SMAC/Diablo-dependent apoptosis induced by nonsteroidal antiinflammatory drugs (NSAIDs) in colon cancer cells.
Nonsteroidal antiinflammatory drugs (NSAIDs) form a paradigm for the chemoprevention of cancer, preventing colonic tumor progression in both experimental animals and humans. However, the mechanisms underlying the antineoplastic effects of NSAIDs are currently unclear. We found that the mitochondrial second mitochondrial-derived activator of caspase (SMAC)/direct inhibitor of apoptosis protein-binding protein with low pI (Diablo) protein translocates into the cytosol during NSAID-induced apoptosis in colon cancer cells. When SMAC/Diablo is disrupted by homologous recombination and RNA interference in these cells, the NSAID-induced apoptosis is abrogated. Biochemical markers of apoptosis, such as caspase activation, cytosolic release of cytochrome c and apoptosis-inducing factor, and mitochondrial membrane potential change, are accordingly decreased. These results establish that SMAC/Diablo is essential for the apoptosis induced by NSAIDs in colon cancer cells.


Unwanted sex among young adults in the United States: the role of physical disability and cognitive performance.
This study examined associations between unwanted sexual experiences and both physical disability and cognitive performance in a nationally representative sample of young adults. We used data from 11,878 participants (ages 26-32) in Waves I, III, and IV of the National Longitudinal Study of Adolescent Health (Add Health). Logistic regressions determined associations between physical disability and level of cognitive performance (using a modified Peabody Picture Vocabulary Test) and the odds of experiencing physically forced and nonphysically coerced sex. Approximately 24% of females and 4% of males reported unwanted sexual experiences. Compared to respondents without disabilities, females with a physical disability had greater odds of experiencing forced sex (OR = 1.49; 95% CI [1.06, 2.08]), whereas males with a physical disability had greater odds of coerced sex (OR = 1.90; 95% CI [1.02, 3.52]). Compared to those with average cognitive performance scores, females with scores above 110 had slightly higher odds of coerced sex (OR = 1.20; 95% CI [1.03-1.41]). Further research on pathways underlying these associations is needed to inform prevention efforts.


Human parvovirus B19.
Parvovirus B19 (B19) was discovered in 1974 and is the only member of the family Parvoviridae known to be pathogenic in humans. Despite the inability to propagate the virus in cell cultures, much has been learned about the pathophysiology of this virus, including the identification of the cellular receptor (P antigen), and the control of the virus by the immune system. B19 is widespread, and manifestations of infection vary with the immunologic and hematologic status of the host. In healthy immunocompetent individuals B19 is the cause of erythema infectiosum and, particularly in adults, acute symmetric polyarthropathy. Due to the tropism of B19 to erythroid progenitor cells, infection in individuals with an underlying hemolytic disorder causes transient aplastic crisis. In the immunocompromised host persistent B19 infection is manifested as pure red cell aplasia and chronic anemia. Likewise, the immature immune response of the fetus may render it susceptible to infection, leading to fetal death in utero, hydrops fetalis, or development of congenital anemia. B19 has also been suggested as the causative agent in a variety of clinical syndromes, but given the common nature, causality is often difficult to infer. Diagnosis is primarily based on detection of specific antibodies by enzyme-linked immunosorbent assay or detection of viral DNA by dot blot hybridization or PCR. Treatment of persistent infection with immunoglobulin reduces the viral load and results in a marked resolution of anemia. Vaccine phase I trials show promising results.


Identifying robust correlates of risk preference: A systematic approach using specification curve analysis.
People's risk preferences are thought to be central to many consequential real-life decisions, making it important to identify robust correlates of this construct. Various psychological theories have put forth a series of candidate correlates, yet the strength and robustness of their associations remain unclear because of disparate operationalizations of risk preference and analytic limitations in past research. We addressed these issues with a study involving several operationalizations of risk preference (all collected from each participant in a diverse sample of the German population; N = 916), and by adopting an exhaustive modeling approach-specification curve analysis. Our analyses of 6 candidate correlates (household income, sex, age, fluid intelligence, crystallized intelligence, years of education) suggest that sex and age have robust and consistent associations with risk preference, whereas the other candidate correlates show weaker and more (domain-) specific associations (except for crystallized intelligence, for which there were no robust associations). The results further demonstrate the important role of construct operationalization when assessing people's risk preferences: Self-reported propensity measures picked up various associations with the proposed correlates, but (incentivized) behavioral measures largely failed to do so. In short, the associations between the 6 candidate correlates and risk preference depend mostly on how risk preference is measured, rather than whether and which control variables are included in the model specifications. The present findings inform several theories that have suggested candidate correlates of risk preference, and illustrate how personality research may profit from exhaustive modeling techniques to improve theory and measurement of essential constructs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Dependence of Incidence Angle and Flux Density in the Damage Effect of Atomic Oxygen on Kapton Film.
Kapton film is a polymeric material widely used on low-Earth-orbit (LEO) spacecraft surfaces. In the LEO environment, atomic oxygen (AO) is spaceflight materials' most destructive environmental factor. The erosion mechanism of AO on Kapton films has long been an important issue, where the parameter dependence of the AO effect has received increasing attention. Studies of AO energy and cumulative flux have been extensively carried out, while the influence mechanism of the incidence angle and flux density is not fully understood. The AO incidence angle and flux density in space are diverse, which may cause different damage effects on aerospace materials. In this paper, the dependence of the incidence angle and flux density in the damaging effect of AO on Kapton films was investigated using ground-based AO test technology and the reactive molecular dynamics (ReaxFF MD) simulation technique. Firstly, the ground-based experiment obtained the mass loss data of Kapton films under the action of AO with a variable incidence angle and flux density. Then, the mass loss, temperature rise, product, and erosion yield of Kapton during AO impact with different incidence angles and dose rates were calculated using the ReaxFF MD method. The influences of the incidence angle and flux density on the damage mechanism of the AO effect were discussed by comparing the simulation and test results. The results show that the AO effect in the lower incidence angle range (0-60°) is independent of the incidence angle and depends only on the amount of impacted atomic oxygen. AO in the higher incidence angle range (60-90°) has a surface stripping effect, which causes more significant mass loss and a temperature rise while stripping raised macromolecules from rough surfaces, and the erosion effect increases with the increasing incidence angle and amount of impacted atomic oxygen. There is a critical value for the influence of flux density on the AO effect. Above this critical value, AO has a reduced erosive capacity due to a lower chance of participating in the reaction. The amount of each main product from the AO effect varies with the incidence angle and flux density. Nonetheless, the total content of the main products is essentially constant, around 70%. This work will contribute to our understanding of the incidence angle and flux density dependence of the AO effect and provide valuable information for the development of standards for ground simulation tests.


Metrizamide computed tomographic cisternography for the diagnosis of occult lesions of the hypothalamic-hypophyseal axis in children.
In children, hypothalamic-hypophyseal syndromes such as diabetes insipidus, precocious puberty, growth retardation, and panhypopituitarism can be due either to structural lesions or to functional disorders of the cerebral endocrine complex. When clinical and endocrinological parameters fail to distinguish between these etiologies, neuroradiographical diagnosis becomes extremely important. Although conventional intravenously enhanced computed tomography (IVCT) is satisfactory for the diagnosis of lesions larger than 1 cm, metrizamide CT cisternography (MCTC) greatly improves the diagnostic yield for smaller juxtapituitary masses in the suprasellar cistern, clearly defines their sizes and relationships with contiguous structures, and definitively confirms the diagnosis of empty sella syndrome. Six patients with endocrinopathies and normal or ambiguous IVCT findings are presented to illustrate how MCTC can influence their management and outcome without the patient discomfort and technical complexity associated with pneumoencephalography.


Forward with Dementia: process evaluation of an Australian campaign to improve post-diagnostic support.
Forward with Dementia is a co-designed campaign to improve communication of dementia diagnosis and post-diagnostic support. Webinars, a website, social and traditional media, and promotions through project partners were used to disseminate campaign messages to health and social care professionals (primary audience) and people with dementia and carers (secondary audience). The campaign ran between October 2021 and June 2022, with 3-months follow-up. The RE-AIM framework was used for process evaluation. Measurements included surveys and interviews, a log of activities (e.g. webinars, social media posts) and engagements (e.g. attendees, reactions to posts), and Google Analytics. There were 29,053 interactions with campaign activities. More than three-quarters of professionals (n = 63/81) thought webinars were very or extremely helpful. Professionals and people with dementia and carers reported that the website provided appropriate content, an approachable tone, and was easy to use. Following campaign engagement, professionals planned to (n = 77/80) or had modified (n = 29/44) how they communicated the diagnosis and/or provided post-diagnostic information and referrals. Qualitative data suggested that the campaign may have led to benefits for some people with dementia and carers. Forward with Dementia was successful in terms of reach, appropriateness, adoption and maintenance for professionals, however flow-through impacts on people with dementia are not clear. Targeted campaigns can potentially change health professionals' communication and support around chronic diseases such as dementia.


Biophysical virus particle specific characterization to sharpen the definition of virus stability.
Vaccine thermostability is key to successful global immunization programs as it may have a significant impact on the continuous cold-chain maintenance logistics, as well as affect vaccine potency. Modern biological and biophysical techniques were combined to in-depth characterize the thermostability of a formulated rabies virus (RABV) in terms of antigenic and genomic titer, virus particle count and aggregation state. Tunable resistive pulse sensing (TRPS) and nanoparticle tracking analysis (NTA) were used to count virus particles while simultaneously determining their size distribution. RABV antigenicity was assessed by NTA using a monoclonal antibody that recognize a rabies glycoprotein (G protein) conformational epitope, enabling to specifically count antigenic rabies viruses. Agreement between antigenicity results from NTA and conventional method, as ELISA, was demonstrated. Additionally, NTA and ELISA showed mirrored loss of RABV antigenicity during forced degradation studies performed between 5 °C and 45 °C temperature exposure for one month. Concomitant with decreased antigenicity, emergence of RABV particle populations larger than those expected for rabies family viruses was observed, suggesting RABV aggregation induced by thermal stress. Finally, using a kinetic-based modeling approach to explore forced degradation antigenicity data (NTA, ELISA), a two-step model accurately describing antigenicity loss was identified. This model predicted a RABV shelf-life of more than 3 years at 5 °C; significant loss of antigenicity was predicted for samples maintained several months at ambient temperature. This thorough characterization of RABV forced degradation study originally provided a time-temperature mapping of RABV stability.


Admission of dentist in Brazilian Universal Health System (SUS): a priority agenda for the strengthening of Smiling Brazil.
This article aims at: i) describing and analyzing the expansion of dental care in the Unified Health System (SUS); ii) Identifying and analyzing the characteristics of hiring dentists' in the public service; iii) characterizing public vacancies, their duties and remuneration. In this descriptive case study, databases of the Ministry of Health were consulted and public tender notices. The findings indicate that 48% of the dentists enrolled in the National Registry of Health Establishments (CNES) perform care in the SUS, in 13 years there was an increase of 118% of the municipalities with oral health teams (eSB) implanted. The population coverage estimated by eSB increased by 10.46% between the years 2007 and 2015. The main mechanism for joining the Dental Specialties Centers (CEO) was the public tender. Primary care salaries ranged from 1.05 to 12.67 Brazilian minimum wages, to 40-hour weekly jobs, and to CEOs from 3.35 to 7.05. It is concluded that, among other measures, the planning of HRH strategies is necessary. The continuity of successes regulatory measures of labor contracts and support to local managers enter the agenda of priority actions of oral health policy.


Effects of recombinant interferon-tau on ovine lentivirus replication.
As a pregnancy recognition signal, sheep trophoblast cells secrete a type I interferon, ovine interferon-tau (OvIFN-tau), which has potent antiviral activity. We studied the effects of a recombinant protein (rOv-IFN-tau) on the replication of ovine lentivirus (OvLV) in goat synovial membrane cells. The amount of provirus DNA, as measured by polymerase chain reaction (PCR), the virus titers, and the number of OvLV-induced syncytia were 76.5%, 82%, and 95%, respectively, lower in cultures treated with rOv-IFN-tau than in placebo-treated controls (p < 0.01). rOv-IFN-tau also reduced OvLV reverse transcriptase activity and protected cells from OvLV-induced cell lysis, but the effect was less dramatic. The antiviral activity increased with the concentration up to a maximum with 256 antiviral units of rOv-IFN-tau per ml.


Real time ultrasound diagnosis of non-vaterian duodenal adenoma--a brief case report.
Non-vaterian duodenal adenomas are rare lesions, usually present with bleeding and abdominal pain. Sonography is often the first imaging procedure in patients with vague upper abdominal complaints, unsuspected duodenal pathology may be encountered. It is now widely accepted as the first choice for the investigation of abdominal masses. Oral water load is recognised as a good procedure for the detection of a bowel-related mass during sonographic examination. In our case, we used the real-time ultrasound with water ingestion to detect the location of the duodenal lesion and its relationship to the neighboring structure. This report demonstrates that conventional real-time ultrasound is still a simple method to diagnose duodenal lesions.


Reduction of inequalities in medical visits in Brazil: analysis of the Northeastern and Southeastern regions between 2003 and 2008.
To analyze the socioeconomic inequalities in medical visits (MV) in the past year in Brazil. Data from adults aged ≥ 20 years old who participated in the Brazilian National Household Surveys and living in the Northeastern (2003; n = 75,652 and 2008, n = 79,779) and Southeastern (2003; n = 76,029 and 2008; n = 79,356) regions were analyzed according to MV. We compared MVs according to demographic and health variables in the first (D1) and last (D10) per capita family income deciles. All analyses considered the complex cluster design. The proportion of people who had MV during this period increased in the Northeastern (from 61.2 to 66.9%) and the Southeastern (from 67.9 to 73.5%) regions. The absolute difference (AD) in the use of MV, according to D1 and D10 in this period, was equal to 6.4 percentage points (pp) in the Northeastern and 4.2 pp in the Southeastern regions. Significant reduction in inequalities was observed among men without chronic diseases, in those who had a positive perception of their health, and among those without health insurance which included MV. The Southeastern region has also showed significant reduction among those with chronic disease (8 pp) and with negative health self-perception (6 pp). The increasing number of MVs was found in Brazil. However, persistent inequalities were observed between the poorest and the richest, higher in the Northeastern than in the Southeastern region. More effective and equitable policies to reduce health inequalities should be adopted in Brazil.


Multiplexed detection and characterization of rare tumor cells in Hodgkin's lymphoma with multicolor quantum dots.
The multicolor and multiplexing capabilities of semiconductor quantum dots (QDs) are most promising for improving the sensitivity and specificity of in vitro molecular and cellular diagnostics. Here, we report the use of multiplexed QDs and wavelength-resolved imaging to detect and characterize a class of low-abundant tumor cells in Hodgkin's lymphoma. Known as the Hodgkin's and Reed-Sternberg (HRS) cells, this class of malignant cells is a pathological hallmark in clinical diagnosis, but it comprises only about 1% of the heterogeneous infiltrating cells in lymph node tissues. To overcome this cellular heterogeneity and rarity problem, we have developed multicolor QD-antibody conjugates to simultaneously detect a panel of four protein biomarkers (CD15, CD30, CD45, and Pax5) directly on human tissue biopsies. This multiplexing approach allows rapid detection and differentiation of rare HRS cells from infiltrating immune cells such as T and B lymphocytes. We have also carried out clinical translation studies involving six confirmed Hodgkin's lymphoma patients, two suspicious lymphoma cases, and two patients with reactive lymph nodes (but not lymphoma). The results indicate that a distinct QD staining pattern (CD15 positive, CD30 positive, CD45 negative, and Pax5 positive) can be used to not only detect Hodgkin's lymphoma but also differentiate it from benign lymphoid hyperplasia.


Human Milk Macronutrients Content: Effect of Advanced Maternal Age.
Little is known about the effect of advanced maternal age upon macronutrients of human milk. This study was designed to study contents of macronutrients (fat, lactose, and protein) in human milk collected in the first 2 weeks of life in older (≥35 years) compared with younger (<35 years) mothers. Seventy-two lactating mothers (38 older, 34 younger) of newborns were recruited within the first 3 days of delivery. Macronutrient contents were measured at 72 hours, 7 days, and 14 days after delivery using infrared transmission spectroscopy. The groups did not differ in terms of maternal prepregnancy weight, height, and diet or infant birth weight or gestational age. They differed significantly in terms of maternal age and maternal weight after pregnancy. Fat content in colostrum and carbohydrate content in mature milk were significantly higher in the older mothers group. Moreover, carbohydrates in mature milk correlated positively with maternal age. Fat content at an infant age of 7 days and 2 weeks was not affected by maternal age. There was no significant relationship between maternal body weight for height (or body mass index) and energy, protein, fat or lactose content at any stage. Fat content of colostrum and carbohydrate content of mature milk obtained from mothers with advanced age are elevated compared with those of younger mothers. Moreover, there is a positive correlation between maternal age and carbohydrate content in mature milk. The biological significance of our findings is yet to be determined.


[Effect of the night shift work on micturition patterns of nurses].
To compare the effects of rotational night shifts on the micturition patterns of female nurses. A total of 58 nurses without lower urinary tract symptoms were recruited, who worked in the Peking University People's Hospital during January and June in 2014. The nurses aged 20-43 years were divided into two groups, the night-shift group (n=28) and the non-shift group (n=30). The alcohol or coffee intaking were forbidden. In the night-shift group, nurses had worked on rotational shifts for at least 6 months. Their average age was (26.75±4.11) years. In the non-shift group, nurses took regular day-time work, whose average age was (27.80±5.60) years. A voiding diary was kept for 7 consecutive days at the end of 6 months, starting 2 days before their night duties until 4 days after completion of their night duties. For comparison, the non-shift group with regular shifts completed a 7-day voiding diary. In the 7-day recording voiding diary, the nurses were required to have the normal intake of liquid about 1 500-2 000 mL/d. The frequency volume charts of nocturia, the 8-hour interval urine production and frequency were compared between the two groups. Nocturia frequency was increased in the night-shift group [0.5 (0-2.4)] compared with the non-shift group [0 (0-2), P=0.02]. The volume of nocturia was increased in the night-shift group [125 mL (0-660 mL)] compared with the non-shift group [0 mL (0-340 mL), P<0.01]. The 8-hour interval indices showed that urine production changed with shift (P<0.01). In the consecutive 7 days, the nocturnal volume of the night-shift group increased on the day after night shift. When the night-shift nurses returned to daytime duty, the volume of urine decreased but nocturnal urine production remained high, and the frequency of nocturia also increased significantly (P<0.05). Compared with the 8-hour interval indices, the night-shift group's voiding volume [(542.35±204.66) mL] and voiding frequency (2.24±0.69) were more than those of the non-shift group at the afternoon time (from 2 pm to 10 pm). During the 8 h interval night time (from 10 pm to 6 am), the volume of nocturia in the night-shift group [(309.74±162.74) mL] was more than that in the non-shift group [(199.38±153.98) mL, P=0.01]; the frequency of nocturia in the night-shift group (1.31±0.52) was increased than that in the non-shift group (0.82±0.55, P<0.01). The rotational shifts affect the micturition patterns of nurses who go through the night shift work, which increases the volume and frequency of the nocturia.


Modulation of the anchorage-independent phenotype of human lung fibroblasts obtained from fibrotic tissue following culture with retinoid and corticosteroid.
Fibroblast heterogeneity has been documented in fibrotic tissue from lung and skin. Differences have been demonstrated in proliferative rates in fibroblasts derived from fibrotic lung tissue as compared to normal. Fibroblast lines derived from adult fibrotic lung tissue and neonatal normal lung tissue exhibit colony growth in soft agarose culture, whereas fibroblast cell lines from normal adult lung tissue do not. The characteristic of anchorage-independent growth is consistent with the aggressive nature of the disease and with developmental lung growth. In this study, fibrotic lung fibroblasts were exposed to growth and differentiating factors to determine whether the anchorage-independent phenotype can be modulated. The results indicate that treatment of fibrotic lung fibroblasts with retinoic acid, known to modify matrix gene expression and induce differentiation, inhibits the cells ability to form colonies under soft agarose growth. Treatment with all-trans-retinoic acid yielded the greatest effect inhibiting both IPF and neonatal lung fibroblast anchorage-independent growth approximately 90% at 10(-6) M. Treatment of IPF fibroblasts with all-trans-retinoic acid also inhibited corticosteroid-induced colony growth. Modulation of the "fibrotic" fibroblast phenotype through retinoid therapy may prove beneficial as a potential therapeutic strategy.


The SITLESS project: exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: study protocol for a randomised controlled trial.
Older adults are the fastest growing segment of the world's population. Recent evidence indicates that excessive sitting time is harmful to health, independent of meeting the recommended moderate to vigorous physical activity (PA) guidelines. The SITLESS project aims to determine whether exercise referral schemes (ERS) can be enhanced by self-management strategies (SMSs) to reduce sedentary behaviour (SB), increase PA and improve health, quality of life and function in the long term, as well as psychosocial outcomes in community-dwelling older European citizens from four countries, within a three-armed pragmatic randomised controlled trial, compared with ERS alone and also with general recommendations about PA. A total of 1338 older adults will be included in this study, recruited from four European countries through different existing primary prevention pathways. Participants will be randomly allocated into an ERS of 16 weeks (32 sessions, 45-60 min per session), ERS enhanced by seven sessions of SMSs and four telephone prompts, or a control group. Outcomes will be assessed at baseline, month 4 (end of ERS intervention), month 16 (12 months post intervention) and month 22 (18 months post intervention). Primary outcomes will include measures of SB (time spent sedentary) and PA (counts per minute). Secondary outcomes will include muscle and physical function, health economics' related outcomes, anthropometry, quality of life, social networks, anxiety and depressive symptoms, disability, fear of falling, executive function and fatigue. A process evaluation will be conducted throughout the trial. The full analysis set will follow an intention-to-treat principle and will include all randomised participants for whom a baseline assessment is conducted. The study hypothesis will be tested with mixed linear models with repeated measures, to assess changes in the main outcomes (SB and PA) over time (baseline to month 22) and between study arms. The findings of this study may help inform the design and implementation of more effective interventions to reduce SB and increase PA levels, and hence improve long-term health outcomes in the older adult population. SITLESS aims to support policy-makers in deciding how or whether ERS should be further implemented or restructured in order to increase its adherence, impact and cost-effectiveness. ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.


Blood cell flow cytometry in paroxysmal nocturnal hemoglobinuria: a tool for measuring the extent of the PNH clone.
The membrane expression of nine glycosyl phosphatidyl inositol (GPI)-linked molecules was analyzed by flow cytometry on circulating cells from 18 patients affected by paroxysmal nocturnal hemoglobinuria (PNH). The results allowed us to select CD66b, CD14, CD59, CD24 and CD59 monoclonal antibodies as the most suitable reagents for discriminating between normal and PNH cells in PMN, monocytes, RBC and B or T lymphocytes, respectively. In order to assess whether the analysis of distinct cell populations could provide differential information on the extent of the disease, we compared the proportion of residual normal cells in RBC, monocyte and PMN populations. The mean percentage of unaffected cells was higher in RBC as compared to PMN (50.5 +/- 18.7 vs 17.7 +/- 19.7, P < 0.0001). The proportion of normal PMN was, in turn, significantly greater than that of normal monocytes (17.7 +/- 19.7 vs 8.7 +/- 11.0; P < 0.05). The percentage of CD14+ monocytes was directly related to Hb concentration and platelet (Plt) count, and inversely to percent lysis at the Ham's test. The percentage of CD66b+ PMN was directly related to Plt count and Hb level, while the percentage of CD59+ RBC was associated, in an inverse fashion, only to the Ham's test. No significant correlation was found between cell marker expression and PMN count, reticulocytosis, bilirubin and serum LDH. By dividing the patients into two groups, according to high (> 10 percent) or low (< 10 percent) percentage of CD14+ monocytes, a statistical analysis showed that the main hematological parameters were significantly different.


Characteristics of vitiligo in Korean children.
Eighty Korean children (ages 8 months-12 years) with clinical and/or histopathologic diagnoses of vitiligo were evaluated; 39 boys and 41 girls. The mean age at first visit was 7.9 years and the mean age at onset was 5.6 years. The most common site of onset was the head/neck area (58.8%), followed by the trunk and lower limbs. The children were compared with a control group of 422 adults with vitiligo. Children comprised 16% of the total vitiligo patients and adults comprised 84%. A family history of vitiligo was found in 11 (13.8%) children, compared to 10.7% in the adult group; poliosis in 20 (25. 0%); halo nevi in 2 (2.5%), compared to 4.0% in the adult group; combined autoimmune and endocrine diseases in 1 (1.3%), compared to 7.6% in the adult group; and segmental vitiligo in 26 (32.5%), compared to 13.0% in the adult group. The combined diseases were significantly less often found in children than adults (p < 0.01), and segmental vitiligo was significantly more often associated with children (p < 0.0001). Our study did not show a higher prevalence of vitiligo in girls as reported in other studies, which may indicate racial differences. Of the total 502 patients, only 1 patient with segmental vitiligo had halo nevi. Sixty-four percent of the children with vitiligo responded to treatment, compared to 57% of the adults.


Phase-separated thin film structures for efficient polymer blend light-emitting diodes.
We report laterally and vertically phase-separated thin film structures in conjugated polymer blends created by polymer molecular weight variation. We find that micrometer-scale lateral phase separation is critical in achieving high initial device efficiency of light-emitting diodes, whereas improved balance of charge carrier mobilities and film thickness uniformity are important in maintaining high efficiency at high voltages. The optoelectronic properties of these blend thin films and devices are strongly influenced by the polymer chain order/disorder and the interface state formed at polymer/polymer heterojunctions.


Genetic analysis in Streptomyces chrysomallus.
A circular linkage map was developed for Streptomyces chrysomallus, a producer of actinomycin C. The map order of various marker loci was deduced from matings and to a minor extent from protoplast fusions. The map strongly resembles that of Streptomyces coelicolor A3(2). The recombination frequencies were low and highly variable (from 10(-9) to 5 X 10(-6]. Plasmid pIJ303 expressed its thiostrepton resistance gene in S. chrysomallus but did not promote chromosomal transfer or induce the Ltz+ phenotype. The data provide a background of genetics for investigations of antibiotic synthesis in this strain.


Oyster reproduction is compromised by acidification experienced seasonally in coastal regions.
Atmospheric carbon dioxide concentrations have been rising during the past century, leading to ocean acidification (OA). Coastal and estuarine habitats experience annual pH variability that vastly exceeds the magnitude of long-term projections in open ocean regions. Eastern oyster (Crassostrea virginica) reproduction season coincides with periods of low pH occurrence in estuaries, thus we investigated effects of moderate (pH 7.5, pCO2 2260 µatm) and severe OA (pH 7.1, pCO2 5584 µatm; and 6.7, pCO2 18480 µatm) on oyster gametogenesis, fertilization, and early larval development successes. Exposure at severe OA during gametogenesis caused disruption in oyster reproduction. Oogenesis appeared to be more sensitive compared to spermatogenesis. However, Eastern oyster reproduction was resilient to moderate OA projected for the near-future. In the context of projected climate change exacerbating seasonal acidification, OA of coastal habitats could represent a significant bottleneck for oyster reproduction which may have profound negative implications for coastal ecosystems reliant on this keystone species.


Tumor necrosis factor-alpha-angiotensin interactions and regulation of blood pressure.
To compare the levels of tumor necrosis factor-alpha (TNF) produced by medullary thick ascending limb tubules (MTAL) obtained from normotensive and angiotensin II (Ang II)-dependent hypertensive rats and determine whether TNF participates in a mechanism that opposes elevation of blood pressure by Ang II. We have previously demonstrated that in-vitro administration of Ang II increases production of TNF and prostaglandin E2 (PGE2) by the MTAL. We hypothesize that production of TNF and PGE2 by the MTAL is elevated in in-vivo models of Ang II-dependent hypertension and acts to modulate the pressor effects of Ang II. Thus, inhibition of TNF should disclose whether this cytokine acts to modulate Ang II-induced hypertension. MTAL tubules obtained from normotensive and Ang II-dependent hypertensive rats were isolated by enzymatic digestion and sieving. Tubules were cultured in the absence of exogenous Ang II. TNF and PGE2 levels were measured by enzyme-linked immunosorbent assay. Anti-TNF antiserum was administered intravenously to normotensive and Ang II-dependent hypertensive rats and their mean arterial pressures were measured. Production of TNF and PGE2 was significantly greater in MTAL tubules isolated from Ang II hypertensive rats than it was in those from normotensive controls. Administration of anti-TNF antiserum exacerbated the Ang II-mediated increase in mean arterial pressure. The higher levels of production of TNF and PGE2 by MTAL tubules isolated from Ang II hypertensive rats compared with those of normotensive controls are consistent with results of in-vitro experiments showing that administration of Ang II increases production of TNF and PGE2 by the MTAL. TNF and PGE2 participate in a counter-regulatory mechanism that opposes the pressor actions of Ang II.


Quality control data of physiological and immunological biomarkers measured in serum and plasma.
In two work packages of the MARK-AGE project, 37 immunological and physiological biomarkers were measured in 3637 serum, plasma or blood samples in five batches during a period of 4 years. The quality of the serum and plasma samples was very good as judged by the low number of biomarker measurements (only 0.2%) that were rejected because of a high hemolysis, icteria or lipemia of the samples. Using quality control samples, day-to-day and batch variations were determined. The mean inter-assay variation of the five batches were all below 8%, with an average inter-assay coefficient of variation of all biomarkers of 4.0%. Also the precision of the measurements was very good, because all measurements were between 90% and 115% of the defined target values. A possible mix-up of samples was determined by comparison of the extreme testosterone levels of men and women. It was concluded that 3% of the sample identification could be mixed-up. Considering the complex procedure from collection to analysis, including preparation, handling, shipment and storage, of the samples in the MARK-AGE project, both the quality of the samples and the quality of the measurements are very good.


Strategies for replacing animals in biomedical research.
In 1959, Russell and Burch published their recommendations for applying the Three Rs (reduction, refinement and replacement alternatives) to the use of animals in scientific experimentation. At this time, they could not have predicted the effect of this fundamental concept on academic and industrial animal experimentation and in biomedical education. Although more than 30 years have passed, their ideas are gaining respectability and wide acceptance. This article reviews the recent advances in the use of non-animal methods in biomedical research, and discusses the outlook for the further implementation of 'alternatives'.


An acquired defect in IgG-dependent phagocytosis explains the impairment in antibody-mediated cellular depletion in Lupus.
B cells play important roles in autoimmune diseases ranging from multiple sclerosis to rheumatoid arthritis. B cells have also long been considered central players in systemic lupus erythematosus. However, anti-CD20-mediated B cell depletion was not effective in two clinical lupus studies, whereas anti-B lymphocyte stimulator, which inhibits B cell survival, was effective. Others and we previously found that anti-CD20-based depletion was surprisingly ineffective in tissues of lupus-prone mice, but that persistent high doses eventually led to depletion and ameliorated lupus. Lupus patients might also have incomplete depletion, as suggested in several studies, and which could have led to therapeutic failure. In this study, we investigated the mechanism of resistance to Ab-mediated cellular depletion in murine lupus. B cells from lupus-prone mice were easily depleted when transferred into normal environments or in lupus-prone mice that lacked serum Ig. Serum from lupus-prone mice transferred depletion resistance, with the active component being IgG. Because depletion is FcγR-dependent, we assayed macrophages and neutrophils exposed to lupus mouse serum, showing that they are impaired in IgG-mediated phagocytosis. We conclude that depletion resistance is an acquired, reversible phagocytic defect depending on exposure to lupus serum IgG. These results have implications for optimizing and monitoring cellular depletion therapy.


Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways.
Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.


Quorum sensing in nitrogen-fixing rhizobia.
Members of the rhizobia are distinguished for their ability to establish a nitrogen-fixing symbiosis with leguminous plants. While many details of this relationship remain a mystery, much effort has gone into elucidating the mechanisms governing bacterium-host recognition and the events leading to symbiosis. Several signal molecules, including plant-produced flavonoids and bacterially produced nodulation factors and exopolysaccharides, are known to function in the molecular conversation between the host and the symbiont. Work by several laboratories has shown that an additional mode of regulation, quorum sensing, intercedes in the signal exchange process and perhaps plays a major role in preparing and coordinating the nitrogen-fixing rhizobia during the establishment of the symbiosis. Rhizobium leguminosarum, for example, carries a multitiered quorum-sensing system that represents one of the most complex regulatory networks identified for this form of gene regulation. This review focuses on the recent stream of information regarding quorum sensing in the nitrogen-fixing rhizobia. Seminal work on the quorum-sensing systems of R. leguminosarum bv. viciae, R. etli, Rhizobium sp. strain NGR234, Sinorhizobium meliloti, and Bradyrhizobium japonicum is presented and discussed. The latest work shows that quorum sensing can be linked to various symbiotic phenomena including nodulation efficiency, symbiosome development, exopolysaccharide production, and nitrogen fixation, all of which are important for the establishment of a successful symbiosis. Many questions remain to be answered, but the knowledge obtained so far provides a firm foundation for future studies on the role of quorum-sensing mediated gene regulation in host-bacterium interactions.


[The role of chlamydial infection in the genesis of tuboperitoneal sterility in women].
The incidence of chlamydial infection in women with tuboperitoneal sterility is 49.5%. Clinically inflammatory diseases of the pelvic organs in such an infection are characterized by a primary chronic course with frequent recurrences and involvement of the cervix uteri, urethra, internal genitals, with moderately manifest clinical symptoms. Therapy of chlamydial infection should be combined with individual selection of therapeutic measures with due consideration for the inflammatory process phase and site, for the type of pathologic changes, general and immune status.


Evoked Response Strength in Primary Auditory Cortex Predicts Performance in a Spectro-Spatial Discrimination Task in Rats.
The extent to which the primary auditory cortex (A1) participates in instructing animal behavior remains debated. Although multiple studies have shown A1 activity to correlate with animals' perceptual judgments (Jaramillo and Zador, 2011; Bizley et al., 2013; Rodgers and DeWeese, 2014), others have found no relationship between A1 responses and reported auditory percepts (Lemus et al., 2009; Dong et al., 2011). To address this ambiguity, we performed chronic recordings of evoked local field potentials (eLFPs) in A1 of head-fixed female rats performing a two-alternative forced-choice auditory discrimination task. Rats were presented with two interleaved sequences of pure tones from opposite sides and had to indicate the side from which the higher-frequency target stimulus was played. Animal performance closely correlated (rrm = 0.68) with the difference between the target and distractor eLFP responses: the more the target response exceeded the distractor response, the better the animals were at identifying the side of the target frequency. Reducing the evoked response of either frequency through stimulus-specific adaptation affected performance in the expected way: target localization accuracy was degraded when the target frequency was adapted and improved when the distractor frequency was adapted. Target frequency eLFPs were stronger on hit trials than on error trials. Our results suggest that the degree to which one stimulus stands out over others within A1 activity may determine its perceptual saliency for the animals and accordingly bias their behavioral choices.SIGNIFICANCE STATEMENT The brain must continuously calibrate the saliency of sensory percepts against their relevance to the current behavioral goal. The inability to ignore irrelevant distractors characterizes a spectrum of human attentional disorders. Meanwhile, the connection between the neural underpinnings of stimulus saliency and sensory decisions remains elusive. Here, we record local field potentials in the primary auditory cortex of rats engaged in auditory discrimination to investigate how the cortical representation of target and distractor stimuli impacts behavior. We find that the amplitude difference between target- and distractor-evoked activity predicts discrimination performance (rrm = 0.68). Specific adaptation of target or distractor shifts performance either below or above chance, respectively. It appears that recent auditory history profoundly influences stimulus saliency, biasing animals toward diametrically-opposed decisions.


[A case of pyogenic spondylitis mimicking spinal invasion of lung cancer].
A 65-year-old man who had suffered from traumatic spinal cord injury had chronic lumbar pain. He had exacerbation of lumbar pain and intermittent fever and consulted several doctors, but the cause of the lumbar pain was unknown. An orthopedic specialist took an MRI. Spinal MRI showed increased signal intensity at the level of T10-11 and a mass in his right lower lung field, so he was referred to our hospital. Two transbronchial lung biopsy procedures failed to obtain malignant cells. CT guided biopsy showed fibrous and hyalinizing tissue contained plasma cells and lyphocytes. Staphylococcus aureus was cultured from the second bronchial lavage fluids of brush and blood cultures, so we began administration of ampicillin-sulbactam. Avoiding threatened or actual cord compression due to collapse resulting from spinal instability, posterior fusion with instrumentation was done through the back of his chest wall. At once, bone biopsy was done, and showed no malignant cells. As soon as antibacterial treatment was stopped after the operation, he had bloody sputa and fever. The antibacterial agent was resumed and the symptoms improved. The mass decreased in size and lumbar pain improved gradually, so we concluded the diagnosis was pyogenic spondylitis caused by S. aureus. After about 5 months of antibacterial treatment, the tumor substantially diminished.


Forty new specimens of Ichthyornis provide unprecedented insight into the postcranial morphology of crownward stem group birds.
Ichthyornis has long been recognized as a pivotally important fossil taxon for understanding the latest stages of the dinosaur-bird transition, but little significant new postcranial material has been brought to light since initial descriptions of partial skeletons in the 19th Century. Here, we present new information on the postcranial morphology of Ichthyornis from 40 previously undescribed specimens, providing the most complete morphological assessment of the postcranial skeleton of Ichthyornis to date. The new material includes four partially complete skeletons and numerous well-preserved isolated elements, enabling new anatomical observations such as muscle attachments previously undescribed for Mesozoic euornitheans. Among the elements that were previously unknown or poorly represented for Ichthyornis, the new specimens include an almost-complete axial series, a hypocleideum-bearing furcula, radial carpal bones, fibulae, a complete tarsometatarsus bearing a rudimentary hypotarsus, and one of the first-known nearly complete three-dimensional sterna from a Mesozoic avialan. Several pedal phalanges are preserved, revealing a remarkably enlarged pes presumably related to foot-propelled swimming. Although diagnosable as Ichthyornis, the new specimens exhibit a substantial degree of morphological variation, some of which may relate to ontogenetic changes. Phylogenetic analyses incorporating our new data and employing alternative morphological datasets recover Ichthyornis stemward of Hesperornithes and Iaceornis, in line with some recent hypotheses regarding the topology of the crownward-most portion of the avian stem group, and we establish phylogenetically-defined clade names for relevant avialan subclades to help facilitate consistent discourse in future work. The new information provided by these specimens improves our understanding of morphological evolution among the crownward-most non-neornithine avialans immediately preceding the origin of crown group birds.


[Sensitivity of group A beta-hemolytic Streptococcus isolated from pediatric pharyngotonsillitis to erythromycin and clarithromycin: a primary care multicenter study].
The recent increase in the prevalence of macrolide-resistant group A beta-haemolytic Streptococcus (BHSGA) strains reported in some areas in Spain and several neighboring countries underscores the need to perform a periodic surveillance, with the adequate methodology, of the level of its susceptibility to these antimicrobials which are frequently used in our country for the treatment of acute streptococcal pharingotonsillitis and respiratory tract infections. The susceptibility of 293 isolates of BHSGA to the macrolides erythromycin and clarithromycin was evaluated by the broth microdilution procedure recommended by the NCCLS (1997). The isolates were prospectively obtained from children with acute pharyngotonsillitis (n = 757) who were seen at primary care centers in ten Spanish cities. An overall prevalence of 8.9 and 7.8% erythromycin- and clarithromycin-resistant BHSGA isolates was respectively found. The percentage of resistant isolates varied considerably among the different cities subjected to study (0-33%). Overall, the intrinsic activity of clarithromycin (MIC50 and MIC90 of 0.007 and 0.25 mg/ml, respectively) was slightly higher than that of erythromycin (MIC50 and MIC90 of 0.015 and 0.5 mg/ml, respectively). All strains studied were uniformly susceptible to penicillin. Macrolide antibiotics, erythromycin and clarithromycin, continue to be highly active against BHSGA. The mean level of resistant strains found in Spain from community acquired infections and recovered prospectively is comparable to that of our neighboring countries.


Behavior of breast cancer cells under oxygen concentration gradients in a microfluidic device.
The tumor microenvironment (TME) is known as a chronic hypoxic environment, with spatiotemporal variation in oxygen concentration depending on the distance from blood vessels and the blood supply. In our previous studies, cancer cell behavior was observed under hypoxic conditions with spatial variation of oxygen concentration (oxygen concentration gradients); however, that under oxygen concentration gradients at low oxygen levels found in the TME has not been studied. In this study, we investigated the behavior of breast cancer cells at various oxygen concentration gradients, generated using a microfluidic device with oxygen concentration controllability. The results showed that cell distribution was altered in response to oxygen concentration, and tended to increase in a specific region at around 5% O2. Evaluation of changes in cell numbers due to proliferation, migration, and cell death indicated that proliferation strongly affected cell distribution.


Probable ancestors of Hungarian ethnic groups: an admixture analysis.
The history of Hungary starts in the 9th century with the arrival of the Magyars in the Carpathian Basin. They spoke, like modern Hungarians, an Uralic language belonging to the Finno-Ugric language group. Their original composition probably included Iranian and Turkish people, while other populations were already present in the territory (Avars, Slavs, Germans). Some of the Hungarian ethnic groups claim to be descendants of ancient Magyars settlers (such as the Orség), others of Huns, Turks or Iranians. We collected and compared the previously published gene frequencies of eight ethnic groups and seven hypothetical ancestral populations, including Uralics, applying a model of admixture. The results, most of which confirm historical hypotheses or the oral tradition, show that only one ethnic group (Orség) highly resembles the Uralic population.


Design of Highly Fluorinated Peptides for Cell-based 19F NMR.
The design of imaging agents with high fluorine content is essential for overcoming the challenges associated with signal detection limits in 19F MRI-based molecular imaging. In addition to perfluorocarbon and fluorinated polymers, fluorinated peptides offer an additional strategy for creating sequence-defined 19F magnetic resonance imaging (MRI) imaging agents with a high fluorine signal. Our previously reported unstructured trifluoroacetyllysine-based peptides possessed good physiochemical properties and could be imaged at high magnetic field strength. However, the low detection limit motivated further improvements in the fluorine content of the peptides as well as removal of nonspecific cellular interactions. This research characterizes several new highly fluorinated synthetic peptides composed of highly fluorinated amino acids. 19F NMR analysis of peptides TB-1 and TB-9 led to highly overlapping, intense fluorine resonances and acceptable aqueous solubility. Flow cytometry analysis and fluorescence microscopy further showed nonspecific binding could be removed in the case of TB-9. As a preliminary experiment toward developing molecular imaging agents, a fluorinated EGFR-targeting peptide (KKKFFKK-βA-YHWYGYTPENVI) and an EGFR-targeting protein complex E1-DD bioconjugated to TB-9 were prepared. Both bioconjugates maintained good 19F NMR performance in aqueous solution. While the E1-DD-based imaging agent will require further engineering, the success of cell-based 19F NMR of the EGFR-targeting peptide in A431 cells supports the potential use of fluorinated peptides for molecular imaging.


Hearing Loss in Infants with Microcephaly and Evidence of Congenital Zika Virus Infection - Brazil, November 2015-May 2016.
Congenital infection with Zika virus causes microcephaly and other brain abnormalities (1). Hearing loss associated with other congenital viral infections is well described; however, little is known about hearing loss in infants with congenital Zika virus infection. A retrospective assessment of a series of 70 infants aged 0-10 months with microcephaly and laboratory evidence of Zika virus infection was conducted by the Hospital Agamenon Magalhães in Brazil and partners. The infants were enrolled during November 2015-May 2016 and had screening and diagnostic hearing tests. Five (7%) infants had sensorineural hearing loss, all of whom had severe microcephaly; however, one child was tested after receiving treatment with an ototoxic antibiotic. If this child is excluded, the prevalence of sensorineural hearing loss was 5.8% (four of 69), which is similar to that seen in association with other congenital viral infections. Additional information is needed to understand the prevalence and spectrum of hearing loss in children with congenital Zika virus infection; all infants born to women with evidence of Zika virus infection during pregnancy should have their hearing tested, including infants who appear normal at birth.


Generation and Retention of Defective RNA3 from Cucumber Mosaic Virus and Relevance of the 2b Protein to Generation of the Subviral RNA.
A defective RNA3 (D3Yα) of strain Y of cucumber mosaic virus (CMV-Y) was examined on host-specific maintenance, experimental conditions, and a viral factor required for its generation in plants. D3Yα was stably maintained in cucumber but not in tomato plants for 28 days post inoculation (dpi). D3Yα was generated in Nicotiana tabacum or N. benthamiana after prolonged infection in the second and the third passages, but not in plants of N. benthamiana grown at low temperature at 28 dpi or infected with CMV-Y mutant that had the 2b gene deleted. Collectively, we suggest that generation and retention of D3Yα depends on potential host plants and experimental conditions, and that the 2b protein has a role for facilitation of generation of D3Yα.


Embolism resistance explains mortality and recovery of five subtropical evergreen broadleaf trees to persistent drought.
Subtropical evergreen broadleaf forests (SEBF) are experiencing and expected to suffer more frequent and severe drought events. However, how the hydraulic traits directly link to the mortality and recovery of SEBF trees remains unclear. In this study, we conducted a drought-rewatering experiment on tree seedlings of five dominant species to investigate how the hydraulic traits were related to tree mortality and the resistance and recovery of photosynthesis (A) and transpiration (E) under different drought severities. Species with greater embolism resistance (P50 ) survived longer than those with a weaker P50 . However, there was no general hydraulic threshold associated with tree mortality, with the lethal hydraulic failure varying from 64% to 93% loss of conductance. The photosynthesis and transpiration of tree species with a greater P50 were more resistant to and recovered faster from drought than those with lower P50 . Other plant traits could not explain the interspecific variation in tree mortality and drought resistance and recovery. These results highlight the unique importance of embolism resistance in driving carbon and water processes under persistent drought across different trees in SEBFs. The absence of multiple efficient drought strategies in SEBF seedlings implies the difficulty of natural seedling regeneration under future droughts, which often occurs after destructive disturbances (e.g., extreme drought events and typhoon), suggesting that this biome may be highly vulnerable to co-occurring climate extremes.


Constitutive expression of the steroid sulfatase gene supports the growth of MCF-7 human breast cancer cells in vitro and in vivo.
Many human breast tumors are driven by high intratumor concentrations of 17beta-estradiol that appear to be locally synthesized. The role of aromatase is well established, but the possible contribution of the steroid sulfatase (STS), which liberates estrogens from their biologically inactive sulfates, has been inadequately assessed and remains unclear. To evaluate the role of STS further, we transduced estrogen-dependent MCF-7 human breast cancer cells with a retroviral vector directing the constitutive expression of the human STS gene. Gene integration was confirmed by Southern hybridization, production of the appropriately sized messenger RNA by Northern hybridization, and expression of functional protein by metabolism of [(3)H]estrone sulfate to [(3)H]estrone. Maximum velocity estimates of estrone formation are 64.2 pmol estrone/mg protein.h in STS-transduced cells (STS Clone 20), levels comparable to those seen in some human breast tumors. Lower levels of endogenous activity are seen in MCF-7 cells (13.0 pmol estrone/mg protein.h) and in cells transduced with vector lacking the STS gene (Vector 3 cells; 12.0 pmol estrone/mg protein.h). 17beta-Estradiol sulfate induces expression of the progesterone receptor messenger RNA only in STS Clone 20 cells, whereas estrone sulfate produces the greatest stimulation of anchorage-independent growth in these cells. STS Clone 20 cells retain responsiveness to antiestrogens, which block the ability of estrogen sulfate to increase the proportion of cells in both the S and G(2)/M phases of the cell cycle. Consistent with these in vitro observations, only STS Clone 20 cells exhibit a significant increase in the proportion of proliferating tumors in nude ovariectomized mice supplemented with 17beta-estradiol sulfate. The primary activity in vivo appears to be from intratumor STS, rather than hepatic STS. Surprisingly, 17beta-estradiol sulfate appears more effective than 17beta-estradiol when both are administered at comparable concentrations. This effect, which is seen only in STS Clone 20 cells, may reflect differences in the cellular pharmacology of exogenous estrogens compared with those released by the activity of intracellular STS. These studies directly demonstrate that intratumor STS activity can support estrogen-dependent tumorigenicity in an experimental model and may contribute to the promotion of human breast tumors.


MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes.
We tested the hypothesis that miR-133a regulates DNA methylation by inhibiting Dnmt-1 (maintenance) and Dnmt-3a and -3b (de novo) methyl transferases in diabetic hearts by using Ins2(+/-) Akita (diabetic) and C57BL/6J (WT), mice and HL1 cardiomyocytes. The specific role of miR-133a in DNA methylation in diabetes was assessed by two treatment groups (1) scrambled, miR-133a mimic, anti-miR-133a, and (2) 5mM glucose (CT), 25 mM glucose (HG) and HG+miR-133a mimic. The levels of miR-133a, Dnmt-1, -3a and -3b were measured by multiplex RT-PCR, qPCR and Western blotting. The results revealed that miR-133a is inhibited but Dnmt-1 and -3b are induced in Akita suggesting that attenuation of miR-133a induces both maintenance (Dnmt-1) - and de novo - methylation (Dnmt-3b) in diabetes. The up regulation of Dnmt-3a in Akita hearts elicits intricate and antagonizing interaction between Dnmt-3a and -3b. In cardiomyocytes, over expression of miR-133a inhibits but silencing of miR-133a induces Dnmt-1, -3a and -3b elucidating the involvement of miR-133a in regulation of DNA methylation. The HG treatment up regulates only Dnmt-1 and not Dnmt-3a and -3b suggesting that acute hyperglycemia triggers only maintenance methylation. The over expression of miR-133a mitigates glucose mediated induction of Dnmt-1 illustrating the role of miR-133a in regulation of DNA methylation in diabetes.


Effect of GH status on IGF-I and IGF-II concentrations and serum IGF binding profiles in pigs.
The present study was conducted to determine 1) whether porcine growth hormone (pGH) affected insulin-like growth factor (IGF)-II concentrations in growing pigs and 2) the distribution of [125I]IGF-I and [125I]IGF-II binding activity and immunoreactive IGF-I and IGF-II in serum from control, pGH-treated and hypophysectomized (hypox) pigs. Seven weeks of pGH treatment had no effect on serum IGF-II concentrations, but after 11 wk serum IGF-II had increased by up to 50%. In normal pig serum, [125I]IGF-I bound to specific insulin-like growth factor binding proteins (IGF-BP) of 40 kDa (87.5%) and 150 kDa (12.5%). Treatment with pGH increased the proportion of IGF-I bound to the large IGF-BP (approximately 48%). In contrast, [125I]IGF-II partitioned to specific IGF-BP of 450 kDa (30%), 150 kDa (46%) and 40 kDa (23%). After treatment with pGH, binding of IGF-II to the 150-kDa IGF-BP increased to 57% of total specific binding. Binding of IGF-I and IGF-II to the 150-kDa IGF-BP was virtually abolished in hypox pig serum. IGF-I immunoreactivity was predominantly associated with the 150-kDa IGF-BP (67 to 83%), with the remainder bound to the small IGF-BP. There was no detectable free IGF-I in pig serum. Treatment with pGH did not affect the distribution of immunoreactive IGF-I between the two IGF-BP complexes, although there was a marked elevation in total serum IGF-I concentration. Immunoreactive IGF-II was detected in all three IGF-BP complexes. In control serum, the largest quantity (46%) of immunoreactive IGF-II was associated with the 40-kDa IGF-BP. Thirty-four percent was bound to the 150-kDa IGF-BP complex. Administration of pGH led to an increased association with the 150-kDa complex (50%) and a concomitant decrease in IGF-II associated with the 40-kDa species (35%). In summary, IGF-II concentrations in the pig are elevated by prolonged pGH treatment. Furthermore, there is a unique large IGF-BP in postnatal pig serum that specifically binds IGF-II but not IGF-I.


Pineal gland involvement in retina-induced experimental allergic uveitis.
A form of experimental allergic uveitis (EAU) can be elicited in guinea pigs by injection of an extract of homologous retina homogenate (S preparation). These guinea pigs exhibit clinical and histological ocular disease as well as cellular and humoral immune responses to S preparation. Recent studies have shown an immunofluorescent crossreactivity of the sera of these animals (anti-S) with retinal photoreceptors and pinealocytes. The experiments presented in this paper demonstrate pineal gland involvement during the course of S preparation-induced EAU. There is lymphocytic infiltration of the pineal gland, with corresponding loss of antigen reactivity and some disturbance in cell structure. Pineal gland infiltrate can be seen before observable retinal involvement. Similarity of the reactive substances in retinal photoreceptors and pinealocytes is demonstrated by a reaction of identity in immunodiffusion studies and similar mobilities in immunoelectrophoretic studies of S preparation and pineal gland extract with anti-S serum. The relationship of the retinal and pineal substances to each other, as well as their role in disease development in the animal model and possibly in human uveitides, are discussed.


A novel route for ATP acquisition by the remnant mitochondria of Encephalitozoon cuniculi.
Mitochondria use transport proteins of the eukaryotic mitochondrial carrier family (MCF) to mediate the exchange of diverse substrates, including ATP, with the host cell cytosol. According to classical endosymbiosis theory, insertion of a host-nuclear-encoded MCF transporter into the protomitochondrion was the key step that allowed the host cell to harvest ATP from the enslaved endosymbiont. Notably the genome of the microsporidian Encephalitozoon cuniculi has lost all of its genes for MCF proteins. This raises the question of how the recently discovered microsporidian remnant mitochondrion, called a mitosome, acquires ATP to support protein import and other predicted ATP-dependent activities. The E. cuniculi genome does contain four genes for an unrelated type of nucleotide transporter used by plastids and bacterial intracellular parasites, such as Rickettsia and Chlamydia, to import ATP from the cytosol of their eukaryotic host cells. The inference is that E. cuniculi also uses these proteins to steal ATP from its eukaryotic host to sustain its lifestyle as an obligate intracellular parasite. Here we show that, consistent with this hypothesis, all four E. cuniculi transporters can transport ATP, and three of them are expressed on the surface of the parasite when it is living inside host cells. The fourth transporter co-locates with mitochondrial Hsp70 to the E. cuniculi mitosome. Thus, uniquely among eukaryotes, the traditional relationship between mitochondrion and host has been subverted in E. cuniculi, by reductive evolution and analogous gene replacement. Instead of the mitosome providing the parasite cytosol with ATP, the parasite cytosol now seems to provide ATP for the organelle.


Fat embolism: a comprehensive review.
Fat embolism as a cause or as a contributing factor to the death of injured patients is probably not diagnosed in many instances. Treatment is beneficial in moderate cases of fat at embolism; severe cases result in death and mild cases usually resolve without treatment. Awarness of the symptoms is important. Treatment should be directed to the symptoms rather than to the disease. Respiratory support seems to be the most effective treatment.


Analysis of potential transfer of continuous glass filament from Eclipse cigarettes.
This study was designed to determine if a prototype of the Eclipse cigarettes, which uses a special form of continuous glass filament (CGF) as an insulator around the carbon heat source, yielded CGFs via mainstream smoke. A method was developed that used electrostatic precipitation with a greater than 99% collection efficiency of mass to capture CGFs transferred to mainstream smoke. The cigarettes were smoked using an exaggerated puffing condition that was more than twice the Federal Trade Commission (FTC) standard. The cigarettes were subjected to handling procedures that simulated commercial shipping conditions prior to smoking. CGFs were intentionally added to a series of smoke condensate samples to determine CGF recovery efficiency. The recovery efficiency was determined for a series of four internal standards added to smoke condensate. The recovery efficiency was 86% for the Eclipse 5-014 prototype. The number of CGFs in smoke condensate collected from the Eclipse 5-014 prototype was approximately 0.06 +/- 0.02 CGFs per cigarette (+/- standard deviation), including the background counts of CGFs and 0.03 CGFs per cigarette, when corrected for background contributions. The number of CGFs found in smoke condensates for this prototype was not statistically distinguishable from zero or background in these experiments, which were capable of detecting transfer rates of greater than 0.2 CGFs per cigarette.


Relationships Between Model Estimates and Actual Match-Performance Indices in Professional Australian Footballers During an In-Season Macrocycle.
To assess and compare the validity of internal and external Australian football (AF) training-load measures for predicting match exercise intensity (MEI/min) and player-rank score (PRScore) using a variable dose-response model. A cohort of 25 professional AF players (23 ± 3 y, 188.3 ± 7.2 cm, 87.7 ± 8.4 kg) completed a 24-wk in-season macrocycle. In-season internal training and match load were quantified using session rating of perceived exertion (sRPE) and external load from satellite and accelerometer data. Using a training-impulse (TRIMP) calculation, external load (au) was represented as distance (TRIMPDist), distance ≥4.16 m/s (TRIMPHSDist), and PlayerLoad (TRIMPPL). In-season training load, MEI/min, and PRScore were applied to a variable dose-response model, which provided estimates of MEI/min and PRScore. Predicted MEI/min and PRScore were correlated with actual measures from each match. The magnitude of the difference between MEI/min and PRScore estimates for each model input and the difference between the precision of internal and external load measures to predict MEI/min and PRScore were calculated using the effect size ± 90% confidence interval (CI). Estimates of MEI/min demonstrated very large associations with actual MEI/min (r, 90% CI) (eg, TRIMPDist .76 ± .13, and sRPESkills .73 ± .14). Estimates of PRScore demonstrated associations of large magnitude with actual PRScore using the same inputs. Precision of actual MEI/min was lowest using sRPE compared with (ES ± 90% CI) TRIMPDist, -.67 ± .34, and TRIMPPL, -.91 ± .39. There were trivial and unclear differences in the precision of PRScore estimates between TRIMP and sRPE inputs. Dose-response models from multiple training-load inputs can predict within-individual variation of MEI/min and PRScore. Internal and external training-input methods exhibited comparable predictive power.


Chromosomal insertions of Tn917 in Bacillus subtilis.
We describe 46 insertions of the Streptococcus faecalis transposon Tn917 into the chromosome of Bacillus subtilis. These insertion mutations were mapped genetically. Some caused auxotrophic requirements, and others were cryptic. These insertions were scattered around the B. subtilis chromosome. The mutant strains were useful in several ways for mapping and cloning B. subtilis genes and were added to the Bacillus Genetic Stock Center collection. Among the auxotrophic markers were a new serine auxotrophy and deletion-insertions that caused auxotrophy in one case for homoserine and threonine, in another case for uracil and either cysteine or methionine, and in a third case for leucine, isoleucine, and valine.


[Differential expression profiles of MicroRNA during the development of human cord blood CD34(+)CD38(-) cells to CD34(+)CD38(+) cells].
To establish a basis for deep investigation of the role of microRNA (miRNA) in the regulation of hematopoiesis, differential expression profiles of miRNA between human cord blood CD34(+)CD38(-) and CD34(+)CD38(+) cells were analyzed. Mononuclear cells from cord blood (CB) of healthy donors were separated by Ficoll-Hypaque density gradients. CD34(+)CD38(-) and CD34(+)CD38(+) cells were sorted by using FACS Vantage SE. Their mRNA were then extracted and hybridized to miRNA microarray chip. The resulting data were analyzed with GeneSpring and informatics technique. The results showed that eleven miRNAs were found to be downregulated and 73 miRNAs to be upregulated by at least two-fold in the CD34(+)CD38(+) cells of CB, compared with the CD34(+)CD38(-) cells, which maintained CD34(+)CD38(-) cells' self-renewal and multiple lineage potential, that were defined as "stemness" miRNAs. 12 of the 84 genes (14.29%) were common to 33 hematopoietic-expressed miRNAs expressed by CD34(+) cells from both peripheral blood and bone marrow in Georgantas's study, which included 10 upregulated miRNAs (hsa-miR-23b, -26b, -92, -107, -130a, -181a, -197, -213, -222, -223) and 2 downregulated ones (hsa-miR-16a, -155). Some "stemness" miRNAs undergo CD34 antigen-like expression pattern during development and commmitted differeniation of hematopoietic stem cell/progenitors. Hematopoiesis-associated miRNA clusters and putative target genes could be found with informatics technique. It is concluded that the hematopoietic "stemness" miRNAs play important roles in normal hematopoiesis: miRNA expression profiles of hematopoietic stem cell/progenitors --> their gene expression profiles --> their self-renewal and lineage-commmitted differeniation.


Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis.
Fas-associated death domain protein (FADD) is an adaptor protein bridging death receptors with initiator caspases. Thus, its function and localization are assumed to be cytoplasmic, although the localization of endogenous FADD has not been reported. Surprisingly, the data presented here demonstrate that FADD is mainly nuclear in several adherent cell lines. Its accumulation in the nucleus and export to the cytoplasm required the phosphorylation site Ser-194, which was also required for its interaction with the nucleocytoplasmic shuttling protein exportin-5. Within the nucleus, FADD interacted with the methyl-CpG binding domain protein 4 (MBD4), which excises thymine from GT mismatches in methylated regions of chromatin. The MBD4-interacting mismatch repair factor MLH1 was also found in a complex with FADD. The FADD-MBD4 interaction involved the death effector domain of FADD and a region of MBD4 adjacent to the glycosylase domain. The FADD-binding region of MBD4 was downstream of a frameshift mutation that occurs in a significant fraction of human colorectal carcinomas. Consistent with the idea that MBD4 can signal to an apoptotic effector, MBD4 regulated DNA damage-, Fas ligand-, and cell detachment-induced apoptosis. The nuclear localization of FADD and its interaction with a genome surveillance/DNA repair protein that can regulate apoptosis suggests a novel function of FADD distinct from direct participation in death receptor signaling complexes.


Volumetric assessment of normal fetal lungs using three-dimensional ultrasound.
We attempted to construct normal reference centiles of fetal lung volume (LV) for clinical application by using three-dimensional (3-D) ultrasound (US) during normal gestation. A prospective study was performed on 195 healthy fetuses with gestational age (GA) ranging from 20 to 40 weeks for the assessment of fetal LV using a 3-D US volume scanner with a mixture of cross-sectional and serial measurements. Polynomial regression analysis was calculated to find the best-fit model between GA, right lung volume (RLV), left lung volume (LLV) and total lung volume (TLV). In addition, common fetal growth parameters, such as biparietal diameter (BPD), occipitofrontal diameter (OFD), head circumference (HCi), abdominal circumference (ACi), femur length (FL) and estimated fetal weight (EFW) were also measured to demonstrate the correlations between RLV, LLV, TLV and these parameters. Our results showed that RLV, LLV and TLV were highly correlated with GA. Using GA as the independent variable and RLV, LLV and TLV as the dependent variable, the best-fit regression equations were: RLV (mL) = 0.067 GA(2) - 1.2464 GA + 2.7825 (r = 0.95, n = 173, p < 0.0001), LLV (mL) = 0.0573 GA(2) - 1.599 GA + 12.454 (r = 0.95, n = 159, p < 0.0001) and TLV (mL) = 0.1263 GA(2) - 2.982 GA + 17.448 (r = 0.96, n = 152, p < 0.0001). For clinical use, a chart of normal growth centiles of fetal LV in utero was then calculated based on this equation. Furthermore, RLV, LLV and TLV were also highly correlated with the common fetal growth parameters during normal gestation (all p < 0.0001). In conclusion, the 3-D US nomograms of the fetal lung volume established in this study can be utilized as useful references in prenatal detection of fetal pulmonary pathologic status and relevant abnormalities.


Number of sites-based solver for determining coverages from steady-state mean-field micro-kinetic models.
Kinetic models parameterized by ab-initio calculations have led to significant improvements in understanding chemical reactions in heterogeneous catalysis. These studies have been facilitated by implementations which determine steady-state coverages and rates of mean-field micro-kinetic models. As implemented in the open-source kinetic modeling program, CatMAP, the conventional solution strategy is to use a root-finding algorithm to determine the coverage of all intermediates through the steady-state expressions, constraining all coverages to be non-negative and to properly sum to unity. Though intuitive, this root-finding strategy causes issues with convergence to solution due to these imposed constraints. In this work, we avoid explicitly imposing these constraints, solving the mean-field steady-state micro-kinetic model in the space of number of sites instead of solving it in the space of coverages. We transform the constrained root-finding problem to an unconstrained least-squares minimization problem, leading to significantly improved convergence in solving micro-kinetic models and thus enabling the efficient study of more complex catalytic reactions.


Effects of chair yoga therapy on physical fitness in patients with psychiatric disorders: A 12-week single-blind randomized controlled trial.
Since falls may lead to fractures and have serious, potentially fatal outcomes, prevention of falls is an urgent public health issue. We examined the effects of chair yoga therapy on physical fitness among psychiatric patients in order to reduce the risk of falls, which has not been previously reported in the literature. In this 12-week single-blind randomized controlled trial with a 6-week follow-up, inpatients with mixed psychiatric diagnoses were randomly assigned to either chair yoga therapy in addition to ongoing treatment, or treatment-as-usual. Chair yoga therapy was conducted as twice-weekly 20-min sessions over 12 weeks. Assessments included anteflexion in sitting, degree of muscle strength, and Modified Falls Efficacy Scale (MFES) as well as QOL, psychopathology and functioning. Fifty-six inpatients participated in this study (36 men; mean ± SD age, 55.3 ± 13.7 years; schizophrenia 87.5%). In the chair yoga group, significant improvements were observed in flexibility, hand-grip, lower limb muscle endurance, and MFES at week 12 (mean ± SD: 55.1 ± 16.6 to 67.2 ± 14.0 cm, 23.6 ± 10.6 to 26.8 ± 9.7 kg, 4.9 ± 4.0 to 7.0 ± 3.9 kg, and 114.9 ± 29.2 to 134.1 ± 11.6, respectively). Additionally, these improvements were observable six weeks after the intervention was over. The QOL-VAS improved in the intervention group while no differences were noted in psychopathology and functioning between the groups. The intervention appeared to be highly tolerable without any notable adverse effects. The results indicated sustainable effects of 20-min, 12-week, 24-session chair yoga therapy on physical fitness. Chair yoga therapy may contribute to reduce the risk of falls and their unwanted consequences in psychiatric patients.


Rickettsia rickettsii and Rickettsia montana from Ixodid ticks in Connecticut.
Dermacentor variabilis, infected with spotted fever group rickettsiae, parasitized 8 of 70 raccoons captured in Newtown, Connecticut. The spotted fever agent, Rickettsia rickettsii, was isolated and identified from 4 adult D. variabilis and from 1 nymphal Ixodes texanus removed from raccoons. This verifies the presence of this etiologic agent in ticks in an area where 6 people had clinical signs and symptoms of Rocky Mountain spotted fever (RMSF) and antibodies to R. rickettsii. These are the first isolations of R. rickettsii from D. variabilis in southern New England and the first identified rickettsiae from I. texanus. No rickettsiae were isolated from Ixodes muris or I. cookei. Rickettsia montana was recovered in Vero cell culture from a D. variabilis collected in East Haddam, Connecticut where RMSF is not known to be prevalent.


Aspiration Pneumonia Caused by Prevotella Causing Prothorax after Pulmonary Puncture: a Case Report.
Aspiration pneumonia in patients in immunocompetent populations is rare, and secondary pyothorax due to puncture operations during treatment has been reported rarely. We report a confirmed case of aspiration pneumonia caused by Prevotella. The pathogen was detected and confirmed using percutaneous lung puncture and high-throughput next-generation sequencing (NGS). The patient developed secondary pyothorax, severe rash, and exacerbation of symptoms following the lung puncture. Finally, after adjusting the antibiotic regimen and performing chest drainage and washout, the patient's lesions were absorbed, symptoms improved, and the rash disappeared. Prevotella aspiration pneumonia can occur in immunocompetent individuals, and invasive bronchoscopic alveolar lavage may be considered as an option to reduce the risk of infectious organism translocation.


Benign mixed tumor of the vagina.
A case of benign mixed tumor of the vagina is presented and the literature on this rare type of vaginal tumor is reviewed. The origin is likely to be the paravestibular glands, as the tumor is always located near the introitus. Follow-up studies indicate benign biologic behavior, and simple excision is the treatment of choice.


Evidence for a new Graves disease susceptibility locus at chromosome 18q21.
Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.


Putting public health infrastructures to the test: introducing HPV vaccination in Austria and the Netherlands.
This article presents two cases of policymaking concerning the vaccine against Human Papilloma Virus (HPV), which is sexually transmitted and carcinogenic. Our analysis focuses on its introduction in Austria and the Netherlands. In both contexts, we find prevention and screening to be at once complementary and competing public health logics and we draw on the concept of 'infrastructure' to understand their roles in shaping the reception of the vaccine. We reveal how the HPV vaccine had to be made 'good enough', much like the Pap smear (Casper and Clarke ), by means of diverse tinkering practices that transformed both the technology and the infrastructures in which they emerged. At the same time, it was important that the vaccine would not come to problematise Pap smear-based screening. The article points to the contextually contingent nature of policymaking around new medical technologies, and the skillful care with which public health infrastructures such as immunisation and screening programmes are handled and tinkered with.


Spectrum of tumorigenic phenotypes among adenovirus 2-, adenovirus 12-, and simian virus 40-transformed Syrian hamster cells defined by host cellular immune-tumor cell interactions.
The tumor-inducing capacities of adenovirus type 2-, adenovirus type 12-, and SV40-transformed LSH hamster embryo cell define a spectrum of four distinct tumorigenic phenotypes: type I, nononcogenic for newborn hamsters but oncogenic for nude mice; type II, oncogenic for newborn hamsters but nononcogenic in syngeneic adults; type III, oncogenic for both newborns and syngeneic adults; and type IV, almost equally oncogenic for syngeneic and allogeneic adult hamsters. Modulation of the cellular immune response of the recipient hamster by immunosuppression or by alloimmunization alters tumor susceptibility, suggesting that dynamic transformed cell-host cellular immune interactions determine the tumorigenic phenotype of a transformed cell line. There is no correlation between the immunogenicities of the transformed cell lines tested and their tumor-inducing capacities. However, a strong correlation exists between the ability of transformed hamster embryo cells expressing phenotype IV to produce tumors in allogeneic CB hamsters and their resistance to cytolysis in vitro by activated macrophages. These data suggest that, in addition to transformation, DNA viruses may convey specific tumorigenic phenotypes to the cells that they infect by inducing cellular traits that determine the inherent susceptibility or resistance of a cell to host cell-mediated immune destruction.


Treatment of gastrointestinal cytomegalovirus infection with twice-daily foscarnet: a pilot study of safety, efficacy, and pharmacokinetics in patients with AIDS.
Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.


Use of the HESI Admission Assessment to predict student success.
This study examined the value of the HESI Admission Assessment in predicting student success. Associate degree (N = 68) and baccalaureate (N = 69) nursing students took the HESI Admission Assessment after acceptance into the nursing programs for the purpose of identifying their academic weaknesses and focusing their remediation efforts. Findings indicated that the HESI Admission Assessment was a valid predictor of students' academic ability to succeed in the nursing programs. In the associate degree nursing program, HESI Admission Assessment scores were significantly positively correlated with 88.89% of all nursing course grades in the program and 100% of the beginning-level course grades. In the baccalaureate nursing program, HESI Admission Assessment scores were significantly positively correlated with 50.00% of all nursing course grades in the program and 80.00% of beginning-level course grades. Furthermore, associate degree nursing students who completed the program had significantly higher HESI Admission Assessment scores than those who did not complete the program.


[Attitudes to the seeking of psychiatric help from mental health care professionals and actually seeking help: differences in Europe].
Little is known about attitudes to seeking help from mental health care professionals. To investigate these attitudes and their correlates, and find out whether these attitudes are associated with the use of care services. Data were derived from the European Study of Epidemiology of Mental Disorders, a survey that is representative of the adult population of six countries (n = 8,796). Almost a third of respondents were of the opinion that professional help was worse than or equivalent to no help at all, in relation to serious psychiatric problems. Females, respondents under the age of 65, with a higher income, living in Spain or Italy, with a mood disorder, and those who had previously sought mental health care, more often stated that they would seek professional help if beset by a serious mental health problem. All these groups, except for the younger than 65, also reported more often that they would feel comfortable discussing mental health problems with a professional or that they were receiving this kind of help. All these attitudes were associated with an increased chance that persons would use professional help if beset by mental health problems. Definite steps need to be taken to increase the visibility and credibility of the mental health services.


Preoperative and intraoperative evaluation in ovarian malignancy.
The survival rate for patients with all stages of ovarian cancer has not improved over the past quarter of a century. A review of 100 consecutive patients treated for ovarian cancer was undertaken to evaluate preoperative and intraoperative measures. The study revealed that one-third of patients has only physical examination, other than routine preoperative tests, prior to laparotomy, and that 11% did not have a pelvic examination. Eighty-three percent of the incisions were inadequate for evaluation of the upper abdomen for sites of other primary malignancies that could metastasize to the ovary and mimic ovavian cancer, or for evaluating known sites of metastasis from ovarian cancer such as the diaphragm, liver, and upper aortic lymph nodes. Specifically, the aortic nodes were not described in 92% of reports, the diaphragm in 84%, the stomach in 76%, the pancreas in 76%, the colon in 70%, and the liver in 59%. The ovary was not resected or biopsied for histologic confirmation in one-third of the cases. It is proposed that the efficacious use of adjuvant therapy for women with ovarian cancer must be preceded by careful preoperative and intraoperative evaluation of all women with presumed ovarian malignancy.


CD4 T cells require ICOS-mediated PI3K signaling to increase T-Bet expression in the setting of anti-CTLA-4 therapy.
The transcription factor T-bet controls the Th1 genetic program in T cells for effective antitumor responses. Anti-CTLA-4 immunotherapy elicits dramatic antitumor responses in mice and in human patients; however, factors that regulate T-bet expression during an antitumor response mediated by anti-CTLA-4 remain to be elucidated. We were the first to report that treatment with anti-CTLA-4 led to an increase in the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice, our data revealed that CD4(+)ICOS(hi) T cells can act as effector T cells, which produce the Th1 cytokine IFN-γ. We also showed in a small retrospective analysis that an increased frequency of CD4(+)ICOS(hi) T cells correlated with better clinical outcome and the absence of ICOS or its ligand (ICOSL) in mouse models led to impaired tumor rejection. Here, we show that CD4(+)ICOS(hi) T cells from anti-CTLA-4-treated patients had an increase in signaling via the phospoinositide-3-kinase (PI3K) pathway and an increase in expression of T-bet. An ICOS-specific siRNA transfected into human T cells led to diminished PI3K signaling and T-bet expression. Therefore, we hypothesized that ICOS, and specifically ICOS-mediated PI3K signaling, was required for T-bet expression. We conducted studies in ICOS-deficient and ICOS-YF mice, which have a single amino acid change that abrogates PI3K signaling by ICOS. We found that ICOS-mediated PI3K signaling is required for T-bet expression during an antitumor response elicited by anti-CTLA-4 therapy. Our data provide new insight into the regulation of T-bet expression and suggest that ICOS can be targeted to improve Th1 antitumor responses.


Taking the Monte-Carlo gamble: How not to buckle under the pressure!
Consistent buckling distortions of a large membrane patch (200 × 200 Å) are observed during molecular dynamics (MD) simulations using the Monte-Carlo (MC) barostat in combination with a hard Lennard-Jones (LJ) cutoff. The buckling behavior is independent of both the simulation engine and the force field but requires the MC barostat-hard LJ cutoff combination. Similar simulations of a smaller patch (90 × 90 Å) do not show buckling, but do show a small, systematic reduction in the surface area accompanied by ~1 Å thickening suggestive of compression. We show that a mismatch in the way potentials and forces are handled in the dynamical equations versus the MC barostat results in a compressive load on the membrane. Moreover, a straightforward application of elasticity theory reveals that a minimal compression of the linear dimensions of the membrane, inversely proportional to the edge length, is required for buckling, explaining this differential behavior. We recommend always using LJ force or potential-switching when the MC barostat is employed to avoid undesirable membrane deformations.


Multiple reversal olfactory learning in honeybees.
In multiple reversal learning, animals trained to discriminate a reinforced from a non-reinforced stimulus are subjected to various, successive reversals of stimulus contingencies (e.g. A+ vs. B-, A- vs. B+, A+ vs. B-). This protocol is useful to determine whether or not animals "learn to learn" and solve successive discriminations faster (or with fewer errors) with increasing reversal experience. Here we used the olfactory conditioning of proboscis extension reflex to study how honeybees Apis mellifera perform in a multiple reversal task. Our experiment contemplated four consecutive differential conditioning phases involving the same odors (A+ vs. B- to A- vs. B+ to A+ vs. B- to A- vs. B+). We show that bees in which the weight of reinforced or non-reinforced stimuli was similar mastered the multiple olfactory reversals. Bees which failed the task exhibited asymmetric responses to reinforced and non-reinforced stimuli, thus being unable to rapidly reverse stimulus contingencies. Efficient reversers did not improve their successive discriminations but rather tended to generalize their choice to both odors at the end of conditioning. As a consequence, both discrimination and reversal efficiency decreased along experimental phases. This result invalidates a learning-to-learn effect and indicates that bees do not only respond to the actual stimulus contingencies but rather combine these with an average of past experiences with the same stimuli.


Second-Generation Tyrosine Kinase Inhibitors (Tki) as Salvage Therapy for Resistant or Intolerant Patients to Prior TKIs.
With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second-and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.


Preparation and chiro-optical characterization of polyaniline doped with (+) or (-)-2-pyrrolidone-5-carboxylic acid (PCA).
Optically active polyaniline (PANI) salts were readily generated in solution via the enantioselective acid doping of neutral emeraldine base (EB) form of PANI with either (+) or (-)-2-pyrrolidone-5-carboxylic acid (PCA) in dimethylsulfoxide (DMSO) and dimethylformamide (DMF) solvents. Strong mirror imaged circular dichroism (CD) spectra were obtained for the deep green polymer solutions obtained with (+) or (-) PCA, suggesting that the acid doping is enantioselective, with one helical screw of the polymer chain being preferentially produced depending on the nature of enantiomer. It was observed that molar concentration of PCA as well as nature of solvent plays a very important role in the generation of optically active PANI. The generated optically active PANI did not show any loss of optical activity up to 200 h.