Prediagnostic Proinflammatory Dietary Potential Is Associated with All-Cause Mortality among African-American Women with High-Grade Serous Ovarian Carcinoma.
Chronic inflammation is associated with ovarian carcinogenesis; yet, the impact of inflammatory-related exposures on outcomes has been understudied. Given the poor survival of women diagnosed with ovarian cancer, especially African-Americans, we examined whether diet-associated inflammation, a modifiable source of chronic systemic inflammation measured by the dietary inflammatory index (DII), was associated with all-cause mortality among African-American women with ovarian carcinoma. Data were available from 490 ovarian carcinoma patients enrolled in a population-based case-control study of African-American women with ovarian cancer, the African-American Cancer Epidemiology Study. Energy-adjusted DII (E-DII) scores were calculated based on prediagnostic dietary intake of foods alone or foods and supplements, which was self-reported using the 2005 Block Food Frequency Questionnaire. Cox proportional hazards regression was used to estimate risk of mortality overall and for the most common histotype, high-grade serous carcinoma. Additionally, we assessed interaction by age at diagnosis and smoking status. Women included in this study had a median age of 57 y, and the majority of women were obese (58%), had late-stage disease (Stage III or IV, 66%), and had high-grade serous carcinoma (64%). Greater E-DII scores including supplements (indicating greater inflammatory potential) were associated with an increased risk of mortality among women with high-grade serous carcinoma (HR1-unit change: 1.08; 95% CI: 1.01, 1.17). Similar associations were observed for the E-DII excluding supplements, although not statistically significant (HR1-unit change: 1.07; 95% CI: 0.97, 1.17). There was an interaction by smoking status, where the positive association with mortality was present only among ever smokers (HRQuartile 4/Quartile 1: 2.36; 95% CI: 1.21, 4.60) but not among never smokers. Greater inflammatory potential of prediagnostic diet may adversely impact prognosis among African-American women with high-grade serous carcinoma, and specifically among ever smokers.


The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with weight changes in obese Japanese men: a 4-year follow-up study.
The aim of this study was to investigate whether the Trp64Arg polymorphism of the beta(3)-adrenergic receptor gene (ADRB3) is associated with weight changes in obese Japanese men at 4-year follow-up. The participants were 145 obese Japanese men [age: 35.8+/-5.3 y; body mass index (BMI): 27.5+/-3.3 kg/m(2)]. The participants were divided into two groups according to the Trp64Arg genotype: (1) with the Arg64 allele of the ADRB3 (Trp64Arg and Arg64Arg genotypes, n=50); (2) without the Arg64 allele of the ADRB3 (Trp64Trp genotype, n=95). The ADRB3 genotyping was performed by denaturing high performance liquid chromatography (DHPLC). Body weight, BMI, and blood pressure were determined at baseline and at 4 years. After 4 years, the participants with the Arg allele of the ADRB3 significantly increased their body weight (2.1+/-4.7 kg, p=0.002) and BMI (0.64+/-1.6 kg/m(2), p=0.006) whereas the participants without the Arg allele of the ADRB3 did not significantly change in these parameters (body weight: -0.36+/-4.2 kg, p=0.41; BMI: -0.24+/-1.5 kg/m(2), p=0.12). The results in this study showed that the Arg allele of the ADRB3 is associated with long-term changes in body weight in obese individuals. This polymorphism may become an indicator in personalized weight loss programs in obese men.


Turkish female immigrants' intentions to participate in preconception carrier screening for hemoglobinopathies in the Netherlands: an empirical study.
Preconception carrier screening for hemoglobinopathies (HbPs) is debated in the Netherlands. Intentions to participate in preconception carrier screening for HbPs as well as informed reproductive options were assessed in 109 Turkish female immigrants. Participants completed a structured questionnaire. 83.5% of 109 Turkish female immigrants intended to participate in preconception carrier screening. Intention to participate was related to the desire to reduce uncertainty about having offspring affected by HbPs, but not with socio-demographic variables, risk-estimation and worrying. If the tests concerning carrier status for HbPs were confirmative for both partners, 36.3% (n = 33) of the women with the intention of preconception carrier screening would refrain from getting children of their own, including 14.3% (n = 13) opting for adoption, 37.4% (n = 34) would decide to become pregnant and to opt for prenatal testing on HbPs. Finally, among 37.4% of the women opting for prenatal testing, 30.3% (n = 10) would terminate an affected pregnancy, 18.2% (n = 6) not and 51.5% (n = 17) could not decide (1 missing value). A large majority of Turkish female immigrants would participate in preconception carrier screening for HbPs.


Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebo-controlled trial.
Live probiotic bacteria and dietary prebiotic oligosaccharides (together termed synbiotics) increasingly are being used in infancy, but evidence of long-term safety is lacking. In a randomized, placebo-controlled, double-blind trial, we studied the safety and long-term effects of feeding synbiotics to newborn infants. Between November 2000 and March 2003, pregnant mothers carrying infants at high risk for allergy were randomly assigned to receive a mixture of 4 probiotic species (Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii ssp shermanii) or a placebo for 4 weeks before delivery. Their infants received the same probiotics with 0.8 g of galactooligosaccharides, or a placebo, daily for 6 months after birth. Safety data were obtained from clinical examinations and interviews at follow-up visits at ages 3, 6, and 24 months and from questionnaires at ages 3, 6, 12, and 24 months. Growth data were collected at each time point. Of the 1018 eligible infants, 925 completed the 2-year follow-up assessment. Infants in both groups grew normally. We observed no difference in neonatal morbidity, feeding-related behaviors (such as infantile colic), or serious adverse events between the study groups. During the 6-month intervention, antibiotics were prescribed less often in the synbiotic group than in the placebo group (23% vs 28%). Throughout the follow-up period, respiratory infections occurred less frequently in the synbiotic group (geometric mean: 3.7 vs 4.2 infections). Feeding synbiotics to newborn infants was safe and seemed to increase resistance to respiratory infections during the first 2 years of life.


Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial.
Postoperative atrial arrhythmias are common and are associated with considerable morbidity. This study was designed to evaluate the efficacy and safety of vernakalant for the conversion of atrial fibrillation (AF) or atrial flutter (AFL) after cardiac surgery. This was a prospective, randomized, double-blind, placebo-controlled trial of vernakalant for the conversion of AF or AFL after coronary artery bypass graft, valvular surgery, or both. Patients were randomly assigned 2:1 to receive a 10-minute infusion of 3 mg/kg vernakalant or placebo. If AF or AFL was present after a 15-minute observation period, then a second 10-minute infusion of 2 mg/kg vernakalant or placebo was given. The primary end point was the conversion of postcardiac surgery AF or AFL to sinus rhythm within 90 minutes of dosing. In patients with AF, 47 of 100 (47%) who received vernakalant converted to SR compared with 7 of 50 (14%) patients who received placebo (P<0.001). The median time to conversion was 12 minutes. Vernakalant was not effective in converting postoperative AFL to sinus rhythm. Two serious adverse events occurred within 24 hours of vernakalant administration (hypotension and complete atrioventricular block). There were no cases of torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation. There were no deaths. Vernakalant was safe and effective in the rapid conversion of AF to sinus rhythm in patients who had AF after cardiac surgery. clinicaltrials.gov. Identifier: NCT00125320.


Microtubule Imaging Reveals Cytoskeletal Deficit Predisposing the Retinal Ganglion Cell Axons to Atrophy in DBA/2J.
Glaucoma is characterized by progressive loss of the retinal ganglion cells (RGCs) and their axons. Here we test an outstanding notion that microtubules (MTs) within RGC axons degrade before the loss of morphology ("MT hypothesis"). The integrity of axonal MTs was interrogated by intrinsic second-harmonic generation (SHG) microscopy. Using DBA/2J mice as a model of glaucoma and DBA/2J-Gpnmb+ as a nonglaucomatous control, the relationship between MT disruption and morphology was quantitatively examined as a function of age and sex in the fresh retinal wholemounts. The mean SHG density (i.e., the mean SHG intensity per thickness) was significantly lower in DBA/2J than in DBA/2J-Gpnmb+ and also depended on sex and age. The loss of SHG density, indicating MT disruption within intact RGC axons, occurred in a sectorial manner near the loss of the retinal nerve fiber bundles. The decay rate of SHG density was approximately 97% higher than that of thickness. Collectively, the results indicate that the breakdown of MTs is pathology of glaucoma and likely a precursor of morphological atrophy. Based on a new finding that SHG density is highly variable and spatially discrete, a new model of RGC degeneration is proposed. This study validates SHG retinal imaging for elucidating the role and mechanism of MT deficiency in the course of glaucoma pathogenesis.


Novel nanofiberous membrane fabricated via electrospinning of wastage fuzzes of mechanized carpet used for dye removal of the carpet dyeing wastewater.
Novel nanofibrous membrane was fabricated by using electrospinning of wastage fuzzes of mechanized carpet which was used to remove the dye of the textile wastewater. SEM images showed that nanofibers with average diameters of 200 nm were successfully fabricated by electrospinning technique. The physicochemical properties of electrospun nanofiberous membranes were studied by differential scanning calorimetry (DSC), energy-dispersive X-ray (EDX), and Fourier transform infrared (FTIR) spectroscopy. FTIR confirmed the presence of C≡N, C=N, and C‒N groups in the electrospun nanofibers which are the main functional groups of polyacrilonitrile (PAN). The resulting membrane showed dye retention of 96% of carpet dyeing wastewater, demonstrating the high separation potential of such membrane for wastewater treatment. We believe that simple approaches such as the present one would open up enormous possibilities in effective uses of wastage fuzzes of textile industry, considering the fact that electrospinning is a cost-effective method for the mass scale production of nanofibers.


Patient-physician communication about end-of-life care for patients with severe COPD.
Since patients with chronic obstructive pulmonary disease (COPD) infrequently discuss treatment preferences about end-of-life care with physicians, the goal of the present study was to identify which specific areas of communication about end-of-life care occur between patients with severe COPD and their physicians, and how patients rate the quality of this communication. A total of 115 patients with oxygen-dependent COPD, identified in pulmonary clinics in three hospitals and through an oxygen delivery company, were enrolled in this study. A 17-item quality of communication questionnaire (QOC) was administered to patients, along with other measures, including satisfaction with care. The patients reported that most physicians do not discuss how long the patients have to live, what dying might be like or patients' spirituality. Patients rated physicians highly at listening and answering questions. Areas patients rated relatively low included discussing prognosis, what dying might be like and spirituality/religion. Patients' assessments of physicians' overall communication and communication about treatment correlated well with the QOC. Patients' overall satisfaction with care also correlated significantly with the QOC. In conclusion, this study identifies areas of communication that physicians do not address and areas that patients rate poorly, including talking about prognosis, dying and spirituality. These areas may provide targets for interventions to improve communication about end-of-life care for patients with chronic obstructive pulmonary disease. Future studies should determine the responsiveness of these items to interventions, and the effect such interventions have on patient satisfaction and quality of care.


Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species.
Dendritic cells (DCs) are professional antigen-presenting cells that hold great therapeutic potential. Multiple DC subsets have been described, and it remains challenging to align them across tissues and species to analyze their function in the absence of macrophage contamination. Here, we provide and validate a universal toolbox for the automated identification of DCs through unsupervised analysis of conventional flow cytometry and mass cytometry data obtained from multiple mouse, macaque, and human tissues. The use of a minimal set of lineage-imprinted markers was sufficient to subdivide DCs into conventional type 1 (cDC1s), conventional type 2 (cDC2s), and plasmacytoid DCs (pDCs) across tissues and species. This way, a large number of additional markers can still be used to further characterize the heterogeneity of DCs across tissues and during inflammation. This framework represents the way forward to a universal, high-throughput, and standardized analysis of DC populations from mutant mice and human patients.


Contralateral Prophylactic Mastectomy in Patients with Breast Cancer.
Introduction: The rate of contralateral prophylactic mastectomy (CPM) increased within the recent years. The main reasons are: genetic testing, availability of breast reconstruction, more often use of preoperative breast MRI, improvement of postoperative aesthetic results and reimbursement of breast reconstruction. The purpose of this study was to analyze the indication of CPM, it's evolution and the surgical techniques used for this type of surgery. Materials and methods: This prospective study enrolled patients with unilateral breast cancer for which conservative treatment was not an option and underwent CPM concomitant with therapeutic mastectomy, using different techniques, followed by immediate breast reconstruction using alloplastic materials. Results: A total of 45 patients with unilateral breast cancer underwent therapeutic mastectomy and CPM followed by immediate breast reconstruction, between January 2015-December 2020. The mean age was 43.5 years, 64,44% patients had stage I and II breast cancer and 22,22% were triplenegative. The indications for CPM were: pathogenic mutation of BRCA or of other genes associated with high risk of breast cancer, strong family history, suspicious findings on breast MRI, extended micro-calcifications, dense breasts, and extreme anxiety. Conclusions: A growing rate of bilateral mastectomy for unilateral breast cancer was observed. Availability of immediate breast reconstruction and reimbursement plays an important role for patients in choosing CPM. Factors associated with CPM include: young age, pathogenic BRCA mutation, significant family history and triple-negative disease. The rate of immediate postoperative complications was low. CPM is a valid option to reduce the risk of contralateral breast cancer and to achieve a good aesthetic outcome for patients with unilateral breast cancer with high risk of contralateral breast cancer.


Intercalation of collagen and soybean peptides into Zn-Al layered double hydroxide.
In order to develop a new type biocompatible organic/inorganic nanohybrid material, an intercalation of collagen peptides (CP) and soybean peptide (SP) into Zn-Al layered double hydroxide (LDH) by the coprecipitation reaction has been investigated. The peptide/LDH has been characterized by chemical analysis, powder X-ray diffraction (XRD), Raman spectroscopy, thermal gravimetric analysis (TG) and transmission electron microscopy (TEM). According to the XRD patterns and Raman spectra, the solid products were found to contain peptide and to show broad diffraction peaks with LDH structures. The CP/LDH and SP/LDH possess the expanding LDH structure, d(00l) = 2-3 nm, confirming that both peptides were intercalated into the LDH interlayer space with low organized stacking arrangement.


Atrazine-selective polymers prepared by molecular imprinting of trialkylmelamines as dummy template species of atrazine
Synthetic polymer receptors selective for atrazine have been prepared by molecular imprinting using trialkylmelamines as template molecules in place of atrazine. Trialkylmelamines were shown to be useful as templates for introducing affinity for atrazine into ethylene glycol dimethacrylate-methacrylic acid copolymers. The polymers showed the selective binding capacity for triazine herbicides including atrazine, whereas agrochemicals in other categories were not adsorbed to the imprinted polymers. The group selectivity demonstrated was comparable with that of the original atrazine imprinted polymers. Use of the nonagrochemical template molecules as a substitution to atrazine has made it possible to synthesize herbicide-receptor polymers free from troubles caused by analyte contaminants, which are desired for analytical applications.


The biology of long-term bone marrow cultures and its application to bone marrow transplantation.
Long-term bone marrow cultures have been applied to the study and to the treatment of hemopoietic disease. The incidence of murine primitive (stem) cells with the ability to repopulate irradiated bone morrow stroma is similar to that of cells able to repopulate the hemopoietic system of potentially lethally irradiated mice. In human bone marrow, cells with in vitro repopulating ability have been estimated as 0.5% to 1% of the CD34+ cells. The increase in primitive cells in the circulation seen after administration of growth factors has been exploited by harvesting those cells for use together with bone marrow in autologous transplants. The ability of primitive cells (harvested after granulocyte colony-stimulating factor plus chemotherapy) to reconstitute irradiated marrow stromas indicates that their repopulation capacity in vitro is at least as good as that of bone marrow. This is confirmed by experimental data in mice showing that small volumes of peripheral blood (after granulocyte colony-stimulating factor administration) are capable of long-term repopulation. The regulator capacity of marrow stroma has been exploited to purge bone marrow cultures from patients with acute myeloblastic leukemia in first remission and from treated patients with chronic myelogenous leukemia before using the cultured cells for autologous transplant. The results to date, although preliminary, indicate a role for this methodology in the treatment of leukemia.


Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety.
To provide primary care clinicians with a better understanding of management issues in posttraumatic stress disorder (PTSD) and guide clinical practice with recommendations on the appropriate management strategy. The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty invited by the chair were Edna B. Foa, Ronald C. Kessler, Alexander C. McFarlane, and Arieh Y. Shalev. The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles. Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. PTSD is often a chronic and recurring condition associated with an increased risk of developing secondary comorbid disorders, such as depression. Selective serotonin reuptake inhibitors are generally the most appropriate choice of first-line medication for PTSD, and effective therapy should be continued for 12 months or longer. The most appropriate psychotherapy is exposure therapy, and it should be continued for 6 months, with follow-up therapy as needed.


Autoimmune Hypothyroidism As a Predictor of Mortality in Chronic Hypersensitivity Pneumonitis.
Chronic hypersensitivity pneumonitis (CHP) is a fibrotic parenchymal lung disease that occurs when inhalation of environmental antigens leads to immune dysregulation. Autoimmune features have recently been identified as potentially important among patients with CHP. However, the relationship between hypothyroidism (HT) and CHP is unknown. In this study, we investigate the prevalence and impact of HT among patients with CHP. We conducted a retrospective, case-control analysis. We identified 121 patients at the University of Chicago Interstitial Lung Disease Center with a multidisciplinary diagnosis of CHP. These patients were matched 3:1 according to age, sex, and race to 363 control subjects with asthma from 2006 to 2015. We analyzed demographics, clinical characteristics, and survival between both groups and assessed the relationship of HT with CHP. Survival analysis was performed using Cox proportional hazards modeling. Patients with CHP had higher prevalence of HT (25.6%, n = 31) compared to controls (10.7%, n = 39; OR, 2.86; 95% CI, 1.62-4.99; P < 0.0001). Compared to CHP alone, patients with CHP/HT were more likely to be female (80.6 vs 51.1%, P = 0.004), have increased incidence of autoimmune disease (19.4 vs 3.3%, P = 0.009), antinuclear antibody seropositivity (80.6 vs 57.0%, P = 0.019), and higher TSH levels (4.0 vs 1.9 mIU/L, P < 0.0001). HT was a significant independent predictor of mortality among CHP patients with seropositive ANA (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). HT is common in patients with CHP and may carry prognostic significance in patients with features of autoimmunity. Further research exploring common pathogenic pathways between autoimmune HT and CHP may illuminate the association of HT with survival.


How calling emerges and develops during COVID-19: a qualitative study of medical students.
The presence of calling in medicine has been shown to be related to a preponderance of positive outcomes among medical students. However, only a few studies examined the antecedents of calling. Of this group, little is known about how a calling emerges and develops in a crisis situation. This study examines the processes underlying the emergence and development of calling when confronted with COVID-19. Semi-structured interviews were conducted with medical students (N = 28) from China from February to March 2020. Medical students reported their experiences about the emergence of calling, its antecedents, and its outcomes in the context of the COVID-19 pandemic. Interviews were transcribed and analyzed using a thematic analysis approach. Four main themes were identified: (1) the definition of calling, (2) the trajectories of calling development, (3) the factors leading to the emergence of calling, and (4) the outcomes of the emergence of calling. Medical students conceptualized calling as both self- and other-oriented regarding serving the common good. Three calling paths were revealed: significantly enhanced, growing out of nothing, and remaining unchanged. Work sense-making and identity formation interact to facilitate the emergence of calling. The emergence of a calling affects career and study-related outcomes. Our findings advance the concept of how the calling of medical students emerges and develops in response to life events through work sense-making and identity formation. Academic institutions and medical educators could leverage these events to facilitate calling discernment among medical students.


The creation and physiological relevance of divergent hydroxylation patterns in the flavonoid pathway.
Flavonoids and biochemically-related chalcones are important secondary metabolites, which are ubiquitously present in plants and therefore also in human food. They fulfill a broad range of physiological functions in planta and there are numerous reports about their physiological relevance for humans. Flavonoids have in common a basic C(6)-C(3)-C(6) skeleton structure consisting of two aromatic rings (A and B) and a heterocyclic ring (C) containing one oxygen atom, whereas chalcones, as the intermediates in the formation of flavonoids, have not yet established the heterocyclic C-ring. Flavonoids are grouped into eight different classes, according to the oxidative status of the C-ring. The large number of divergent chalcones and flavonoid structures is from the extensive modification of the basic molecules. The hydroxylation pattern influences physiological properties such as light absorption and antioxidative activity, which is the base for many beneficial health effects of flavonoids. In some cases antiinfective properties are also effected.


Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.
E75 is an immunogenic peptide from the HER2/neu protein, which is overexpressed in many breast cancer patients. We have conducted two overlapping E75 vaccine trials to prevent recurrence in node-positive (NP) and node-negative (NN) breast cancer patients. E75 (HER2/neu 369-377) + granulocyte macrophage colony-stimulating factor was given intradermally to previously treated, disease-free NP breast cancer patients in a dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented. One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91). Human leucocyte antigen A2 (HLA-A2) and HLA-A3 patients were vaccinated (n = 101), whereas all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a dose-dependent immunologic response to the vaccine was shown. Planned primary analysis revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls (P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus 14.8%); however, a significant difference in the pattern of recurrence persisted. E75 is safe and effective in raising a dose-dependent HER2/neu immunity in HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These findings warrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster to prevent breast cancer recurrences.


Plasma leptin concentrations correlate with luteinizing hormone secretion in early postpartum Holstein cows.
We tested the hypothesis that hypothalamic-pituitary activity, bioassayed by LH pulse frequency, in dairy cattle during early lactation is related to measures of energy status and to circulating profiles of free fatty acids (FFA), insulin, insulin-like growth factor-I (IGF-I), leptin, and growth hormone (GH). On d 14 postpartum, before first ovulation and during the period of negative energy balance (-23.4 +/- 2.4 Mcal/d of metabolizable energy), blood plasma was sampled from 18 multiparous cows at 10-min intervals for 8 h. All samples were assayed for LH and GH and hourly samples were assayed for FFA, insulin, IGF-I, and leptin. Milk yield and composition, body condition score, and energy balance were also measured. Frequency of LH pulses was correlated positively with energy balance (r = 0.51) and plasma leptin concentrations (r = 0.73), and negatively with milk fat content (r = -0.52). Amplitude of the LH pulses was correlated only with leptin (r = 0.53). Frequency of GH pulses was not correlated with any measure of LH secretion, but was correlated negatively with plasma concentrations of insulin (r = -0.62) and IGF-I (r = -0.61). First ovulation was observed 34 +/- 4 d after parturition. These observations reveal an important linkage between pulsatile LH secretion and blood leptin concentrations during the early postpartum period in dairy cows, when their energy balance is negative, and may explain the delay in ovulation.


Research in trauma.
Successful research in clinical trauma requires the researcher to be exposed to many injured patients, have a personal commitment to research conducted at inconvenient hours and be inquisitive so as to identify clinical problems that need scientific answers. Once initiated, a research project necessitates the collection and storage of clinical data on a weekly basis before patient discharge. A computer data program facilitates later retrieval and statistical analysis. Departmental support of the clinical investigator is mandatory. Although the personal commitments for producing first-rate clinical research may seem excessive, the rewards are commensurate.


Yeast functional genomic screens lead to identification of a role for a bacterial effector in innate immunity regulation.
Numerous bacterial pathogens manipulate host cell processes to promote infection and ultimately cause disease through the action of proteins that they directly inject into host cells. Identification of the targets and molecular mechanisms of action used by these bacterial effector proteins is critical to understanding pathogenesis. We have developed a systems biological approach using the yeast Saccharomyces cerevisiae that can expedite the identification of cellular processes targeted by bacterial effector proteins. We systematically screened the viable yeast haploid deletion strain collection for mutants hypersensitive to expression of the Shigella type III effector OspF. Statistical data mining of the results identified several cellular processes, including cell wall biogenesis, which when impaired by a deletion caused yeast to be hypersensitive to OspF expression. Microarray experiments revealed that OspF expression resulted in reversed regulation of genes regulated by the yeast cell wall integrity pathway. The yeast cell wall integrity pathway is a highly conserved mitogen-activated protein kinase (MAPK) signaling pathway, normally activated in response to cell wall perturbations. Together these results led us to hypothesize and subsequently demonstrate that OspF inhibited both yeast and mammalian MAPK signaling cascades. Furthermore, inhibition of MAPK signaling by OspF is associated with attenuation of the host innate immune response to Shigella infection in a mouse model. These studies demonstrate how yeast systems biology can facilitate functional characterization of pathogenic bacterial effector proteins.


Central analgesic activity of the aqueous and ethanolic extracts of the leaves of Albizia lebbeck: role of the GABAergic and serotonergic pathways.
Albizia lebbeck Benth. is extensively used in Indian traditional medicine for treating several painful and inflammatory disorders. The possible central analgesic activity and the underlying mechanism of action of the aqueous (AE) and ethanolic extracts (EE) of the leaves of A. lebbeck were investigated in Wistar rats using Eddy's hot plate and the tail flick tests. In order to investigate the underlying mechanism of action, rats were pretreated with naloxone, bicuculline or methysergide and then were administered a per os (p.o.) dose of AE or EE. AE and EE caused a significant (p<0.05) elevation in the mean basal reaction time in the hot plate method and an increase in the latency time in the tail flick method. In rats pretreated with bicuculline and methysergide, a significant (p<0.05) reduction in the analgesic activity was observed in comparison to AE and EE. Thus, AE and EE exhibited significant central analgesic activity and act possibly via the GABAergic and serotonergic pathways. The flavonoids and saponins found in the leaves could be responsible for the observed effect.


Lung magnetic resonance imaging with diffusion weighted imaging provides regional structural as well as functional information without radiation exposure in primary antibody deficiencies.
Primary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique. Prospective evaluation of 18 patients with Common Variable Immunodeficiency and X-linked Agammaglobulinemia. On the same day, patients underwent Magnetic Resonance Imaging with Diffusion Weighted Imaging sequences, High Resolution Computerized Tomography and Pulmonary Function Tests, including diffusing capacity factor for carbon monoxide. Images were scored using a modified version of the Bhalla scoring system. Magnetic Resonance Imaging was non-inferior to High Resolution Computerized Tomography in the capacity to identify bronchial and parenchymal abnormalities. HRCT had a higher capacity to identify peripheral airways abnormalities, defined as an involvement of bronchial generation up to the fifth and distal (scores 2-3). Bronchial scores negatively related to pulmonary function tests. One third of consolidations and nodules had Diffusion Weighted Imaging restrictions associated with systemic granulomatous disease and systemic lymphadenopathy. Lung Magnetic Resolution Imaging detected an improvement of bronchial and parenchymal abnormalities, in recently diagnosed patients soon after starting Ig replacement. Magnetic Resonance Imaging with Diffusion Weighted Imaging was a reliable technique to detect lung alterations in patients with Primary Antibody Deficiencies.


High Throughput Procedure for Comparative Analysis of In Vivo Cardiac Glucose or Amino Acids Use in Cardiovascular Pathologies and Pharmacological Treatments.
The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of methods to investigate changes in substrates' use in cardiac metabolism in vivo are complex and not suitable for high throughput testing necessary to understand and reverse these pathologies. Thus, this study aimed to develop a simple method that would allow for the analysis of cardiac metabolic substrate use. The developed methods involved the subcutaneous injection of stable 13C isotopomers of glucose, valine, or leucine with mass spectrometric analysis for the investigation of its entry into cardiac metabolic pathways that were deducted from 13C alanine and glutamate enrichments in heart extracts. The procedures were validated by confirming the known effects of treatments that modify glucose, free fatty acids, and amino acid metabolism. Furthermore, we studied changes in the energy metabolism of CD73 knock-out mice to demonstrate the potential of our methods in experimental research. The methods created allowed for fast estimation of cardiac glucose and amino acid use in mice and had the potential for high-throughput analysis of changes in pathology and after pharmacological treatments.


Fast free-vibration modal analysis of 2-D physics-based deformable objects.
This paper presents an accurate, very fast approach for the deformations of two-dimensional physically based shape models representing open and closed curves. The introduced models are much faster than other deformable models (e.g., finite-element methods). The approach relies on the determination of explicit deformation governing equations that involve neither eigenvalue decomposition, nor any other computationally intensive numerical operation. The approach was evaluated and compared with another fast and accurate physics-based deformable shape odel, both in terms of deformation accuracy and computation time. The conclusion is that the introduced model is completely accurate and is deformed very fast on current personal computers (Pentium III), achieving more than 380 contour deformations per second.


Contradictory Effects of Superoxide and Hydrogen Peroxide on KCa3.1 in Human Endothelial Cells.
Reactive oxygen species (ROS) are generated in various cells, including vascular smooth muscle and endothelial cells, and regulate ion channel functions. KCa3.1 plays an important role in endothelial functions. However, the effects of superoxide and hydrogen peroxide radicals on the expression of this ion channel in the endothelium remain unclear. In this study, we examined the effects of ROS donors on KCa3.1 expression and the K(+) current in primary cultured human umbilical vein endothelial cells (HUVECs). The hydrogen peroxide donor, tert-butyl hydroperoxide (TBHP), upregulated KCa3.1 expression, while the superoxide donors, xanthine/xanthine oxidase mixture (X/XO) and lysopho-sphatidylcholine (LPC), downregulated its expression, in a concentration-dependent manner. These ROS donor effects were prevented by antioxidants or superoxide dismustase. Phosphorylated extracellular signal-regulated kinase (pERK) was upregulated by TBHP and downregulated by X/XO. In addition, repressor element-1-silencing transcription factor (REST) was downregulated by TBHP, and upregulated by X/XO. Furthermore, KCa3.1 current, which was activated by clamping cells with 1 µM Ca(2+) and applying the KCa3.1 activator 1-ethyl-2-benzimidazolinone, was further augmented by TBHP, and inhibited by X/XO. These effects were prevented by antioxidants. The results suggest that hydrogen peroxide increases KCa3.1 expression by upregulating pERK and downregulating REST, and augments the K(+) current. On the other hand, superoxide reduces KCa3.1 expression by downregulating pERK and upregulating REST, and inhibits the K(+) current. ROS thereby play a key role in both physiological and pathological processes in endothelial cells by regulating KCa3.1 and endothelial function.


DNA damage and DNA damage-inducible protein Gadd45 following ischemia in the P7 neonatal rat.
Cerebral ischemia in adult rodents leads to the production of several types of lesions in the genomic DNA, followed by the activation of the damage-response indicator Gadd45. Our purpose was to investigate the structural changes that occur in chromatin DNA and repair processes after ischemic injury in neonatal brain. Neonatal ischemia was induced by the permanent left MCA occlusion in association with 1 h occlusion of the left common carotid artery in 7-day-old Wistar pups. Oligonucleosome fragments that are recognized as the characteristic DNA ladder was observed in a delayed fashion. Double-strand breaks result in high molecular weight fragments of 50- and 300-kbp as demonstrated by pulsed-field gel electrophoresis, and visualized by the TUNEL assay at 24 h of recovery. In contrast, DNA single-strand breaks, shown by the use of DNA polymerase I-mediated biotin-dATP nick translation were not so abundant. Gadd45 immunoreactivity was sequentially increased in vulnerable neurons in the infarct (4 to 24 h) and in sublethally injured neurons in the penumbra (24-48 h). Taken together, these findings suggest that Gadd45 responds to DNA damage following neonatal ischemia. Furthermore, repairing processes seem to be more active in the penumbra and therefore Gadd45 could have also a protective role in cerebral ischemia.


The effects of parametric speaker sound on salivary hormones and a subjective evaluation.
Recently, a parametric speaker system has been developed. However, the safety of the parametric speaker for the human body has not yet been demonstrated. Therefore, we studied the effects of parametric speaker sound on salivary hormones and carried out a subjective evaluation. Nine male subjects participated in this study. They completed three consecutive sessions: a 20-min quiet period as a baseline, a 45-min mental task period with either a general or parametric speaker, and a 20-min recovery period. The subjects were evaluated by the salivary cortisol and chromogranin A (CgA) concentrations. In addition, they took the Kwansei-Gakuin sleepiness scale (KSS) test before and after the task and also a sound quality evaluation test after it. Two experiments, one with a general speaker (general condition) and the other with a parametric speaker (parametric condition), were conducted at the same time of day on separate days. To examine the effects of the parametric speaker, a two-way repeated measures ANOVA (speaker factor and time factor) was conducted. The results showed that the cortisol concentration was significantly lower during the parametric condition than during the general condition. Furthermore, the sound quality evaluation found a "warm" sensation during the parametric condition to be lower than that during the general condition. A "noisy" sensation during the parametric condition tended to be higher than during the general speaker. However, the CgA concentration and the KSS score were not significantly different for either the speaker factor or the time factor. The results suggested that the burden of the parametric speaker was smaller than that of general speaker, especially on the HPA-axis in the endocrine system.


Discovery and validation of candidate smoltification gene expression biomarkers across multiple species and ecotypes of Pacific salmonids.
Early marine survival of juvenile salmon is intimately associated with their physiological condition during smoltification and ocean entry. Smoltification (parr-smolt transformation) is a developmental process that allows salmon to acquire seawater tolerance in preparation for marine living. Traditionally, this developmental process has been monitored using gill Na+/K+-ATPase (NKA) activity or plasma hormones, but gill gene expression offers the possibility of another method. Here, we describe the discovery of candidate genes from gill tissue for staging smoltification using comparisons of microarray studies with particular focus on the commonalities between anadromous Rainbow trout and Sockeye salmon datasets, as well as a literature comparison encompassing more species. A subset of 37 candidate genes mainly from the microarray analyses was used for TaqMan quantitative PCR assay design and their expression patterns were validated using gill samples from four groups, representing three species and two ecotypes: Coho salmon, Sockeye salmon, stream-type Chinook salmon and ocean-type Chinook salmon. The best smoltification biomarkers, as measured by consistent changes across these four groups, were genes involved in ion regulation, oxygen transport and immunity. Smoltification gene expression patterns (using the top 10 biomarkers) were confirmed by significant correlations with NKA activity and were associated with changes in body brightness, caudal fin darkness and caudal peduncle length. We incorporate gene expression patterns of pre-smolt, smolt and de-smolt trials from acute seawater transfers from a companion study to develop a preliminary seawater tolerance classification model for ocean-type Chinook salmon. This work demonstrates the potential of gene expression biomarkers to stage smoltification and classify juveniles as pre-smolt, smolt or de-smolt.


Phenol sulfotransferase in humans: properties, regulation, and function.
Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of phenolic and catechol drugs and neurotransmitters. All human tissues that have been studied in detail contain at least two forms of PST. One form is thermolabile (TL), catalyzes the sulfate conjugation of micromolar concentrations of dopamine and other phenolic monoamines, and is relatively resistant to inhibition by 2,6-dichloro-4-nitrophenol (DCNP). The other form is thermostable (TS), catalyzes the sulfate conjugation of micromolar concentrations of simple phenols such as p-nitrophenol, and is relatively sensitive to DCNP inhibition. These two forms of PST have been physically separated and partially purified from several human tissues, including an easily accessible tissue, the blood platelet. The biochemical properties of platelet PST are very similar to those of PST in human brain, liver, and small intestine. Individual differences in the basal activity of TS PST in the platelet are correlated with individual variations in the activity of this form of the enzyme in human cerebral cortex (r = .94, n = 15, P less than 0.001). In addition, both platelet TS and TL PST activities are correlated significantly with the extent of sulfate conjugation of orally administered drugs such as acetaminophen and methyldopa. These latter observations are compatible with the conclusions that platelet PST activity may reflect the activity of the enzyme at sites of drug metabolism, and that variation in PST activity is one factor responsible for individual differences in the sulfate conjugation of orally administered drugs.


A bacterial virulence factor with a dual role as an adhesin and a solute-binding protein: the crystal structure at 1.5 A resolution of the PEB1a protein from the food-borne human pathogen Campylobacter jejuni.
The PEB1a protein is an antigenic factor exposed on the surface of the food-borne human pathogen Campylobacter jejuni, which has a major role in adherence and host colonisation. PEB1a is also the periplasmic binding protein component of an aspartate/glutamate ABC transporter essential for optimal microaerobic growth on these dicarboxylic amino acids. Here, we report the crystal structure of PEB1a at 1.5 A resolution. The protein has a typical two-domain alpha/beta structure, characteristic of periplasmic extracytoplasmic solute receptors and a chain topology related to the type II subfamily. An aspartate ligand, clearly defined by electron density in the interdomain cleft, forms extensive polar interactions with the protein, the majority of which are made with the larger domain. Arg89 and Asp174 form ion-pairing interactions with the main chain alpha-carboxyl and alpha-amino-groups, respectively, of the ligand, while Arg67, Thr82, Lys19 and Tyr156 co-ordinate the ligand side-chain carboxyl group. Lys19 and Arg67 line a positively charged groove, which favours binding of Asp over the neutral Asn. The ligand-binding cleft is of sufficient depth to accommodate a glutamate. This is the first structure of an ABC-type aspartate-binding protein, and explains the high affinity of the protein for aspartate and glutamate, and its much weaker binding of asparagine and glutamine. Stopped-flow fluorescence spectroscopy indicates a simple bimolecular mechanism of ligand binding, with high association rate constants. Sequence alignments and phylogenetic analyses revealed PEB1a homologues in some Gram-positive bacteria. The alignments suggest a more distant homology with GltI from Escherichia coli, a known glutamate and aspartate-binding protein, but Lys19 and Tyr156 are not conserved in GltI. Our results provide a structural basis for understanding both the solute transport and adhesin/virulence functions of PEB1a.


Impact of population based indoor residual spraying in combination with mass drug administration on malaria incidence and test positivity in a high transmission setting in north eastern Uganda.
Mass drug administration (MDA) and indoor residual spraying (IRS) are potent malaria burden reduction tools. The impact of combining MDA and IRS is not well documented. We evaluated the impact of MDA + IRS compared to IRS alone at a high transmission site in Eastern Uganda. A quasi-experimental study was implemented in Toroma and Kapujan subcounties in north eastern Uganda. Both subcounties received four rounds of IRS using primiphos-methyl (Acttellic SC300) 6-8 months apart from December 2016 to December 2018. Eligible residents of Kapujan simultaneously received MDA using dihydroartemesinin-piperaquine (DHA-PQ). Health facility data was used to monitor malaria case incidence rate and test positivity rates. In the MDA + IRS arm, malaria incidence dropped by 83% (IRR: 0·17 (0.16-0.18); p < 0.001) in children under 5 year and by 78% (IRR: 0·22 (0.22-0.23); p < 0.001) in persons aged ≥ 5 years from the pre-intervention to the intervention period. In the IRS arm malaria incidence dropped by 47% (IRR: 0.53 (0.51, 0.56); p < 0.001) in children under 5 years and by 71% 0.29 (0.28, 0.30); p < 0.001) in persons aged ≥ 5 years. A drastic drop occurred immediately after the intervention after which cases slowly increased in both arms. Malaria test positivity rate (TPR) dropped at a rate of 21 (p = 0.003) percentage points per 1000 persons in the MDA + IRS arm compared to the IRS arm. There was a mean decrease of 60 (p-value, 0.040) malaria cases among children under five years and a mean decrease in TPR of 16·16 (p-value, 0.001) in the MDA + IRS arm compared to IRS arm. MDA significantly reduced malaria burden among children < 5 years however the duration of this impact needs to be further investigated.


Giant arachnoid granulation mimicking dural sinus thrombosis.
Arachnoid granulations (AG) are composed of dense, collagenous connective tissue that includes clusters of arachnoid cells. They tend to invaginate into the dural sinuses, through which cerebrospinal fluid enters the venous system. AG are most commonly seen at the junction between the middle and lateral thirds of the transverse sinuses near the entry sites of the superficial veins. Presently described is the case of a 21-year-old female who presented at the clinic with recurrent headaches. Magnetic resonance (MR) imaging revealed a 3.5-cm lesion, which extended from confluens sinuum through the superior sagittal sinus. The lesion had created a scallop-shaped area of erosion in the neighboring occipital bone. To exclude sinus thrombosis, MR venography was performed, which displayed a maintained venous flow around the lesion. Headaches were treated symptomatically with medical therapy. Giant AG can be misdiagnosed as dural sinus thrombosis. MR imaging combined with MR venography is the most useful diagnostic tool to differentiate giant AG from dural sinus thrombosis.


A unique case of a postrhinoplasty epidermoid cyst.
The first case of a postrhinoplasty cyst lined with unusual stratified squamous epithelium, unlike the other published mucous ones, is described in this article. There are two different theories accounting for this complication: namely mucosal herniation and the free graft theory. Although the cyst was very close to the marginal rim incision, there was no connection between the cyst and vestibuler skin. Thus the free graft theory is more logical than the herniation theory to explain the development of this cyst.


Cognitive impairment and the blood-brain barrier in chronic kidney disease: role of the uremic toxins
Patients with chronic kidney disease (CKD) have an increased risk of cognitive disorders, presenting as vascular dementia, compared with the general population. These cognitive disorders occur early during the course of the kidney disease and evolve in parallel with the decline in glomerular filtration rate. They affect 30 to 80 % of patients with stage 5 CKD. Kidney transplantation only partially improves cognitive impairment. In this narrative review, we summarize the epidemiology and recent clinical and experimental data on cognitive impairment in CKD and discuss the potential specific mechanisms. Among the factors associated with cognitive impairment, the accumulation of uremic toxins such as indoxyl sulfate appears to be a specific risk factor for cognitive decline. These toxins have an endothelial toxicity that can disrupt the cerebral endothelium. The rupture of the blood-brain barrier (BBB) is a mechanism implicated in several neurodegenerative pathologies and systemic diseases with cerebral tropism. Recent experimental findings in CKD indicate that disruption of the BBB appears to be an important mechanism behind cognitive impairment in CKD. In murine models of CKD, increased BBB permeability is linked to memory impairment and aryl hydrocarbon receptor activation following accumulation of circulating indoxyl sulfate. This disruption of the BBB could also have harmful consequences for stroke susceptibility and drug neurotoxicity in CKD patients.


MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by selective motor neuron degeneration. Abnormal protein aggregation and impaired protein degradation pathways may contribute to the disease pathogenesis. Although it has been reported that autophagy is altered in patients and animal model of ALS, little is known about the role of autophagy in motor neuron degeneration in this disease. Our previous study shows that rapamycin, an MTOR-dependent autophagic activator, accelerates disease progression in the SOD1(G93A) mouse model of ALS. In the present report, we have assessed the role of the MTOR-independent autophagic pathway in ALS by determining the effect of the MTOR-independent autophagic inducer trehalose on disease onset and progression, and on motor neuron degeneration in SOD1(G93A) mice. We have found that trehalose significantly delays disease onset prolongs life span, and reduces motor neuron loss in the spinal cord of SOD1(G93A) mice. Most importantly, we have documented that trehalose decreases SOD1 and SQSTM1/p62 aggregation, reduces ubiquitinated protein accumulation, and improves autophagic flux in the motor neurons of SOD1(G93A) mice. Moreover, we have demonstrated that trehalose can reduce skeletal muscle denervation, protect mitochondria, and inhibit the proapoptotic pathway in SOD1(G93A) mice. Collectively, our study indicated that the MTOR-independent autophagic inducer trehalose is neuroprotective in the ALS model and autophagosome-lysosome fusion is a possible therapeutic target for the treatment of ALS.


Earner-carer model at the crossroads: reforms and outcomes of Sweden's family policy in comparative perspective.
Following the 2006 election, the Swedish earner-carer model of family policy seems to have come to an important crossroads, and questions have been raised about the future course of policies. Will the prototypical earner-carer model in Sweden persist? The separate reforms in cash transfers, services, and tax systems in several respects seem to point in contradictory directions, simultaneously introducing new principles of social care. In this article, past and present reforms and potential outcomes of policies are discussed from an institutional and comparative perspective. Reviewing research on outcomes of earner-carer policies for gendered patterns of productive and reproductive work, class-based stratification, child well-being, fertility, and work-family conflict, the article also contributes to the discussion about future challenges for family policy institutions in Sweden and other advanced welfare states.


Corynebacterium antarcticum sp. nov., Corynebacterium marambiense sp. nov., Corynebacterium meridianum sp. nov., and Corynebacterium pygosceleis sp. nov., isolated from Adélie penguins (Pygoscelis adeliae).
A taxonomic study was conducted on 16 bacterial strains isolated from wild Adélie penguins (Pygoscelis adeliae) from Seymour (Marambio) Island and James Ross Island. An initial screening by repetitive sequence-based PCR fingerprinting divided the strains studied into four coherent groups. Phylogenetic analysis based on 16S rRNA gene sequences assigned all groups to the genus Corynebacterium and showed that Corynebacterium glyciniphilum and Corynebacterium terpenotabidum were the closest species with 16S rRNA gene sequence similarities between 95.4 % and 96.5 %. Further examination of the strains studied with ribotyping, MALDI-TOF mass spectrometry, comprehensive biotyping and calculation of average nucleotide identity and digital DNA-DNA hybridisation values confirmed the separation of the four groups from each other and from the other Corynebacterium species. Chemotaxonomically, the four strains P5828T, P5850T, P6136T, P7210T representing the studied groups were characterised by C16:0 and C18:1ω9c as the major fatty acids, by the presence of meso-diaminopimelic acid in the peptidoglycan, the presence of corynemycolic acids and a quinone system with the predominant menaquinone MK-9(H2). The results of this study show that the strains studied represent four new species of the genus Corynebacterium, for which the names Corynebacterium antarcticum sp. nov. (type strain P5850T = CCM 8835T = LMG 30620T), Corynebacterium marambiense sp. nov. (type strain P5828T = CCM 8864T = LMG 31626T), Corynebacterium meridianum sp. nov. (type strain P6136T = CCM 8863T = LMG 31628T) and Corynebacterium pygosceleis sp. nov. (type strain P7210T = CCM 8836T = LMG 30621T) are proposed.


Label-free enrichment of primary human skeletal progenitor cells using deterministic lateral displacement.
Skeletal stem cells (SSCs) are present in bone marrow (BM) and offer great potential for bone regenerative therapies. However, in the absence of a unique marker, current sorting approaches remain challenging in the quest for simple strategies to deliver SSCs with consistent regeneration and differentiation capacities. Microfluidics offers the possibility to sort cells marker-free, based on intrinsic biophysical properties. Recent studies indicate that SSCs are stiffer than leukocytes and are contained within the larger cell fraction in BM. This paper describes the use of deterministic lateral displacement (DLD) to sort SSCs based on cell size and stiffness. DLD is a technology that uses arrays of micropillars to sort cells based on their diameter. Cell deformation within the device can change the cell size and affect sorting - here evidenced using human cell lines and by fractionation of expanded SSCs. Following sorting, SSCs remained viable and retained their capacity to form clonogenic cultures (CFU-F), indicative of stem cell potential. Additionally, larger BM cells showed enhanced capacity to form CFU-F. These findings support the theory that SSCs are more abundant within the larger BM cell fraction and that DLD, or other size-based approaches, could be used to provide enriched SSC populations with significant implications for stem cell research and translation to the clinic.


PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking.
Osteoclast bone resorption activity is critically regulated to maintain bone homeostasis. Osteoclasts resorb bone by producing protons and acid hydrolase via lysosomal secretion, however, a detailed mechanism remains elusive. PMEPA1 is a vesicular membrane protein, which binds to the NEDD4 family member of ubiquitin ligases. We have previously reported that Pmepa1 is highly expressed in bone resorbing osteoclasts, and regulates bone resorption. Here, we investigated the mechanism of bone resorption regulated by PMEPA1. Mutant mice lacking NEDD4-binding domains of PMEPA1 displayed enhanced bone volume, and reduced bone resorption activity in comparison with those of WT mice. Analysis with pH-sensitive fluorescence probe revealed that proton secretion from osteoclasts significantly decreased in Pmepa1 mutant osteoclasts. Immunofluorescence analysis revealed that PMEPA1 was colocalized with NEDD4, V0A3, and V0D2 subunits of vacuolar ATPase, which regulate the proton production of osteoclasts. In addition, Nedd4 knockdown reduced bone resorption and proton secretion of osteoclasts. Furthermore, Pmepa1 mutation and Nedd4 knockdown altered the cytoplasmic distribution of components of V-ATPase and expression of autophagy-related proteins, suggesting that lysosomal secretion is affected. Collectively, these findings indicate that PMEPA1 controls proton secretion from osteoclasts via NEDD4 by regulating vesicular trafficking, and NEDD4 is an important regulator of bone resorption.


Recreational and occupational physical activities and risk of breast cancer.
Physical activity has been hypothesized to reduce breast cancer risk, but an inverse association has not been consistently reported. In this review, we critically evaluate for coherence, validity, and bias the epidemiologic studies on recreational or occupational physical activity, discuss the biologic plausibility of the association, and identify areas for future research. Results from seven of nine studies suggest that higher levels of occupational physical activity may be associated with a reduction in risk, at least among a subgroup of women. Eleven of 16 investigations on recreational exercise reported a 12%-60% decrease in risk among premenopausal and postmenopausal women, although a dose-response trend was not evident in most of the studies. The reduction in risk associated with exercise was more likely to be observed in case-control studies than in cohort studies. Most investigations incompletely assessed physical activity, which contributed to conflicting findings on the optimal time period, duration, frequency, or intensity of activity to minimize risk. Physical activity may exert its effects through changes in menstrual characteristics, reduced body size, or alterations in immune function. In summary, most epidemiologic studies of physical activity reported a reduction in the risk of breast cancer among physically active women. Future research studies should focus on using a cohort design to rule out recall bias as a possible explanation for the decrease in risk associated with exercise, on improving assessment of lifetime physical activity from all sources to clarify whether there is a dose-response relation or an optimal time period, duration, frequency, or intensity of activity, and on elucidating the underlying mechanisms for the inverse association.


Probing graphene edges via Raman scattering.
We present results of a Raman scattering study from the region near the edges of n-graphene layer films. We find that a Raman band (D) located near 1344 cm(-1) (514.5 nm excitation) originates from a region next to the edge with an apparent width of approximately 70 nm (upper bound). The D-band was found to exhibit five important characteristics: (1) a single Lorentzian component for n = 1, and four components for n = 2-4, (2) an intensity I(D) approximately cos(4) theta, where theta is the angle between the incident polarization and the average edge direction, (3) a local scattering efficiency (per unit area) comparable to the G-band, (4) dispersive behavior ( approximately 50 cm(-1)/eV for n = 1), consistent with the double resonance (DR) scattering mechanism, and (5) a scattering efficiency that is almost independent of the crystallographic orientation of the edge. High-resolution transmission electron microscope images reveal that our cleaved edges exhibit a sawtooth-like roughness of approximately 3 nm (i.e., approximately 20 times the C-C bond length). We propose that in the double resonance Raman scattering process the photoelectron scatters diffusely from our edges, obscuring the recently proposed strong variation in the scattering from armchair versus zigzag symmetry edges based on theoretical arguments.


[Methods for studying eugenol].
A steady tendency toward the extensive use of phytogenous medicinal products well apparent in the recent years involves dental materials. Over one third of the dentistry products contain eugenol, the main component of the clove essential oil. This study is focused on the development of a method for the detection and quantitative measurement ofeugenol in a variety of stomatological products, includling filling materials, and other preparations. The samples for analysis were prepared taking into account physical and chemical properties of the substance of interest, such as high partial pressure over the liquid phase. We investigated the equilibrium vapour phase by capillary gas chromatography with the use of a mass-spectral detector. A method for the detection and quantitative assay of eugenol in dental materials and-filling agents was developed. Its sensitivity limit is 10 ng/ml for liquid samples and 25 mcg/g for solid ones. Metrologic characteristics of the method make it suitable for the detection of eugenol in dental fillings after their long-term contact with biological tissues.


[THE HISTORY OF SKIN GRAFTING, ANCIENT TIMES AND CIVILIZATIONS. THE FIRST MENTIONS].
The article dials with the history of medicine practiced by the first civilizations. The facts of discovery and analysis of ancient medical treatises by modern researchers are reported. Special emphasis is laid on the achievements of medical practitioners in Ancient Egypt and India that promoted the development of operative treatment including skin grafting.


Alcohol use, driver, and crash characteristics among injured motorcycle drivers.
Motorcycle drivers have the highest frequency of alcohol use among all road users. This study examines alcohol use among a large sample of injured motorcycle drivers and examines how crash characteristics differ with the use of alcohol. Over 3000 motorcycle drivers who crashed between January 1, 1991, and December 31, 1992, were studied. All fatally injured drivers in 11 California counties and a sample of nonfatally injured drivers treated in 28 hospitals were included in the study if a crash report and medical record were available. Among drivers tested for alcohol use, 42% tested positive for the presence of alcohol. Drinking drivers were more likely to be speeding and less likely to wear a helmet, and more frequently had single motorcycle crashes than nondrinking drivers. Crash characteristics, but not alcohol use, were predictive of increased injury severity. Alcohol use remains a significant factor in motorcycle crashes and is an important area for injury prevention efforts.


Evaluation of blood glucose values in critically ill patients before and after implementation of an intensive insulin infusion protocol.
This retrospective study evaluated the effect of an intensive insulin infusion protocol on blood glucose values in five intensive care units at Baylor University Medical Center. The protocol involved an equation in which the hourly blood glucose value and an adjusted multiplier were used to determine the insulin infusion rate. The default target blood glucose range was 90 to 120 mg/dL. Results showed that blood glucose values taken by diabetic fingerstick were significantly better in March 2006, after initiation of the protocol, than in March 2005, before use of the protocol, for the percentage of patients both with a blood glucose value >150 mg/dL (P < 0.001) and with a blood glucose value >120 mg/dL (P < 0.001). The percentage of patients with a blood glucose value ≤80 mg/dL was not significantly different between the two time periods (P > 0.10). The increased number of diabetic fingerstick values within a desired range was achieved without a significantly higher number of blood glucose values ≤80 mg/dL. It can be theorized that wide use of the protocol was at least partly responsible for the significant change in blood glucose values.


Immune Dysfunctions and Immunotherapy in Colorectal Cancer: The Role of Dendritic Cells.
Colorectal cancer (CRC), a multi-step malignancy showing increasing incidence in today's societies, represents an important worldwide health issue. Exogenous factors, such as lifestyle, diet, nutrition, environment and microbiota, contribute to CRC pathogenesis, also influencing non neoplastic cells, including immune cells. Several immune dysfunctions were described in CRC patients at different disease stages. Many studies underline the role of microbiota, obesity-related inflammation, diet and host reactive cells, including dendritic cells (DC), in CRC pathogenesis. Here, we focused on DC, the main cells linking innate and adaptive anti-cancer immunity. Variations in the number and phenotype of circulating and tumor-infiltrating DC have been found in CRC patients and correlated with disease stages and progression. A critical review of DC-based clinical studies and of recent advances in cancer immunotherapy leads to consider new strategies for combining DC vaccination strategies with check-point inhibitors, thus opening perspectives for a more effective management of this neoplastic disease.


Most Likely to Succeed: Long-Run Returns to Adolescent Popularity.
Sociological explanations for economic success tend toward measures of embeddedness in longstanding social institutions, such as race and gender, or personal skills represented mainly by educational attainment. In this paper we seek a distinctively social foundation for success by investigating the long-term association between high school popularity and income. Using rich longitudinal data, we find a clear and persistent association between the number of friendship nominations received and adult income, even after accounting for the mediating influences of diverse personal, family, and work characteristics. This skill is distinct from conventional personality measures such as the Big Five, and persists long into adulthood. We hypothesize that popularity encapsulates a socioemotional skill recognized by peers as the practice of being a good friend rather than an indicator of social status.


Strain differences in haematological response to chloramphenicol succinate in mice: implications for toxicological research.
Much toxicological research continues to be done using genetically undefined "outbred" stocks of mice and rats, although the case for using isogenic strains has been made repeatedly in the literature over a period of more than two decades. Also, very few studies are conducted using more than one strain, with the result that genetic variation in response is seldom apparent to the investigator. Here we report qualitative and quantitative strain differences in the haematological response to chloramphenicol succinate (CAPS) when administered by gavage at 500-2500 mg/kg for 7 days, to four inbred strains of mouse (C3H/He, CBA/Ca, BALB/c and C57BL/6) and one outbred stock (CD-1). CAPS caused anaemia and reticulocytopenia in all mouse strains, and leucopenia in the inbred strains but not in the outbred CD-1 stock. All four inbred strains showed significant (P<0.01) responses to CAPS at lower dose levels than in CD-1 mice, which were phenotypically more variable than the inbred animals. A simulated experiment, using a sample of records from the present study, showed that the use of two mice at each dose level using CD-1, CBA, BALB/c and C57BL/6 (48 total mice), would have given a more sensitive experiment than the use of 47 CD-1 mice alone, and would also have shown that the response is partly strain dependent. These studies provide additional evidence that inbred strains, because of their greater sensitivity and other valuable properties, should be more widely used in toxicology.


Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance.


Functional traits, convergent evolution, and periodic tables of niches.
Ecology is often said to lack general theories sufficiently predictive for applications. Here, we examine the concept of a periodic table of niches and feasibility of niche classification schemes from functional trait and performance data. Niche differences and their influence on ecological patterns and processes could be revealed effectively by first performing data reduction/ordination analyses separately on matrices of trait and performance data compiled according to logical associations with five basic niche 'dimensions', or aspects: habitat, life history, trophic, defence and metabolic. Resultant patterns then are integrated to produce interpretable niche gradients, ordinations and classifications. Degree of scheme periodicity would depend on degrees of niche conservatism and convergence causing species clustering across multiple niche dimensions. We analysed a sample data set containing trait and performance data to contrast two approaches for producing niche schemes: species ordination within niche gradient space, and niche categorisation according to trait-value thresholds. Creation of niche schemes useful for advancing ecological knowledge and its applications will depend on research that produces functional trait and performance datasets directly related to niche dimensions along with criteria for data standardisation and quality. As larger databases are compiled, opportunities will emerge to explore new methods for data reduction, ordination and classification.


Control failure likelihood and spatial dependence of insecticide resistance in the tomato pinworm, Tuta absoluta.
Insecticide resistance is a likely cause of field control failures of Tuta absoluta, but the subject has been little studied. Therefore, resistance to ten insecticides was surveyed in seven representative field populations of this species. The likelihood of control failures was assessed, as well as weather influence and the spatial dependence of insecticide resistance. No resistance or only low resistance levels were observed for pyrethroids (bifenthrin and permethrin), abamectin, spinosad, Bacillus thuringiensis and the mixture deltamethrin + triazophos (<12.5-fold). In contrast, indoxacarb exhibited moderate levels of resistance (up to 27.5-fold), and chitin synthesis inhibitors exhibited moderate to high levels of resistance (up to 222.3-fold). Evidence of control failures was obtained for bifenthrin, permethrin, diflubenzuron, teflubenzuron, triflumuron and B. thuringiensis. Weather conditions favour resistance to some insecticides, and spatial dependence was observed only for bifenthrin and permethrin. Insecticide resistance in field populations of the tomato pinworm prevails for the insecticides nowadays most frequently used against them-the chitin synthesis inhibitors (diflubenzuron, triflumuron and teflubenzuron). Local selection favoured by weather conditions and dispersal seem important for pyrethroid resistance evolution among Brazilian populations of T. absoluta and should be considered in designing pest management programmes.