A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein.
The complement inhibitor factor H (fH) interacts via its seventh short consensus repeat (SCR) domain with multiple ligands including heparin, streptococcal M protein and C-reactive protein (CRP). The aim of this study was to localize the residues in SCR 7 required for these interactions. We initially built a homology model of fH SCR 6-7 using the averaged NMR structures of fH SCR 15-16 and vaccinia control protein SCR 3-4 as templates. Electrostatic potentials of the model's surface demonstrated a co-localization of three clusters of positively charged residues on SCR 7, labeled site A (R369 and K370), site B (R386 and K387) and site C (K392). These residues, localized to the linker region preceding SCR 7 and to the end of a "hypervariable loop" in SCR 7, were systematically replaced with uncharged alanine residues in an fH construct containing SCR 1-7. The resulting proteins were expressed in the methylotrophic yeast, Pichia pastoris. By ELISA analysis we demonstrated: first, that substituting site A inhibited heparin and CRP binding; secondly, that substituting site B inhibited binding to heparin, CRP and M protein; and thirdly, that substituting site C clearly inhibited only heparin binding.


Fetal surgery for anesthesiologists.
We aimed to review the current clinical status and advances in endoscopic and open surgical interventions on the fetus in terms of indications, technical aspects and reported outcomes. In numbers, there has been a move away from open toward fetoscopic surgery. The indications for each access modality are, however, different, and hence cannot substitute each other. Complications of monochorionic twinning are the leading indication today. Other increasingly frequent indications are severe congenital diaphragmatic hernia and myelomeningocele, and to a certain extent valvuloplasty by needle puncture. Although maternal safety is not at stake, rupture of the membranes and preterm delivery remain a problem. Today, there is level I evidence that fetoscopic laser surgery for twin-to-twin-transfusion syndrome is the preferred therapy. This has triggered the interest of several units to embark on fetoscopic surgery, although the complexity and the overall rare indications act as a limitation to sufficient turnover. Fetal surgery seems safe and has therefore become a clinical reality. With the current state of technology, open and endoscopic interventions do not compete, each having their indications. Although the stage of technical experimentation is over, most interventions remain investigational. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience. Healthcare providers and individual centers should be encouraged to consider viability and efficacy of new treatment programs.


[The effect of purified mouse GM-CSF on CFU-C colony growth in serum-free cultures].
We investigated the effect of the ingredients in serum-free cultures, in which serum was completely replaced by albumin, cholesterol and transferrin, on the growth of murine granulocyte/macrophage progenitor cells (colony forming unit in culture: CFU-C) stimulated by serum-free PWM-SCM and the influences of purified granulocyte-macrophage colony stimulating factor (GM-CSF) in serum-free cultures. The results were as follows: 1) The number of CFU-C colonies reached a peak after 4 days of incubation. 2) A linear relationship was observed between the number of CFU-C colonies and the number of inoculated bone marrow cells. 3) Serum-free cultures could support CFU-C colony growth to the same degree as that in serum-containing cultures. Also, no significant differences were found in the types of colonies grown in both cultures. 4) Bovine serum albumin (BSA) and cholesterol were considered to play the most important roles among the ingredients in serum-free cultures. 5) Purified GM-CSF supported CFU-C colony growth in serum-free cultures and more than a half of the colonies formed were GM-colonies. These results showed the usefulness of our serum-free cultures for studying the granulopoiesis in vitro without the influences of various substances in the serum.


Daily SARS-CoV-2 Nasal Antigen Tests Miss Infected and Presumably Infectious People Due to Viral Load Differences among Specimen Types.
In a recent household transmission study of SARS-CoV-2, we found extreme differences in SARS-CoV-2 viral loads among paired saliva, anterior nares swab (ANS), and oropharyngeal swab specimens collected from the same time point. We hypothesized these differences may hinder low-analytical-sensitivity assays (including antigen rapid diagnostic tests [Ag-RDTs]) by using a single specimen type (e.g., ANS) from reliably detecting infected and infectious individuals. We evaluated daily at-home ANS Ag-RDTs (Quidel QuickVue) in a cross-sectional analysis of 228 individuals and a longitudinal analysis (throughout infection) of 17 individuals enrolled early in the course of infection. Ag-RDT results were compared to reverse transcription-quantitative PCR (RT-qPCR) results and high, presumably infectious viral loads (in each, or any, specimen type). The ANS Ag-RDT correctly detected only 44% of time points from infected individuals on cross-sectional analysis, and this population had an inferred limit of detection of 7.6 × 106 copies/mL. From the longitudinal cohort, daily Ag-RDT clinical sensitivity was very low (<3%) during the early, preinfectious period of the infection. Further, the Ag-RDT detected ≤63% of presumably infectious time points. The poor observed clinical sensitivity of the Ag-RDT was similar to what was predicted based on quantitative ANS viral loads and the inferred limit of detection of the ANS Ag-RDT being evaluated, indicating high-quality self-sampling. Nasal Ag-RDTs, even when used daily, can miss individuals infected with the Omicron variant and even those presumably infectious. Evaluations of Ag-RDTs for detection of infected or infectious individuals should be compared with a composite (multispecimen) infection status to correctly assess performance. IMPORTANCE We reveal three findings from a longitudinal study of daily nasal antigen rapid diagnostic test (Ag-RDT) evaluated against SARS-CoV-2 viral load quantification in three specimen types (saliva, nasal swab, and throat swab) in participants enrolled at the incidence of infection. First, the evaluated Ag-RDT showed low (44%) clinical sensitivity for detecting infected persons at all infection stages. Second, the Ag-RDT poorly detected (≤63%) time points that participants had high and presumably infectious viral loads in at least one specimen type. This poor clinical sensitivity to detect infectious individuals is inconsistent with the commonly held view that daily Ag-RDTs have near-perfect detection of infectious individuals. Third, use of a combination nasal-throat specimen type was inferred by viral loads to significantly improve Ag-RDT performance to detect infectious individuals.


Visual ability of patients seeking outpatient low vision services in the United States.
Most patients with low vision are elderly and have functional limitations from other health problems that could add to the functional limitations caused by their visual impairments. To identify factors that contribute to visual ability measures in patients who present for outpatient low vision rehabilitation (LVR) services. As part of a prospective, observational study of new patients seeking outpatient LVR, 779 patients from 28 clinical centers in the United States were enrolled in the Low Vision Rehabilitation Outcomes Study (LVROS) from April 25, 2008, through May 2, 2011. The Activity Inventory (AI), an adaptive visual function questionnaire, was administered to measure overall visual ability and visual ability in 4 functional domains (reading, mobility, visual motor function, and visual information processing) at baseline before LVR. The Geriatric Depression Scale, Telephone Interview for Cognitive Status, and Medical Outcomes Study 36-Item Short-Form Health Survey physical functioning questionnaires were also administered to measure patients' psychological, cognitive, and physical health states, respectively. Predictors of visual ability and functional domains as measured by the AI. Among the 779 patients in the LVROS sample, the mean age was 76.4 years, 33% were male, and the median logMAR visual acuity score was 0.60 (0.40-0.90 interquartile range). Correlations were observed between logMAR visual acuity and baseline visual ability overall (r = -0.42) and for all functional domains. Visual acuity was the strongest predictor of visual ability (P < .001) and reading ability (P < .001) and had a significant independent effect on the other functional domains. Physical ability was independently associated with (P < .001) overall visual ability as well as mobility and visual motor function. Depression had a consistent independent effect (P < .001) on overall visual ability and on all functional domains, whereas cognition had an effect on only reading and mobility (P < .001). Visual ability is a multidimensional construct, with visual acuity, depression, physical ability, and cognition explaining more than one-third of the variance in visual ability as measured by the AI. The significant contributions of the nonvisual factors to visual ability measures and the rehabilitation potential (ie, ceiling) effects they may impose on LVR are important considerations when measuring baseline visual ability and ultimately LVR outcomes in ongoing clinical research.


Orthodontic relapse and the mandibular third molar: a literature review.
This review of the literature considers the role of the mandibular third molars in orthodontic relapse. Theories attempting to resolve the mystery of relapse following orthodontic treatment are presented. While the literature supports the conclusion that there are valid reasons to remove third molars, it does not greatly support prophylactic removal and removal to avoid orthodontic relapse.


Socioeconomic Disparities in Cataract Prevalence, Characteristics, and Management.
To review the current literature on socioeconomic disparities relationship with cataract prevalence, characteristics, and management. Cataracts are an important cause of preventable visual impairment in both the developing and industrialized world. Cataract surgery is a highly effective operation with an excellent risk profile. Furthermore, cataract surgery has been shown to have significant positive functional, social, and economic implications for patients. Several medical conditions have been shown to have correlation with socioeconomic factors and cataract is among several forms of visual impairment that demonstrate this relationship. Disparities in prevalence, clinical characteristics, and management are documented in the ophthalmic literature. A better understanding of these socioeconomic factors and their clinical relevance is critical to alleviating the burden of cataract-related visual impairment in an aging population.


[Characteristics of the gene pool of the Gagauz population of Moldova].
Population genetic data on Gagauzes from Moldova are reported for the first time. Blood groups AB0 and Rh and biochemical markers of genes HP, TF, GC, and PGM1 were determined in 190 Gagauzes. The following allelic frequencies were determined: AB0*0, 0.5241; AB0*A, 0.3279; RH*d, 0.4571; HP*1, 0.3544; TF*C1, 0.7472; TF*C2, 0.1770; TFC3, 0.0730; TF*B, 0.0028; GC*1F, 0.1025; GC*1S, 0.5932; GC*2, 0.3043; PGM1*1+, 0.5286; PGM*1-, 0.1000; PGM1*2+, 0.2607; and PGM1*2-, 0.1107. The data obtained indicate that the gene pool of Gagauzes is similar to those of neighboring southeastern European populations.


Multicomponent analysis of replacement liquids of electronic cigarettes using chromatographic techniques.
The electronic cigarette (e-cig) is an invention of the past few years and its popularity is rapidly growing all over the world. A rapid multicomponent analytical protocol for the analysis of the replacement liquids (e-liquids) of e-cig was developed using gas (GC) and liquid chromatography (LC)-mass spectrometry (MS). GC-MS-based methods were developed for the determination of the main humectants and polycyclic aromatic hydrocarbons (PAHs). For the determination and quantification of nicotine (NIC) and nitrosamines, appropriate LC-MS-based methods were developed. The approbated methods were applied for the analysis of 263 e-liquid samples obtained from the Greek market. The instruments response was linear; the limits of quantification ranged from 0.003 μg/mL for three PAHs to 1.187 μg/mL for glycerol. The precision was <16% for all analytes, while the mean accuracy ranged from 99.1% for NIC to 106.6% for the flavor 2,5-dimethylpyrazine. The measured concentrations of NIC were correlated with the theoretical concentrations as reported by the manufacturers. An analog relation between the concentration of the glycerol and of propylene glycol was noticed. The frequency of detection of flavors ranged from 30.4% for the methyl cyclopentenolone to 5.3% for 3.4-dimethoxybenzaldehyde. Nitrosamines and PAHs were not detected in any sample. Because a similar analytical protocol was not available from the existing literature so far, our study offers the advantage of complete analytical methods for rapid and simultaneous multicomponent identification.


The use of semi-quantitative urine test-strip (Micral Test) for microalbuminuria screening in patients with diabetes mellitus.
Microalbuminuria is an early marker of prognostic significance in diabetic renal disease. However, testing for microalbuminuria in a timed sample of urine using the double antibody radioimmunoassay (RIA) method is cumbersome and requires special laboratory facilities. Recently, a test strip for microalbuminuria, the Micral Test was available and we evaluated the performance of this test strip as a screening method for detection of microalbuminuria. One hundred consecutive diabetic patients who were tested to be dipstick-negative (Albustix) for proteinuria were enrolled for the study. Micral Tests were performed on a paired first morning and random urine specimen from the same patient and the results compared with a timed 24-hour urine measurement of urine albumin excretion using the RIA method. Eighteen specimens were tested positive by the RIA method with a urinary albumin range of 32-177 mg/24 hours. With the Micral Test, the following sensitivity, specificity, positive and negative predictive values were obtained: 66.7%. 97.6%, 85.7% and 93.0% for the first morning urine specimens, and 77.8%, 91.5%, 66.7% and 94.9% for the random urine specimens. These results suggest that Micral Test with either the first morning or random urine specimen offers a simple, reliable, rapid and convenient method for screening of microalbuminuria in the diabetic patient.


Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.
Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.


Increasing rates of sex-discordant twins no longer correspond to decreasing perinatal mortality rates.
To analyze dizygotic twinning rates and outcomes over a 25-year period. Birth and fetal death certificates from 1980-2004 in Washington State, USA, were analyzed retrospectively to find factors associated with the increase in sex-discordant twins through time. "Low" and "high" fertility treatment groups were defined according to demographic traits. Perinatal mortality was defined as fetal or neonatal death of one or both twins and Weinberg's rule was used to estimate mortality for monozygotic and dizygotic pairs. Controlling simultaneously for maternal age, race, parity, and education did not eliminate the trend of increasing sex-discordant twins from 1992-2004 (M-H chi2 P=0.001). The "low" fertility group had a non-significant decline in sex-discordant twins (M-H chi2 P=0.24), whereas the "high" fertility group had a significant increase (M-H chi2 P=0.001). Perinatal mortality decreased for monozygtic twin pairs throughout the study period, but decreased until the mid-1990s and then increased slightly through 2004 for the dizygotic twin pairs. Advancing maternal age and increasing use of fertility treatments are largely responsible for the increase in dizygotic twins from 1980-2004 and may also be responsible for the stalling of the decline in perinatal mortality rate.


High Erk activity suppresses expression of the cell cycle inhibitor p27Kip1 in colorectal cancer cells.
The molecular heterogeneity of human cancer cells at the level of signaling protein activities remains poorly understood. Using a panel of 64 colorectal (CRC) cancer cell lines the activity status of the MAP kinases Erk1 and Erk2 was investigated. Erk1/2 activity varied greatly within the CRC cell line panel and was not detectably associated with the speed of cell growth in 10 CRC lines analyzed. As expected, mutations in K-Ras or B-Raf were often, albeit not always, linked to high Erk1/2 activity. The phosphorylation of several known Erk1/2 targets investigated did not generally reflect Erk1/2 activity in the 10 CRC lines analyzed. However, the reduction of Erk1/2 activity with MEK inhibitors generally abolished cell growth but only led to an increase of cellular p27Kip1 levels in CRC cells with high Erk1/2 activity levels. The results indicate that high Erk1/2 activation is utilized by some CRC lines to override the cell cycle brake p27Kip1, while others presumably rely on different mechanisms in order to inactivate this important cell cycle brake. Such detailed knowledge of the molecular diversity of cancer cell signaling mechanisms may eventually help to develop molecularly targeted, patient-specific therapeutic strategies and treatments.


Apocrine carcinoma as triple-negative breast cancer: novel definition of apocrine-type carcinoma as estrogen/progesterone receptor-negative and androgen receptor-positive invasive ductal carcinoma.
Apocrine carcinoma, a subtype of invasive ductal carcinoma of the breast, expresses androgen receptor (AR), but often lacks estrogen receptor (ER) and progesterone receptor (PgR). In the present study, the author immunohistochemically defined apocrine-type carcinoma as ER-/PgR-/AR+ invasive ductal carcinoma and analyzed the significance of apocrine-type carcinoma as triple-negative breast cancer. Four hundred and forty breast cancers from 429 cases were immunostained for estrogen receptor, progesterone receptor, androgen receptor, human epidermal growth factor receptor type 2 (HER2), p53, Ki-67 and epidermal growth factor receptor. The lesions included 58 in situ malignancies (including 13 apocrine-type lesions) and 325 invasive ductal carcinomas (including 44 apocrine type). Of 91 estrogen receptor-negative invasive ductal carcinomas, 44 (48%) belonged to apocrine-type carcinoma, and overexpression of human epidermal growth factor receptor type 2 and p53 was observed in 23 (52%) and 33 (75%), respectively. Histologically, 22 (50%) were categorized as classical apocrine carcinoma. Among 281 non-apocrine invasive ductal carcinomas, 30 (11%) were quadruple-negative (ER-/PgR-/AR-/HER2-) and 17 (6%) were hormone receptor-negative and human epidermal growth factor receptor type 2-overexpressed. Invasive ductal carcinomas in the triple-negative breast cancer category (n= 51) were divided into triple-negative, androgen receptor-positive (apocrine, n= 21) and quadruple-negative (non-apocrine, n= 30). p53 overexpression was more often seen in the apocrine-type triple-negative breast cancer (18/21 = 86%) than in the non-apocrine type (14/30 = 46%) (P< 0.05). Ki-67 labeling was significantly higher in the non-apocrine type (58%) than in the apocrine type (37%) (P< 0.01). Epidermal growth factor receptor is consistently expressed in triple-negative breast cancers (16/16 = 100% in apocrine and 18/20 = 90% in non-apocrine). Androgen receptor should be added to immunohistochemical panels, since apocrine-type invasive ductal carcinoma, resembling basal-like phenotypes, may show clinical behaviors different from the basal-like triple-negative breast cancer.


Folding protein models with a simple hydrophobic energy function: the fundamental importance of monomer inside/outside segregation.
The present study explores a "hydrophobic" energy function for folding simulations of the protein lattice model. The contribution of each monomer to conformational energy is the product of its "hydrophobicity" and the number of contacts it makes, i.e., E(h,c) = -Sigma N/i=1 c(i)h(i) = -(h.c) is the negative scalar product between two vectors in N-dimensional cartesian space: h = (h1,., hN), which represents monomer hydrophobicities and is sequence-dependent; and c = (c(1),., c(N)), which represents the number of contacts made by each monomer and is conformation-dependent. A simple theoretical analysis shows that restrictions are imposed concomitantly on both sequences and native structures if the stability criterion for protein-like behavior is to be satisfied. Given a conformation with vector c, the best sequence is a vector h on the direction upon which the projection of c - c is maximal, where c is the diagonal vector with components equal to c, the average number of contacts per monomer in the unfolded state. Best native conformations are suggested to be not maximally compact, as assumed in many studies, but the ones with largest variance of contacts among its monomers, i.e., with monomers tending to occupy completely buried or completely exposed positions. This inside/outside segregation is reflected on an apolar/polar distribution on the corresponding sequence. Monte Carlo simulations in two dimensions corroborate this general scheme. Sequences targeted to conformations with large contact variances folded cooperatively with thermodynamics of a two-state transition. Sequences targeted to maximally compact conformations, which have lower contact variance, were either found to have degenerate ground state or to fold with much lower cooperativity.


Directional selection for flowering time leads to adaptive evolution in Raphanus raphanistrum (Wild radish).
Herbicides have been the primary tool for controlling large populations of yield depleting weeds from agro-ecosystems, resulting in the evolution of widespread herbicide resistance. In response, nonherbicidal techniques have been developed which intercept weed seeds at harvest before they enter the soil seed bank. However, the efficiency of these techniques allows an intense selection for any trait that enables weeds to evade collection, with early-flowering ecotypes considered likely to result in early seed shedding. Using a field-collected wild radish population, five recurrent generations were selected for early maturity and three generations for late maturity. Phenology associated with flowering time and growth traits were measured. Our results demonstrate the adaptive capacity of wild radish to halve its time to flowering following five generations of early-flowering selection. Early-maturing phenotypes had reduced height and biomass at maturity, leading to less competitive, more prostrate growth forms. Following three generations of late-flowering selection, wild radish doubled its time to flowering time leading to increased biomass and flowering height at maturity. This study demonstrates the potential for the rapid evolution in growth traits in response to highly effective seed collection techniques that imposed a selection on weed populations within agro-ecosystems at harvest.


[The differential diagnosis of splenic angiosarcoma and idiopathic myelofibrosis].
The authors have made an analysis of literature and their own data on the differential diagnosis between angiosarcoma of the spleen and idiopathic myelofibrosis that is considered to be necessary due to the similarity of laboratory and clinical symptoms of these diseases.


Prevention of traumatic stress in mothers of preterms: 6-month outcomes.
Symptoms of posttraumatic stress disorder are a well-recognized phenomenon in mothers of preterm infants, with implications for maternal health and infant outcomes. This randomized controlled trial evaluated 6-month outcomes from a skills-based intervention developed to reduce symptoms of posttraumatic stress disorder, anxiety, and depression. One hundred five mothers of preterm infants were randomly assigned to (1) a 6- or 9-session intervention based on principles of trauma-focused cognitive behavior therapy with infant redefinition or (2) a 1-session active comparison intervention based on education about the NICU and parenting of the premature infant. Outcome measures included the Davidson Trauma Scale, the Beck Depression Inventory II, and the Beck Anxiety Inventory. Participants were assessed at baseline, 4 to 5 weeks after birth, and 6 months after the birth of the infant. At the 6-month assessment, the differences between the intervention and comparison condition were all significant and sizable and became more pronounced when compared with the 4- to 5-week outcomes: Davidson Trauma Scale (Cohen's d = -0.74, P < .001), Beck Anxiety Inventory (Cohen's d = -0.627, P = .001), Beck Depression Inventory II (Cohen's d = -0.638, P = .002). However, there were no differences in the effect sizes between the 6- and 9-session interventions. A brief 6-session intervention based on principles of trauma-focused cognitive behavior therapy was effective at reducing symptoms of trauma, anxiety, and depression in mothers of preterm infants. Mothers showed increased benefits at the 6-month follow-up, suggesting that they continue to make use of techniques acquired during the intervention phase.


Chatbots, generative AI, and scholarly manuscripts: WAME recommendations on chatbots and generative artificial intelligence in relation to scholarly publications.
This statement revises our earlier "WAME Recommendations on ChatGPT and Chatbots in Relation to Scholarly Publications" (January 20, 2023). The revision reflects the proliferation of chatbots and their expanding use in scholarly publishing over the last few months, as well as emerging concerns regarding lack of authenticity of content when using chatbots. These recommendations are intended to inform editors and help them develop policies for the use of chatbots in papers published in their journals. They aim to help authors and reviewers understand how best to attribute the use of chatbots in their work and to address the need for all journal editors to have access to manuscript screening tools. In this rapidly evolving field, we will continue to modify these recommendations as the software and its applications develop.


Race independently predicts prostate specific antigen testing frequency following a prostate carcinoma diagnosis.
The goals of the current study were to describe patterns of prostate specific antigen (PSA) surveillance for prostate carcinoma progression in a community-based cohort of patients and to identify independent clinical and sociodemographic factors that predict the frequency of surveillance. Patients diagnosed with localized prostate carcinoma from October 1, 1991 to December 31, 1992 in New Haven and Hartford, Connecticut, were identified. Data were collected through standardized outpatient medical record review. Multivariate statistical methods were used to determine the factors that independently predicted the frequency of surveillance. Six hundred fifty-eight men with localized prostate carcinoma were included in the cohort. Forty-five percent of all patients were tested at least once annually, and 69% were tested at least once every 2 years. Multivariate models indicated that African American men were half as likely as Caucasian men to receive annual testing (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.24-0.97). Men diagnosed at age 70 years or older were 38% less likely to have annual testing than men diagnosed between the ages of 65 and 69 (OR, 0.62; 95% CI, 0.41-0.94). A higher Gleason score and PSA at presentation also were associated independently with higher rates of annual PSA surveillance. Postdiagnosis PSA surveillance is common, although not universal. African American men were at significantly greater risk for receiving less frequent testing compared with Caucasian men. This disparity in access to care may explain, in part, previously observed racial differences in survival in prostate carcinoma. Further research is needed to identify the reasons for the racial disparity in PSA surveillance and to design interventions to lessen these differences.


Improving model-based functional near-infrared spectroscopy analysis using mesh-based anatomical and light-transport models.
Significance: Functional near-infrared spectroscopy (fNIRS) has become an important research tool in studying human brains. Accurate quantification of brain activities via fNIRS relies upon solving computational models that simulate the transport of photons through complex anatomy. Aim: We aim to highlight the importance of accurate anatomical modeling in the context of fNIRS and propose a robust method for creating high-quality brain/full-head tetrahedral mesh models for neuroimaging analysis. Approach: We have developed a surface-based brain meshing pipeline that can produce significantly better brain mesh models, compared to conventional meshing techniques. It can convert segmented volumetric brain scans into multilayered surfaces and tetrahedral mesh models, with typical processing times of only a few minutes and broad utilities, such as in Monte Carlo or finite-element-based photon simulations for fNIRS studies. Results: A variety of high-quality brain mesh models have been successfully generated by processing publicly available brain atlases. In addition, we compare three brain anatomical models-the voxel-based brain segmentation, tetrahedral brain mesh, and layered-slab brain model-and demonstrate noticeable discrepancies in brain partial pathlengths when using approximated brain anatomies, ranging between - 1.5 % to 23% with the voxelated brain and 36% to 166% with the layered-slab brain. Conclusion: The generation and utility of high-quality brain meshes can lead to more accurate brain quantification in fNIRS studies. Our open-source meshing toolboxes "Brain2Mesh" and "Iso2Mesh" are freely available at http://mcx.space/brain2mesh.


Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis.
Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-α, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis.


Increased Male-Male Mounting Behaviour in Desert Locusts during Infection with an Entomopathogenic Fungus.
Same-sex sexual behaviour occurs across diverse animal taxa, but adaptive explanations can be difficult to determine. Here we investigate male-male mounting (MMM) behaviour in female-deprived desert locust males infected with the entomopathogenic fungus Metarhizium acridum. Over a four-week period, infected locusts performed more MMM behaviours than healthy controls. Among infected locusts, the probability of MMM, and the duration of time spent MMM, significantly increased with the mounting locust's proximity to death. In experimental trials, infected locusts were also significantly more likely than controls to attempt to mount healthy males. Therefore, we demonstrate that MMM is more frequent among infected than healthy male locusts, and propose that this may be explained by terminal reproductive effort and a lowered mate acceptance threshold in infected males. However, during experimental trials mounting attempts were more likely to be successful if the mounted locusts were experimentally manipulated to have a reduced capacity to escape. Thus, reduced escape capability resulting from infection may also contribute to the higher frequency of MMM among infected male locusts. Our data demonstrate that pathogen infection can affect same-sex sexual behaviour, and suggest that the impact of such behaviours on host and pathogen fitness will be a novel focus for future research.


The 25-km Discontinuity: Implications for Lunar History.
The lunar velocity profile and laboratory data on terrestrial and lunar rocks are constraints on models of lunar history. They show that shock-induced microcracks are absent from the rocks present in the moon today at depths of 25 to 60 kilometers. All possible causes of this observation are examined, and the most likely explanations are that either the rocks at depths of 25 to 60 kilometers formed after the major impacts ceased or the microcracks have annealed at temperatures of about 600 degrees C over geologically long times.


Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution.
A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC=6.25-12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5-25 μg/mL. Although not the most active, 4-NH(2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21.


The growing impact of alpha-fetoprotein in the field of liver transplantation for hepatocellular cancer: time for a revolution.
The role of alpha-fetoprotein (AFP) in the specific setting of the diagnosis and prognosis of patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still controversial. Recently, a marked interest for this marker has been reported, mainly related to its ability to predict the outcome of HCC patients after LT. The growing number of papers in PubMed indicates that AFP has begun a "second life" in the particular context of LT. Looking at the most recent International Guidelines on HCC, it looks obvious that time is ripe to reevaluate the value of AFP in relation to its prognostic ability to identify HCC patients at high-risk for drop-out before and recurrence after LT. Many discrepancies exist worldwide regarding the use of biomarkers in HCC. In contrast to the Western world, AFP is widely used in Asian countries, the reason why being unclear. Indeed, in the (merely Western-dominated) HCC treatment algorithms, the role of AFP as a prognostic tumor marker is still considered to be "under investigation". One should however realize that the underestimation of the value of AFP in the LT context will hamper further refinements of both the liver allograft allocation process and the selection of the best candidates for this procedure. Moreover, AFP has an important role to play in the monitoring of bridging and/or downstaging procedures bringing eventually the patient to transplantation. So, time has come to reconsider the role and value of AFP (dynamics) in the field of transplant oncology.


[From bench to bicycle. Risk assessment in connection with sports activities and exercise programs in the primary and secondary prevention of cardiovascular diseases].
Due to encouraging results of studies investigating the effects of physical activity and training on cardiovascular diseases and due to the integration of preventive strategies into disease management programs by public health organizations, it is expected that a larger population, including cardiovascular patients, will increasingly participate in physical activity, fitness programs, and sports. However, a reduction in cardiovascular events and all-cause mortality by regular physical activity is accompanied by an increased mortality during exertion, as yet, there is no satisfactory definition of risk for all cardiovascular diseases and patient groups. A cost-effective preparticipation screening has to consider both the low incidence of events resulting from different diseases which requires subtle diagnostics and the intention of granting the larger population simple access to exercise programs and sports. There is a substantial difference in the risk profile for fatal events in athletes and young fitness program participants on the one hand and older (> 35 years) exercising people with a higher incidence of common cardiovascular diseases on the other. Additionally, a potential exercise-induced progression of chronic heart diseases should be excluded. New imaging techniques, laboratory markers, and genetic indicators will hopefully improve the quality of risk assessment. Establishing standards for diagnostics and risk assessment as well as different types of exercise and training programs, all of which need to be transformed into national guidelines, could help to reduce risks without limiting access to physical exercise and therapy. However, an element of risk will remain if rational cost-effectiveness ratios are to be applied.


Fractures in access to and assessment of trauma systems.
Trauma is a major public health problem and organized systems of trauma care have been shown to substantially reduce trauma-related mortality. Currently California and many other states have incompletely developed systems of trauma care delivery. This study was undertaken to determine how frequently patients incurring serious trauma in California receive treatment at a trauma center. Hospital discharge records for 360,743 acute trauma patients for 1995 to 1997 were analyzed. Abbreviated Injury Scale scores were calculated from discharge diagnosis codes. Severity of trauma and the need for trauma center treatment was defined by eight Abbreviated Injury Scale criteria combined with patient age and type of injury. According to study criteria, 67,718 patients needed trauma center care and 56% were treated at a trauma center. Among patients less than 55 years of age, 62% were treated at a trauma center compared with 40% of those aged 55 years or more (p < 0.0001). For patients less than 55 years old with brain injuries, 66% were treated at a trauma center compared with 44% for patients aged 55 years or more (p < 0.0001). Of the 29,849 patients who met Abbreviated Injury Scale criteria but were not treated at trauma centers, 59% were in counties with designated trauma centers and 41% were in counties without trauma centers. Only 56% of seriously injured patients in California were treated at trauma centers, despite most of the injuries occurring in the catchment areas of designated trauma care systems. Substantial undertriage of serious trauma patients to trauma centers appears to be occurring, especially in older persons and in persons with brain injuries. Efforts to understand why undertriage is occurring so frequently are hampered by fragmentation of the systems of care, inadequate data management systems, and lack of trauma care performance reporting by non-trauma center hospitals.


Synthesis, Purification and Crystallization of Guanine-rich RNA Oligonucleotides.
Guanine-rich RNA oligonucleotides display many novel structural motifs in recent crystal structures. Here we describe the procedures of the chemical synthesis and the purification of such RNA molecules that are suitable for X-ray crystallographic studies. Modifications of the previous purification methods allow us to obtain better yields in shorter time. We also provide 24 screening conditions that are very effective in crystallization of the guanine-rich RNA oligonucleotides. Optimal crystallization conditions are usually achieved by adjustment of the concentration of the metal ions and pH of the buffer. Crystals obtained by this method usually diffract to high resolution.


L-galactono-1,4-lactone dehydrogenase is required for the accumulation of plant respiratory complex I.
Mitochondrial NADH-ubiquinone oxidoreductase (complex I) is the largest enzyme of the oxidative phosphorylation system, with subunits located at the matrix and membrane domains. In plants, holocomplex I is composed of more than 40 subunits, 9 of which are encoded by the mitochondrial genome (NAD subunits). In Nicotiana sylvestris, a minor 800-kDa subcomplex containing subunits of both domains and displaying NADH dehydrogenase activity is detectable. The NMS1 mutant lacking the membrane arm NAD4 subunit and the CMSII mutant lacking the peripheral NAD7 subunit are both devoid of the holoenzyme. In contrast to CMSII, the 800-kDa subcomplex is present in NMS1 mitochondria, indicating that it could represent an assembly intermediate lacking the distal part of the membrane arm. L-galactono-1,4-lactone dehydrogenase (GLDH), the last enzyme in the plant ascorbate biosynthesis pathway, is associated with the 800-kDa subcomplex but not with the holocomplex. To investigate possible relationships between GLDH and complex I assembly, we characterized an Arabidopsis thaliana gldh insertion mutant. Homozygous gldh mutant plants were not viable in the absence of ascorbate supplementation. Analysis of crude membrane extracts by blue native and two-dimensional SDS-PAGE showed that complex I accumulation was strongly prevented in leaves and roots of Atgldh plants, whereas other respiratory complexes were found in normal amounts. Our results demonstrate the role of plant GLDH in both ascorbate biosynthesis and complex I accumulation.


An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1.
Latexin, the only known mammalian carboxypeptidase inhibitor, has no detectable sequence similarity with plant and parasite inhibitors, but it is related to a human putative tumor suppressor protein, TIG1. Latexin is expressed in the developing brain, and we find that it plays a role in inflammation, as it is expressed at high levels and is inducible in macrophages in concert with other protease inhibitors and potential protease targets. The crystal structure of mouse latexin, solved at 1.83 A resolution, shows no structural relationship with other carboxypeptidase inhibitors. Furthermore, despite a lack of detectable sequence duplication, the structure incorporates two topologically analogous domains related by pseudo two-fold symmetry. Surprisingly, these domains share a cystatin fold architecture found in proteins that inhibit cysteine proteases, suggesting an evolutionary and possibly functional relationship. The structure of the tumor suppressor protein TIG1 was modeled, revealing its putative membrane binding surface.


Recent progress of core-substituted naphthalenediimides: highlights from 2010.
Core-substituted naphthalenediimides (cNDIs) are rapidly emerging as a powerful strategy to create functional nanomaterials and their implications in biological and supramolecular chemistry are significant. Recent developments in the synthesis of cNDIs have allowed several groups to probe the function of this interesting class of dye molecules in a molecular and supramolecular sense. Core-substitution of the NDI can be seen as an opportunity to extend the planar, rigid core and could be used to prepare novel structures for applications in organic, biosupramolecular chemistry, biomedicine, materials science and organic solar cells. In this Emerging Area, we provide up-to-date recent progress in the field of cNDIs. We begin with a general discussion and the applications of cNDIs in the field of supramolecular chemistry i.e. generation of nanostructures such as vesicles and nanotubes etc., and we also discuss advances in artificial photosynthesis. Following this is a section on their implications in the field of sensors, particularly DNA intercalation, anion sensing and NDI based pH sensors. Finally, we explore the recent development of cNDIs in organic solar cell applications. We conclude with our views on the prospects of cNDIs in future research.


Induction and multi-sensitive end-product repression in two converging pathways degrading aromatic substances in Pseudomonas fluorescens.
1. Control of enzyme formation has been examined in the pathways degrading mandelate and p-hydroxymandelate in Pseudomonas fluorescens. 2. The first three enzymes form a group which is common to both pathways and which is co-ordinately induced or repressed. The genes controlling these enzymes are assumed to form a ;regulon'. This group of enzymes is induced by mandelate or p-hydroxymandelate and repressed by benzoate and by p-hydroxybenzoate (the immediate end products resulting from the action of this group of enzymes). 3. Repression is independently exerted by end products of enzymes controlled by succeeding regulons, i.e. by catechol, by protocatechuate and finally by succinate and acetate. 4. The pattern is repeated further along the pathway, so that benzoate oxidase (controlled by the second regulon) is repressed by its immediate end product, catechol, and again by succinate and acetate. 5. Pyrocatechase, an enzyme controlled by the third regulon, is repressed by succinate and acetate. 6. There is a parallel system of multi-sensitive repression mechanisms controlling production of the enzymes that degrade the hydroxy compounds. Again, the enzymes of each regulon are repressed by the immediate end product of their action and by the end products of each succeeding group of enzymes. 7. Repressor activity appears to be exerted by compounds that are likely to occur as such in the external environment or that occur at points of convergence of the degradative pathways of the cell. 8. The net effect of this control system, involving both induction and end-product repression, appears to be that cells will not form inducible degradative enzymes if the end products are already being supplied from without or are being produced by degradation of some alternative source of carbon and energy.


Posterior Reversible Encephalopathy Syndrome Secondary to Hypertensive Encephalopathy Brought on by a MAO Inhibitor: A Case Report.
An elderly woman was admitted to the Family Medicine inpatient service for altered mental status after being brought to the emergency room by a concerned neighbor, who had come across the patient speaking incoherently. Initial evaluation was notable for elevated blood pressures, but extensive lab testing and head computed tomographic imaging were within normal limits. However, subsequent magnetic resonance imaging showed white matter changes consistent with posterior reversible encephalopathy syndrome (PRES), a neurologic syndrome characterized by headache, altered mental status, loss of vision, and seizures as well as radiographic findings of posterior cerebral white matter edema. Multiple etiologies of PRES have been described and include hypertensive encephalopathy, immunosuppressant medications, and eclampsia. This case describes an episode of PRES secondary to hypertensive encephalopathy brought about by an inappropriate dose of a monoamine oxidase (MAO) inhibitor. The patient had significant improvement in symptoms with removal of the offending agent and control of her blood pressure. While PRES generally has a good prognosis, prompt recognition, and management are important in preventing significant disease morbidity and mortality.


Effects of transcutaneous electrical nerve stimulation on rats with post-operative ileus.
Post-operative ileus (POI) is a type of bowel dismotility causing accumulation of gas and fluid. Transcutaneous electrical nerve stimulation (TENS) has been frequently used for medical applications such as pain treatment and nervous stimulation. In this experimental animal model of POI, our aim is to investigate the effects of TENS on POI, and to demonstrate histopathological changes in rat intestine after TENS application. The present study is an experimental animal model of POI. Sixteen Wistar-Albino male rats in two groups were used and laparotomy was performed. After colorectum and small intestine were manipulated, activated charcoal and Nile red were ad-ministered by oral gavage. Electrodes were placed to the abdomen skin of the rats and TENS method was used. Rats in two groups were sacrificed on 24 h. The esophagus, stomach, and all intestines of the rats were resected and a direct X-ray and computerized tomography scan, and 'J' images were taken, and the progression of active coals was measured radiologically. Histopathological and microscopic evaluation was performed. The median of activated charcoal measure was 429 mm (178-594) in TENS group, 203 mm (149-313) in the control group, respectively, and these were statistically significant (p=0.004963). There was a significant difference between the two groups in terms of histopathological necrosis (p=0.041). In addition, the amount of Nil Red (550 nm) in the GI track is increased after 8 h of gavage with sequential applications of TENS. This study demonstrated the protective and therapeutic efficacy of TENS in POI in a rat model by radiologically and histopathologically. In clinical practice, TENS may be examined on POI. Further studies are warranted to validate and generalize our findings, and to assess the impact of TENS for post-operative pain also.


Low-carbohydrate diet review: shifting the paradigm.
What does a clinician need to know about low-carbohydrate (LC) diets? This review examines and compares the safety and the effectiveness of a LC approach as an alternative to a low-fat (LF), high-carbohydrate diet, the current standard for weight loss and/or chronic disease prevention. In short-term and long-term comparison studies, ad libitum and isocaloric therapeutic diets with varying degrees of carbohydrate restriction perform as well as or better than comparable LF diets with regard to weight loss, lipid levels, glucose and insulin response, blood pressure, and other important cardiovascular risk markers in both normal subjects and those with metabolic and other health-related disorders. The metabolic, hormonal, and appetite signaling effects of carbohydrate reduction suggest an underlying scientific basis for considering it as an alternative approach to LF, high-carbohydrate recommendations in addressing overweight/obesity and chronic disease in America. It is time to embrace LC diets as a viable option to aid in reversing diabetes mellitus, risk factors for heart disease, and the epidemic of obesity.


A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?
Although it has been suggested that coexpression of minK related peptide (MiRP1) is required for reconstitution of native rapid delayed-rectifier current (I(Kr)) by human ether-a-go-go related gene (HERG), currents resulting from HERG (I(HERG)) and HERG plus MiRP1 expression have not been directly compared with native I(Kr). We compared the pharmacological and selected biophysical properties of I(HERG) with and without MiRP1 coexpression in Chinese hamster ovary (CHO) cells with those of guinea-pig I(Kr) under comparable conditions. Comparisons were also made with HERG expressed in Xenopus oocytes. MiRP1 coexpression significantly accelerated I(HERG) deactivation at potentials negative to the reversal potential, but did not affect more physiologically relevant deactivation of outward I(HERG), which remained slower than that of I(Kr). MiRP1 shifted I(HERG) activation voltage dependence in the hyperpolarizing direction, whereas I(Kr) activated at voltages more positive than I(HERG). There were major discrepancies between the sensitivity to quinidine, E-4031 and dofetilide of I(HERG) in Xenopus oocytes compared to I(Kr), which were not substantially affected by coexpression with MiRP1. On the other hand, the pharmacological sensitivity of I(HERG) in CHO cells was indistinguishable from that of I(Kr) and was unaffected by MiRP1 coexpression. We conclude that the properties of I(HERG) in CHO cells are similar in many ways to those of native I(Kr) under the same recording conditions, and that the discrepancies that remain are not reduced by coexpression with MiRP1. These results suggest that the physiological role of MiRP1 may not be to act as an essential consituent of the HERG channel complex carrying native I(Kr).


More than a filter: Feature-based attention regulates the distribution of visual working memory resources.
Across 2 experiments we revisited the filter account of how feature-based attention regulates visual working memory (VWM). Originally drawing from discrete-capacity ("slot") models, the filter account proposes that attention operates like the "bouncer in the brain," preventing distracting information from being encoded so that VWM resources are reserved for relevant information. Given recent challenges to the assumptions of discrete-capacity models, we investigated whether feature-based attention plays a broader role in regulating memory. Both experiments used partial report tasks in which participants memorized the colors of circle and square stimuli, and we provided a feature-based goal by manipulating the likelihood that 1 shape would be probed over the other across a range of probabilities. By decomposing participants' responses using mixture and variable-precision models, we estimated the contributions of guesses, nontarget responses, and imprecise memory representations to their errors. Consistent with the filter account, participants were less likely to guess when the probed memory item matched the feature-based goal. Interestingly, this effect varied with goal strength, even across high probabilities where goal-matching information should always be prioritized, demonstrating strategic control over filter strength. Beyond this effect of attention on which stimuli were encoded, we also observed effects on how they were encoded: Estimates of both memory precision and nontarget errors varied continuously with feature-based attention. The results offer support for an extension to the filter account, where feature-based attention dynamically regulates the distribution of resources within working memory so that the most relevant items are encoded with the greatest precision. (PsycINFO Database Record


Knowledge of Good Samaritan Laws and Beliefs About Arrests Among Persons Who Inject Drugs a Year After Policy Change in Baltimore, Maryland.
Delivering and receiving prompt medical care during an overdose are imperative to ensure survival. Good Samaritan laws encourage people to call 911 during an overdose by providing immunity from selected drug arrests (eg, low-level possession). However, it is unclear whether persons who inject drugs (PWID) are aware of and understand these laws and their implications. We examined awareness among PWID of the 2015 Good Samaritan law in Maryland and their beliefs about whether they could be arrested for calling 911 or having an overdose. We surveyed 298 PWID in Baltimore, Maryland. We estimated the proportion who knew what the Good Samaritan law addressed and who believed they could be arrested for calling 911 or overdosing. We used a multivariate model to assess the association between harm-reduction services and knowledge of the Good Samaritan law or beliefs about getting arrested for calling 911 or overdosing. Of PWID, 56 of 298 (18.8%) knew what the Good Samaritan law addressed, 43 of 267 (16.1%) believed they could be arrested for calling 911, and 32 of 272 (11.8%) believed they could be arrested for having an overdose. After adjusting for demographic characteristics, accessing the syringe services program was associated with accurate knowledge and the belief that PWID could be arrested for calling 911; however, training in overdose reversal was not associated. Most PWID were unaware of the Good Samaritan law; this lack of awareness is a barrier to preventing overdose deaths. Educating PWID about Good Samaritan laws is essential, and such education should include police to ensure that law enforcement is congruent with Good Samaritan laws and does not perpetuate mistrust between police and PWID.


Standing on the shoulders of giants: young aphids piggyback on adults when searching for a host plant.
Upon the detection of imminent peril, pea aphids (Acyrthosiphon pisum) often drop off their host plant. Dropping in response to insect enemies is intermittent in nature, but when a mammalian herbivore feeds on their host plant, a large mixed-age group of aphids usually drops off the plant at once. Aphids that reach the ground are confronted with new, hostile environmental conditions and must therefore quickly walk toward a suitable host plant. The longer it takes an aphid to reach a host plant, the more it is exposed to the risks of starvation, desiccation and predation. We found that young nymphs, which have limited mobility and high mortality on the ground, quickly climb on conspecific (not necessarily parental) adults and cling to them before the latter start walking in search of a plant. This "riding" behavior is likely to be adaptive for the nymphs, for it shortens their journey and the time they spend off a host plant. Adults however, seem to be irritated by the riding nymphs, as they often actively try to remove them. After dropping from the host plant, young aphid nymphs travel at least part of the way back to a plant on the backs of adults. For the riding behavior to take place, nymphs need to successfully find adults and withstand removal attempts.


Prion replication environment defines the fate of prion strain adaptation.
The main risk of emergence of prion diseases in humans is associated with a cross-species transmission of prions of zoonotic origin. Prion transmission between species is regulated by a species barrier. Successful cross-species transmission is often accompanied by strain adaptation and result in stable changes of strain-specific disease phenotype. Amino acid sequences of host PrPC and donor PrPSc as well as strain-specific structure of PrPSc are believed to be the main factors that control species barrier and strain adaptation. Yet, despite our knowledge of the primary structures of mammalian prions, predicting the fate of prion strain adaptation is very difficult if possible at all. The current study asked the question whether changes in cofactor environment affect the fate of prions adaptation. To address this question, hamster strain 263K was propagated under normal or RNA-depleted conditions using serial Protein Misfolding Cyclic Amplification (PMCA) conducted first in mouse and then hamster substrates. We found that 263K propagated under normal conditions in mouse and then hamster substrates induced the disease phenotype similar to the original 263K. Surprisingly, 263K that propagated first in RNA-depleted mouse substrate and then normal hamster substrate produced a new disease phenotype upon serial transmission. Moreover, 263K that propagated in RNA-depleted mouse and then RNA-depleted hamster substrates failed to induce clinical diseases for three serial passages despite a gradual increase of PrPSc in animals. To summarize, depletion of RNA in prion replication reactions changed the rate of strain adaptation and the disease phenotype upon subsequent serial passaging of PMCA-derived materials in animals. The current studies suggest that replication environment plays an important role in determining the fate of prion strain adaptation.


Rationale for early intervention in acute stroke.
Ischemic stroke occurs after an abrupt reduction in cerebral blood flow, usually related to thrombosis of an intracranial or extracranial artery. The presenting symptoms and signs of stroke vary greatly, depending on the region of the brain involved. Most individuals are unaware of the warning signs or symptoms of stroke and do not seek medical care immediately after stroke onset. Recently, thrombolytic therapy with intravenous tissue plasminogen activator (t-PA) has been shown to be effective for treatment of selected stroke patients if administered <3 hours after stroke onset. This therapy is now approved for stroke treatment, but relatively few stroke patients currently receive t-PA. Neuroprotective agents that improve the intrinsic ability of brain parenchyma to withstand ischemia are currently undergoing intensive clinical evaluation. Their development has been facilitated by significant scientific advances in the understanding of the pathophysiology of acute ischemic neuronal injury. Strategies aimed at interfering with these fundamental processes of ischemic neuronal injury have shown encouraging results in several preliminary clinical trials. However, these agents probably must also be administered within a few hours of stroke onset to be beneficial. Eventually, combined neuroprotective and thrombolytic therapy will likely be used for acute stroke treatment. This strategy's success will depend on increased public and professional education efforts dealing with stroke recognition, evaluation, and treatment.


The alcohol withdrawal syndrome.
The alcohol withdrawal syndrome (AWS) is a common management problem in hospital practice for neurologists, psychiatrists and general physicians alike. Although some patients have mild symptoms and may even be managed in the outpatient setting, others have more severe symptoms or a history of adverse outcomes that requires close inpatient supervision and benzodiazepine therapy. Many patients with AWS have multiple management issues (withdrawal symptoms, delirium tremens, the Wernicke-Korsakoff syndrome, seizures, depression, polysubstance abuse, electrolyte disturbances and liver disease), which requires a coordinated, multidisciplinary approach. Although AWS may be complex, careful evaluation and available treatments should ensure safe detoxification for most patients.


Identification of genomic regions that interact with a viable allele of the Drosophila protein tyrosine phosphatase corkscrew.
Signaling by receptor tyrosine kinases (RTKs) is critical for a multitude of developmental decisions and processes. Among the molecules known to transduce the RTK-generated signal is the nonreceptor protein tyrosine phosphatase Corkscrew (Csw). Previously, Csw has been demonstrated to function throughout the Drosophila life cycle and, among the RTKs tested, Csw is essential in the Torso, Sevenless, EGF, and Breathless/FGF RTK pathways. While the biochemical function of Csw remains to be unambiguously elucidated, current evidence suggests that Csw plays more than one role during transduction of the RTK signal and, further, the molecular mechanism of Csw function differs depending upon the RTK in question. The isolation and characterization of a new, spontaneously arising, viable allele of csw, csw(lf), has allowed us to undertake a genetic approach to identify loci required for Csw function. The rough eye and wing vein gap phenotypes exhibited by adult flies homo- or hemizygous for csw(lf) has provided a sensitized background from which we have screened a collection of second and third chromosome deficiencies to identify 33 intervals that enhance and 21 intervals that suppress these phenotypes. We have identified intervals encoding known positive mediators of RTK signaling, e.g., drk, dos, Egfr, E(Egfr)B56, pnt, Ras1, rolled/MAPK, sina, spen, Src64B, Star, Su(Raf)3C, and vein, as well as known negative mediators of RTK signaling, e.g., aos, ed, net, Src42A, sty, and su(ve). Of particular interest are the 5 lethal enhancing intervals and 14 suppressing intervals for which no candidate genes have been identified.


[The reclassification assistant: Drug reclassification made easy].
In Switzerland, just over 700 veterinary medicinal products are authorized. Nevertheless, in practice veterinarians are often confronted with extraordinary situations in which a suitable veterinary medicinal product is not authorized, unavailable or otherwise not applicable. For livestock and horses in particular, this poses a challenge for pharmacotherapy due to food safety regulations. In these cases, the reclassification assistant can be used to determine whether and how a medicinal product containing the appropriate drug can be reclassified and correctly applied in food-producing animals. The users will be guided step by step with selectable options through the online assistant. If the desired reclassification is permitted in the legal framework, information on the withdrawal periods to be observed for the chosen medicinal product will be provided. This online assistant follows an algorithm based on the reclassification cascade and applicable food safety regulations.


Adaptation of lipid metabolism, tissue composition and flesh quality in gilthead sea bream (Sparus aurata) to the replacement of dietary fish oil by linseed and soyabean oils.
Linseed (LO) and soyabean (SO) oils were evaluated as fish-oil (FO) substitutes in the diets of marketable-sized gilthead sea bream (Sparus aurata). Practical diets were designed factorially with the lipid added as follows (%): FO 100, LO 60+FO 40, LO 80+FO 20, SO 60+FO 40, SO 80+FO 20. The effects of experimental diets on growth, fatty acids patterns in liver and muscle, flesh quality variables and activities of selected enzymes involved in lipid synthesis and catabolism were determined at the end of a 7-month trial. Fatty acid composition of liver and muscle generally reflected the fatty acid composition of the diets. The n-3 PUFA levels were significantly reduced by the inclusion of vegetable oils. This tendency was more pronounced for EPA than for docosahexaenoic acid. The n-3:n-6 fatty acid ratio reached the lowest values in fish fed the SO diets; this was associated with a higher liver lipid deposition. No differences were found in fillet texture and pH. However, under conditions of forced peroxidation, muscles from fish fed the SO diets had lower peroxidation levels. Vegetable oil substitution decreased lipogenesis in liver and this effect was greatest at the highest substitution level. In contrast, muscle beta-oxidation enzymes had increased activities with vegetable oil substitution. Thus, the lower hepatic lipogenesis was correlated with an increased lipid utilisation in muscle. It is concluded that growth and lipid metabolism were affected by experimental diets.


Surface-Controlled Water Flow in Nanotube Membranes.
The independent effect of nanotube surface chemistry and structure on the flow of water under nanoscale confinement is demonstrated in this paper for the first time via the synthesis of novel carbon nitride nanotube (CNNT) membranes. Using a combination of experiments and high-fidelity molecular dynamics (MD) simulations, it is shown here that the hydrophilization of the sp2 carbon structure, induced by the presence of the C-N bonds, decreases the pure water permeance in CNNTs when compared with pristine and turbostratic carbon nanotubes (CNTs). The MD simulations are based on a model true to the chemical structure of the synthesized nanotubes, built from spectroscopy measurements and calibrated potentials using droplet experiments. The effect on permeance is explained in terms of solid-liquid interactions at the nanotube wall with increased water viscosity and decreased surface diffusion near the CNNT wall, when compared to CNTs. A model directly linking the solid-liquid interactions to the water permeance is presented, showing good agreement with both experiments and MD simulations. This work opens the way to tailoring surface chemistry and structure inside nanotube membranes for a wide range of transport and separation processes.


IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling.
IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation. In Th2-dominant inflammatory disorders such as asthma, IL-11 is simultaneously induced. However, the relationship(s) between IL-11 and IL-13 in these responses has not been defined, and the role(s) of IL-11 in the genesis of the tissue effects of IL-13 has not been evaluated. We hypothesized that IL-11, signaling via the IL-11Ralpha-gp130 receptor complex, plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of IL-11, IL-11Ralpha, and gp130 in lungs from wild-type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of IL-11Ralpha on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Ralpha. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Ralpha loci and that these alterations are ameliorated in the absence of IL-11Ralpha. Lastly, they provide insight into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, matrix metalloproteinases, mucin genes, and gob-5 and stimulates and activates TGF-beta1 via IL-11Ralpha-dependent pathways. When viewed in combination, these studies demonstrate that IL-11Ralpha plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.


Calorie intake, olive oil consumption and mammographic density among Spanish women.
High mammographic density (MD) is one of the main risk factors for development of breast cancer. To date, however, relatively few studies have evaluated the association between MD and diet. In this cross-sectional study, we assessed the association between MD (measured using Boyd's semiquantitative scale with five categories: <10%, 10-25%, 25-50%, 50-75% and >75%) and diet (measured using a food frequency questionnaire validated in a Spanish population) among 3,548 peri- and postmenopausal women drawn from seven breast cancer screening programs in Spain. Multivariate ordinal logistic regression models, adjusted for age, body mass index (BMI), energy intake and protein consumption as well as other confounders, showed an association between greater calorie intake and greater MD [odds ratio (OR) = 1.23; 95% confidence interval (CI) = 1.10-1.38, for every increase of 500 cal/day], yet high consumption of olive oil was nevertheless found to reduce the prevalence of high MD (OR = 0.86;95% CI = 0.76-0.96, for every increase of 22 g/day in olive oil consumption); and, while greater intake of whole milk was likewise associated with higher MD (OR = 1.10; 95%CI 1.00-1.20, for every increase of 200 g/day), higher consumption of protein (OR = 0.89; 95% CI 0.80-1.00, for every increase of 30 g/day) and white meat (p for trend 0.041) was found to be inversely associated with MD. Our study, the largest to date to assess the association between diet and MD, suggests that MD is associated with modifiable dietary factors, such as calorie intake and olive oil consumption. These foods could thus modulate the prevalence of high MD, and important risk marker for breast cancer.


[Monoclonal antibodies to Rho(D)-antigen of the Rhesus system. Obtaining the EBV-transformed B-lymphoblastoid human cell lines secreting IgG-anti-D antibodies].
Human B-lymphoblastoid cell lines producing specific anti-D antibodies against Rh0(D) antigen have been established by EBV-transformation. The strong influence of the donor's immune status (serum titer of anti-D antibodies, intravenous booster injection prior to bleeding) is shown. The cell lines cloned by limiting dilution continuously produce anti-D antibodies in culture for 7 months or longer which is sufficient to support large-scale production of anti-D antibodies based on the cultivation of cryopreserved cells. Anti-D IgGl monoclonal antibodies obtained react with Rh-positive and Du cells but not with Rh-negative cells in serological tests. These human monoclonal antibodies could be useful in the prevention of Rh hemolytic disease of newborns.


Secretion of human meprin from intestinal epithelial cells depends on differential expression of the alpha and beta subunits.
Human meprin (N-benzoyl-l-tyrosyl-p-aminobenzoic acid hydrolase, EC 126.96.36.199), an astacin-type metalloprotease, is expressed by intestinal epithelial cells as a dimeric protein complex of alpha and beta subunits. In transfected cells, intracellular proteolytic removal of the membrane anchor from the alpha subunit results in its secretion, while the beta subunit and alpha/beta heterodimers are retained at the cell membrane. We investigated the consequence of differential intracellular processing of alpha and beta subunits in the human small and large intestine using subunit-specific immunohistochemistry, in situ hybridization and biosynthetic studies in organ culture. In the ileum, both subunits localize to the brush-border membrane of villus enterocytes. In contrast, the beta subunit is not expressed in the colon, which leads to the secretion of the alpha subunit. We conclude that differential expression of meprin alpha and beta subunits is a unique means of targeting the proteolytic activity of the alpha subunit either to the brush-border membrane in the ileum or to the lumen in the colon, suggesting dual functions of cell-associated and luminal meprin. Meprin alpha and beta subunits are also coexpressed in distinct lamina propria leukocytes, suggesting an additional role for this protease in leukocyte function in the intestinal mucosa.


Behavior of E. coli with Variable Surface Morphology Changes on Charged Semiconductor Interfaces.
Bacterial behavior is often controlled by structural and composition elements of their cell wall. Using genetic mutant strains that change specific aspects of their surface structure, we modified bacterial behavior in response to semiconductor surfaces. We monitored the adhesion, membrane potential, and catalase activity of the Gram-negative bacterium Escherichia coli (E. coli) that were mutant for genes encoding components of their surface architecture, specifically flagella, fimbriae, curli, and components of the lipopolysaccharide membrane, while on gallium nitride (GaN) surfaces with different surface potentials. The bacteria and the semiconductor surface properties were recorded prior to the biofilm studies. The data from the materials and bioassays characterization supports the notion that alteration of the surface structure of the E. coli bacterium resulted in changes to bacterium behavior on the GaN medium. Loss of specific surface structure on the E. coli bacterium reduced its sensitivity to the semiconductor interfaces, while other mutations increase bacterial adhesion when compared to the wild-type control E. coli bacteria. These results demonstrate that bacterial behavior and responses to GaN semiconductor materials can be controlled genetically and can be utilized to tune the fate of living bacteria on GaN surfaces.


Cast changes: synthetic versus plaster.
A review of the changes in casting since the introduction of improved synthetic casting materials in the 1970s is presented. There is very little in the literature on nursing implications regarding the newer casting materials. Improvements in synthetic materials used in the casting of children include a fiberglass-free, latex-free casting polymer, with child-friendly prints now available. Though the use of synthetic casting predominates the market, plaster of Paris is still the mainstay for serial casting and casting requiring superior moldability and conformability. The advantages and disadvantages of synthetic and plaster of Paris casting, as well as nursing care of the child in each type of cast are summarized.


[Porosome: a new organelle and the universal secretion machine in cells].
A new cell organelle, porosome, discovered in the mid 1990's and its demonstration as the universal secretory machinery in cells is described. In contrast to the generally accepted belief that the secretory vesicle membrane is totally incorporated into the plasma membrane during cell secretion, it has been shown that secretory vesicles transiently dock and fuse with the porosome base via SNARE proteins to expel vesicular contents under intravesicular pressure which is generated by active transport of water through water channels located at the secretory vesicle membrane.


Anticonvulsion effect of acupuncture might be related to the decrease of neuronal and inducible nitric oxide synthases.
To measure the levels of hippocampal nitric oxide synthase isoforms in penicillin induced epilepsy and to test the effect of electroacupuncture (EA) on changes of these levels during epilepsy, we injected penicillin into rat hippocampus to make an epilepsy model and performed electroacupuncture treatment on "Feng Fu" (DU 16) and "Jin Suo" (DU 8) points in Wistar rats. Nitric oxide synthase (NOS) mRNA levels of rat hippocampus were determined by reverse transcription-polymerase chain reaction (RT-PCR). The neuronal nitric oxide synthase (nNOS) mRNA markedly increased (p<0.01) and inducible nitric oxide synthase (iNOS) mRNA significantly emerged during epilepsy, whereas no significant change in epithelial nitric oxide synthase (eNOS) mRNA was observed. EA inhibited the epilepsy and decreased nNOS (p<0.01) and iNOS (p<0.01) correspondingly but had no effect on the amount of eNOS mRNA. The data suggest that penicillin-induced epilepsy caused an increase in nNOS and iNOS, and the EA anticonvulsant effect might be related to the decrease of these nitric oxide synthases.


Thigh grafts: a preferable alternative to catheters when upper extremity access sites are exhausted.
Hemodialysis patients with failed upper extremity (arm) access sites comprise 5-10% of the dialysis population. In these patients, arm vessels are either unsuitable for access placement due to trauma or peripheral vascular disease, or have been exhausted following dialysis usage. Synthetic grafts in the lower extremity (thigh) would benefit these patients, but surgeons are often reluctant to place them, due to concerns of infection and vascular complications. As a result, these patients receive tunneled central venous catheters as their permanent dialysis access. Recent studies have shown, however, that survival and complication rates of thigh grafts are similar to arm grafts and fistulas. Moreover, thigh grafts have lower infection and mortality rates than catheters and provide higher blood flows and dialysis adequacy. In this editorial we argue that thigh grafts are the better option in patients who have lost all arm access sites; they should be placed in preference to tunneled central venous catheters.


Efficient three-dimensional ray-tracing model for electromagnetic propagation prediction in complex indoor environments.
A three-dimensional ray-tracing model for the use of the uniform theory of diffraction and geometrical optics in radio channel characterizations of indoor environments is presented in this paper. Based on the environment information chosen by the proposed modeling approach, the model is effectively applied by utilizing a technique in which multiple reflections, transmissions, and diffractions are considered via the ray-path classification into four different categories. Ray paths belonging to each ray category are determined by using different methods. Our theoretical results are compared with narrowband and wideband measurements. The good agreement with these measurements indicates that our prediction model works well for such indoor communication applications.


The contributions of normal variation and genetic background to mammalian gene expression.
Qualitative and quantitative variability in gene expression represents the substrate for external conditions to exert selective pressures for natural selection. Current technologies allow for some forms of genetic variation, such as DNA mutations and polymorphisms, to be determined accurately on a comprehensive scale. Other components of variability, such as stochastic events in cellular transcriptional and translational processes, are less well characterized. Although potentially important, the relative contributions of genomic versus epigenetic and stochastic factors to variation in gene expression have not been quantified in mammalian species. In this study we compared microarray-based measures of hepatic transcript abundance levels within and between five different strains of Mus musculus. Within each strain 23% to 44% of all genes exhibited statistically significant differences in expression between genetically identical individuals (positive false discovery rate of 10%). Genes functionally associated with cell growth, cytokine activity, amine metabolism, and ubiquitination were enriched in this group. Genetic divergence between individuals of different strains also contributed to transcript abundance level differences, but to a lesser extent than intra-strain variation, with approximately 3% of all genes exhibiting inter-strain expression differences. These results indicate that although DNA sequence fixes boundaries for gene expression variability, there remain considerable latitudes of expression within these genome-defined limits that have the potential to influence phenotypes. The extent of normal or expected natural variability in gene expression may provide an additional level of phenotypic opportunity for natural selection.


Proteomic Identification of eEF1A1 as a Molecular Target of Curcumol for Suppressing Metastasis of MDA-MB-231 Cells.
Curcumol, a major volatile component in Rhizoma Curcumae, exhibits a potent antimetastatic effect on breast cancer cells. However, its molecular mechanism remains poorly understood. In this study, we employed two-dimensional gel electrophoresis-based proteomics to investigate the cellular targets of curcumol in MDA-MB-231 cells and identified 10 differentially expressed proteins. Moreover, Gene Ontology analysis revealed that these proteins are mainly involved in nine types of cellular components, seven different biological processes, and nine kinds of molecular functions, and 35 pathways (p < 0.05) were enriched by KEGG pathway analysis. Specially, eEF1A1, a well-characterized actin binding protein, draws our attention. Curcumol decreased eEF1A1 expression at both mRNA and protein levels. EEF1A1 expression was shown to be correlated with the invasiveness of cancer cells. Importantly, overexpression of eEF1A1 significantly reversed the inhibition of curcumol regarding the invasion and adhesion of MDA-MB-231 cells (p < 0.05). Together, our data suggest that eEF1A1 may be a potential molecular target underlying the antimetastatic effect of curcumol.


Topotecan in advanced colorectal cancer.
Colorectal cancer is the third most common cause of cancer-related death in both men and women. Surgery is the primary form of treatment, with greater than 90% of patients surviving 5 years or more. The remaining patients have metastatic disease, for which treatment options are limited. The fluoropyrimidine, 5-fluorouracil, elicits favorable tumor response rates in patients with metastatic disease, but has little impact on survival. Based on the observation that colorectal tumors have increased levels of topoisomerase I relative to normal tissue, investigations have focused on the camptothecin derivatives, particularly topotecan, as an effective treatment. Topotecan demonstrated antitumor activity in preclinical studies, causing significant growth delay of xenografts in thymectomized, irradiated mice. Clinical studies with topotecan have not yielded as promising results, with response rates of approximately 7% to 10%, but modifications in dosing schedule or combinations with other agents may enhance antitumor activity.


Development of drugs for Epstein-Barr virus using high-throughput in silico virtual screening.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ∼ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases. In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease. The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process. Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease.


An exploration of women's reasons for termination timing in the setting of fetal abnormalities.
Over 3% of pregnancies are complicated by a fetal abnormality, of which, approximately 80% are terminated. Despite early screening options, women often present at the cusp of legal limits for termination. A qualitative study was conducted with women terminating pregnancies for fetal abnormalities. Semi-structured interviews explored reasons for termination timing. Analysis utilized latent content and constant comparative methods. Of 30 participants between 13+4 and 23+5 weeks gestation, their median age was 35 years, 73.3% were white, 70% were religiously affiliated, and 60% had children. The median time from abnormality identification until termination was 16.5 days (range 2-73). The major themes for termination timing included (1) an abrupt shift in "low-risk" pregnancy perception; (2) challenging medical interactions; (3) an emotional decision-making process; and (4) termination access barriers. Timing of termination for fetal abnormalities is attributable to multiple issues. Future research should identify optimal prenatal counseling strategies, address systemic barriers, and identify patient decision-making resources.


Aerobic fitness, not energy expenditure, influences subsequent increase in adiposity in black and white children.
Low levels of energy expenditure and aerobic fitness have been hypothesized to be risk factors for obesity. Longitudinal studies to determine whether energy expenditure influences weight gain in whites have provided conflicting results. To date, no studies have examined this relationship in blacks or whether aerobic fitness influences weight gain in white or black children. One hundred fifteen children, 72 white (55 girls and 17 boys) and 43 black (24 girls and 19 boys) were recruited for this study. Aerobic fitness, resting, total, and activity-related energy expenditure and body composition were measured at baseline. The children returned annually for 3 to 5 repeated measures of body composition. The influence of the initial measures of energy expenditure and fitness on the subsequent rate of increase in adiposity was examined, adjusting for initial body composition, age, ethnicity, gender, and Tanner stage. Because 20 children did not attain maximum oxygen consumption, the sample size for the combined analysis was 95. Initial fat mass was the main predictor of increasing adiposity in this cohort of children, with greater initial fat predicting a higher rate of increase of adiposity. There was also a significant negative relationship between aerobic fitness and the rate of increasing adiposity (F(1,82) = 3.92). With every increase of.1 L/minute of fitness, there was a decrease of.081 kg fat per kg of lean mass gained. None of the measures of energy expenditure significantly predicted increasing adiposity in white or black children. Initial fat mass was the dominant factor influencing increasing adiposity; however, aerobic fitness was also a significant independent predictor of increasing adiposity in this cohort of children. Resting, total, or activity-related energy expenditure did not predict increasing adiposity. It seems that aerobic fitness may be more important than absolute energy expenditure in the development of obesity in white or black children. energy expenditure, fitness, longitudinal, obesity.


Repeat cycles of rituximab on clinical relapse in ANCA-associated vasculitis: identifying B cell biomarkers for relapse to guide retreatment decisions.
To assess clinical and B cell biomarkers to predict relapse after rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using retreatment on clinical relapse strategy. 35 patients with AAV received treatment with 2×1000 mg rituximab, repeated on clinical relapse (up to 5 cycles). Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS) and peripheral B cell subsets using highly sensitive flow cytometry (HSFC) as previously described; both performed at baseline and every 3 months. Response rates were high: >83%, with median time-to-relapse of 82 weeks for cycle 1 (C1) and >54 weeks for all cycles. Prior to rituximab, AAV was characterised by naïve B-lymphopenia compared to healthy controls. This dysregulation was more marked in patients with raised C-reactive protein (CRP) (p<0.05). In C1, no clinical feature predicted relapse. However, repopulation of naïve B cell at 6 months was associated with a reduced risk of relapse (HR: 0.326, 95% 0.114 to 0.930, p=0.036). Relapse rates at 12 and 18 months were 0% and 14% with naïve repopulation at 6 months, and 31% and 54% without naïve repopulation. Responses to B cell depletion therapy are long-lasting and relapse post-treatment may be predicted by absence of naïve B cell repopulation at 6 months. Naïve B-lymphopenia may be a biomarker of disease activity in AAV.


Care coordination in managed care. Creating a quality continuum for high risk elderly patients.
The portion of the American population 65 years and older is growing rapidly, and the group 85 years and older is the largest growing segment of our population. The country's largest health maintenance organization, Kaiser Permanente, in Fontana, California, experienced a 9% growth in its membership between 1996 and 1997. Following the Kaiser national Model of Care recommendations, Fontana's Kaiser Permanente created their department of Extended Care Services and implemented programs that coordinated patient care across the continuum to meet the needs of its members who were 65 years and older. The programs included new member screening and orientation, telephonic care coordination, and a volunteer-based care call program. They also developed a medical management model that included a consultative geriatric assessment clinic and a primary care clinic as well as provision of team-based care to members residing in skilled nursing facilities.


Propofol Affects Cortico-Hippocampal Interactions via β3 Subunit-Containing GABAA Receptors.
General anesthetics depress neuronal activity. The depression and uncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However, the molecular targets involved in this process are not fully characterized. GABAA receptors, especially the type with β3 subunits, represent a main molecular target of propofol. We therefore hypothesized that GABAA receptors with β3 subunits mediate the propofol-induced disturbance of cortico-hippocampal interactions. We used local field potential (LFP) recordings from chronically implanted cortical and hippocampal electrodes in wild-type and β3(N265M) knock-in mice. In the β3(N265M) mice, the action of propofol via β3subunit containing GABAA receptors is strongly attenuated. The analytical approach contained spectral power, phase locking, and mutual information analyses in the 2-16 Hz range to investigate propofol-induced effects on cortico-hippocampal interactions. Propofol caused a significant increase in spectral power between 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in the β3(N265M) mutant. Propofol strongly decreased phase locking of 6-12 Hz oscillations in wild-type mice. This decrease was attenuated in the β3(N265M) mutant. Finally, propofol reduced the mutual information between 6-16 Hz in wild-type mice, but only between 6 and 8 Hz in the β3(N265M) mutant. GABAA receptors containing β3 subunits contribute to frequency-specific perturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions of propofol.


Ultrastructural characteristics, biological activity and pharmacological relevance of synthetic malaria pigment (beta-haematin).
Malaria pigment (haemozoin, HZ) is the detoxification product of haemoglobin-derived haem of intraerythrocytic malaria parasites. At schizont rupture, haemozoin accumulates inside host phagocytic cells. The chemical structure and the spectroscopic characteristics of haemozoin are identical to those of beta-haematin (BH), a synthetic pigment obtained from Ferriprotoporphyrin IX (Fe (III) PPIX) in acidic conditions. The process of BH formation is the target of quinoline antimalarials. Here, we summarise the results of our studies on the ultrastructural characteristics, biological and pharmacological relevance of synthetic vs. native haemozoin. 1) By electron microscopy, native HZ and synthetic BH appear as dark brown crystals, morphologically indistinguishable and are internalised by phagocytes at the same extent. 2) Both HZ and BH modulate the production of cytokines (TNF and NO) and increase the susceptibility to lipid peroxidation of mouse or human phagocytes. The antioxidant status of the phagocytes regulates the susceptibility to BH/HZ-mediated effects. 3) The process of BH formation from Fe(III)PPIX, hence haem detoxification, can be inhibited by electrochemically-reduced, Fe(II)PPIX molecules. Maintaining iron in the reduced state can thus be considered a new pharmacological target. This was confirmed by the observation that thiol-reducing agents (NAC, cystein) were able to inhibit BH formation and were toxic to parasites in vitro.