A consensus on fungal polymerase chain reaction diagnosis?: a United Kingdom-Ireland evaluation of polymerase chain reaction methods for detection of systemic fungal infections.
The limitations of classical diagnostic methods for invasive fungal infections (IFIs) have led to the development of molecular techniques to aid in the detection of IFIs. Despite good published performance, interlaboratory reproduction of these assays is variable, and no consensus has been reached for an optimal method. This publication describes the first multicenter study of polymerase chain reaction methods, for the detection of Aspergillus and Candida species, currently used in the UK and Ireland by distribution and analysis of multiple specimen control panels. All three Candida methods were comparable, achieving a satisfactory level of detection (10 cfu), and the method of preference was dependent on the requirements of the particular laboratory. The results for the five Aspergillus assays were more variable, but two methods (2Asp and 4Asp) were superior (10(1) conidia). Formally, the overall performances of the two Aspergillus assays were comparable (kappa statistic = 0.77). However, on the Roche LightCycler, there was a clear sample-type effect that greatly reduced the detection limit of the 4Asp method when testing whole blood samples. Therefore, the preferred Aspergillus method relied on the amplification platform available to the user. This study represents the initial process to achieve a consensus method for the diagnosis of IFIs.


Possible therapeutic applications of cannabis in the neuropsychopharmacology field.
Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids. These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they have also shown numerous therapeutic properties. These properties are mostly associated with their ability to modulate the activity of an intercellular communication system, the so-called endocannabinoid system, which is highly active in the CNS and has been found altered in many neurological disorders. Specifically, this includes the neuropsychopharmacology field, with diseases such as schizophrenia and related psychoses, anxiety-related disorders, mood disorders, addiction, sleep disorders, post-traumatic stress disorder, anorexia nervosa and other feeding-related disorders, dementia, epileptic syndromes, as well as autism, fragile X syndrome and other neurodevelopment-related disorders. Here, we gather, from a pharmacological and biochemical standpoint, the recent advances in the study of the therapeutic relevance of the endocannabinoid system in the CNS, with especial emphasis on the neuropsychopharmacology field. We also illustrate the efforts that are currently being made to investigate at the clinical level the potential therapeutic benefits derived from elevating or inhibiting endocannabinoid signaling in animal models of neuropsychiatric disorders.


Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy.
To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.


A rights-based approach to indoor air pollution.
Household indoor air pollution from open-fire cookstoves remains a public health and environmental hazard which impacts negatively on people's right to health. Technologically improved cookstoves designed to reduce air pollution have demonstrated their efficacy in laboratory studies. Despite the tremendous need for such stoves, in the field they have often failed to be effective, with low rates of long-term adoption by users, mainly due to poor maintenance of the stoves. In poor, rural, isolated communities, there is unlikely to be a single behavioral or technological "fix" to this problem. In this paper, we suggest that improved cookstoves are an important health intervention to which people have a right, as they do to family planning, vaccination, and essential primary care medicines. Like these other necessary elements in the fulfillment of the right to health, access to clean indoor air should be incorporated into state health strategies, policies, and plans. State infrastructure and health systems should support public and private sector delivery of improved cookstove services, and ensure that such services reach all communities, even those that are poor, located remotely, and likely not to be served by the market. We suggest that community health workers could play a critical role in creating demand for, implementing facilitation and delivery of, and monitoring these cookstoves and related services. Through this approach, improved cookstoves could become an appealing, available, and sustainable option for the rural poor. In this paper, we adopt a human rights-based approach to overcome the problem of indoor air pollution, and we use Nepal as an example.


The impact of parental migration on health status and health behaviours among left behind adolescent school children in China.
One out of ten of China's population are migrants, moving from rural to urban areas. Many leave their families behind resulting in millions of school children living in their rural home towns without one or both their parents. Little is known about the health status of these left behind children (LBC). This study compares the health status and health-related behaviours of left behind adolescent school children and their counterparts in a rural area in Southern China. A cross-sectional study was conducted among middle school students in Fuyang Township, Guangdong, China (2007-2008). Information about health behaviours, parental migration and demographic characteristics was collected using a self-administered questionnaire. Overweight/obesity and stunting were defined based on measurements of height and weight. Univariate and multivariate analyses were used to estimate the differences in health outcomes between LBC and non-LBC. 18.1% of the schoolchildren had one or both parents working away from home. Multivariate analysis showed that male LBC were at higher risk of skipping breakfast, higher levels of physical inactivity, internet addiction, having ever smoked tobacco, suicide ideation, and being overweight. LBC girls were more likely to drink excessive amounts of sweetened beverage, to watch more TV, to have ever smoked or currently smoke tobacco, to have ever drunk alcohol and to binge drinking. They were also more likely to be unhappy, to think of planning suicide and consider leaving home. Our findings suggest that parental migration is a risk factor for unhealthy behaviours amongst adolescent school children in rural China. Further research is required in addition to the consideration of the implications for policies and programmes to protect LBC.


ST2249-MRSA-III: a second major recombinant methicillin-resistant Staphylococcus aureus clone causing healthcare infection in the 1970s.
Typing of healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) from Australia in the 1970s revealed a novel clone, ST2249-MRSA-III (CC45), present from 1973 to 1979. This clone was present before the Australian epidemic caused by the recombinant clone, ST239-MRSA-III. This study aimed to characterize the genome of ST2249-MRSA-III to establish its relationship to other MRSA clones. DNA microarray analysis was conducted and a draft genome sequence of ST2249 was obtained. The recombinant structure of the ST2249 genome was revealed by comparisons to publicly available ST239 and ST45 genomes. Microarray analysis of genomic DNA of 13 ST2249 isolates showed gross similarities with the ST239 chromosome in a segment around the origin of replication and with ST45 for the remainder of the chromosome. Recombination breakpoints were precisely determined by the changing pattern of nucleotide polymorphisms in the genome sequence of ST2249 isolate SK1585 compared with ST239 and ST45. One breakpoint was identified to the right of oriC, between sites 1014 and 1065 of the gene D484_00045. Another was identified to the left of oriC, between sites 1185 and 1248 of D484_01632. These results indicate that ST2249 inherited approximately 35.3% of its chromosome from an ST239-like parent and 64.7% from an ST45-like parent. ST2249-MRSA-III resulted from a major recombination between parents that resemble ST239 and ST45. Although only limited Australian archival material is available, the oldest extant isolate of ST2249 predates the oldest Australian isolate of ST239 by 3 years. It is therefore plausible that these two recombinant clones were introduced into Australia separately.


The benefits of pair bond tenure in the cooperatively breeding pied babbler (Turdoides bicolor).
The benefits of stable pair bonds (that persist between breeding attempts) have been well described, but are relatively less well known in cooperatively breeding species. If pair bonds are beneficial, then it is possible that the bond between the behaviorally and socially dominant pair may influence factors such as reproductive success and group stability in cooperative species. Here, we used long-term data to investigate the relationships between pair bond tenure, reproductive success, and group stability in the cooperatively breeding pied babbler (Turdoides bicolor). Pair bond tenure positively influenced both the number of offspring recruited annually per pair and total reproductive success (over entire pair bond duration), indicating that pair bond tenure has an important influence on reproductive success. The likelihood of immigration into the group was lower for groups containing a bonded pair with long tenure, indicating that the duration of pair bonds may impact group stability. These findings suggest that pair tenure, a hitherto relatively unexplored factor in cooperative species, may have an important influence on group dynamics.


Hip abductor strength and lower extremity running related injury in distance runners: A systematic review.
Determine the association between hip abduction strength and lower extremity running related injury in distance runners. Systematic review. Prospective longitudinal and cross sectional studies that quantified hip abduction strength and provided diagnosis of running related injury in distance runners were included and assessed for quality. Effect size was calculated for between group differences in hip abduction strength. Of the 1841 articles returned in the initial search, 11 studies matched all inclusion criteria. Studies were grouped according to injury: iliotibial band syndrome, patellofemoral pain syndrome, medial tibial stress syndrome, tibial stress fracture, and Achilles tendinopathy, and examined for strength differences between injured and non-injured groups. Meaningful differences were found in the studies examining iliotibial band syndrome. Three of five iliotibial band syndrome articles found weakness in runners with iliotibial band syndrome; two were of strong methodological rigor and both of those found a relationship between weakness and injury. Other results did not form associative or predictive relationships between weakness and injury in distance runners. Hip abduction weakness evaluated by hand held dynamometer may be associated with iliotibial band syndrome in distance runners as suggested by several cross sectional studies but is unclear as a significant factor for the development of patellofemoral pain syndrome, medial tibial stress syndrome, tibial stress fracture or Achilles tendinopathy according to the current literature. Future studies are needed with consistent methodology and inclusion of all distance running populations to determine the significance of hip abduction strength in relationship to lower extremity injury.


Seasonal variation in the chemical composition, antioxidant activity, and total phenolic content of Artemisia absinthium essential oils.
The genus Artemisia belonging to the Compositae (Asteraceae) family and many traditional uses from the Artemisia species were reported. Artemisia absinthium is one of the species in this genus and commonly used in the food industry in the preparation of aperitifs, bitters, and spirits. Evaluation of the effect of different harvesting stages on the composition of essential oil and antioxidant capacity of A. absinthium. Essential oils from the aerial parts of A. absinthium, collected in three stages (preflowering, flowering, and after-flowering) from plants grown in the North Khorasan province of Iran were obtained by steam distillation and the chemical composition of the oils was analyzed by gas chromatography-mass spectrometry and antioxidant activity and total phenolic content were determined by 2-diphenyl-1-picrylhydrazyl assay and Folin-Ciocalteu method. Analysis of the isolated oils revealed the presence of 44 compounds, mainly alpha-pinene, sabinene, beta-pinene, alpha-phellandrene, p-cymene and chamazulene. Alpha-phellandrene, and chamazulene were major compounds in preflowering stage, but beta-pinene and alpha-phellandrene were major in flowering and past-flowering stages. Flowering stage had highest yield and after flowering stage had lowest yield. The essential oil of preflowering stage had the highest amount of antioxidant compound (chamazulene). Preflowering stage with highest amount of phenolic compounds had the strongest antioxidant activity with the lowest amount of EC50. This study showed that the harvesting stage had significant effects on chemical composition and antioxidant properties of essential oils, and chamazulene is main compound for antioxidant activity in A. absinthium.


Do Clear Cell Papillary Renal Cell Carcinomas Have Malignant Potential?
There have been no recurrences or metastases of clear cell papillary renal cell carcinoma (CCPRCC) in 268 reported cases with follow-up in the English-language literature. We identified all our cases of CCPRCC (1990 to 2013), reviewing all cases that preceded the formal designation of the entity. Immunohistochemical stains were performed on 32 cases during their initial workup. In addition, stains for carbonic anhydrase IX and cytokeratin 7 were performed on 2 cases, one with atypical follow-up and the other with a more compact morphology, although not performed initially. An extended panel with AMACR, CD10, and renal cell carcinoma (RCC) was added to the case with atypical follow-up. Fluorescence in situ hybridization for chromosomes 3p, 7, and 17 was performed on the latter case and on another clinically presumed metastatic tumor. In classic cases, immunohistochemical staining was not performed. Fifty-eight patients (31 women; 27 men) with follow-up data were included in our study; 39 cases were from our consult service. The patients' ages ranged from 36 to 83 years. Thirty-five patients had cystic or partially cystic lesions; 6 tumors were multifocal, 3 of which were bilateral. The majority (53 patients; 91.4%) presented with stage pT1 disease (size range, 0.2 to 8 cm), 2 patients presented with pT2 disease (8.5 and 10.3 cm), 1 patient presented with pT3 disease (6.5 cm sarcomatoid RCC focally extending out of the kidney), and pathologic stage was unavailable in 2 cases. Treatment consisted of 29 partial nephrectomies, 26 radical nephrectomies, 2 cryoablations, and 1 cyst ablation. The resection margins were negative in all but one case, with this case disease free after a 26-month period. Two patients had intraoperative tumor disruption and were disease free at 9 and 34 months. Five patients had synchronous ipsilateral renal cell carcinomas (non-CCPRCC). Mean follow-up time was 21 months (range, 1 to 175 mo), with all but 3 patients having no evidence of disease. One patient was presumed to have contralateral disease on the basis of imaging findings and is alive and well 37 months after multiple partial nephrectomies. Metastatic disease to the lung was clinically presumed in 1 patient in whom a higher-grade lesion may have been missed during sampling of the predominantly cystic pT1b tumor and tissue confirmation of the metastases was not obtained. Another case presented with multiple skeletal and pulmonary metastases 8 months after resection of pT3 sarcomatoid CCPRCC. The patient with the sarcomatoid RCC died of multifocal skeletal and pulmonary metastatic disease 13 months after resection of the renal tumor. Our study, the largest to date with follow-up, along with others, suggests that pure CCPRCC is an indolent tumor and should be renamed "clear cell papillary neoplasm of low malignant potential" to reflect their biology.


Flaviramulus basaltis gen. nov., sp. nov., a novel member of the family Flavobacteriaceae isolated from seafloor basalt.
Four yellow-pigmented, Gram-negative, motile strains were isolated from the glassy rind of submarine basaltic lava from the Jan Mayen area of the Norwegian/Greenland Sea at a depth of 1300 m below sea level. The four strains had identical 16S rRNA gene sequences and were indistinguishable in all phenotypic and chemotypic tests performed, indicating that they belonged to the same species. The strains had an obligately aerobic chemo-organotrophic metabolism. The strains were capable of growth at temperatures between -2 and 34 degrees C, at pH between 6.5 and 8.6, and at sea salt concentrations between 3 and 60 g l(-1). The strains were able to utilize organic acids, amino acids and sugars but not alcohols; they were also capable of hydrolysing a wide range of macromolecules. The predominant fatty acids were 15 : 0 iso, 15 : 1 iso, 15 : 0 iso 3-OH and 17 : 0 iso 3-OH. The mean DNA G+C content of the strains was 31.4 mol%. 16S rRNA gene sequence analysis indicated that the strains were affiliated to the genera Gaetbulibacter and Algibacter. However, phenotypic characteristics, especially aerobic metabolism, suggested that the strains should be placed within a new genus. On the basis of the polyphasic characterization of the four strains, it is suggested that the strains be included in the family Flavobacteriaceae as representatives of a novel species in a new genus, for which the name Flaviramulus basaltis gen. nov., sp. nov. is proposed. The type strain is H35(T) (=CIP 109091(T)=DSM 18180(T)).


Older adults' experience of health promotion: a theory for nursing practice.
Understanding older adults' experience of health promotion is essential in effectively preserving health and functional ability and thereby reducing health care costs among members of this rapidly expanding group. During 5 months of participant observation of 80 older adults (ages of 62-88), data from 31 semistructured interviews, as well as the Health Self-Determinism Index (HSDI) designed to measure intrinsic motivation for health (Cox, Miller, & Mull, 1987), were analyzed using methods common to grounded theory (Glaser & Strauss, 1967). Patterns central to maintaining health that provide essential theoretical grounding for health promotion practice with older adults were discovered.


Risk behaviors among Italian healthcare students: a cross-sectional study for health promotion of future healthcare workers.
Risk behaviors are frequent among young adults and they are particularly relevant when considering healthcare students. The study is aimed to examine the prevalence of smoking, binge drinking, physical inactivity, and excessive bodyweight in a population of healthcare students attending an Italian university. Healthcare students filled an anonymous multiple-choice questionnaire on the occasion of the occupational health visit that preceded their hospital internship. The questionnaire covered socio-demographic characteristics (including student's working status and cohabitation) and risk behaviors. We evaluated the prevalence of risk behaviors and their association with socio-demographic characteristics. The sample consisted of 494 students (65% women): 23.2% were smokers, 7.9% had excessive bodyweight, 35% did not practice any physical activity and 50% reported binge drinking at least once in the last 12 months. We found associations of male sex (30.5%) and being nursing students (29.9%) with smoking habit. The frequency of binge drinking was higher in men (38.4%), working students (53.9%), and among those who lived without family (50%). Physical inactivity was associated with female sex (44.2%) and living without family (57.1%). Finally, the co-presence of 2 risk behaviors or more was higher in men (36.8%), in nursing students (39.6%) and in working students (44.7%). Our findings regarding the prevalence of risk behaviors and their potential association with socio-demographic factors may be a clue to the definition of targeted strategies aimed at reducing of risk behaviors among healthcare students.


Aryl-bis-(scorpiand)-aza receptors differentiate between nucleotide monophosphates by a combination of aromatic, hydrogen bond and electrostatic interactions.
Bis-polyaza pyridinophane scorpiands bind nucleotides in aqueous medium with 10-100 micromolar affinity, predominantly by electrostatic interactions between nucleotide phosphates and protonated aliphatic amines and assisted by aromatic stacking interactions. The pyridine-scorpiand receptor showed rare selectivity toward CMP with respect to other nucleotides, whereby two orders of magnitude affinity difference between CMP and UMP was the most appealing. The phenanthroline-scorpiand receptor revealed at pH 5 strong selectivity toward AMP with respect to other NMPs, based on the protonation of adenine heterocyclic N1. The results stress that the efficient recognition of small biomolecules within scorpiand-like receptors relies mostly on the electrostatic and H-bonding interactions despite the competitive interactions in the bulk solvent, thus supporting further optimisation of this versatile artificial moiety.


Quantifying the performance of individual players in a team activity.
Teamwork is a fundamental aspect of many human activities, from business to art and from sports to science. Recent research suggest that team work is of crucial importance to cutting-edge scientific research, but little is known about how teamwork leads to greater creativity. Indeed, for many team activities, it is not even clear how to assign credit to individual team members. Remarkably, at least in the context of sports, there is usually a broad consensus on who are the top performers and on what qualifies as an outstanding performance. In order to determine how individual features can be quantified, and as a test bed for other team-based human activities, we analyze the performance of players in the European Cup 2008 soccer tournament. We develop a network approach that provides a powerful quantification of the contributions of individual players and of overall team performance. We hypothesize that generalizations of our approach could be useful in other contexts where quantification of the contributions of individual team members is important.


Anorexia nervosa in a woman totally blind since birth.
A 19-year-old woman, blind since birth, lost 26 kg over a 7-month period. This was achieved by restriction of food intake, excessive exercise, laxative abuse, and self-induced vomiting. Although the visual experience is often believed to be an integral component of body-shape perception and the overvaluation of thinness in contemporary society, it does not preclude the development of anorexia nervosa.


Abnormal Vertical Eye Movements as a Clue for Diagnosis of Niemann-Pick Type C.
Adult-onset Niemann-Pick Type C is a rare neurogenetic lysosomal disorder, whose diagnosis is often delayed and missed because of its heterogeneous clinical presentations and rarity as well as the lack of awareness of characteristic eye findings among neurologists. Impaired smooth pursuits, saccades, and optokinetic nystagmus in the vertical direction, with relatively normal eye movements in the horizontal direction, and ataxia features on finger chase testing, tandem walking, and gait ataxia. Impairment of vertical eye movements in combination with ataxia, cognitive impairment, and/or psychiatric symptoms in an adult patient should always raise clinical suspicion of Niemann-Pick Type C.


User-determined end of net life in Senegal: a qualitative assessment of decision-making related to the retirement of expired nets.
Procurement and distribution of long-lasting insecticidal nets (LLINs) in the African region has decreased from 145 million in 2010 to 66 million nets in 2012. As resources for LLIN distribution appear to stagnate, it is important to understand the users' perception of the life span of a net and at what point and why they stop using it. In order to get the most value out of distributed nets and to ensure that they are used for as long as possible, programmes must communicate to users about how to assess useful net life and how to extend it. Data were collected from 114 respondents who participated in 56 in-depth interviews (IDIs) and eight focus group discussions (FGDs) in August 2012 in eight regions in Senegal. Households were eligible for the study if they owned at least one net and had an available household member over the age of 18. Data were coded by a team of four coders in ATLAS.ti using a primarily deductive approach. Respondents reported assessing useful net life using the following criteria: the age of net, the number and size of holes and the presence of mosquitoes in the net at night. If they had the means to do so, many respondents preferred the acquisition of a new net rather than the continued use of a very torn net. However, respondents would preferentially use newer nets, saving older, but useable nets for the future or sharing them with family or friends. Participants reported observing alternative uses of nets, primarily for nets that were considered expired. The results indicate that decisions regarding the end of net life vary among community members in Senegal, but are primarily related to net integrity. Additional research is needed into user-determined end of net life as well as care and repair behaviours, which could extend useful net life. The results from this study and from future research on this topic should be used to understand current behaviours and develop communication programmes to prolong the useful life of nets.


Anodal and Cathodal tDCS Over the Right Frontal Eye Fields Impacts Spatial Probability Processing Differently in Pro- and Anti-saccades.
Learning regularities that exist in the environment can help the visual system achieve optimal efficiency while reducing computational burden. Using a pro- and anti-saccade task, studies have shown that probabilistic information regarding spatial locations can be a strong modulator of frontal eye fields (FEF) activities and consequently alter saccadic behavior. One recent study has also shown that FEF activities can be modulated by transcranial direct current stimulation, where anodal tDCS facilitated prosaccades but cathodal tDCS prolonged antisaccades. These studies together suggest that location probability and tDCS can both alter FEF activities and oculomotor performance, yet how these two modulators interact with each other remains unclear. In this study, we applied anodal or cathodal tDCS over right FEF, and participants performed an interleaved pro- and anti-saccade task. Location probability was manipulated in prosaccade trials but not antisaccade trials. We observed that anodal tDCS over rFEF facilitated prosaccdes toward low-probability locations but not to high-probability locations; whereas cathodal tDCS facilitated antisaccades away from the high-probability location (i.e., same location as the low-probability locations in prosaccades). These observed effects were specific to rFEF as tDCS over the SEF in a separate control experiment did not yield similar patterns. These effects were also more pronounced in low-performers who had slower saccade reaction time. Together, we conclude that (1) the overlapping spatial endpoint between prosaccades (i.e., toward low-probability location) and antisaccades (i.e., away from high-probability location) possibly suggest an endpoint-selective mechanism within right FEF, (2) anodal tDCS and location probability cannot be combined to produce a bigger facilitative effect, and (3) anodal rFEF tDCS works best on low-performers who had slower saccade reaction time. These observations are consistent with the homeostasis account of tDCS effect and FEF functioning.


[The seroepidemiology of rubella in a female population of reproductive age in León, Guanajuato].
In order to assess the seroepidemiology of protective antibodies against rubella among women from León, Guanajuato, Mexico, a prospective study was done. The sample consisted in 176 serum samples from urban and rural women at reproductive age, drawn from June 1990 to June 1991. Samples were tested by the classic hemagglutination inhibition method, titers of 1:8 or higher were considered as positive. Global positivity was 71 per cent (125 sera). Seropositivity did not increase with women's age; the lowest values were seen at the rural zones (58.9%). This survey showed a lower seropositivity than the previously reported in Mexico, and confirms data from new official studies. With this information authors suggest that the utility and viability of a national vaccination program should be reviewed and propose that it could be risky that individual clinicians to recommend children vaccination because the lack of coordination could increase adult cases of rubella.


Early-vision brain responses which predict human visual segmentation and learning.
Brain processes underlying visual segmentation have been widely studied, being part of the basic processes underlying perception. However, the underlying constraints on perceptual thresholds, set by neuronal processing, remain unclear. Here, the relationship between human visual performance and brain activity was examined using the backward-masked texture segmentation task. Performance showed dependence on the time-interval between target and mask as well as on the amount of prior practice. Correspondingly, early components of human event-related potentials (ERPs) recorded over occipital electrodes showed strong interactions between target and mask responses, suggesting interference with perception processes when the presented mask interacts with sustained target processing. These interactions, revealing an otherwise undetected extended processing time course beyond the early component of the target response, enabled us to quantify individual neuronal thresholds that closely matched the behavioral thresholds (r = 0.93, p = 0.00003). Furthermore, these neuronal thresholds could be improved by practice, suggesting neuronal mechanisms affected by perceptual learning. Predicting performance level not directly detected in the ERP but rather by further interactions shown here in early stages of the visual hierarchy may have important implications in the study of human perception. Practice seems to reduce the temporal interactions between the successive stimuli, revealing brain processes underlying perceptual learning.


Early use of non invasive ventilation in patients with amyotrophic lateral sclerosis: what benefits?
The aim of this study was to analyze the efficacy of an early start of NIV in ALS patients, evaluating respiratory and ventilatory parameters. Functional respiratory parameters and arterial blood gas analysis were evaluated in forty-six patients. All patients were informed about the benefits and possible adverse effects of therapeutic support with NIV and divided in two groups based on the compliance to early start therapy with NIV (Group A) or not (Group B). Among 46 ALS patients consecutively visited in our Unit, we included 20 patients in the Group A and 16 in the Group B. We have emphasized the importance of the early use of NIV stressing the difference between two groups analyzed, particularly in terms of pulmonary function tests and arterial blood gas analysis. Significant correlation was observed between Vital Capacity (VC), Forced Expiratory volume in one second (FEV1), and maximal inspiratory pressures (PImax). Our study highlights the importance of noninvasive mechanical ventilation as a treatment for ALS patients and also shows the early start of NIV as an important approach in order to postpone the functional decline and the decrease of respiratory muscle strength.


Does college major matter for women's and men's health in midlife? Examining the horizontal dimensions of educational attainment.
Studies on how education shapes adult health have largely conceptualized education as the quantity of schooling attained, coined the "vertical dimension" of education. While this dimension is important, heterogeneity within levels of education (the "horizontal dimension") may also shape health. Using data from the 2010-2014 American Community Survey on adults aged 45-64 with a Bachelor's degree (N = 667,362), we investigate the association between a key indicator of adult health (physical functioning) and an understudied horizontal dimension of education (college major). We find that physical functioning in midlife varies significantly by college major. For instance, the odds of poor functioning for men who majored in Psychology/Social Work were 1.9 (95% CI: 1.7, 2.1) times greater than for men who majored in Business. However, all college graduates, regardless of major, report better functioning than non-graduates. We also find that inequalities in midlife functioning across majors largely reflect differences in human capital skills and financial returns in the labor market. Taken together our findings suggest that college major is an important component of health stratification and should be integrated into the literature on health inequalities.


Frequency and clinicopathological characteristics of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia.
The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania's Alzheimer's Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study.


Global quieting of high-frequency seismic noise due to COVID-19 pandemic lockdown measures.
Human activity causes vibrations that propagate into the ground as high-frequency seismic waves. Measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic caused widespread changes in human activity, leading to a months-long reduction in seismic noise of up to 50%. The 2020 seismic noise quiet period is the longest and most prominent global anthropogenic seismic noise reduction on record. Although the reduction is strongest at surface seismometers in populated areas, this seismic quiescence extends for many kilometers radially and hundreds of meters in depth. This quiet period provides an opportunity to detect subtle signals from subsurface seismic sources that would have been concealed in noisier times and to benchmark sources of anthropogenic noise. A strong correlation between seismic noise and independent measurements of human mobility suggests that seismology provides an absolute, real-time estimate of human activities.


Examining the influence of aggressive driving behavior on driver injury severity in traffic crashes.
In this paper, we capture the moderating effect of aggressive driving behavior while assessing the influence of a comprehensive set of variables on injury severity. In doing so, we are able to account for the indirect effects of variables on injury severity through their influence on aggressive driving behavior, as well as the direct effect of variables on injury severity. The methodology used in the paper to accommodate the moderating effect of aggressive driving behavior takes the form of two models--one for aggressive driving and another for injury severity. These are appropriately linked to obtain the indirect and direct effects of variables. The data for estimation is obtained from the National Motor Vehicle Crash Causation Study (NMVCCS). From an empirical standpoint, we consider a fine age categorization until 20 years of age when examining age effects on aggressive driving behavior and injury severity. There are several important results from the empirical analysis undertaken in the current paper based on post-crash data collection on aggressive behavior participation just prior to the crash and injury severity sustained in a crash. Young drivers (especially novice drivers between 16 and 17 years of age), drivers who are not wearing seat belt, under the influence of alcohol, not having a valid license, and driving a pick-up are found to be most likely to behave aggressively. Situational, vehicle, and roadway factors such as young drivers traveling with young passengers, young drivers driving an SUV or a pick-up truck, driving during the morning rush hour, and driving on roads with high speed limits are also found to trigger aggressive driving behavior. In terms of vehicle occupants, the safest situation from a driver injury standpoint is when there are two or more passengers in the vehicle, at least one of whom is above the age of 20 years. These and many other results are discussed, along with implications of the result for graduated driving licensing (GDL) programs.


Patients' Experience of Myositis and Further Validation of a Myositis-specific Patient Reported Outcome Measure - Establishing Core Domains and Expanding Patient Input on Clinical Assessment in Myositis. Report from OMERACT 12.
The Outcome Measures in Rheumatology (OMERACT) myositis working group was established to examine patient-reported outcomes (PRO) as well as to validate patient-reported outcome measures (PROM) in myositis. Qualitative studies using focus group interviews and cognitive debriefing of the myositis-specific Myositis Activities Profile (MAP) were used to explore the experience of adults living with polymyositis (PM) and dermatomyositis (DM). Preliminary results underscore the importance of patient input in the development of PROM to ensure content validity. Results from multicenter focus groups indicate the range of symptoms experienced including pain, fatigue, and impaired cognitive function, which are not currently assessed in myositis. Preliminary cognitive debriefing of the MAP indicated that while content was deemed relevant and important, several activities were not included; and that questionnaire construction and wording may benefit from revision. A research agenda was developed to continue work toward optimizing PRO assessment in myositis with 2 work streams. The first would continue to conduct and analyze focus groups until saturation in the thematic analysis was achieved to develop a framework that encompassed the patient-relevant aspects of myositis. The second would continue cognitive debriefing of the MAP to identify potential areas for revision. There was agreement that further work would be needed for inclusion body myositis and juvenile dermatomyositis, and that the inclusion of additional contributors such as caregivers and individuals from the pharmaceutical/regulatory spheres would be desirable. The currently used PROM do not assess symptoms or the effects of disease that are most important to patients; this emphasizes the necessity of patient involvement. Our work provides concrete examples for PRO identification.


Bilateral Legg-Calve-Perthes Disease and Kienbock's Disease in a Child With Factor V Leiden Thrombophilia: A Case Report.
Background: The etiology of multifocal osteonecrosis is not definitively known; however, hypercoagulable state is a very plausible cause. Methods: We present an unusual case of a 12-year-old boy with a history of Legg-Calve-Perthes disease presenting with right wrist pain who was subsequently diagnosed with Kienbock's disease. The finding of multifocal osteonecrosis prompted testing for a hypercoagulable state that was positive for Factor V Leiden thrombophilia. A thorough literature review using Medline database was conducted to investigate associations between inherited hypercoagulable states and multifocal osteonecrosis. Results: Our literature review identified 2 similar cases of multifocal osteonecrosis associated with a hypercoagulable disorder in adult patients. There were no reports among the pediatric patient population. Meta-analysis has demonstrated a potential link between Legg-Calve-Perthes disease and Factor V Leiden thrombophilia. Conclusions: This study offers further evidence to support the theory that multifocal osteonecrosis may be linked to a hypercoagulable state. Patients presenting with multifocal osteonecrosis should undergo screening for hypercoagulable states. Further investigation is needed to ascertain the potential benefit of prophylactic anticoagulation in patients with a known hypercoagulable state and multifocal osteonecrosis.


Gas-phase production of gold-decorated silica nanoparticles.
Gold-decorated silica nanoparticles were synthesized in a two-step process in which silica nanoparticles were produced by chemical vapor synthesis using tetraethylorthosilicate (TEOS) and subsequently decorated using two different gas-phase evaporative techniques. Both evaporative processes resulted in gold decoration of the silica particles. This study compares the mechanisms of particle decoration for a production method in which the gas and particles remain cool to a method in which the entire aerosol is heated. Results of transmission electron microscopy and visible spectroscopy studies indicate that both methods produce particles with similar morphologies and nearly identical absorption spectra, with peak absorption at 500-550 nm. A study of the thermal stability of the particles using heated-TEM indicates that the gold decoration on the particle surface remains stable at temperatures below 900 °C, above which the gold decoration begins to both evaporate and coalesce.


Acceptance of repeat esophagogastroduodenoscopy to detect gastric cancer in a Chinese immigrant cohort.
To study the feasibility of using repeat esophagogastroduodenoscopy (EGD) to screen for Helicobacter pylori infection and gastric cancer in an Asian immigrant cohort. Immigrants in the United States (US) from countries with high per capita rates of gastric cancer remain at higher risk for gastric cancer. The existence of the possibly modifiable risk factor of H. pylori infection and the poor outcomes associated with late-stage disease make screening higher-risk groups with EGD an appealing possibility. It is unknown whether Asian immigrants in the US would accept an EGD-based strategy for gastric cancer screening. Cross-sectional study of adult Chinese immigrants in New York City with dyspepsia who underwent EGD in an earlier gastric cancer detection study, who were offered a second EGD four years later. Our main outcome measure was acceptance or refusal of repeat EGD. Seventy-three of the 115 Chinese participants in the earlier study were successfully contacted for this current study. Twenty-three of 73 (32%) underwent repeat EGD. Leading reasons given for declining were lack of symptoms and lack of time. Significantly associated with acceptance of repeat EGD was the belief that EGD will find stomach cancer "nearly always" in someone who has it (P=0.0054; odds ratio=14.0, 2.1 to 94.2 95% confidence interval). Acceptance of repeat EGD for gastric cancer detection in a cohort of Chinese immigrants was relatively low despite the mitigation of cost and language factors, 2 major barriers to healthcare access. Relocation seemed to be a factor as well. In this population, perceptions of the benefits of EGD may influence acceptance of testing for cancer detection purposes.


Loss of function associated with novel mutations of the SCN5A gene in patients with Brugada syndrome.
Ventricular fibrillation is one of the leading causes of death in North America. Brugada syndrome is characterized by ST segment elevation on the right precordial leads V1 through V3 and right bundle branch block, and may cause sudden death. Mutations in the SCN5A gene encoding the cardiac voltage-gated Na+ channel (hNav1.5) are associated with Brugada syndrome. In this study, three novel mutations on the SCN5A gene were identified and characterized in different patients with Brugada syndrome. Blood samples were collected from patients with Brugada syndrome for gene screening. Mutations found on the SCN5A gene in these patients were reproduced in vitro on hNav1.5 background. Wild type and mutant channels expressed in tsA201 cells were characterized using the patch clamp technique in whole cell configuration and/or confocal microscopy. No current could be recorded from cells expressing the hNav1.5/G1740R mutant, incubated at 37 degrees C. However, at a lower incubation temperature (22 degrees C), macroscopic Na+ currents were recorded. Confocal microscopy study confirmed that at 37 degrees C, hNav1.5/G1740R mutant channels were retained in the endoplasmic reticulum. The E473X and N1774+12X mutants produced truncated proteins and did not express any currents; however, coexpression of each of these mutants with wild type channels shows 50% reduction of Na+ currents. This study confirms that the loss of function of cardiac Na+ channels is the basis of the Brugada syndrome clinical phenotype.


Mental health-related quality of life and the timing of motherhood: a 16-year longitudinal study of a national cohort of young Australian women.
We examine timing of motherhood in a longitudinal cohort of young Australian women, and its relationship with mental health-related quality of life (SF-36 MHI-5), and with sociodemographic, health behaviour and health-related variables. We analysed longitudinal self-report data from a nationally representative cohort of 10,332 Australian women born 1973-1978, surveyed 6 times between 1996 (aged 18-23) and 2012 (aged 34-39). Group-based trajectory modelling identified four groups. Normative Mothers (46%, mean age at motherhood 30.5 years) made the transition to motherhood close to the Australian median age. Early Mothers (25%, 25.2 years) and Very Early Mothers (7%, 20.0 years) made this transition earlier; Not Mothers (22%) had not given birth. Generalised linear mixed models showed that all groups improved mean MHI-5 scores over time. Patterns of group differences were complex: Normative and Early Mothers scored consistently highest; Very Early Mothers scored lowest at most surveys; Not Mothers' scores increased relative to others over time. Most effects disappeared after adjustment for confounders. Early and Very Early Mothers showed multiple indicators of social disadvantage, while Not Mothers had very low rates of marriage. Timing of motherhood is embedded in sociodemographic and personal contexts. Women with socioeconomic advantages were characterised by higher mental health-related quality of life and later transition to motherhood, but adjustment for relative advantage attenuated differences in mental health-related quality of life. The overall findings suggest a pattern of positive adaptation to circumstances, with mental health-related quality of life improving through early adulthood regardless of timing of motherhood.


Systematic review of the validity and reliability of consumer-wearable activity trackers.
Consumer-wearable activity trackers are electronic devices used for monitoring fitness- and other health-related metrics. The purpose of this systematic review was to summarize the evidence for validity and reliability of popular consumer-wearable activity trackers (Fitbit and Jawbone) and their ability to estimate steps, distance, physical activity, energy expenditure, and sleep. Searches included only full-length English language studies published in PubMed, Embase, SPORTDiscus, and Google Scholar through July 31, 2015. Two people reviewed and abstracted each included study. In total, 22 studies were included in the review (20 on adults, 2 on youth). For laboratory-based studies using step counting or accelerometer steps, the correlation with tracker-assessed steps was high for both Fitbit and Jawbone (Pearson or intraclass correlation coefficients (CC) > =0.80). Only one study assessed distance for the Fitbit, finding an over-estimate at slower speeds and under-estimate at faster speeds. Two field-based studies compared accelerometry-assessed physical activity to the trackers, with one study finding higher correlation (Spearman CC 0.86, Fitbit) while another study found a wide range in correlation (intraclass CC 0.36-0.70, Fitbit and Jawbone). Using several different comparison measures (indirect and direct calorimetry, accelerometry, self-report), energy expenditure was more often under-estimated by either tracker. Total sleep time and sleep efficiency were over-estimated and wake after sleep onset was under-estimated comparing metrics from polysomnography to either tracker using a normal mode setting. No studies of intradevice reliability were found. Interdevice reliability was reported on seven studies using the Fitbit, but none for the Jawbone. Walking- and running-based Fitbit trials indicated consistently high interdevice reliability for steps (Pearson and intraclass CC 0.76-1.00), distance (intraclass CC 0.90-0.99), and energy expenditure (Pearson and intraclass CC 0.71-0.97). When wearing two Fitbits while sleeping, consistency between the devices was high. This systematic review indicated higher validity of steps, few studies on distance and physical activity, and lower validity for energy expenditure and sleep. The evidence reviewed indicated high interdevice reliability for steps, distance, energy expenditure, and sleep for certain Fitbit models. As new activity trackers and features are introduced to the market, documentation of the measurement properties can guide their use in research settings.


RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation.
RRR-alpha-Tocopheryl succinate (vitamin E succinate, VES) is a potent antitumor agent, inducing DNA synthesis arrest, differentiation, and apoptosis. Because little is known about VES-induced differentiation, studies reported here characterize VES effects on the differentiation status of human breast cancer cell lines and investigate possible molecular mechanisms involved. VES-induced differentiation of human MCF-7 and MDA-MB-435 breast cancer cells was characterized by morphological changes, induction of lipid droplets, induction of beta-casein mRNA expression, and down-regulation of Her2/neu protein. In contrast, VES treatment of normal human mammary epithelial cells, MCF-10A cells, and T-47D cells did not induce differentiation. Studies addressing mechanisms showed that neither antibody neutralization of the transforming growth factor-beta signaling pathway nor expression of a dominant-negative mutant of c-Jun N-terminal kinase blocked the ability of VES to induce differentiation; however, treatment of cells with PD 98059, a chemical inhibitor of mitogen-activated protein kinase kinase (MEK1/2), blocked the ability of VES to induce differentiation.


The dominant developmental mutants of tomato, Mouse-ear and Curl, are associated with distinct modes of abnormal transcriptional regulation of a Knotted gene.
The Curl (Cu) and Mouse-ear (Me) mutations of tomato cause two seemingly unrelated developmental syndromes with a wide range of pleiotropic phenotypes. Yet, the distinct morphogenic alterations in shoots, leaves, and inflorescences conferred by the two mutations appear to be caused by unchecked meristematic activity that characterizes dominant mutations in Knotted1 (Kn1)-like genes of monocot plants. We have been unable to separate the two closely linked Cu and Me mutations, and they may lie in the same gene. A homeobox-containing class I Kn1-like gene, TKn2, also maps to the same location. Significantly, the dominant mutations are associated with two aberrant modes of TKn2 transcription. Overexpression of the two in-frame wild-type transcripts of TKn2 is associated with the Cu mutation, whereas misexpression of an abundant and oversized fusion mRNA is associated with the Me mutation. Available molecular evidence strongly suggests that the defective Me-TKn2 transcript is generated via a novel splicing event that merges transcripts of two closely linked genes. The translated fusion product is comprised of most of the 5' end of the adjacent PPi-dependent fructose 6-phosphate phosphotransferase (PFP) transcript spliced in-frame to coding position 64 of the TKn2 transcript, leaving the TKn2 homeobox intact. We suggest that class I Kn1-like genes were selected early during evolution to regulate basic programs of aerial meristems and that subtle alterations in their function may be the basis for the wide diversity in growth parameters of shoot systems, leaves, and inflorescences among plant species.


Identification and characterization of ERV transcripts in goat embryos.
Endogenous retroviruses (ERVs), which are abundant in mammalian genomes, can modulate the expression of nearby genes, and their expression is dynamic and stage-specific during early embryonic development in mice and humans. However, the functions and mechanisms of ERV elements in regulating embryonic development remain unclear. Here, we utilized several methods to determine the contribution of ERVs to the makeup and regulation of transcripts during embryonic genome activation (EGA). We constructed an ERV library and embryo RNA-seq library (IVF_2c and IVF_8c) of goat to serve as our research basis. The GO and KEGG analysis of nearby ERV genes revealed that some ERV elements may be associated with embryonic development. RNA-seq results were consistent with the features of EGA. To obtain the transcripts derived from the ERV sequences, we blasted the ERV sequences with embryonic transcripts and identified three lncRNAs and one mRNA that were highly expressed in IVF-8c rather than in IVF-2c (q-value <0.05). Then, we validated the expression patterns of nine ERV-related transcripts during early developmental stages and knocked down three high-expression transcripts in EGA. The knockdown of lncRNA TCONS_00460156 or mRNA HSD17B11 significantly decreased the developmental rate of IVF embryos. Our findings suggested that some transcripts from ERVs are essential for the early embryonic development of goat, and analyzing the ERV expression profile during goat EGA may help elucidate the molecular mechanisms of ERV in regulating embryonic development.


Relaxation of selection, niche construction, and the Baldwin effect in language evolution.
Deacon has suggested that one of the key factors of language evolution is not characterized by an increase in genetic contribution, often known as the Baldwin effect, but rather by a decrease. This process effectively increases linguistic learning capability by organizing a novel synergy of multiple lower-order functions previously irrelevant to the process of language acquisition. Deacon posits that this transition is not caused by natural selection. Rather, it is due to the relaxation of natural selection. While there are some cases in which relaxation caused by some external factors indeed induces the transition, we do not know what kind of relaxation has worked in language evolution. In this article, a genetic-algorithm-based computer simulation is used to investigate how the niche-constructing aspect of linguistic behavior may trigger the degradation of genetic predisposition related to language learning. The results show that agents initially increase their genetic predisposition for language learning—the Baldwin effect. They create a highly uniform sociolinguistic environment—a linguistic niche construction. This means that later generations constantly receive very similar inputs from adult agents, and subsequently the selective pressure to retain the genetic predisposition is relaxed.


Animal models of maternal nutrition and altered offspring bone structure--bone development across the lifecourse.
It is widely accepted that the likelihood of offspring developing heart disease, stroke, or diabetes in later life, is influenced by the their in utero environment and maternal nutrition. There is increasing epidemiological evidence that osteoporosis in the offspring may also be influenced by the mother's nutrition during pregnancy. This review provides evidence from a range of animal models that supports the epidemiological data; suggesting that lifelong bone development and growth in offspring is determined during gestation.


Bistability in biochemical signaling models.
This Teaching Resource provides lecture notes, slides, and a student assignment for a two-part lecture on the principles underlying bistability in biochemical signaling networks, which are illustrated with examples from the literature. The lectures cover analog, or graded, versus digital, all-or-none, responses in cells, with examples from different types of biological processes requiring each. Rate-balance plots are introduced as a method for determining whether generic one-variable systems exhibit one or several stable steady states. Bifurcation diagrams are presented as a more general method for detecting the presence of bistability in biochemical signaling networks. The examples include an artificial toggle switch, the lac operon in bacteria, and the mitogen-activated protein kinase cascade in both Xenopus oocytes and mammalian cells. The second part of the lecture links the concepts of bistability more closely to the mathematical tools provided by dynamical systems analysis. The examples from the first part of the lecture are analyzed with phase-plane techniques and bifurcation analysis, using the scientific programming language MATLAB. Using these programs as a template, the assignment requires the students to implement a model from the literature and analyze the stability of this model's steady states.


Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine.
The therapeutic efficacy of liposomal clofazimine (L-CLF) was studied in mice infected with Mycobacterium tuberculosis Erdman. Groups of mice were treated with either free clofazimine (F-CLF), L-CLF, or empty liposomes twice a week for five treatments beginning on day 1 (acute), day 21 (established), or day 90 (chronic) postinfection. One day after the last treatment, the numbers of CFU of M. tuberculosis in the spleen, liver, and lungs were determined. F-CLF at the maximum tolerated dose of 5 mg/kg of body weight was ineffective; however, 10-fold-higher doses of L-CLF demonstrated a dose response with significant CFU reduction in all tissues without any toxic effects. In acutely infected mice, 50 mg of L-CLF/kg reduced CFU 2 to 3 log units in all three organs. In established or chronic infection, treated mice showed no detectable CFU in the spleen or liver and 1- to 2-log-unit reduction in the lungs. A second series of L-CLF treatments cleared M. tuberculosis in all three tissues. L-CLF appears to be bactericidal in the liver and spleen, which remained negative for M. tuberculosis growth for 2 months. Thus, L-CLF could be useful in the treatment of tuberculosis.


Is there a relationship between cell phone use and semen quality?
This study was conducted to determine a possible relationship between regular cell phone use and different human semen attributes. The history-taking of men in our university clinic was supplemented with questions concerning cell phone use habits, including possession, daily standby position and daily transmission times. Semen analyses were performed by conventional methods. Statistics were calculated with SPSS statistical software. A total of 371 were included in the study. The duration of possession and the daily transmission time correlated negatively with the proportion of rapid progressive motile sperm (r = -0.12 and r = -0.19, respectively), and positively with the proportion of slow progressive motile sperm (r = 0.12 and r = 0.28, respectively). The low and high transmitter groups also differed in the proportion of rapid progressive motile sperm (48.7% vs. 40.6%). The prolonged use of cell phones may have negative effects on the sperm motility characteristics.


Angiomyolipoma and PEComa are immunoreactive for MyoD1 in cell cytoplasmic staining pattern.
The family of tumors derived from mesenchymal perivascular epithelioid cells (so-called PEComas) includes angiomyolipoma, lymphangioleiomyomatosis, clear cell sugar tumor of the lung, clear cell myomelanocytic tumor of ligamentum teres/falciform ligament, and abdominopelvic sarcoma of perivascular epithelioid cells. These tumors were characterized by coexpression of melanocytic (HMB-45) and muscle markers. MyoD1 transcription factor has crucial role in commitment and differentiation of mesenchymal progenitor cells to myogenic lineage. Antibodies to MyoD1 protein (nuclear immunoreactivity) have been shown highly valuable adjuncts in the diagnosis of rhabdomyosarcomas. To evaluate expression of the transcription factor MyoD1 in PEComas, we performed immunohistochemistry. Monoclonal antibody 5.8A for MyoD1 was used on a series of cases of formalin-fixed, paraffin-embedded angiomyolipoma (n = 19), lymphangioleiomyomatosis (n = 3), clear cell sugar tumor of the lung (n = 1), and abdominopelvic sarcoma of perivascular epithelioid cells (n = 2). All cases showed strong granular immunostaining in the tumor cell cytoplasm with the anti-MyoD1 antibody. Cytoplasmic reactivity was noted in the spindle cells, fat cells, and epithelioid cells. Nuclei were negative in all tumors studied, and a clean background was obtained. Several normal and neoplastic human tissues have also been immunostained for MyoD1 without any positive cytoplasmic staining, with the exception of 2 alveolar soft part sarcomas. Cytoplasmic immunostaining with monoclonal antibody 5.8A for MyoD1 in PEComas may correspond to cross-reactivity with an undetermined cytoplasmic protein. Great caution should be exercised in interpreting the immunostaining results with anti-MyoD1 antibody 5.8A.


Preparation of single cells for imaging/profiling mass spectrometry.
Characterizing chemical changes within individual cells is important for determining fundamental mechanisms of biological processes that will lead to new biological insights and improved disease understanding. Analyzing biological systems with imaging and profiling mass spectrometry (MS) has gained popularity in recent years as a method for creating chemical maps of biological samples. To obtain mass spectra that provide relevant molecular information about individual cells, samples must be prepared so that salts and other cell culture components are removed from the cell surface and that the cell contents are rendered accessible to the desorption beam. We have designed a cellular preparation protocol for imaging/profiling MS that removes the majority of the interfering species derived from the cellular growth medium, preserves the basic morphology of the cells, and allows chemical profiling of the diffusible elements of the cytosol. Using this method, we are able to reproducibly analyze cells from three diverse cell types: MCF7 human breast cancer cells, Madin-Darby canine kidney (MDCK) cells, and NIH/3T3 mouse fibroblasts. This preparation technique makes possible routine imaging/profiling MS analysis of individual cultured cells, allowing for understanding of molecular processes within individual cells.


Two novel mutations identified in the Wiskott-Aldrich syndrome protein gene cause Wiskott-Aldrich syndrome and thrombocytopenia.
Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are rare X-linked genetic disorders caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene. Both disorders are clinically characterized by chronic thrombocytopenia of small platelets. WAS is a more severe form of the disorder and also courses with eczema, and immune dysfunction. In the present study, we investigated two novel mutations of the WASP gene in two Spanish families with patients clinically diagnosed as having XLT and WAS, respectively. In one of the families a missense mutation in exon 12 (1488A>G), resulting in the highly conserved glutamic residue changing to glycine at position 485 (D485G), was identified in several members. Notably, a female of this family, with clinical signs of XLT, was determined as the carrier of the mutation and showed a skewed pattern of X-inactivation, preferentially inactivating the X-chromosome carrying the wild-type allele. In the case of the second family, we describe a WAS patient with a single base deletion in exon 2 (266-267delA), resulting in a frameshift (at codon 78) that creates a stop codon at amino acid 127. As a consequence, there was no WASP expression.


Gendered violence and overdose prevention sites: a rapid ethnographic study during an overdose epidemic in Vancouver, Canada.
North America's overdose epidemic is increasingly driven by fentanyl and fentanyl-adulterated drugs. Supervised consumption sites, including low-threshold models (termed overdose prevention sites; OPS), are now being debated in the United States and implemented in Canada. Despite evidence that gendered and racialized violence shape access to harm reduction among women who use drugs (WWUD), this has not been examined in relation to OPS and amid the overdose epidemic. This study explores how overlapping epidemics of overdose and gendered and racialized violence in Vancouver's Downtown Eastside, one of North America's overdose epicenters, impacts how marginalized WWUD experience OPS. Qualitative analysis using rapid ethnographic fieldwork. Data collection included 185 hours of naturalistic observation and in-depth interviews; data were analyzed thematically using NVivo. Vancouver, Canada. Thirty-five WWUD recruited from three OPS. Participants' experiences of OPS and the public health emergency. The rapid onset and severity of intoxication associated with the use of fentanyl-adulterated drugs in less regulated drug use settings not only amplified WWUD's vulnerability to overdose death but also violence. Participants characterized OPS as safer spaces to consume drugs in contrast to less regulated settings, and accommodation of assisted injections and injecting partnerships was critical to increasing OPS access among WWUD. Peer-administered injections disrupted gendered power relations to allow women increased control over their drug use; however, participants indicated that OPS were also gendered and racialized spaces that jeopardized some women's access. Although women who use drugs in Vancouver, Canada appear to feel that overdose prevention sites address forms of everyday violence made worse by the overdose epidemic, these sites remain 'masculine spaces' that can jeopardize women's access.


Biology and demographic growth parameters of cowpea aphid (Aphis craccivora) on faba bean (Vicia faba) cultivars.
The performance of cowpea aphid, Aphis craccivora Koch. (Hemiptera: Aphididae), on five faba bean, Vicia faba L. (Fabales: Fabaceae) cultivars was evaluated. Colony development, biology, and demographic parameters were studied to measure the cowpea aphid performance. Two methods, whole plant and detached leaf, were used in these experiments. After 14 d , the number of apterous adult, nymphs, and total cowpea aphids were significantly lower in cultivar Gazira2 and highest on cultivar Misr1. Assuming that low aphid numbers per plant represented high resistance, the order of resistant cultivars was as follows: Gazira2 > Misr > Giza3 Improved > Goff1 > Misr1. Aphid infestation significantly inhibited plant growth compared with uninfested plants, as indicated by factorial analysis using plant height (F = 41.38, P < 0.0001). The detached-leaf biological assay showed that the cultivar Gazira2 was less suitable than Misr1 because it had longer prereproductive, reproductive, and post reproductive periods, longer total longevity, and lower number of progeny. Similarly, demographic parameters also justified the suggested lower suitability of Gazira2 compared with Misr1, indicated by significantly lower net reproduction rate, intrinsic rate of increase, finite rate of increase, but longer generation time and doubling time on Gazira2. It was shown that cowpea aphid performed differently on the whole plant as compared with detached leaves. The detached-leaf biological assay is recommended for future experiments because it is more accurate and efficient and it produces reliable data.


Fabrication of electroless nickel plated aluminum freeform mirror for an infrared off-axis telescope.
Freeform mirrors can be readily fabricated by a single point diamond turning (SPDT) machine. However, this machining process often leaves mid-frequency errors (MFEs) that generate undesirable diffraction effects and stray light. In this work, we propose a novel thin electroless nickel plating procedure to remove MFE on freeform surfaces. The proposed procedure has a distinct advantage over a typical thick plating method in that the machining process can be endlessly repeated until the designed mirror surface is obtained. This is of great importance because the sophisticated surface of a freeform mirror cannot be optimized by a typical SPDT machining process, which can be repeated only several times before the limited thickness of the nickel plating is consumed. We will also describe the baking process of a plated mirror to improve the hardness of the mirror surface, which is crucial for minimizing the degradation of that mirror surface that occurs during the polishing process. During the whole proposed process, the changes in surface figures and textures are monitored and cross checked by two different types of measurements, as well as by an interference pattern test. The experimental results indicate that the proposed thin electroless nickel plating procedure is very simple but powerful for removing MFEs on freeform mirror surfaces.


Community health and socioeconomic issues surrounding concentrated animal feeding operations.
A consensus of the Workgroup on Community and Socioeconomic Issues was that improving and sustaining healthy rural communities depends on integrating socioeconomic development and environmental protection. The workgroup agreed that the World Health Organization's definition of health, "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity," applies to rural communities. These principles are embodied in the following main points agreed upon by this workgroup. Healthy rural communities ensure a) the physical and mental health of individuals, b) financial security for individuals and the greater community, c) social well-being, d ) social and environmental justice, and e) political equity and access. This workgroup evaluated impacts of the proliferation of concentrated animal feeding operations (CAFOs) on sustaining the health of rural communities. Recommended policy changes include a more stringent process for issuing permits for CAFOs, considering bonding for manure storage basins, limiting animal density per watershed, enhancing local control, and mandating environmental impact statements.


Boston keratoprosthesis type 1 for herpes simplex and herpes zoster keratopathy.
The aim of this study was to evaluate and compare the outcomes of Boston keratoprosthesis type 1 (Kpro-1) in eyes with herpes simplex virus (HSV) and herpes zoster virus (HZV) keratopathy. A retrospective review was performed of the medical records of every patient treated with a Boston Kpro-1 at the University of Iowa Hospitals and Clinics between January 1, 2008 and July 1, 2012. Eyes with visual loss due to HSV or HZV keratopathy were included in the statistical analysis. The main outcome measures were graft retention, postoperative complications, and visual outcome. Nine eyes met the inclusion criteria, including 5 eyes in the HSV group and 4 eyes in the HZV group. The graft retention rate was 100% in the HSV group after a mean follow-up of 48.4 months, compared with 25% in the HZV group after 50.5 months (P = 0.048). There were 3 cases of microbial keratitis, including 2 eyes that also developed endophthalmitis, in the HZV group, compared with no cases in the HSV group (P = 0.048). There was significantly better best-corrected visual acuity at the most recent examination in the HSV group than in the HZV group (P = 0.019). All 5 HSV eyes had improved best-corrected visual acuity compared with preoperative acuity, whereas only 1 HZV eye experienced a similar result (P = 0.048). Kpro-1 is associated with an excellent prognosis for graft retention, acceptably low prevalence of sight-threatening complications, and highly satisfactory visual improvement in eyes with HSV keratopathy, but not in eyes with HZV keratopathy.


Interventions for Enhancing Adherence to Antiretroviral Therapy (ART): A Systematic Review of High Quality Studies.
We sought to review the effectiveness of interventions designed to improve adherence to antiretroviral therapy (ART) from studies included in a recent Cochrane review that reported a clinical and an adherence outcome, with at least 80% follow-up for 6 months or more. Data were extracted independently and in duplicate, with an adjudicator for disagreements. Risk of bias was assessed using the Cochrane Risk of Bias tool. Of 182 relevant studies in the Cochrane review, 49 were related to ART. Statistical pooling was not warranted due to heterogeneity in interventions, participants, treatments, adherence measures and outcomes. Many studies had high risk of bias in elements of design and outcome ascertainment. Only 10 studies improved both adherence and clinical outcomes. These used the following interventions: adherence counselling (two studies); a once-daily regimen (compared to twice daily); text messaging; web-based cognitive behavioral intervention; face-to-face multi-session intensive behavioral interventions (two studies); contingency management; modified directly observed therapy; and nurse-delivered home visits combined with telephone calls. Patient-related adherence interventions were the most frequently tested. Uniform adherence measures and higher quality studies of younger populations are encouraged.


Cold-water coral distributions in the drake passage area from towed camera observations--initial interpretations.
Seamounts are unique deep-sea features that create habitats thought to have high levels of endemic fauna, productive fisheries and benthic communities vulnerable to anthropogenic impacts. Many seamounts are isolated features, occurring in the high seas, where access is limited and thus biological data scarce. There are numerous seamounts within the Drake Passage (Southern Ocean), yet high winds, frequent storms and strong currents make seafloor sampling particularly difficult. As a result, few attempts to collect biological data have been made, leading to a paucity of information on benthic habitats or fauna in this area, particularly those on primarily hard-bottom seamounts and ridges. During a research cruise in 2008 six locations were examined (two on the Antarctic margin, one on the Shackleton Fracture Zone, and three on seamounts within the Drake Passage), using a towed camera with onboard instruments to measure conductivity, temperature, depth and turbidity. Dominant fauna and bottom type were categorized from 200 randomized photos from each location. Cold-water corals were present in high numbers in habitats both on the Antarctic margin and on the current swept seamounts of the Drake Passage, though the diversity of orders varied. Though the Scleractinia (hard corals) were abundant on the sedimented margin, they were poorly represented in the primarily hard-bottom areas of the central Drake Passage. The two seamount sites and the Shackleton Fracture Zone showed high numbers of stylasterid (lace) and alcyonacean (soft) corals, as well as large numbers of sponges. Though data are preliminary, the geological and environmental variability (particularly in temperature) between sample sites may be influencing cold-water coral biogeography in this region. Each area observed also showed little similarity in faunal diversity with other sites examined for this study within all phyla counted. This manuscript highlights how little is understood of these isolated features, particularly in Polar regions.


Mycobacterium tuberculosis escapes from the phagosomes of infected human osteoclasts reprograms osteoclast development via dysregulation of cytokines and chemokines.
Spinal tuberculosis is a condition characterized by massive resorption of the spinal vertebrae due to the infection with Mycobacterium tuberculosis (Mtb). However, the pathogenesis of spinal tuberculosis has not been established because it was almost completely eradicated by the establishment of antibiotic treatment in the mid-20th century. In this study, we investigated the inflammatory responses of human multinucleated osteoclasts infected with virulent Mtb strain. We found that the intracellular Mtb infection of multinuclear osteoclasts resulted in the rapid growth of Mtb and an osteolytic response, rather than inflammation. In response to Mtb infection, the mononuclear osteoclast precursors produced proinflammatory cytokines including tumor necrosis factor (TNF)-α, an intrinsic characteristic they share with macrophages. In contrast, highly fused multinucleated osteoclasts incapacitated the production of these cytokines. Instead, the intracellular Mtb inside multinuclear osteoclasts escaped from the endosome/phagosome, leading to a different pattern of osteoclast activation, with the production of chemokines such as CCL5, CCL17, CCL20, CCL22, CCL24, and CCL25. Moreover, intracellular infection with an avirulent Mtb strain resulted in diminished production of these chemokines. These findings indicate that intracellular Mtb infection in multinuclear osteoclasts reprograms osteoclast development via the dysregulation of cytokines and chemokines.


Atrial Rotor Dynamics Under Complex Fractional Order Diffusion.
The mechanisms of atrial fibrillation (AF) are a challenging research topic. The rotor hypothesis states that the AF is sustained by a reentrant wave that propagates around an unexcited core. Cardiac tissue heterogeneities, both structural and cellular, play an important role during fibrillatory dynamics, so that the ionic characteristics of the currents, their spatial distribution and their structural heterogeneity determine the meandering of the rotor. Several studies about rotor dynamics implement the standard diffusion equation. However, this mathematical scheme carries some limitations. It assumes the myocardium as a continuous medium, ignoring, therefore, its discrete and heterogeneous aspects. A computational model integrating both, electrical and structural properties could complement experimental and clinical results. A new mathematical model of the action potential propagation, based on complex fractional order derivatives is presented. The complex derivative order appears of considering the myocardium as discrete-scale invariant fractal. The main aim is to study the role of a myocardial, with fractal characteristics, on atrial fibrillatory dynamics. For this purpose, the degree of structural heterogeneity is described through derivatives of complex order γ = α + jβ. A set of variations for γ is tested. The real part α takes values ranging from 1.1 to 2 and the imaginary part β from 0 to 0.28. Under this scheme, the standard diffusion is recovered when α = 2 and β = 0. The effect of γ on the action potential propagation over an atrial strand is investigated. Rotors are generated in a 2D model of atrial tissue under electrical remodeling due to chronic AF. The results show that the degree of structural heterogeneity, given by γ, modulates the electrophysiological properties and the dynamics of rotor-type reentrant mechanisms. The spatial stability of the rotor and the area of its unexcited core are modulated. As the real part decreases and the imaginary part increases, simulating a higher structural heterogeneity, the vulnerable window to reentrant is increased, as the total meandering of the rotor tip. This in silico study suggests that structural heterogeneity, described by means of complex order derivatives, modulates the stability of rotors and that a wide range of rotor dynamics can be generated.


Novel Clostridium difficile Anti-Toxin (TcdA and TcdB) Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model.
Clostridium difficile (C. difficile) infection (CDI) is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA), and cytotoxin, toxin B (TcdB), which are necessary for C. difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4) and anti-TcdB (CANmAbB4 and CANmAbB1) antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail) provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively) in a hamster gastrointestinal infection (GI) model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C. difficile toxins and their potential as therapeutic agents in treating CDI.


Trials of implantable monitoring devices in heart failure: which design is optimal?
Implantable monitoring devices have been developed to detect early evidence of heart failure (HF) decompensation, with the hypothesis that early detection might enable clinicians to commence therapy sooner than would otherwise be possible, and potentially to reduce the rate of hospitalization. In addition to the usual challenges inherent to device trials (such as the difficulty of double-blinding and potential for bias), studies of implantable monitoring devices present unique difficulties because they involve assessment of therapeutic end points for diagnostic devices. Problems include the lack of uniform approaches to treatment in study protocols for device alerts or out-of-range values, and the requirement of levels of evidence traditionally associated with therapeutic devices to establish effectiveness and safety. In this Review, the approaches used to deal with these issues are discussed, including the use of objective primary end points with blinded adjudication, identical duration of follow-up and number of encounters for patients in active monitoring and control groups, and treatment recommendations between groups that are consistent with international guidelines. Remote monitoring devices hold promise for reducing the rate of hospitalization among patients with HF. However, optimization of regulatory approaches and clinical trial design is needed to facilitate further evaluation of the effectiveness of combining health information technology and medical devices.


Targeting Rac1 by the Yersinia effector protein YopE inhibits caspase-1-mediated maturation and release of interleukin-1beta.
Yersinia bacteria can take control of the host cell by injecting so-called Yop effector proteins into the cytosol of the cells to which they adhere. Using Yersinia enterocolitica strains that are deficient for one or more Yops, we could show that YopE and, to a lesser extent, YopT interfere with the caspase-1-mediated maturation of prointerleukin-1beta in macrophages. In addition, overexpression of YopE and YopT was shown to prevent the autoproteolytic activation of caspase-1 in a way that is dependent on their inhibitory effect on Rho GTPases. Expression of constitutive-active or dominant-negative Rho GTPase mutants or treatment with Rho GTPase inhibitors confirmed the role of Rho GTPases and, in particular, Rac1 in the autoactivation of caspase-1. Rac1-induced caspase-1 activation was mediated by its effect on LIM kinase-1, which is targeting the actin cytoskeleton. Rac-1 and LIM kinase-1 dominant-negative mutants were shown to inhibit caspase-1 activation induced by overexpression of Asc, which is a caspase-1-activating adaptor protein. Moreover, Rac1 as well as YopE and YopT significantly modulated caspase-1 oligomerization. These results highlight a previously unknown function of Rho GTPases in the activation of caspase-1 and give new insight on the role of YopE in immune-escape mechanisms of Yersinia.


Harmine mediated neuroprotection via evaluation of glutamate transporter 1 in a rat model of global cerebral ischemia.
Global cerebral ischemia (GCI) causes energy deficiency results in excessive release of glutamate from neurons. Astrocytic glutamate transporters play a predominant role in keeping extracellular glutamate concentrations below excitotoxic levels. Glutamate transporter 1 (GLT-1) may account for more than 90% of glutamate uptake in adult forebrain. Preclinical findings implicate that Harmine present neuroprotection effects in a rat model of amyotrophic lateral sclerosis disease, and the beneficial effects were specifically due to up-regulation of GLT-1. However, no experiments have explored the potential of Harmine to provide neuroprotection in the setting of GCI. The current study was designed to determine whether Harmine could attenuate cerebral infarction as well as improve neuronal survival after GCI. Furthermore, to test whether the mechanisms were associated with up-regulating of GLT-1, we used a GLT-1 specific inhibitor dihydrokainate (DHK) and analysis the expression of GLT-1 mRNA and protein in cortex of brain. We also examined whether Harmine treatment affected astrocytes activation via immunofluorescence. Our results showed that post-GCI administration of Harmine could attenuate cerebral infarct volume and decrease neurons death. It also caused significantly elevation of GLT-1 mRNA and protein and remarkably attenuation of astrocyte activation. We provide novel clues in understanding the mechanisms of which Harmine exerts its neuroprotective activity in neurological disorders.


Is the dissociability of working memory systems for name identity, visual-object identity, and spatial location maintained in old age?
The dissociability of working memory for name identity (verbal information), visual objects, and spatial location was explored in 3 experiments. Consistent with previous results, the 3 working memory systems were dissociable in younger adults. Both younger and older adults showed involvement of name identity in an object identity task, and older adults showed this involvement in a spatial memory task. Results were interpreted as showing that the systems are generally separable but that involvement of 1 with another is possible and more likely in older adults. A 4th, correlational study showed that there is generalized decline in working memory systems in old age, with the age differences in memory mediated to a moderate extent by age-related differences in speed of processing. It was speculated that the specific, possibly strategic changes are independent of and take place against a backdrop of generalized loss of nervous system integrity.


Pigments versus structure: examining the mechanism of age-dependent change in a carotenoid-based colour.
Within-population colour variation is widespread in animals, yet the determinants of variable coloration have been relatively neglected by ecologists. Age-dependent expression of conspicuous coloration is prevalent, particularly in birds. Such patterns can be generated by multiple combinations of demographic heterogeneity or within-individual change; longitudinal analyses are necessary to establish the importance of these processes. Further, although pigment-based colours are composite traits, produced by multiple component mechanisms (e.g. feather microstructure and carotenoid pigmentation), the contributions of these mechanisms to components of age dependence are rarely considered, even though doing so may yield information about the ecological causes for age-dependent coloration. We used a large-scale, longitudinal study of carotenoid-based plumage coloration in great tits (Parus major) to show age dependence of plumage coloration is driven almost exclusively by within-individual effects in the first 2 years of life. Using wavelength-specific analyses, we show that feather microstructure, while sensitive to annual variation, is independent of age, with increased carotenoid deposition driving changes in coloration. However, estimates of local carotenoid availability did not explain the change in coloration within individuals, suggesting that pigment availability may not be limiting. We thus show that it is individual-level changes in the pigment component of carotenoid-based coloration that determines age-dependent colour expression in great tits. More generally, our study highlights the utility of wavelength-specific analyses in determining the mechanisms underlying changes in expression of composite colour traits.


Improving the drug load and in vitro performance of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) using polymeric precipitation inhibitors.
In this study, the influence of the polymeric precipitation inhibitor (PPI) PVP/VA 64 (polyvinylpyrrolidone-co-vinyl acetate) on the physical stability and in vitro performance of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) containing the model drug simvastatin (SIM) was investigated. A heating-cooling cycle was employed to dissolve (i) the drug in the SNEDDS preconcentrate, generating super-SNEDDS, or (ii) the drug and PPI generating PPI super-SNEDDS, both containing drug loads of 200% and 250% (with regard to the equilibrium solubility of SIM in the blank SNEDDS). PPI super-SNEDDS were prepared at PPI concentrations of 1%, 10% and 20% (w/w), respectively. The formulations were characterized using polarized light microscopy, dynamic light scattering, rheological profiling and dynamic in vitro lipolysis. The physical stability of PPI super-SNEDDS correlated with an increase in viscosity due to the additionally dissolved PVP/VA 64. PPI super-SNEDDS with drug loads of 200% and 250% containing 20% (w/w) PPI showed no drug recrystallization after more than 6 months of storage at room temperature, whereas PPI-free super-SNEDDS (250% drug load) recrystallized within two hours after equilibration to room temperature. All formulations formed nanosized droplets after emulsification in Milli-Q water. The droplet size was not affected by the PPI, but increased slightly with increasing drug load (z-average of 47.3 ± 0.4 nm for SNEDDS with 200% drug load and 55.6 ± 1.3 nm for SNEDDS with 250% drug load). PPI super-SNEDDS with a drug load of 200% containing 20% (w/w) PVP/VA 64 showed an improved performance during dynamic in vitro lipolysis, maintaining a 2.5-fold higher degree of supersaturation after 15 min of digestion compared to PPI-free super-SNEDDS of the same drug load. In conclusion, the study demonstrated the feasibility of stabilizing higher drug loads and improving the in vitro performance of super-SNEDDS by incorporating PVP/VA 64 into the preconcentrate.


Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids.
Synthetic molecules that recognize specific sequences within cellular DNA are potentially powerful tools for investigating chromosome structure and function. Here, we designed antigene peptide nucleic acids (agPNAs) to target the transcriptional start sites for the human progesterone receptor B (hPR-B) and A (hPR-A) isoforms at sequences predicted to be single-stranded within the open complex of chromosomal DNA. We found that the agPNAs were potent inhibitors of transcription, showing for the first time that synthetic molecules can recognize transcription start sites inside cells. Breast cancer cells treated with agPNAs showed marked changes in morphology and an unexpected relationship between the strictly regulated levels of hPR-B and hPR-A. We confirmed these phenotypes using siRNAs and antisense PNAs, demonstrating the power of combining antigene and antisense strategies for gene silencing. agPNAs provide a general approach for controlling transcription initiation and a distinct option for target validation and therapeutic development.


Adenosine: front and center in linking nutrition and metabolism to neuronal activity.
Many individuals with epilepsy benefit from consuming a ketogenic diet, which is similar to the more commonly known Atkins diet. The underlying molecular reason for this has not been determined. However, in this issue of the JCI, Masino et al. have elucidated the mechanism responsible for the antiepileptic effects of the ketogenic diet in mice. The diet is shown to decrease expression of the enzyme adenosine kinase (Adk), which is responsible for clearing the endogenous antiepileptic agent adenosine (Ado) from the extracellular CNS space. Decreased expression of Adk results in increased extracellular Ado, activation of inhibitory Ado A1 receptors, and decreased seizure generation, the desired therapeutic effect. The authors' work serves to emphasize the importance of controlling Adk expression, not only as the mechanism of action of the ketogenic diet, but also as a potential target of future therapies.


Are patients willing participants in the new wave of community-based medical education in regional and rural Australia?
Community-based medical education is growing to meet the increased demand for quality clinical education in expanded settings, and its sustainability relies on patient participation. This study investigated patients' views on being used as an educational resource for teaching medical students. Questionnaire-based survey. Patients attending six rural and 11 regional general practices in New South Wales over 18 teaching sessions in November 2008, who consented to student involvement in their consultation. Patient perceptions, expectations and acceptance of medical student involvement in consultations, assessed by surveys before and after their consultations. 118 of 122 patients consented to medical student involvement; of these, 117 (99%) completed a survey before the consultation, and 100 (85%) after the consultation. Patients were overwhelmingly positive about their doctor and practice being involved in student teaching and felt they themselves played an important role. Pre-consultation, patients expressed reluctance to allow students to conduct some or all aspects of the consultation independently. However, after the consultation, they reported they would have accepted higher levels of involvement than actually occurred. Patients in regional and rural settings were willing partners in developing skills of junior medical students, who had greater involvement in patient consultations than previously reported for urban students. Our study extends the findings from urban general practice that patients are underutilised partners in community-based medical training. The support of patients from regional and rural settings could facilitate the expansion of primary care-based medical education in these areas of workforce need.