A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis.
We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET). Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome. A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests. Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy. This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy.


Prevalence of respiratory symptoms among 7 and 11 year old schoolchildren and association with asthma.
A new self administered questionnaire completed by parents was used to study the prevalences of wheeze, shortness of breath, and cough in 2503 Southampton schoolchildren aged 7 and 11 together with exacerbating factors and background information including treatment and diagnosis. The questionnaire had a response rate of 84% and was found to be highly repeatable with respect to current symptoms. The overall prevalences of wheeze and shortness of breath in the current year (1986) were 12.1% and 8.5% respectively. Social class, home ownership, parental smoking, and presence of a family pet were unrelated to symptom prevalence. According to the parents the overall diagnosis rate for asthma was 9.5%. In common with other studies, however, we found considerable evidence for undertreatment. The symptoms of wheeze and nocturnal and morning breathlessness occurred more commonly in boys, but this sex ratio decreased with increasing age. The prevalences of wheeze and shortness of breath were similar in the two age groups. In contrast, there were only small differences between the sexes with respect to cough whereas, among children without wheeze or shortness of breath, there was a fall in the prevalence of cough from 18.9% at 7 years to 8.7% at 11 years. When controlling for the other respiratory symptoms, wheeze was the only symptom significantly related to parental asthma. The fall in the prevalence of cough between the two age groups is unlikely to be related to changes in asthma prevalence and, when not associated with wheeze, may be an indicator of separate pathology.


Nutrition and Altitude: Strategies to Enhance Adaptation, Improve Performance and Maintain Health: A Narrative Review.
Training at low to moderate altitudes (~ 1600-2400 m) is a common approach used by endurance athletes to provide a distinctive environmental stressor to augment training stimulus in the anticipation of increasing subsequent altitude- and sea-level-based performance. Despite some scientific progress being made on the impact of various nutrition-related changes in physiology and associated interventions at mountaineering altitudes (> 3000 m), the impact of nutrition and/or supplements on further optimization of these hypoxic adaptations at low-moderate altitudes is only an emerging topic. Within this narrative review we have highlighted six major themes involving nutrition: altered energy availability, iron, carbohydrate, hydration, antioxidant requirements and various performance supplements. Of these issues, emerging data suggest that particular attention be given to the potential risk for poor energy availability and increased iron requirements at the altitudes typical of elite athlete training (~ 1600-2400 m) to interfere with optimal adaptations. Furthermore, the safest way to address the possible increase in oxidative stress associated with altitude exposure is via the consumption of antioxidant-rich foods rather than high-dose antioxidant supplements. Meanwhile, many other important questions regarding nutrition and altitude training remain to be answered. At the elite level of sport where the differences between winning and losing are incredibly small, the strategic use of nutritional interventions to enhance the adaptations to altitude training provides an important consideration in the search for optimal performance.


Assessment of preoperative anxiety: comparison of measures in patients awaiting surgery for breast cancer.
We have compared three measurements of anxiety to determine their equivalence in assessing anxiety before surgery. Forty-four patients awaiting breast cancer surgery completed the state scale of the state-trait anxiety inventory (STAI), the hospital anxiety and depression scale (HAD) and a 100-mm visual analogue scale (VAS). Analysis restricted to correlations between the scales gave the misleading impression that VAS scores were inconsistent with those of the HAD and STAI. However, when scores were considered in relation to normative cut-off values to categorize anxiety levels, the three scales showed good agreement. We conclude that the scales were equivalent in their assessment of anxiety before surgery, but that reference to normative data was important in establishing such equivalence and in determining the patient's state.


Biofilm history and oxygen availability interact to affect habitat selection in a marine invertebrate.
In marine systems, oxygen availability varies at small temporal and spatial scales, such that current oxygen levels may not reflect conditions of the past. Different studies have shown that marine invertebrate larvae can select settlement sites based on local oxygen levels and oxygenation history of the biofilm, but no study has examined the interaction of both. The influence of normoxic and hypoxic water and oxygenation history of biofilms on pre-settlement behavior and settlement of the bryozoan Bugula neritina was tested. Larvae used cues in a hierarchical way: the oxygen levels in the water prime larvae to respond, the response to different biofilms is contingent on oxygen levels in the water. When oxygen levels varied throughout biofilm formation, larvae responded differently depending on the history of the biofilm. It appears that B. neritina larvae integrate cues about current and historical oxygen levels to select the appropriate microhabitat and maximize their fitness.


Exploring health visiting professionals' evaluations of early parent-infant interactions.
Objective: To examine the accuracy of Health Visitors (HVs) evaluations of the quality of parent-infant interactions. Background: HVs have been identified as key professionals in the early identification of difficulties in parent-infant interactions. Method: A sample of 56 HVs, 4 Family Health Nurses (FHNs) and 14 Community Nursery Nurses (CNNs) recruited from two National Health Service (NHS) Trusts, viewed video footage of six early parent-infant interactions which had been categorised as 'sensitive', 'mixed', and 'problematic' using the CARE-Index. Participants evaluated the quality of the parent-infant interactions shown in these videos using the Parent-Infant Interaction Rating Questionnaire (PIIRQ). Results: On average, participants correctly rated the problematic videos as lowest in quality, the mixed as higher in quality than the problematic videos, and the sensitive videos as highest in quality. Interestingly, within the problematic category participants rated the 'unresponsive' pattern of interaction as significantly lower in quality than the 'controlling' interaction. Conclusions: Findings suggest participants were relatively accurate in their evaluations of parent-infant interactions. However, they indicate that participants were more likely to be concerned about unresponsive, as opposed to controlling, interactive behaviours. Recommendations for further research include exploration of potential differences in how health-visiting professionals evaluate particular patterns of parent-infant interactions.


[Acute effects of the breathing of industrial waste and of sulfur dioxide on the respiratory health of children living in the industrial area of Puchuncaví, Chile].
This study investigated the acute effect of air pollution on the respiratory health of children living in the industrial area of Puchuncaví, in Region V of Chile. The 114 children studied were from 6 to 12 years old; 57 of them had chronic respiratory symptoms and 57 did not. Each day for 66 days the air was checked for levels of sulfur dioxide (SO2) and of breathable particles that were < 10 microns (PM10). The children were selected and classified according to their susceptibility to chronic respiratory disease by means of a questionnaire used with 882 children living within the area of the emissions from a copper foundry and a thermoelectric plant. Each day, each studied child's peak expiratory flow (PEF) and incidence of respiratory symptoms were checked and recorded. Using regression models (generalized estimation equations), estimates were made of the association of SO2 and PM10 levels with PEF and the incidence of cough, expectoration, episodes of wheezing, dyspnea, and use of bronchodilators. Among the children who were initially symptomatic, an increase of 50 micrograms/m3 in the daily mean level of SO2 caused a reduction of -1.42 L/min (95% confidence interval (95% CI): -2.84 to -0.71) in the PEF of the following day. An increase of 30 micrograms/m3 in the cumulative concentration of PM10 over three days produced a PEF reduction of -2.84 L/min (95% CI: -4.26 to 0.00). With respect to symptoms, an increase of 30 micrograms/m3 in the weekly mean level of PM10 was related with a 26% increase (odds ratio (OR) = 1.26; 95% CI: 1.01 to 1.57) in the incidence of cough and of 23% (OR = 1.23; 95% CI: 1.00 to 1.50) in the incidence of expectoration. An increase of 50 micrograms/m3 in the mean level of SO2 for three days was associated with a 5% increase (OR = 1.05; 95% CI: 1.00 to 1.10) in the incidence of expectoration. An increase of 30 micrograms/m3 in the daily average of PM10 increased the use of bronchodilators two days later by 10% (OR = 1.10; 95% CI: 1.03 to 1.18). Among the initially asymptomatic children, a significant effect from PM10 exposure was found after an increase of 30 micrograms/m3 in the mean daily PM10 level, with a reduction of -1.34 L/min (95% CI: -2.68 to -0.67) in the PEF of the following day. A similar increase in the cumulative exposure over three days was associated with an increase of 9% in the incidence of episodes of wheezing (OR = 1.09; 95% CI: 1.01 to 1.31). It is concluded that high levels of PM10 and SO2 affect the respiratory health of children living in the industrial area of Puchuncaví.


Data bases for the assessment of medical technologies. Examples from Europe.
The assessment of medical technologies has to answer several questions ranging from safety and effectiveness to complex economical, social, and health policy issues. The type of data needed to carry out such evaluation depends on the specific questions to be answered, as well as on the stage of development of a technology. Basically two types of data may be distinguished: (a) general demographic, administrative, or financial data which has been collected not specifically for technology assessment; (b) the data collected with respect either to a specific technology or to a disease or medical problem. On the basis of a pilot inquiry in Europe and bibliographic research, the following categories of type (b) data bases have been identified: registries, clinical data bases, banks of factual and bibliographic knowledge, and expert systems. Examples of each category are discussed briefly. The following aims for further research and practical goals are proposed: criteria for the minimal data set required, improvement to the registries and clinical data banks, and development of an international clearinghouse to enhance information diffusion on both existing data bases and available reports on medical technology assessments.


Vertical variation of ice particle size in convective cloud tops.
A novel technique is used to estimate derivatives of ice effective radius with respect to height near convective cloud tops (dre /dz) from airborne shortwave reflectance measurements and lidar. Values of dre /dz are about -6 μm/km for cloud tops below the homogeneous freezing level, increasing to near 0 μm/km above the estimated level of neutral buoyancy. Retrieved dre /dz compares well with previously documented remote sensing and in situ estimates. Effective radii decrease with increasing cloud top height, while cloud top extinction increases. This is consistent with weaker size sorting in high, dense cloud tops above the level of neutral buoyancy where fewer large particles are present, and with stronger size sorting in lower cloud tops that are less dense. The results also confirm that cloud-top trends of effective radius can generally be used as surrogates for trends with height within convective cloud tops. These results provide valuable observational targets for model evaluation.


Lowering the tone: mechanisms of immunodominance among epitopes with low affinity for MHC.
Past studies of immunodominance among T-cell epitopes have focused on peptides with high affinity for their restriction element, assuming epitopes of low affinity to be immunologically irrelevant. Here, Paul Fairchild and David Wraith challenge this assumption by reviewing evidence that such peptides may contribute to T-cell repertoire selection and autoimmune disease, and suggest approaches to immunotherapy based on exploitation of these peptides.


A Family Systems Curriculum: Evaluating Skills and Empathy.
Training residents in family-centered approaches offers an opportunity to investigate how learners translate skills to real clinical encounters. Previous evaluations of a family systems curriculum have relied on self-assessment and narrative reflection to assess resident learning. Assessment of learning using encounter observation and objective tools, including evaluation of empathy, allows for a deeper understanding of how residents transform curricular education into clinical practice. We evaluated resident learning from a longitudinal family systems curriculum delivered during the third year of a four-year residency training program. Using the Family-Centered Observation Form (FCOF), we analyzed seven pre- and postcurriculum videotaped encounters for changes in family-centered interviewing skills. We assessed changes in empathy before and after the curriculum using the Jefferson Empathy Scale. There was a trend toward improvement in all family-centered skills, as measured by the FCOF, though the improvements were only statistically significant in the area of rapport building. Statistically significant improvement in empathy occurred for all participants. Narrative reflection demonstrated that residents found the curriculum valuable in ways that we were unable to objectively measure. Training in family systems can enhance patient interactions and may improve empathy. Evaluation of family-centered skills is challenging and takes a significant amount of time and planning. The FCOF can help learners identify how to use family-centered concepts and skills in a typical family medicine outpatient visit. Further study is needed to determine whether patients seen by doctors who use family-oriented skills have better experiences or outcomes.


Comparison of polyacrylamide and agarose support media for detection of oligoclonal IgG bands in CSF.
Parallel samples of cerebrospinal fluid (CSF) from 120 patients clinically suspected of having multiple sclerosis were electrophoresed using agarose or 7% polyacrylamide. 57 samples showed oligoclonal IgG patterns in polyacrylamide but only 34 showed bands after concentration and electrophoresis in agarose. The concentrations of IgG and albumin were also measured in each sample and IgG/albumin ratios calculated. The sensitivities of the three methods for the detection of intrathecally synthesised IgG were compared. Electrophoresis in 7% polyacrylamide gave the highest proportion of significant results. In an attempt to increase the sensitivity of the agarose method, silver staining was performed on unconcentrated samples run in agarose. This did not alter the pattern of electrophoresis in samples containing oligoclonal IgG, but the sensitivity of the technique was lower than that of polyacrylamide.


Treatment variation by insurance status for breast cancer patients.
Few studies have examined the relationship of insurance status with the presentation and treatment of breast cancer. Using a state cancer registry, we compared tumor presentation and surgical treatments at presentation by insurance status (private insurance, Medicare, Medicaid, or uninsured). Student's t-test, Chi-square test, and ANOVA were used for comparison. P-values reflect a comparison to insured patients. From 1996 to 2005, there were 6876 cases of invasive breast cancer with either private (n = 3975), Medicare (n = 2592), Medicaid (n = 193), or no insurance (n = 116). The median age (years) at presentation was 55 for private, 76 for Medicare, 54 for Medicaid and 54 for uninsured. The mean and median tumor size (mm) were 18.5 and 15 for private; 20.9 and 15 for Medicare; 24.2 and 18 for Medicaid; and 29.5 and 17 for uninsured, respectively; (p < 0.001 for all). Fewer women with Medicare and Medicaid presented with node negative breast cancers: private, 73.4% node negative; Medicare, 79.5% (p < 0.001); Medicaid, 60.9% (p < 0.001); and uninsured, 58% (p = 0.005). Significantly more uninsured women had no surgical treatment of their breast cancer: 15.5% versus 4.3% for private (p < 0.001). Among women with non-metastatic T1/T2 tumors, 71.5% with private insurance underwent breast-conserving surgery (BCS), compared with 64.2% of Medicare (p < 0.001), 65% of Medicaid (p = 0.097), and 65.4% of uninsured (p = 0.234). The rate of reconstruction following mastectomy was higher for private insurance (36.6%), compared with Medicare (3.8%, p < 0.0001), Medicaid (26.1%, p = 0.31), and uninsured (5.0%, p = 0.0038). The presentation of breast cancer in women with no insurance and Medicaid is significantly worse than those with private insurance. Of concern are the lower proportions of BCS and reconstruction among patients who are uninsured or have Medicaid. Reduction of disparities in breast cancer presentation and treatment may be possible by increasing enrollment of uninsured, program-eligible women in a state-supported screening and treatment program.


How do the efficacy and safety of abatacept and infliximab compare in the treatment of active RA?
Since the introduction of biologic therapies that target tumor necrosis factor (TNF), short-term and long-term outlooks for many patients with rheumatoid arthritis have greatly improved. Not all patients, however, respond to therapy with these agents. Furthermore, despite favorable overall profiles for safety and tolerability, some concerns remain in this regard. Following the emergence of next-generation biologic agents with new targets, a key question for clinicians concerns the relative efficacy and safety of the different biologic therapies. A study by Schiff et al. directly compared the biologic T-cell costimulation blocker abatacept and the anti-TNF agent infliximab. The results of the 6-month, placebo-controlled trial demonstrated a similar efficacy for both drugs; however, in the 6-month treatment extension period, outcomes of efficacy differed in favor of abatacept. Overall, abatacept had a relatively more-acceptable safety and tolerability profile compared to infliximab.


Adapting a multifaceted U.S. HIV prevention education program for girls in Ghana.
We adapted a U.S. HIV prevention program to address knowledge gaps and cultural pressures that increase the risk of infection in adolescent Ghanaian girls. The theory-based nine-module HIV prevention program combines didactics and games, an interactive computer program about sugar daddies, and tie-and-dye training to demonstrate an economic alternative to transactional sex. The abstinence-based study was conducted in a church-affiliated junior secondary school in Nsawam, Ghana. Of 61 subjects aged 10-14 in the prevention program, over two thirds were very worried about becoming HIV infected. A pre-post evaluation of the intervention showed significant gains in three domains: HIV knowledge (p = .001) and self efficacy to discuss HIV and sex with men (p < .001) and with boys (p < .001). Responses to items about social norms of HIV risk behavior were also somewhat improved (p = .09). Subjects rated most program features highly. Although short-term knowledge and self-efficacy to address HIV improved significantly, longer term research is needed to address cultural and economic factors placing young women at risk of HIV infection.


Suicides in late life.
Suicide in late life is an enormous public health problem that will likely increase in severity as adults of the baby boom generation age. Data from psychological autopsy studies supplemented with recent studies of suicidal ideation and attempts point to a consistent set of risk factors for the spectrum of suicidal behaviors in late life (suicide ideation, attempts, and deaths). Clinicians should be vigilant for psychiatric illness (especially depression), physical illness, pain, functional impairment, and social disconnectedness. Recent advances in late-life suicide prevention have in common collaborative, multifaceted intervention designs. We suggest that one mechanism shared by all preventive interventions shown to reduce the incidence of late-life suicide is the promotion of connectedness. For the clinician working with older adults, our recommendation is to not only consider risk factors, such as depression, and implement appropriate treatments but to enhance social connectedness as well.


Molecular epidemiological analysis of the transboundary transmission of 2003 highly pathogenic avian influenza H7N7 outbreaks between the Netherlands and Belgium.
The 2003 outbreak of Highly pathogenic avian influenza (HPAI) A(H7N7) in the Netherlands, Belgium and Germany resulted in significant genetic diversification that proved informative for tracing transmission events. Building on previous investigations on the Dutch outbreak, we focused on the potential transnational transmissions between the Netherlands and Belgium. Although no clear epidemiological links could be identified from the tracing data, the transmission network based on concatenated HA-NA-PB2 sequences supports at least three independent introductions from the Netherlands to Belgium and suggests one possible introduction form Belgium back to the Netherlands. Two introductions in the Belgian province of Limburg occurred from nearby farms in the Dutch province of Limburg. One introduction resulted in three secondary infected farms, while a second introduction did not cause secondary infections. The third introduction into Belgium occurred in the north of the Antwerp province, very close to the national border, and originated from the North of the Dutch province Brabant (long distance transmission, >65 km). The virus spread to two additional Belgian farms, one of which may be the source of a secondarily infected farm in the Netherlands. One infected turkey farm in the province of Antwerp (Westmalle) was geographically close to the latter introduction, but genetically clustered with the first introduction event in the Limburg province. Epidemiological tracing data could neither confirm nor exclude whether this outbreak was a result from long distance contacts within Belgium or whether this farm presented a fourth independent transboundary introduction. These multiple transnational transmissions of HPAI in spite of reinforced biosecurity measures and trade restrictions illustrate the importance of international cooperation, legislation and standardization of tools to combat transboundary diseases.


Broadband electro-optical modulator based on transparent conducting oxide.
We report a broadband electro-optical (EO) modulator based on tunable plasmonic metamaterial. Transparent conducting oxides provide an excellent active plasmonic material for optoelectronic applications. By utilizing our indium-tin-oxide- (ITO) based multilayer structure, light absorption of the active ITO layer can be electrically modulated over a large spectrum range. Based on the attenuated total reflectance configuration, bias polarity-dependent modulation up to 37% has been experimentally demonstrated. This EO modulator has advantages of simple design, easy fabrication, compact size, broadband performance, large modulation depth, as well as compatibility with existing silicon photonics platforms.


Microtiming Deviations and Swing Feel in Jazz.
Jazz music that swings has the fascinating power to elicit a pleasant sensation of flow in listeners and the desire to synchronize body movements with the music. Whether microtiming deviations (MTDs), i.e. small timing deviations below the bar or phrase level, enhance the swing feel is highly debated in the current literature. Studies on other groove related genres did not find evidence for a positive impact of MTDs. The present study addresses jazz music and swing in particular, as there is some evidence that microtiming patterns are genre-specific. We recorded twelve piano jazz standards played by a professional pianist and manipulated the natural MTDs of the recordings in systematic ways by quantizing, expanding and inverting them. MTDs were defined with respect to a grid determined by the average swing ratio. The original and manipulated versions were presented in an online survey and evaluated by 160 listeners with various musical skill levels and backgrounds. Across pieces the quantized versions (without MTDs) were rated slightly higher and versions with expanded MTDs were rated lower with regard to swing than the original recordings. Unexpectedly, inversion had no impact on swing ratings except for two pieces. Our results suggest that naturally fluctuating MTDs are not an essential factor for the swing feel.


Parasitic infections during pregnancy need not affect infant antibody responses to early vaccination against Streptococcus pneumoniae, diphtheria, or Haemophilus influenzae type B.
Globally, vaccine-preventable diseases remain a significant cause of early childhood mortality despite concerted efforts to improve vaccine coverage. One reason for impaired protection may be the influence of prenatal exposure to parasitic antigens on the developing immune system. Prior research had shown a decrease in infant vaccine response after in utero parasite exposure among a maternal cohort without aggressive preventive treatment. This study investigated the effect of maternal parasitic infections on infant vaccination in a more recent setting of active anti-parasitic therapy. From 2013-2015, 576 Kenyan women were tested in pregnancy for malaria, soil-transmitted helminths, filaria, and S. haematobium, with both acute and prophylactic antiparasitic therapies given. After birth, 567 infants received 10-valent S. pneumoniae conjugate vaccine and pentavalent vaccine for hepatitis B, pertussis, tetanus, H. influenzae type B (Hib) and C. diphtheriae toxoid (Dp-t) at 6, 10, and 14 weeks. Infant serum samples from birth, 10 and 14 weeks, and every six months until age three years, were analyzed using a multiplex bead assay to quantify IgG for Hib, Dp-t, and the ten pneumococcal serotypes. Antenatal parasitic prevalence was high; 461 women (80%) had at least one and 252 (43.6%) had two or more infections during their pregnancy, with the most common being malaria (44.6%), S. haematobium (43.9%), and hookworm (29.2%). Mixed models comparing influence of infection on antibody concentration revealed no effect of prenatal infection status for most vaccine outcomes. Prevalences of protective antibody concentrations after vaccination were similar among the prenatal exposure groups. These findings are in contrast with results from our prior cohort study performed when preventive anti-parasite treatment was less frequently given. The results suggest that the treatment of maternal infections in pregnancy may be able to moderate the previously observed effect of antenatal maternal infections on infant vaccine responses.


Ecogeography and utility to plant breeding of the crop wild relatives of sunflower (Helianthus annuus L.).
Crop wild relatives (CWR) are a rich source of genetic diversity for crop improvement. Combining ecogeographic and phylogenetic techniques can inform both conservation and breeding. Geographic occurrence, bioclimatic, and biophysical data were used to predict species distributions, range overlap and niche occupancy in 36 taxa closely related to sunflower (Helianthus annuus L.). Taxa lacking comprehensive ex situ conservation were identified. The predicted distributions for 36 Helianthus taxa identified substantial range overlap, range asymmetry and niche conservatism. Specific taxa (e.g., Helianthus deblis Nutt., Helianthus anomalus Blake, and Helianthus divaricatus L.) were identified as targets for traits of interest, particularly for abiotic stress tolerance, and adaptation to extreme soil properties. The combination of techniques demonstrates the potential for publicly available ecogeographic and phylogenetic data to facilitate the identification of possible sources of abiotic stress traits for plant breeding programs. Much of the primary genepool (wild H. annuus) occurs in extreme environments indicating that introgression of targeted traits may be relatively straightforward. Sister taxa in Helianthus have greater range overlap than more distantly related taxa within the genus. This adds to a growing body of literature suggesting that in plants (unlike some animal groups), geographic isolation may not be necessary for speciation.


An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway.
Generation and turnover of phosphoinositides (PIs) must be coordinated in a spatial- and temporal-restricted manner. The small GTPase Rab5 interacts with two PI 3-kinases, Vps34 and PI3Kbeta, suggesting that it regulates the production of 3-PIs at various stages of the early endocytic pathway. Here, we discovered that Rab5 also interacts directly with PI 5- and PI 4-phosphatases and stimulates their activity. Rab5 regulates the production of phosphatidylinositol 3-phosphate (PtdIns[3]P) through a dual mechanism, by directly phosphorylating phosphatidylinositol via Vps34 and by a hierarchical enzymatic cascade of phosphoinositide-3-kinasebeta (PI3Kbeta), PI 5-, and PI 4-phosphatases. The functional importance of such an enzymatic pathway is demonstrated by the inhibition of transferrin uptake upon silencing of PI 4-phosphatase and studies in weeble mutant mice, where deficiency of PI 4-phosphatase causes an increase of PtdIns(3,4)P2 and a reduction in PtdIns(3)P. Activation of PI 3-kinase at the plasma membrane is accompanied by the recruitment of Rab5, PI 4-, and PI 5-phosphatases to the cell cortex. Our data provide the first evidence for a dual role of a Rab GTPase in regulating both generation and turnover of PIs via PI kinases and phosphatases to coordinate signaling functions with organelle homeostasis.


Maternal exposure to perfluoroalkyl acids measured in whole blood and birth outcomes in offspring.
Perfluoralkyl and polyfluoralkyl substances have been measured in plasma and serum of pregnant women as a measure of prenatal exposure. Increased concentrations of individual perfluoroalkyl acids (PFAAs), (typically perfluorooctanoic acid (PFOA) and perfluoroctane sulfonate (PFOS) have been reported to be associated with reductions in birth weight and other birth outcomes. We undertook a study of 14 PFAAs in whole blood (including PFOS, PFHxS, PFHpA, PFOA, PFNA, PFDA and PFUnDA) from 98 pregnant women in Western Australia from 2008 to 2011. Median concentrations (in μg/L) were: PFOS 1.99; PFHxS 0.33; PFOA 0.86; PFNA 0.30; PFDA 0.12 and PFUnDA 0.08. Infants born to women with the highest tertile of PFHxS exposure had an increased odds of being <95% of their optimal birth weight (OR 3.5, 95% CI 1.1-11.5). Conversely, maternal blood concentrations of PFUnDA were associated with non-significant increases in average birth weight (+102g, 95% CI -41, 245) and significant increases in proportion of optimal birth weight (+4.7%, 95% CI 0.7, 8.8) per ln-unit change. This study has reported a range of PFAAs in the whole blood of pregnant women and suggests that PFHxS and PFUnDA may influence foetal growth and warrant further attention. Additional studies are required to identify the sources of PFAA exposure with a view to prevention, in addition to further studies investigating the long term health effects of these ubiquitous chemicals.


Enhancement of positron emission tomography-computed tomography image quality using the principle of stochastic resonance.
Acquisition of higher counts improves visual perception of positron emission tomography-computed tomography (PET-CT) image. Larger radiopharmaceutical doses (implies more radiation dose) are administered to acquire this count in a short time period. However, diagnostic information does not increase after a certain threshold of counts. This study was conducted to develop a post processing method based on principle of "stochastic resonance" to improve visual perception of the PET-CT image having a required threshold counts. PET-CT images (JPEG file format) with low, medium, and high counts in the image were included in this study. The image was corrupted with the addition of Poisson noise. The amplitude of the Poisson noise was adjusted by dividing each pixel by a constant 1, 2, 4, 8, 16, and 32. The best amplitude of the noise that gave best images quality was selected based on high value of entropy of the output image, high value of structural similarity index and feature similarity index. Visual perception of the image was evaluated by two nuclear medicine physicians. The variation in structural and feature similarity of the image was not appreciable visually, but statistically images deteriorated as the noise amplitude increases although maintaining structural (above 70%) and feature (above 80%) similarity of input images in all cases. We obtained the best image quality at noise amplitude "4" in which 88% structural and 95% feature similarity of the input images was retained. This method of stochastic resonance can be used to improve the visual perception of the PET-CT image. This can indirectly lead to reduction of radiation dose.


Reduction in social learning and increased policy uncertainty about harmful intent is associated with pre-existing paranoid beliefs: Evidence from modelling a modified serial dictator game.
Current computational models suggest that paranoia may be explained by stronger higher-order beliefs about others and increased sensitivity to environments. However, it is unclear whether this applies to social contexts, and whether it is specific to harmful intent attributions, the live expression of paranoia. We sought to fill this gap by fitting a computational model to data (n = 1754) from a modified serial dictator game, to explore whether pre-existing paranoia could be accounted by specific alterations to cognitive parameters characterising harmful intent attributions. We constructed a 'Bayesian brain' model of others' intent, which we fitted to harmful intent and self-interest attributions made over 18 trials, across three different partners. We found that pre-existing paranoia was associated with greater uncertainty about other's actions. It moderated the relationship between learning rates and harmful intent attributions, making harmful intent attributions less reliant on prior interactions. Overall, the magnitude of harmful intent attributions was directly related to their uncertainty, and importantly, the opposite was true for self-interest attributions. Our results explain how pre-existing paranoia may be the result of an increased need to attend to immediate experiences in determining intentional threat, at the expense of what is already known, and more broadly, they suggest that environments that induce greater probabilities of harmful intent attributions may also induce states of uncertainty, potentially as an adaptive mechanism to better detect threatening others. Importantly, we suggest that if paranoia were able to be explained exclusively by core domain-general alterations we would not observe differential parameter estimates underlying harmful-intent and self-interest attributions.


PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis.
Peripheral T-cell lymphomas are a heterogeneous group that often requires the use of ancillary testing for accurate diagnosis. This is particularly applicable to the diagnosis of angiommunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unclassified (PTCLU), because of their histologic and immunophenotypic overlap with reactive lymphoid proliferations. Recently, immunohistochemistry for programmed death-1 (PD-1), a marker of follicular helper T cells, was shown to be sensitive in the detection of AITL and PTCLU. The sensitivity of this marker in reactive entities, however, has not been adequately evaluated. We confirm that PD-1 staining is a highly sensitive marker in the diagnosis of peripheral T-cell lymphomas: increased extrafollicular PD-1-positive cells were seen in 93% (76/82) of AITL, 62% (16/26) of PTCLU, and 11% (2/18) of anaplastic-lymphoma-kinase (ALK)-negative anaplastic large-cell lymphomas. The majority of reactive lymphadenopathies including Cat-scratch disease, Kikuchi lymphadenitis, Castleman disease, and reactive follicular hyperplasia showed no PD-1 staining outside follicles. Some reactive lymph nodes, showed increased extrafollicular PD-1-positive cells in a pattern similar to AITL and PTCLU, and include progressive transformation of germinal centers, viral lymphadenitis (Epstein-Barr virusand human immunodeficiency virus) and Rosai-Dorfman disease. This study shows that PD-1-positive cells may be increased in a number of settings other than T-cell lymphomas. We conclude that staining for PD-1 in reactive and atypical lymphadenopathies should be interpreted with caution and in the context of other ancillary immunophenotypic and molecular studies before a diagnosis of AITL or PTCLU is entertained.


Topographical localization of the C-terminal region of the voltage-dependent sodium channel from Electrophorus electricus using antibodies raised against a synthetic peptide.
A peptide corresponding to amino acid residues 1783-1794 near the C terminus of the electric eel sodium channel primary sequence of the eel (Electrophorus electricus) sodium channel has been synthesized and used to raise an antiserum in rabbits. This antiserum specifically recognized the peptide in a solid-phase radioimmunoassay. Specificity of the antiserum for the native channel protein was shown by its specific binding to a 280-kDa protein in immunoblots of eel electroplax membrane proteins. The antiserum also specifically labeled the innervated membrane of the eel electroplax in immunofluorescent studies; noninnervated membrane was not labeled, consistent with the known distribution of sodium channels in this tissue. The membrane topology of the peptide recognized by this antiserum was probed in binding studies using oriented electroplax membrane vesicles. These vesicles were 98% "right-side-out" as determined by [3H]saxitoxin binding. Binding of the antipeptide antiserum to this fraction was measured before and after permeabilization with 0.01% saponin. Specific binding to intact vesicles was low, but this binding increased 10-fold after permeabilization, implying a cytoplasmic orientation for the peptide. Confirmation for this orientation was then sought by localizing the antibody bound to intact electroplax cells with immunogold electron microscopy. Gold particles identifying the antibody were found almost exclusively associated with the cytoplasmic surface of the innervated membrane. Our data imply that the region of the sodium channel primary sequence near the C terminus that is recognized by our antiserum is localized on the cytoplasmic side of the membrane; this localization provides some further constraints on models of sodium channel tertiary structure.


Anomalous magnetic excitations of cooperative tetrahedral spin clusters.
An inelastic neutron scattering study of Cu2Te2O5X2 (X=Cl, Br) shows strong dispersive modes with large energy gaps persisting far above TN, notably in Cu2Te2O5Br2. The anomalous features: a coexisting unusually weak Goldstone-like mode observed in Cu2Te2O5Cl2 and the size of the energy gaps cannot be explained by existing theories, such as our mean-field or random-phase approximation. We argue that our findings represent a new general type of behavior due to intercluster quantum fluctuations and call for development of a new theoretical approach.


Antiviral activity of resveratrol.
Resveratrol is a natural compound produced by certain plants on various stimuli. In recent years, extensive research on resveratrol has been carried out, demonstrating its capacity to prevent a wide variety of conditions, including cardiovascular diseases and cancer, and to control fungal, bacterial and viral infections. In the present review, we summarize the current knowledge of the activity of resveratrol against viral infection and describe the possible molecular pathways through which resveratrol exerts its antiviral activity.


Signal transduction events in chicken interleukin-1 production.
The HD11 chicken macrophage cell line was studied for growth characteristics using different culture media, serum concentrations, and incubation temperatures. Growth curves at 37 C revealed that the cells grew best in RPMI 1640 medium supplemented with 10% colostrum-free bovine serum (CFBS). Growth was not supported by RPMI 1640 medium supplemented with the serum replacement Nu Serum nor by PC-1 culture medium alone. However, coating culture plates with either chicken serum or Nu Serum enhanced HD11 cell growth in the PC-1 medium. Growth at 40 C was equivalent to that obtained at 37 C when RPMI 1640 medium with 10% CFBS or PC-1 medium in plates coated with chicken serum were used. Several stimuli were tested for their ability to induce interleukin-1 (IL-1) in HD11 macrophages under serum-free conditions. Lipopolysaccharide (2.5 micrograms/mL) or silica (50 micrograms/mL), increased extracellular IL-1 significantly after a 24-h treatment. In contrast, a superinduction protocol using phorbol 12-myristate 13-acetate, cycloheximide, butyrate, and actinomycin D did not increase extracellular IL-1 significantly. All three stimulants significantly elevated intracellular IL-1 after treatment. Protein kinase C inhibitors (H7 and retinal) as well as calmodulin-dependent kinase inhibitors (W7 and TFP) significantly diminished IL-1 production in the intracellular and extracellular compartments. Elevated cyclic adenosine 5'-monophosphate (cAMP) actuated by dibutyryl cAMP also increased IL-1 significantly. The dat indicate that both protein kinase C and calmodulin-dependent kinase mechanisms are important in signal transduction leading to IL-1 production.


Perisomatic feedback inhibition underlies cholinergically induced fast network oscillations in the rat hippocampus in vitro.
Gamma frequency network oscillations are assumed to be important in cognitive processes, including hippocampal memory operations, but the precise functions of these oscillations remain unknown. Here, we examine the cellular and network mechanisms underlying carbachol-induced fast network oscillations in the hippocampus in vitro, which closely resemble hippocampal gamma oscillations in the behaving rat. Using a combination of planar multielectrode array recordings, imaging with voltage-sensitive dyes, and recordings from single hippocampal neurons within the CA3 gamma generator, active current sinks and sources were localized to the stratum pyramidale. These proximal currents were driven by phase-locked rhythmic inhibitory inputs to pyramidal cells from identified perisomatic-targeting interneurons. AMPA receptor-mediated recurrent excitation was necessary for the synchronization of interneuronal discharge, which strongly supports a synaptic feedback model for the generation of hippocampal gamma oscillations.


New perspectives for perfusion imaging in echocardiography.
The rapid injection into the coronary circulation of solutions containing microbubbles produces an ultrasonic contrast effect in the myocardium. The time-intensity curves generated by sequential videodensitometric analysis of contrast intensity, which is corrected for myocardial background intensity, resembles the curves used in indicator dilution techniques. Studies done in vitro have demonstrated a direct relation between contrast intensity and amount of microbubbles. In animal studies, measurements derived from these curves correlated with changes in myocardial blood flow assessed by microspheres but with varying controversial results. Differences between investigators in technique of injection and size of microbubbles injected are among the list of factors that will alter the time-intensity curve and explain some of the differences in results between investigators. Several factors limit the application of myocardial contrast echocardiography (MCE) to the quantitation of myocardial blood flow. Nevertheless, the results from multiple investigations suggest that the technique is sensitive to changes in perfusion and may be applicable to the evaluation of regional coronary reserve and assessment of the results of revascularization procedures. Peak intensity and area under the time-intensity curve have provided consistent results between investigators; therefore, these measurements have been used to assess regional coronary reserve in experimental studies and patients with coronary artery disease. Although the results are encouraging, they cannot distinguish well between normal and mild impairments in coronary reserve and are subject to larger reproducibility errors.(ABSTRACT TRUNCATED AT 250 WORDS)


Intramuscular hypoperfusion, adrenergic receptors, and chronic muscle pain.
Despite a high prevalence of chronic muscle pain disorders such as fibromyalgia and regional myofascial pain, there is still limited knowledge about the factors that initiate and perpetuate these pain states. Although there are also likely to be downstream neuropathic changes in the central nervous system and spinal cord that sustain and exacerbate the pain states known as fibromyalgia, the focus of this critical review is on studies that examined the connection between both fibromyalgia and regional myofascial pain and sympathetic function. Specifically, we looked at studies that described Raynaud-like symptoms, cardiovascular dysfunction and altered intramuscular perfusion in chronic muscle pain. Our analysis showed that although the first 2 phenomena were intermittently present, a prominent and consistent feature for regional myofascial pain and to a lesser degree for fibromyalgia was intramuscular hypoperfusion. Several hypotheses can be offered why this hypoperfusion exists, and additional studies comparing and contrasting these theories are needed. This review focuses on one of these theories, namely, agonist-induced beta-adrenergic receptor desensitization as an explanatory model for hypoperfusion. What cannot be done at this time and is needed in the future is to compare and contrast to what degree the regional muscle pain disorder (myofascial) is similar or different from the more generalized disorder (fibromyalgia).


Bioinformatics prediction of overlapping frameshifted translation products in mammalian transcripts.
Exceptionally, a single nucleotide sequence can be translated in vivo in two different frames to yield distinct proteins. In the case of the G-protein alpha subunit XL-alpha-s transcript, a frameshifted open reading frame (ORF) in exon 1 is translated to yield a structurally distinct protein called Alex, which plays a role in platelet aggregation and neurological processes. We carried out a novel bioinformatics screen for other possible dual-frame translated sequences, based on comparative genomics. Our method searched human, mouse and rat transcripts in frames +1 and -1 for ORFs which are unusually well conserved at the amino acid level. We name these conserved frameshifted overlapping ORFs 'matreshkas' to reflect their nested character. Select findings of our analysis revealed that the G-protein coupled receptor GPR27 is entirely contained within a frame -1 matreshka, thrombopoietin contains a matreshka which spans ~70% of its length, platelet glycoprotein IIIa (ITGB3) contains a matreshka with the predicted characteristics of a secreted peptide hormone, while the potassium channel KCNK12 contains a matreshka spanning >400 amino acids. Although the in vivo existence of translated matreshkas has not been experimentally verified, this genome-wide analysis provides strong evidence that substantial overlapping coding sequences exist in a number of human and rodent transcripts.


The development of an attentional bias for angry faces following Pavlovian fear conditioning.
Although it is well documented that fear responses develop following aversive Pavlovian conditioning, it is unclear whether fear learning also manifests in the form of attentional biases for fear-related stimuli. Boschen, Parker, and Neumann (Boschen, M. J., Parker, I., & Neumann, D. L. (2007). Changes in implicit associations do not occur simultaneously to Pavlovian conditioning of physiological anxiety responses. Journal of Anxiety Disorders, 21, 788-803.) showed that despite the acquisition of differential skin conductance conditioned responses to angry faces paired (CS+) and unpaired (CS-) with an aversive shock, development of implicit associations was not subsequently observed on the Implicit Association Test. In the present study, participants (N=76) were assigned either to a Shock or NoShock group and completed a similar aversive Pavlovian conditioning procedure with angry face CS+ and CS- stimuli. Participants next completed a visual probe task in which the angry face CS+ and CS- stimuli were paired with angry face control stimuli and neutral faces. Results confirmed that differential fear conditioning was observed in the Shock group but not in the NoShock group, and that the Shock group subsequently showed a selective attentional bias for the angry face CS+ compared with the CS- and control stimuli during the visual probe task. The findings confirm the interplay between learning-based mechanisms and cognitive processes, such as attentional biases, in models of fear acquisition and have implications for treatment of the anxiety disorders.


Hepatitis C prevalence in HIV-infected heterosexual men and men who have sex with men.
Globally 1% of individuals are infected with hepatitis C virus (HCV). In South Africa (SA) the prevalence ranges between 0.3% and 1%, with few prospective screening data available. Similarly, local data on transmission modes of HCV are limited, but probably include parenteral routes and pre-1992 blood or blood products. The risk of heterosexual transmission of HCV is low but is increased in men who have sex with men (MSM), with co-transmission risk of both HIV and HCV. Given few local data, we sought to better understand HCV characteristics and prevalence in two groups of HIV-infected men. HIV-positive men in the greater Cape Town metropolitan area were recruited. Sexual orientation was self-identified and demographic and other personal data were obtained via a confidential questionnaire. Participants were screened for HCV after a blood draw. Those with positive HCV tests had further HCV RNA confirmation. Risk factors associated with HCV seropositivity were determined. Five hundred HIV-positive men were recruited, 285 (57.0%) MSM and 215 (43.0%) non-MSM, median age 36 years (interquartile range (IQR) 20 - 64) and 37 years (IQR 21 - 56), respectively (p=NS). Overall, 3.4% (n=17) screened HCV-positive, 5.6% MSM (n=16) and 0.5% non-MSM (n=1); 82.4% were viraemic for HCV RNA. In respect of genotype distribution, 50.0% were infected with genotype 1a, 14.3% with genotype 4 and 35.7% with genotype 2. In terms of risk, MSM were more likely to have used drugs (54.4% v. 30.2%; p<0.001) and to have used all five modes of drug administration (13.0% MSM v. 0.5% non-MSM for injected drugs, 36.1% v. 2.3% for inhaled, 10.0% v. 0% for rectal, 48.1% v. 28.8% for smoked and 27.4% v. 2.3% for oral). More MSM than non-MSM (46.3% v. 16.7%) reported having sex while using recreational drugs, and similarly more MSM (21.4% v. 14%) reported having sex with a sex worker (SW). Risk factors for HCV seropositivity included drug use history (odds ratio (OR) 6.28, 95% confidence interval (CI) 1.78 - 22.12; p=0.004) and in MSM, sex with an SW (OR 5.5, 95% CI 2.06 - 14.68; p=0.001) or use of recreational drugs with sex (OR 6.88, 95% CI 2.21 - 21.44; p=0.001). HCV prevalence in HIV-positive MSM is higher than previously appreciated or documented in SA. Risk factors include injection drug use, use of recreational drugs with sex, and sex with SWs. Targeted interventions are required to address this emerging challenge to achieve the viral hepatitis elimination ideal by 2030.


Gender-divergent aetiological factors in obsessive-compulsive disorder.
Among 307 adults with OCD, early onset (age 5-15 years) was more common in men and later onset (age 26-35 years) in women. Early onset was associated with more checking, and late onset with more washing. More women than men had a history of treated depression; 12% of the women but none of the men had a history of anorexia. More women than men were married. Gender-divergent features may reflect differential aetiological factors. Our sample resembled others in the literature in its slight overall female preponderance, low rate of marriage and low fertility, onset mainly before age 35 years, chronicity, and common present and past depression.


Living related liver transplantation for acute fulminant hepatitis B: experience from two possible hyper-acute cases.
Fulminant hepatic failure, which is represented by fulminant hepatitis, is fatal in most cases unless prompt liver transplantation is performed. Even if liver transplantation is performed, irreversible neurological damage is often complicated. In this case report, we describe two cases of fulminant hepatitis induced by acute hepatitis B virus infection, both of which were successfully rescued by living related liver transplantation without significant complications. The case 1 was a 45-year-old Japanese male. He complained general malaise and anorexia. His local physician diagnosed him as acute hepatitis B, and referred to our hospital. Due to severe coagulopathy, plasma exchange was performed 3 times. However, his hepatic coma progressed rapidly along with rapid decrease of both his direct/indirect bilirubin (D/T) ratio and serum blood urea nitrogen (BUN) levels. Living related liver transplantation was performed under the diagnosis of acute fulminant hepatitis B. The case 2 was a 34-year-old Japanese male. His complaints were fever and skin rush. He was referred to our hospital under the diagnosis of acute hepatitis B. On the second day after admission, he developed grade II hepatic coma, which deteriorated into grade III in spite of intensive therapy including plasma exchange. He also demonstrated rapid decrease of both D/T ratio and serum BUN level. Living related liver transplantation was performed on the next day. Both cases recovered without any evidence of neurological sequelae. In general, it is extremely difficult to rescue fulminant hepatitis by conservative treatments, particularly in cases with rapid progression. Although emergency liver transplantation may be an only option to rescue in such a case, living related liver transplantation has an advantage in view of urgent organ donation over cadeveric transplantation.


Macrophage Activation in COVID-19 Patients in Intensive Care Unit.
We report six cases of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, admitted to intensive care unit (ICU), for whom bone marrow aspirate revealed hemophagocytosis. We compared their clinical presentation and laboratory findings to those that can be encountered during a hemophagocytic lymphohistiocytosis. These observations might evoke a macrophage activation mechanism different from the one encountered in the hemophagocytic lymphohistiocytosis (HLH).


R3D Align: global pairwise alignment of RNA 3D structures using local superpositions.
Comparing 3D structures of homologous RNA molecules yields information about sequence and structural variability. To compare large RNA 3D structures, accurate automatic comparison tools are needed. In this article, we introduce a new algorithm and web server to align large homologous RNA structures nucleotide by nucleotide using local superpositions that accommodate the flexibility of RNA molecules. Local alignments are merged to form a global alignment by employing a maximum clique algorithm on a specially defined graph that we call the 'local alignment' graph. The algorithm is implemented in a program suite and web server called 'R3D Align'. The R3D Align alignment of homologous 3D structures of 5S, 16S and 23S rRNA was compared to a high-quality hand alignment. A full comparison of the 16S alignment with the other state-of-the-art methods is also provided. The R3D Align program suite includes new diagnostic tools for the structural evaluation of RNA alignments. The R3D Align alignments were compared to those produced by other programs and were found to be the most accurate, in comparison with a high quality hand-crafted alignment and in conjunction with a series of other diagnostics presented. The number of aligned base pairs as well as measures of geometric similarity are used to evaluate the accuracy of the alignments. R3D Align is freely available through a web server http://rna.bgsu.edu/R3DAlign. The MATLAB source code of the program suite is also freely available for download at that location.


Physician career satisfaction within specialties.
Specialty-specific data on career satisfaction may be useful for understanding physician workforce trends and for counseling medical students about career options. We analyzed cross-sectional data from 6,590 physicians (response rate, 53%) in Round 4 (2004-2005) of the Community Tracking Study Physician Survey. The dependent variable ranged from +1 to -1 and measured satisfaction and dissatisfaction with career. Forty-two specialties were analyzed with survey-adjusted linear regressions After adjusting for physician, practice, and community characteristics, the following specialties had significantly higher satisfaction levels than family medicine: pediatric emergency medicine (regression coefficient = 0.349); geriatric medicine (0.323); other pediatric subspecialties (0.270); neonatal/prenatal medicine (0.266); internal medicine and pediatrics (combined practice) (0.250); pediatrics (0.250); dermatology (0.249);and child and adolescent psychiatry (0.203). The following specialties had significantly lower satisfaction levels than family medicine: neurological surgery (-0.707); pulmonary critical care medicine (-0.273); nephrology (-0.206); and obstetrics and gynecology (-0.188). We also found satisfaction was significantly and positively related to income and employment in a medical school but negatively associated with more than 50 work-hours per-week, being a full-owner of the practice, greater reliance on managed care revenue, and uncontrollable lifestyle. We observed no statistically significant gender differences and no differences between African-Americans and whites. Career satisfaction varied across specialties. A number of stakeholders will likely be interested in these findings including physicians in specialties that rank high and low and students contemplating specialty. Our findings regarding "less satisfied" specialties should elicit concern from residency directors and policy makers since they appear to be in critical areas of medicine.


A comprehensive and integrative reconstruction of evolutionary history for Anomura (Crustacea: Decapoda).
The infraorder Anomura has long captivated the attention of evolutionary biologists due to its impressive morphological diversity and ecological adaptations. To date, 2500 extant species have been described but phylogenetic relationships at high taxonomic levels remain unresolved. Here, we reconstruct the evolutionary history-phylogeny, divergence times, character evolution and diversification-of this speciose clade. For this purpose, we sequenced two mitochondrial (16S and 12S) and three nuclear (H3, 18S and 28S) markers for 19 of the 20 extant families, using traditional Sanger and next-generation 454 sequencing methods. Molecular data were combined with 156 morphological characters in order to estimate the largest anomuran phylogeny to date. The anomuran fossil record allowed us to incorporate 31 fossils for divergence time analyses. Our best phylogenetic hypothesis (morphological + molecular data) supports most anomuran superfamilies and families as monophyletic. However, three families and eleven genera are recovered as para- and polyphyletic. Divergence time analysis dates the origin of Anomura to the Late Permian ~259 (224-296) MYA with many of the present day families radiating during the Jurassic and Early Cretaceous. Ancestral state reconstruction suggests that carcinization occurred independently 3 times within the group. The invasion of freshwater and terrestrial environments both occurred between the Late Cretaceous and Tertiary. Diversification analyses found the speciation rate to be low across Anomura, and we identify 2 major changes in the tempo of diversification; the most significant at the base of a clade that includes the squat-lobster family Chirostylidae. Our findings are compared against current classifications and previous hypotheses of anomuran relationships. Many families and genera appear to be poly- or paraphyletic suggesting a need for further taxonomic revisions at these levels. A divergence time analysis provides key insights into the origins of major lineages and events and the timing of morphological (body form) and ecological (habitat) transitions. Living anomuran biodiversity is the product of 2 major changes in the tempo of diversification; our initial insights suggest that the acquisition of a crab-like form did not act as a key innovation.


Harnessing Cooperative Interactions between Thermoresponsive Aptamers and Gels To Trap and Release Nanoparticles.
We use computational modeling to design a device that can controllably trap and release particles in solution in response to variations in temperature. The system exploits the thermoresponsive properties of end-grafted fibers and the underlying gel substrate. The fibers mimic the temperature-dependent behavior of biological aptamers, which form a hairpin structure at low temperatures (T) and unfold at higher T, consequently losing their binding affinity. The gel substrate exhibits a lower critical solution temperature and thus, expands at low temperatures and contracts at higher T. By developing a new dissipative particle dynamics simulation, we examine the behavior of this hybrid system in a flowing fluid that contains buoyant nanoparticles. At low T, the expansion of the gel causes the hairpin-shaped fibers to extend into the path of the fluid-driven particle. Exhibiting a high binding affinity for these particles at low temperature, the fibers effectively trap and extract the particles from the surrounding solution. When the temperature is increased, the unfolding of the fiber and collapse of the supporting gel layer cause the particles to be released and transported away from the layer by the applied shear flow. Since the temperature-induced conformational changes of the fiber and polymer gel are reversible, the system can be used repeatedly to "catch and release" particles in solution. Our findings provide guidelines for creating fluidic devices that are effective at purifying contaminated solutions or trapping cells for biological assays.


Present-day impact cratering rate and contemporary gully activity on Mars.
The Mars Global Surveyor Mars Orbiter Camera has acquired data that establish the present-day impact cratering rate and document new deposits formed by downslope movement of material in mid-latitude gullies on Mars. Twenty impacts created craters 2 to 150 meters in diameter within an area of 21.5 x 10(6) square kilometers between May 1999 and March 2006. The values predicted by models that scale the lunar cratering rate to Mars are close to the observed rate, implying that surfaces devoid of craters are truly young and that as yet unrecognized processes of denudation must be operating. The new gully deposits, formed since August 1999, are light toned and exhibit attributes expected from emplacement aided by a fluid with the properties of liquid water: relatively long, extended, digitate distal and marginal branches, diversion around obstacles, and low relief. The observations suggest that liquid water flowed on the surface of Mars during the past decade.


Racial disparities in all-cause mortality among younger commercially insured women with incident metastatic breast cancer.
Racial disparities in breast cancer mortality persist and are likely related to multiple factors. Over the past decade, progress has been made in treating metastatic breast cancer, particularly in younger women. Whether disparities exist in this population is unknown. Using administrative claims data between 2000 and 2011 (OptumInsight, Eden Prairie, MN) of members insured through a large national US health insurer, we identified women aged 25-64 years diagnosed with incident metastatic breast cancer diagnosed between November 1, 2000, and December 31, 2008. We examined time from diagnosis to death, with up to 3 years of follow-up. We stratified analyses by geocoded race and socio-economic status, age-at-diagnosis, morbidity score, US region of residence, urban/non-urban, and years of diagnosis. We constructed Kaplan-Meier survival plots and analyzed all-cause mortality using multivariate Cox proportional hazard models. Among 6694 women with incident metastatic breast cancer (78 % Caucasian, 4 % African American, and 18 % other), we found higher mortality rates among women residing in predominantly African American versus Caucasian neighborhoods (hazard ratio (HR) 1.84; 95 % confidence interval, CI 1.39-2.45), women with high versus lower morbidity (HR 1.30 [1.12-1.51]), and women whose incident metastatic diagnosis was during 2000-2004 versus 2005-2008 (HR 1.60 [1.39-1.83]). Caucasian (HR 0.61 [0.52-0.71]) but not African American women (HR not significant) experienced improved mortality in 2005-2008 versus 2000-2004. Despite insured status, African American women and women with multi-morbidity had poorer survival. Only Caucasian women had improved mortality over time. Modifiable risk factors for increased mortality need to be addressed in order to reduce disparities.


Back to the Future: Achieving Health Equity Through Health Informatics and Digital Health.
The rapid proliferation of health informatics and digital health innovations has revolutionized clinical and research practices. There is no doubt that these fields will continue to have accelerated growth and a substantial impact on population health. However, there are legitimate concerns about how these promising technological advances can lead to unintended consequences such as perpetuating health and health care disparities for underresourced populations. To mitigate this potential pitfall, it is imperative for the health informatics and digital health scientific communities to understand the challenges faced by disadvantaged groups, including racial and ethnic minorities, which hinder their achievement of ideal health. This paper presents illustrative exemplars as case studies of contextually tailored, sociotechnical mobile health interventions designed with community members to address health inequities using community-engaged research approaches. We strongly encourage researchers and innovators to integrate community engagement into the development of data-driven, modernized solutions for every sector of society to truly achieve health equity for all.


Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group.
Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.


Tryptophan Dietary Impacts Gut Barrier and Metabolic Diseases.
The intestine has a major role in the digestion and absorption of nutrients, and gut barrier is the first defense line against harmful pathogens. Alteration of the intestinal barrier is associated with enhanced intestinal permeability and development of numerous pathological diseases including gastrointestinal and cardiometabolic diseases. Among the metabolites that play an important role within intestinal health, L Tryptophan (Trp) is one of the nine essential amino acids supplied by diet, whose metabolism appears as a key modulator of gut microbiota, with major impacts on physiological, and pathological pathways. Recently, emerging evidence showed that the Trp catabolism through one major enzyme indoleamine 2,3-dioxygenase 1 (IDO1) expressed by the host affects Trp metabolism by gut microbiota to generate indole metabolites, thereby altering gut function and health in mice and humans. In this mini review, I summarize the most recent advances concerning the role of Trp metabolism in host-microbiota cross-talk in health, and metabolic diseases. This novel aspect of IDO1 function in intestine will better explain its complex roles in a broad range of disease states where the gut function affects local as well as systemic health, and will open new therapeutic strategies.


Myelodysplastic syndromes and the role of iron overload.
The epidemiology of myelodysplastic syndromes (MDS) and iron overload, recent clinical findings that highlight the importance of actively managing iron overload, and recommendations for initiating and maintaining iron chelation therapy (ICT) are summarized. MDS are a variety of hematological disorders with differing time courses. Disease morbidities are primarily due to cytopenias and evolution to acute myeloid leukemia. Iron overload is a serious complication in patients with MDS due to the long-term use of red blood cell transfusions in patients with symptomatic anemia. Clinical consequences of iron overload include end-organ damage and dysfunction, an increased frequency of transplant-related complications, and reduced survival rates. To prevent these complications, recommendations for initiating and maintaining ICT should be followed by clinicians caring for patients with MDS and iron overload. As current therapeutic options for patients with MDS do not always reduce the transfusion burden, many patients will still need long-term transfusion therapy. Strategies for the management of iron overload in MDS should be considered early in the disease course and in appropriate patients in order to prevent negative clinical outcomes associated with excessive iron accumulation.


Can routine surveillance samples from tracheal aspirate predict bacterial flora in cases of ventilator-associated pneumonia?
The aim of this study was to investigate the hypothesis that periodical sampling of the tracheo-bronchial tree in the absence of clinical suspicion of pneumonia is useful to identify bacteria responsible for subsequent late ventilator associated pneumonia (VAP). This was a retrospective observational human study carried out in two medical-surgical intensive care units of two different hospitals. From January 1999 to December 2000, 559 patients, who received invasive respiratory support for more than 48 hours, were screened. Tracheal aspiration (TA) was performed once or twice weekly in all mechanically ventilated patients. The microbiological findings from TA surveillance cultures done in the eight days before suspicion of VAP were compared to those isolated from the positive diagnostic samples done for late onset VAP (after more than four days of mechanical ventilation). The sensitivity, specificity, and positive/negative predictive values of the ability of the surveillance sample to anticipate the VAP pathogen were calculated. Among the microorganisms isolated from TA, 68% were retrieved from diagnostic samples. All VAP pathogens previously isolated were from 43% of the TA samples. If TA was collected 2-4 days before the clinical diagnosis of VAP, pathogens were detected in 58% of samples. In contrast, only 27% were collected more than four days earlier (P<0.05). The positive predictive values for Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus from routine TA samples were 92% and 90%, respectively. The negative predictive values for Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus from routine TA samples were 75% and 89%, respectively. TA cultures in ventilated patients may help to predict pathogens. Early detection may lead to earlier treatment in long term ventilated patients when VAP is suspected.


Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin's disease: an update.
From May 1989 to August 1995, 94 previously untreated patients with Hodgkin's disease stage II with bulky mediastinal involvement (n = 28) or stage III or IV (n = 66) received an abbreviated chemotherapy regimen, Stanford V, +/-radiotherapy (RT). Chemotherapy was given weekly for 12 weeks followed by consolidative RT to sites of initial bulky disease. With a median follow-up of 3 years, the actuarial 6-year survival is 93% and the freedom from progression is 89%. There have been no relapses or deaths among the 28 patients with stage II bulky mediastinal disease. Eight relapses and three deaths have occurred in the group of 66 patients with stage III-IV disease. The abbreviated chemotherapy regimen, Stanford V, in combination with RT is well tolerated and highly effective therapy for bulky, limited stage and advanced stage HD. Lower cumulative exposure to alkylating agents, doxorubicin, bleomycin and limited use of radiation is expected to improved the prospects for fertility and decrease the risks for second neoplasms and late cardiopulmonary toxicity.


Lack of a regulatory function for glutamine synthetase protein in the synthesis of glutamate dehydrogenase and nitrite reductase in Escherichia coli K12.
Synthesis of glutamine synthetase (GS) in anaerobic batch cultures of Escherichia coli was repressed when excess NH4+ was available, but derepressed during growth with a poor nitrogen source. In wild-type bacteria there was only a weak inverse correlation between the activities of GS and glutamate dehydrogenase (GDH) during growth in various media. No positive correlations were found between the activities of GS and nitrite reductase, or between GS and cytochrome c552: both of these proteins were synthesized normally by mutants that contained no active GS. Although activities of GS and GDH were low in two mutants that are unable to synthesize cytochrome c552 or reduce nitrite because of defects in the nirA gene, the nirA defect was separated from the GS and GDH defects by transduction with bacteriophage P1. Attempts to show that catabolite repression of proline oxidase synthesis could be relieved during NH4+ starvation also failed. It is, therefore, unlikely that nitrite reduction or proline oxidation by E. coli are under positive control by GS protein. The regulation of the synthesis of enzymes for the utilization of secondary nitrogen sources in E. coli, therefore, different from that in Klebsiella aerogenes, but is similar to that in Salmonella typhimurium.


Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.
Characterization of the composition of the postsynaptic proteome (PSP) provides a framework for understanding the overall organization and function of the synapse in normal and pathological conditions. We have identified 698 proteins from the postsynaptic terminal of mouse CNS synapses using a series of purification strategies and analysis by liquid chromatography tandem mass spectrometry and large-scale immunoblotting. Some 620 proteins were found in purified postsynaptic densities (PSDs), nine in AMPA-receptor immuno-purifications, 100 in isolates using an antibody against the NMDA receptor subunit NR1, and 170 by peptide-affinity purification of complexes with the C-terminus of NR2B. Together, the NR1 and NR2B complexes contain 186 proteins, collectively referred to as membrane-associated guanylate kinase-associated signalling complexes. We extracted data from six other synapse proteome experiments and combined these with our data to provide a consensus on the composition of the PSP. In total, 1124 proteins are present in the PSP, of which 466 were validated by their detection in two or more studies, forming what we have designated the Consensus PSD. These synapse proteome data sets offer a basis for future research in synaptic biology and will provide useful information in brain disease and mental disorder studies.


Optimization of Culture Protocols to Isolate Leptospira spp. from Environmental Water, Field Investigation, and Identification of Factors Associated with the Presence of Leptospira spp. in the Environment.
The successful culture of Leptospira spp. from the environment is challenging. Here, we optimized the isolation of Leptospira spp. from water samples spiked with different species and initial concentrations of this organism. The time periods between water sampling and the isolation process were varied (0, 2, and 4 weeks). Bacterial cultures were observed under a microscope, and cultures were graded for cell density, weekly, for 12 weeks. Most pathogenic Leptospira spp. were difficult to culture under all conditions. All conditions of water samples spiked with novel species of Leptospira subclade P1 were culture positive within 2 weeks. For Leptospira subclade P2, storing samples for 2 weeks prior to isolation resulted in more successful isolation compared with isolation after other storage conditions. For subclade S1, all samples with initial bacterial concentrations of more than 103 colonies/mL, under all storage conditions, were successfully cultured. These results suggest that storing contaminated water samples for 2 to 4 weeks in the dark at an ambient temperature prior to culturing can improve the isolation of Leptospira spp. from the samples. We implemented this protocol and collected water samples from natural sources accessed by both humans and animals. Leptospira spp. was identified in 32% (35/109) of water samples. The animal species using a water source influenced the likelihood of water samples being contaminated with Leptospira spp. Cultures of Leptospira spp. from environmental samples can provide useful information for understanding the complex interactions between humans, animals and the environment in the transmission of leptospirosis.


Off-pump strategy in high-risk coronary artery bypass reoperations.
To determine the role of off-pump coronary artery bypass grafting in the treatment of patients with severe recurrent angina after coronary artery bypass grafting who are not suitable for percutaneous coronary intervention and are considered too high risk for conventional on-pump revascularization. All patients who needed single- or double-vessel revascularization at reoperation with a predicted operative mortality of 10% or higher between March 4, 1994, and December 31, 2002, were studied. Risk stratification was performed using both the Parsonnet risk scoring system and the European System for Cardiac Operative Risk Evaluation. Active follow-up by questionnaire investigated major adverse cardiac events. This study consisted of 84 patients with a median age of 69 years (interquartile range, 62-75 years); 14 (17%) were female. All patients had class III/IV symptoms. Previous operations included multiple coronary artery bypass grafts (15 patients [18%]) and heart transplantation (1 patient [1%]). Internal thoracic artery graft from a previous operation was patent in 43 patients (51%). Perioperative hemodynamic support with inotropes (35%) and intra-aortic balloon pump (14%) or ventricular assist device (2%) was common. The surgical approach varied for each patient. One operative death (1%) occurred. Estimated survival at 5 and 7 years was 77% and 67%, respectively. Late major adverse cardiac events observed during follow-up were cardiac death (n=66), nonoperative reintervention (n=8), and nonfatal myocardial infarction (n=5). Off-pump coronary artery bypass grafting can mitigate reoperative risk in patients with an estimated risk of 10% or higher who are undergoing single- or double-vessel revascularization with satisfactory long-term outcome.


Older men with low serum estradiol and high serum SHBG have an increased risk of fractures.
Osteoporosis-related fractures constitute a major health concern not only in women but also in men. To study the predictive role of serum sex steroids for fracture risk in men, serum sex steroids were analyzed by the specific gas chromatography-mass spectrometry technique at baseline in older men (n = 2639; mean, 75 yr of age) of the prospective population-based MrOS Sweden cohort. Fractures occurring after baseline were validated (average follow-up of 3.3 yr). The incidence for having at least one validated fracture after baseline was 20.9/1000 person-years. Estradiol (E2; hazard ratio [HR] per SD decrease, 1.34; 95% CI, 1.22-1.49), free estradiol (fE2; HR per SD decrease, 1.41; 95% CI, 1.28-1.55), testosterone (T; HR per SD decrease, 1.27; 95% CI, 1.16-1.39), and free testosterone (fT; HR per SD decrease, 1.32; 95% CI, 1.21-1.44) were all inversely, whereas sex hormone-binding globulin (SHBG; HR per SD increase, 1.41; 95% CI, 1.22-1.63) was directly related to fracture risk. Multivariable proportional hazards regression models, adjusted for age, suggested that fE2 and SHBG (p < 0.001), but not fT, were independently associated with fracture risk. Further subanalyses of fracture type showed that fE2 was inversely associated with clinical vertebral fractures (HR per SD decrease, 1.57; 95% CI, 1.36-1.80), nonvertebral osteoporosis fractures (HR per SD decrease, 1.42; 95% CI, 1.23-1.65), and hip fractures (HR per SD decrease, 1.44; 95% CI, 1.18-1.76). The inverse relation between serum E2 and fracture risk was nonlinear with a strong relation <16 pg/ml for E2 and 0.3 pg/ml for fE2. In conclusion, older Swedish men with low serum E2 and high SHBG levels have an increased risk of fractures.


The Effect of Spacer Morphology on the Aerosolization Performance of Metered-Dose Inhalers.
Respiratory drug delivery has been attracted great interest for the past decades, because of the high incidence of pulmonary diseases. However, despite its invaluable benefits, there are some major drawbacks in respiratory drug delivery, mainly due to the relatively high drug deposition in undesirable regions. One way to improve the efficiency of respiratory drug delivery through metered-dose inhalers (MDI) is placing a respiratory spacer between the inhaler exit and the mouth. The aim of this study was to assess the effect of type and shape of spacer on the aerosolization performance of MDIs. A commercial Beclomethasone Dipropionate (BDP) MDI alone or equipped with two different spacer devices (roller and pear type) widely distributed in the world pharmaceutical market was used. The effect of spacers was evaluated by calculating aerosolization indexes such as fine particle fraction (FPF), mass median aerodynamic diameters (MMAD) and geometric standard deviation (GSD) using the next generation impactor. Although one of the spacers resulted in superior outcomes than the other one, but it was not statistically significant. The results confirmed that the type and shape of spacer did not substantially influence the aerosolization performance of MDIs.


Endogenous regulation of cardiovascular function by apelin-APJ.
Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.


HIV and cART-Associated Dyslipidemia Among HIV-Infected Children.
Persistent dyslipidemia in children is associated with risks of cardiovascular accidents and poor combination antiretroviral therapy (cART) outcome. We report on the first evaluation of prevalence and associations with dyslipidemia due to HIV and cART among HIV-infected Ethiopian children. 105 cART naïve and 215 treatment experienced HIV-infected children were enrolled from nine HIV centers. Demographic and clinical data, lipid profile, cART type, adherence to and duration on cART were recorded. Total, low density (LDLc) and high density (HDLc) cholesterol values >200 mg/dL, >130 mg/dL, <40 mg/dL, respectively; and/or, triglyceride values >150 mg/dL defined cases of dyslipidemia. Prevalence and predictors of dyslipidemia were compared between the two groups. prevalence of dyslipidemia was significantly higher among cART experienced (70.2%) than treatment naïve (58.1%) children (p = 0.03). Prevalence of low HDLc (40.2% versus 23.4%, p = 0.006) and hypertriglyceridemia (47.2% versus 35.8%, p = 0.02) was higher among cART experienced than naïve children. There was no difference in total hypercholesterolemia and high LDLc levels. Nutrition state was associated with dyslipidemia among cART naïve children (p = 0.01). high prevalence of cART-associated dyslipidemia, particularly low HDLc and hypertriglyceridemia was observed among treatment experienced HIV-infected children. The findings underscore the need for regular follow up of children on cART for lipid abnormalities.


Spectrally resolved frequency domain analysis of multi-fluorophore systems undergoing energy transfer.
Complex systems of fluorophores undergoing energy transfer can exhibit a variety of anomalous lifetime behavior when probed with frequency domain methods. When presented in traditional apparent lifetime format the data from such systems can exhibit "nodal" behavior in which the computed lifetime approaches +/-infinity. The location of the nodes is system and frequency dependent. In addition, simpler systems, not undergoing energy transfer, show ill behavior in the region of zero lifetime (tau(m)) and long lifetime (tau(pi)) due to noise in typical measurements. Here, we systematically investigate systems of multiple fluorophores with and without energy transfer to provide insight into frequency domain investigations of complex systems of fluorophores. The results of simulations are compared to data collected from a multi-fluorophore system designed to exhibit fluorescence resonance energy transfer (FRET) using imaging spectroscopic fluorescence lifetime imaging microscopy (ISFLIM). The results are applicable to both cuvette and imaging arrangements.


Recruiting undergraduates to rural practice: what the students can tell us.
There are still large gaps in the evidence base for the effectiveness of Australian undergraduate rural coursework and placements programs designed to increase the numbers of health graduates choosing rural practice. This article reports on an online survey conducted in 2004 of health science students at the University of Tasmania, Australia, designed as a part of a long-term study to test coursework interventions by tracking students' attitudes to, and experience of, rural practice from course entry to eventual practice. All first and final year students in medicine, nursing and pharmacy in the Faculty of Health Science were invited to complete an online survey exploring the undergraduate experience of rural health. The survey was completed by 148 first year and 87 final year students, a response rate of 32.4% and 23.1% respectively. Over one-third (38.5%) of first years and 56.3% of final years indicated a general preference for rural life and practice and almost 90% expected to spend at least some of their career in rural practice. There was a statistically significant relationship between rural practice orientation and rural origin among first years, although this relationship was weaker among final years. Of first years, 82.4%, and 82.7% of final years appear to have made at least some commitment to a particular career path, and two-thirds to a particular practice environment. Rurally oriented first year students were significantly more committed to a career path than those without that orientation, although this did not hold for final years. When asked how much of their careers they expected to spend in capital city, rural, remote and/or overseas practice, both first and final year students' responses were notable for their spread. Few ruled rural or urban practice in or out entirely with most opting for middle range responses of 'most', 'about half' or 'part' of their career. Over half of both years expected to spend some time in remote practice and 75.1% of first years and 66.6% of final years some time in overseas practice. The factors rated most important in relation to career choice were those related directly to the realities of day-to-day professional practice--professional and peer support, work conditions and variety of work. Approximately three-quarters of those entering undergraduate education felt themselves to be at least 'somewhat informed' about rural practice but, apart from medical students, were little better informed by final year. The only perception of rural practice very widely shared (by more than 80% of respondents) was the possibility of developing better patient relations. Many of the other factors frequently identified as major issues in the rural practice literature--locality, flexibility, opportunities for further study, and spouse/partner and children's needs - while recognised by some, do not appear to loom large with undergraduates either in terms of career choice or perceptions of rural practice. Most final year students recalled receiving specific rural health training through rural placements and/or rural curriculum content. Overall recall of coursework was patchy, although placements were well-remembered and there was good support for increases in both. None of those who recalled undertaking rural coursework felt that it had influenced them towards a rural career and over two-thirds (n = 37, 69.8%) felt that this exposure had actually influenced them away from such a career. Three students reported that undertaking a rural placement influenced them towards, and 35 away from, a rural/remote career. The ultimate measure of the success of undergraduate interventions will be workforce changes over time. In the meantime more research is needed into undergraduate experience of rural health to provide the data needed for the careful design of coursework, detailed planning of the placement experience and long-term strategies to address those aspects of rural practice that are of most concern to these emerging health professionals.


Genetic polymorphism of the inhibitory IgG Fc receptor FcgammaRIIb is not associated with clinical outcome in patients with follicular lymphoma treated with rituximab.
Polymorphisms of activating FcgammaRIIIa (CD16) and FcgammaRIIa (CD32a) have been found to predict rituximab response, probably because of the relative efficiency of different FcgammaR variants in performing antibody-dependent cellular cytotoxicity. The inhibitory FcgammaRIIb (CD32b) has an opposing effect on effector cells. Here, we examined whether an FcgammaRIIb 232 isoleucine (I)/threonine (T) polymorphism predicts rituximab response in 101 patients with follicular lymphoma. Eighty-four patients were 232 I/I, 15 were 232 I/T and two were 232 T/T. The response rate was similar among the three groups. The 2-year progression free survival (PFS) and median time to progression (TTP) were not different between I/I and I/T groups. The TTP was not determined in T/T group because of small number of patients. The FcgammaRIIIa 158 V/V and FcgammaRIIa 131 H/H genotypes continued to emerge as independent predictors for higher response rate and longer TTP. This study is the first to determine whether inhibitory FcgammaRIIb play a role in rituximab's anti-tumor effect in humans.


The morphology of the inner ear of squamate reptiles and its bearing on the origin of snakes.
The inner ear morphology of 80 snake and lizard species, representative of a range of ecologies, is here analysed and compared to that of the fossil stem snake Dinilysia patagonica, using three-dimensional geometric morphometrics. Inner ear morphology is linked to phylogeny (we find here a strong phylogenetic signal in the data that can complicate ecological correlations), but also correlated with ecology, with Dinilysia resembling certain semi-fossorial forms (Xenopeltis and Cylindrophis), consistent with previous reports. We here also find striking resemblances between Dinilysia and some semi-aquatic snakes, such as Myron (Caenophidia, Homalopsidae). Therefore, the inner ear morphology of Dinilysia is consistent with semi-aquatic as well as semi-fossorial habits: the most similar forms are either semi-fossorial burrowers with a strong affinity to water (Xenopeltis and Cylindrophis) or amphibious, intertidal forms which shelter in burrows (Myron). Notably, Dinilysia does not cluster as closely with snakes with exclusively terrestrial or obligate burrowing habits (e.g. scolecophidians and uropeltids). Moreover, despite the above similarities, Dinilysia also occupies a totally unique morphospace, raising issues with linking it with any particular ecological category.