and BIRADS-I, respectively. No change in the BIRADS category was observed among BIRADS-II and BIRADS-IV. A significant difference was observed with the chi-square test among BIRADS categories assigned by an additional view and digital breast tomosynthesis with a p-value of < 0.001. There was, however, a substantial agreement among additional views and tomosynthesis with a kappa value of 0.767. Conclusion Our study results suggest that tomosynthesis may be equivalent to, if not more equivalent to, additional imaging in the assessment of mammographically-detected asymmetric densities, thus improving BI-RADS classification and patient management.


Localizing Memory Functions in Brain Tumor Patients: Anatomical Hotspots over 260 Patients.
Memory complaints are common in patients after brain tumor, but is difficult to map memory functions during awake surgery, to preserve them. Thus we analyzed one of the largest data sets on clinical, surgical, and anatomical correlates of memory in patients with brain tumor to date, providing anatomical hotspots for short and long-term memory functions. A total of 260 patients with brain tumor (130 high-grade gliomas; 76 low-grade gliomas [LGG]; 54 meningiomas) were tested on 2 commonly used short-term memory (Digit Span Forward and Corsi Spatial Span) and 2 long-term memory tasks (Narrative Memory and Delayed Recall of Rey Figure). Patients were evaluated before and immediately after surgery and (for LGG) after 4 months and data analyzed by means of analysis of covariance and the voxel-based lesion-symptom mapping technique. As expected, patients with high-grade gliomas were already impaired before surgery, whereas patients with meningioma were largely unimpaired. Patients with LGG were unimpaired before surgery, but showed significant performance drop immediately after, with good recovery within few months. Voxel-based lesion-symptom mapping analyses identified specific anatomical correlates for verbal memory tasks, whereas visuospatial tasks provided good sensitivity to cognitive damage but failed to show anatomical specificity. Anatomical hotspots identified were in line with both previous functional magnetic resonance imaging and clinical studies on other neurological populations. Verbal memory tasks revealed a set of specific anatomical hotspots that might be considered "eloquent" for verbal memory functions, unlike visuospatial tasks, suggesting that commonly used spatial memory tasks might not be optimal to localize the damage, despite an otherwise good sensitivity to cognitive damage.


Predicting the lumbosacral joint centre location from palpable anatomical landmarks.
The kinematics of the lumbar spine have previously been described by considering the bearing of the pelvis and lower back. However earlier studies have not described an intersegmental angle measured about a single point; which is necessary for investigation into movement, posture and balance, and lower back pain and injury. This study used computed tomography (CT) scans of 16 pelves to determine the location of palpable bony landmarks, and the junction of the fifth lumbar and first sacral vertebrae within a pelvis axis system. Data were used to derive equations which express the three-dimensional location of the lumbosacral joint centre as an offset from palpable surface landmarks. The magnitude of X, Y, Z offsets was controlled using individual pelvic geometry, and robustness and repeatability of the method was assessed. Regression equations provided the location of the lumbosacral junction to within 8.2mm (+/- 3.4mm) of its true coordinate. Leave-one-out analyses calculated equation coefficients using 15 of the original pelves, with the 16th acting as a control; average errors increased by 6.7 per cent (+/- 0.1 percent). To the authors' knowledge the current method is the most accurate non-invasive means of locating the lumbosacral junction and may be useful for constructing biomechanical models.


Genetic heterogeneity in Mycobacterium tuberculosis isolates reflected in IS6110 restriction fragment length polymorphism patterns as low-intensity bands.
Mycobacterium tuberculosis isolates with identical IS6110 restriction fragment length polymorphism (RFLP) patterns are considered to originate from the same ancestral strain and thus to reflect ongoing transmission. In this study, we investigated 1,277 IS6110 RFLP patterns for the presence of multiple low-intensity bands (LIBs), which may indicate infections with multiple M. tuberculosis strains. We did not find any multiple LIBs, suggesting that multiple infections are rare in the Netherlands. However, we did observe a few LIBs in 94 patterns (7.4%) and examined the nature of this phenomenon. With single-colony cultures it was found that LIBs mostly represent mixed bacterial populations with slightly different RFLP patterns. Mixtures were expressed in RFLP patterns as LIBs when 10 to 30% of the DNA analyzed originated from a bacterial population with another RFLP pattern. Presumably, a part of the LIBs did not represent mixed bacterial populations, as in some clusters all strains exhibited LIBs in their RFLP patterns. The occurrence of LIBs was associated with increased age in patients. This may reflect either a gradual change of the bacterial population in the human body over time or IS6110-mediated genetic adaptation of M. tuberculosis to changes in the environmental conditions during the dormant state or reactivation thereafter.


DNA mutations of the cat: the good, the bad and the ugly.
The health of the cat is a complex interaction between its environment (nurture) and its genetics (nature). Over 70 genetic mutations (variants) have been defined in the cat, many involving diseases, structural abnormalities and clinically relevant health concerns. As more of the cat's genome is deciphered, less commonly will the term 'idiopathic' be used regarding the diagnosis of diseases and unique health conditions. State-of-the-art health care will include DNA profiling of the individual cat, and perhaps its tumor, to establish the best treatment approaches. Genetic testing and eventually whole genome sequencing should become routine diagnostics for feline health care. Cat breeds have disseminated around the world. Thus, practitioners should be aware of the breeds common to their region and the mutations found in those regional populations. Specific random-bred populations can also have defined genetic characteristics and mutations. This review of 'the good, the bad and the ugly' DNA variants provides the current state of knowledge for genetic testing and genetic health management for cats. It is aimed at feline and general practitioners wanting to update and review the basics of genetics, what tests are available for cats and sources for genetic testing. The tables are intended to be used as references in the clinic. Practitioners with a high proportion of cat breeder clientele will especially benefit from the review. The data presented is extracted from peer-reviewed publications pertaining to mutation identification, and relevant articles concerning the heritable trait and/or disease. The author also draws upon personal experience and expertise in feline genetics.


Are magnetic resonance imaging undetectable prostate tumours clinically significant? Results of histopathological analyses.
To investigate whether tumours at threshold values for detection on magnetic resonance imaging (MRI) represent clinically significant tumours or not, and therefore the utility of MRI in active surveillance (AS) protocols. A retrospective analysis of a single institution database was performed after Institutional Review Board approval. Between 2010 and 2013, 1633 patients underwent robot-assisted laparoscopic prostatectomy (RALP) at a single institution by a single surgeon. Of these, 1361 had complete clinical data and were included in analysis. Multivariate logistic regression was used to assess histopathological grade compared to tumour size whilst controlling for biopsy Gleason score, prostate-specific antigen level, body mass index, race, and age. Of 120 tumours <5 mm in size, four were Gleason score 4 + 3. Of 276 tumours of 5-10 mm, 22 (8.1%) were Gleason score 4 + 3 and one (0.2%) was Gleason score 8. On multivariate regression analyses, tumours of <5 mm were much less likely to be high grade (Gleason score >3 + 4) at RALP compared to larger tumours (3.3% vs 25.1%, P < 0.001), or Gleason score ⩾8 (0.0% vs 7.6%, P < 0.001). Size was further shown to significantly correlate with grade on multivariate regression (P < 0.001). Prostate tumours below the detection threshold for MRI (5 mm) most probably represent clinically insignificant tumours, which alone would not necessitate leaving AS in favour of more aggressive therapy. These findings point to a possible role of MRI in modern AS protocols.