Biochemical and nutritional indices as cardiovascular risk factors among Iranian firefighters.
Limited cardiovascular disease (CVD) risk data are available for firefighters worldwide. This comparative study was aimed at investigating the biochemical and nutritional indices of firefighters in Iran. Individuals' anthropometric measurements, including weight, height, and waist and hip circumferences, were measured and the percent of body fat (BF%) was also obtained. Blood sampling was done in order to determine lipid profile, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), lipoprotein a (Lp(a)) and fasting blood sugar (FBS) concentrations. Systolic and diastolic blood pressures (SBP and DBP) were also measured. The mean ages of firefighters and administrative staff were 42.45 +/- 6.75 and 44.64 +/- 5.83 y, respectively. The prevalence of overweight and obesity was 45% and 24% in firefighters and 54% and 23% in administrative staff, respectively. High waist-to-hip and waist-to-stature ratios were detected in 26.4% and 81.3% of firefighters versus 33.3% and 89.7% of the control group, respectively. No significant differences were observed between the mean of TC, TG, HDL-C, LDL-C and FBS concentrations. The mean of Lp(a) was significantly higher among firefighters (P<0.05). About half of the subjects in both groups had TC >5.17, TG >1.69, HDL-C <1.03 nmol/L and Lp(a) >25 mg/dL. There were no significant differences between the SBP and DBP of subjects. There was no significant difference in smoking habits between the two groups. Considering the high prevalence of overweight and obesity, high TC, TG and Lp(a) and low HDL-C concentrations among all firefighters, it seems necessary to provide fitness-promotion and nutritional education programs for the prevention of obesity-related chronic diseases such as CVD.


Simulated proximity enhances perceptual and physiological responses to emotional facial expressions.
Physical proximity is important in social interactions. Here, we assessed whether simulated physical proximity modulates the perceived intensity of facial emotional expressions and their associated physiological signatures during observation or imitation of these expressions. Forty-four healthy volunteers rated intensities of dynamic angry or happy facial expressions, presented at two simulated locations, proximal (0.5 m) and distant (3 m) from the participants. We tested whether simulated physical proximity affected the spontaneous (in the observation task) and voluntary (in the imitation task) physiological responses (activity of the corrugator supercilii face muscle and pupil diameter) as well as subsequent ratings of emotional intensity. Angry expressions provoked relative activation of the corrugator supercilii muscle and pupil dilation, whereas happy expressions induced a decrease in corrugator supercilii muscle activity. In proximal condition, these responses were enhanced during both observation and imitation of the facial expressions, and were accompanied by an increase in subsequent affective ratings. In addition, individual variations in condition related EMG activation during imitation of angry expressions predicted increase in subsequent emotional ratings. In sum, our results reveal novel insights about the impact of physical proximity in the perception of emotional expressions, with early proximity-induced enhancements of physiological responses followed by an increased intensity rating of facial emotional expressions.


Assessing the impact of clinical guidelines: research lessons learned.
Clinical guidelines are proliferating. Here, a theoretical and practical perspective is presented on how to evaluate the effectiveness of guidelines and lessons learned from impact studies conducted. A nosology of guidelines is presented, along with the rationale for evaluating key dimensions, including degree of implementation, impact on process, outcomes, and cost of care, as well as provider and patient satisfaction. Key methodologic problems in evaluation and some possible ways to address them are addressed. Rapid and practical evaluation of clinical guidelines is a critical step that can both confirm their usefulness and direct their revision and improvement.


The use of complementary and alternative medicine in adults with depressive disorders. A critical integrative review.
Depression has been identified as one of the most frequent indications for CAM use and is a strong predictor of CAM use. The present article provides a critical review of CAM use for depressive disorders including bipolar depression by addressing prevalence of CAM use and CAM users׳ characteristics, motivation, decision-making and communication with healthcare providers. A comprehensive search of 2003-2014 international literature in the Medline, CINAHL, AMED, and SCOPUS databases was conducted. The search was confined to peer-reviewed articles published in English with abstracts and reporting new empirical research findings regarding CAM use and depressive disorders. A considerable level of CAM use was observed among both general and clinical populations of people suffering from depressive disorders, many of whom use CAM concurrently with their conventional medicine. In particular, high rates of CAM use were found among those with bipolar disorder, an illness known to cause substantial impairments in health-related quality of life. Concomitant prescription medication use ranged from 0.52% to as high as 100%. Study design such as the inclusion of bipolar and depression in the same diagnostic category hamper the differentiation and attribution of CAM usage for symptoms. Findings of our review show that enduring impairments in function and persistence of symptoms (as reflected by increased CAM use proportional to severity of illness and comorbidity) are the impetus for sufferers of depressive illness to seek out CAM. The psychosocial factors associated with CAM use in depressive illnesses and severe mental illness are yet to be established. Subsequent research amongst those with depressive disorders would be informative in clarifying the range of motivations associated with mental illness.


Disability in post-earthquake Haiti: prevalence and inequality in access to services.
To assess the prevalence of disability and service needs in post-earthquake Haiti, and to compare the inclusion and living conditions of people with disabilities to those without disabilities. A population-based prevalence survey of disability was undertaken in 2012 in Port-au-Prince region, which was at the centre of the earthquake in 2010. Sixty clusters of 50 people aged 5 + years were selected with probability proportionate to size sampling and screened for disability (Washington Group short set questionnaire). A case-control study was undertaken, nested within the survey, matching cases to controls by age, gender and cluster. There was additional case finding to identify further children with disabilities. Information was collected on: socioeconomic status, education, livelihood, health, activities, participation and barriers. The prevalence of disability was 4.1% (3.4-4.7%) across 3132 eligible individuals. The earthquake was the second leading cause of disability. Disability was more common with increasing age, but unrelated to poverty. Large gaps existed in access of services for people with disabilities. Adults with disabilities were less likely to be literate or work and more likely to visit health services than adults without disabilities. Children with disabilities were less likely to be currently enrolled at school compared to controls. Children and adults with disabilities reported more activity limitations and participation restriction. Further focus is needed to improve inclusion of people with disabilities in post-earthquake Haiti to ensure that their rights are fulfilled. Almost one in six households in this region of Haiti included a person with a disability, and the earthquake was the second leading cause of disability. Fewer than half of people who reported needing medical rehabilitation had received this service. The leading reported barriers to the uptake of health services included financial constraints (50%) and difficulties with transport (40%). People with disabilities did not participate equally in education or employment and had poorer access to health care.


Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut.
Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β-Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3(CNS1mut)). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.


GRP78 Influences Chemoresistance and Prognosis in Cancer.
Resistance to therapy is a major hindrance to patient survival in cancer, underscoring a critical need to elucidate the underlying mechanisms responsible for chemoresistance. Research has demonstrated that endoplasmic reticulum (ER) stress plays a significant role in allowing cells to survive conditions that would normally elicit cell death. Specifically, elevated expression of GRP78, the master regulator of the unfolded protein response (UPR), has been shown to induce chemoresistance and serves as a indictor of poor prognosis in patients. Evaluating the expression of GRP78 and its downstream targets in a wide range of cancers may allow clinicians to predict resistance to a number of commonly used therapies. Moreover, understanding the mechanism(s) of action GRP78 uses to regulate chemoresistance will accelerate the development of more efficacious treatment strategies that target GRP78 to abrogate chemoresistance. This mini-review highlighted the roles of targets downstream of GRP78 and explored their mechanisms related to cellular survival. Furthermore, a summary of the connection between GRP78 expression and patient prognosis was provided. Lastly, strategies for targeting GRP78, in order to improve treatment efficacy, was explored. GRP78 maintains an important role in regulating signaling pathways that control cell survival and this review draws attention to its value as a prognostic marker and therapeutic target.


Cell surface expression of receptor protein tyrosine phosphatase RPTP mu is regulated by cell-cell contact.
RPTP mu is a transmembrane protein tyrosine phosphatase with an adhesion molecule-like ectodomain. It has recently been shown that RPTP mu mediates homophilic interactions when expressed in insect cells. In this study, we have examined how RPTP mu may function as a cell contact receptor in mink lung epithelial cells, which express RPTPmu endogenously, as well as in transfected 3T3 cells. We find that RPTP mu has a relatively short half-life (3-4 hours) and undergoes posttranslational cleavage into two noncovalently associated subunits, with both cleaved and uncleaved molecules being present on the cell surface (roughly at a 1:1 ratio); shedding of the ectodomain subunit is observed in exponentially growing cells. Immunofluorescence analysis reveals that surface expression of RPTPmu is restricted to regions of tight cell-cell contact. RPTPmu surface expression increases significantly with increasing cell density. This density-induced upregulation of RPTP mu is independent of its catalytic activity and is also observed when transcription is driven by a constitutive promoter, indicating that modulation of RPTPmu surface expression occurs posttranscriptionally. Based on our results, we propose the following model of RPTP mu function: In the absence of cell-cell contact, newly synthesized RPTP mu molecules are rapidly cleared from the cell surface. Cell-cell contact causes RPTPmu to be trapped at the surface through homophilic binding, resulting in accumulation of RPTP mu at intercellular contact regions. This contact-induced clustering of RPTPmu may then lead to tyrosine dephosphorylation of intracellular substrates at cell-cell contacts.


Comparing the Self- and External Assessment Versions of the HCL-33 as Screening Instruments for Bipolar Disorder in Older Depressed Patients.
Objectives: The misdiagnosis of bipolar disorder (BD) as major depressive disorder (MDD) is common in depressed older adults. The self-rated HCL-33 and its external assessment version (HCL-33-EA) have been developed to screen for hypomanic symptoms. This study compared the screening ability of these two instruments to discriminate BD from MDD. Methods: A total of 215 patients (107 with BD and 108 with MDD) and their carers were recruited. Patients and their carers completed the HCL-33 and HCL-33-EA, respectively. The consistency of the total score and the positive response to each item between the two scales was calculated with the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient separately. Receiver operating characteristics (ROC) curves were drawn for both instruments. The optimal cut-off points were determined according to the maximum Youden's Index. The areas under the ROC curve (AUC) of the HCL-33 and HCL-33-EA were calculated separately and compared. The sensitivity and specificity at the optimal cut-off values were also calculated separately for the HCL-33 and HCL-33-EA. Results: The intraclass correlation coefficient (ICC) between the total scores of the HCL-33 and HCL-33-EA was 0.823 (95% CI = 0.774-0.862). The positive response rate on all items showed high agreement between the two instruments. ROC curve analysis demonstrated that the total scores of both HCL-33 and HCL-33-EA differentiated well between MDD and BD, while there was no significant difference in the AUCs between the two scales (Z = 0.422, P = 0.673). The optimal cutoff values for the HCL-33 and HCL-33-EA were 14 and 12, respectively. With the optimal cutoff value, the sensitivities of the HCL-33 and HCL-33-EA were 88.8% and 93.5%, and their specificities were 82.4% and 79.6%. Conclusion: Both the HCL-33 and HCL-33-EA had good screening ability for discriminating BD from MDD in depressed older adults.


Species formation through punctuated gradualism in planktonic foraminifera.
Detailed analysis of evolutionary changes in a 10-million-year long Late Neogene lineage of planktonic foraminifera has revealed a pattern that is not consistent with either the gradualistic or the punctuational model of evolution. The lineage was in stasis over a considerable part of its total duration but underwent relatively rapid, but not geologically instantaneous, gradual morphologic change that did not lead to lineage splitting. The term punctuated gradualism is suggested for this evolutionary modality.


Effects of a Personalized Web-Based Decision Aid for Surrogate Decision Makers of Patients With Prolonged Mechanical Ventilation: A Randomized Clinical Trial.
Treatment decisions commonly have to be made in intensive care units (ICUs). These decisions are difficult for surrogate decision makers and often lead to decisional conflict, psychological distress, and treatments misaligned with patient preferences. To determine whether a decision aid about prolonged mechanical ventilation improved prognostic concordance between surrogate decision makers and clinicians compared with a usual care control. Multicenter, parallel, randomized, clinical trial. (ClinicalTrials.gov: NCT01751061). 13 medical and surgical ICUs at 5 hospitals. Adult patients receiving prolonged mechanical ventilation and their surrogates, ICU physicians, and ICU nurses. A Web-based decision aid provided personalized prognostic estimates, explained treatment options, and interactively clarified patient values to inform a family meeting. The control group received information according to usual care practices followed by a family meeting. The primary outcome was improved concordance on 1-year survival estimates, measured with the clinician-surrogate concordance scale (range, 0 to 100 percentage points; higher scores indicate more discordance). Secondary and additional outcomes assessed the experiences of surrogates (psychological distress, decisional conflict, and quality of communication) and patients (length of stay and 6-month mortality). Outcomes assessors were blinded to group allocation. The study enrolled 277 patients, 416 surrogates, and 427 clinicians. Concordance improvement did not differ between intervention and control groups (mean difference in score change from baseline, -1.7 percentage points [95% CI, -8.3 to 4.8 percentage points]; P = 0.60). Surrogates' postintervention estimates of patients' 1-year prognoses did not differ between intervention and control groups (median, 86.0% [interquartile range {IQR}, 50.0%] vs. 92.5% [IQR, 47.0%]; P = 0.23) and were substantially more optimistic than results of a validated prediction model (median, 56.0% [IQR, 43.0%]) and physician estimates (median, 50.0% [IQR, 55.5%]). Eighty-two intervention surrogates (43%) favored a treatment option that was more aggressive than their report of patient preferences. Although intervention surrogates had greater reduction in decisional conflict than control surrogates (mean difference in change from baseline, 0.4 points [CI, 0.0 to 0.7 points]; P = 0.041), other surrogate and patient outcomes did not differ. Contamination among clinicians could have biased results toward the null hypothesis. A decision aid about prolonged mechanical ventilation did not improve prognostic concordance between clinicians and surrogates, reduce psychological distress among surrogates, or alter clinical outcomes. Decision support in acute care settings may require greater individualized attention for both the cognitive and affective challenges of decision making. National Institutes of Health.


Using Cell-Based Strategies to Break the Link between Bronchopulmonary Dysplasia and the Development of Chronic Lung Disease in Later Life.
Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have changed the course of lung injury and enabled the survival of infants born as early as 23-24 weeks of gestation, BPD still remains a common complication of extreme prematurity, and there is no specific treatment for it. Furthermore, children, adolescents, and adults who were born very preterm and developed BPD have an increased risk of persistent lung dysfunction, including early-onset emphysema. Therefore, it is possible that early-life pulmonary insults, such as extreme prematurity and BPD, may increase the risk of COPD later in life, especially if exposed to secondary challenges such as respiratory infections and/or smoking. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal and adult lung injuries. This paper summarizes the long-term pulmonary outcomes of preterm birth and BPD and discusses the recent advances of cell-based therapies for lung diseases, with a particular focus on BPD and COPD.


Lung CT Analysis and Retrieval as a Diagnostic Aid.
Image retrieval is currently a very active research field due to the large amount of visual data being produced in most modern hospitals. Most often, the goal is to aid the diagnostic process. Unfortunately, only very few medical image retrieval systems are currently used in clinical routine. One of the application domains for image retrieval is the analysis and retrieval of lung CTs. A first user study in the United States shows that these systems allow improving the diagnostic quality.This article describes the approach to an aid for lung CT diagnostics. The analysis incorporates several steps and the goal is to automate the process as much as possible for easy integration into diagnostics. Thus, several automatic steps are proposed from a selection of the most characteristic slices, to an automatic segmentation of the lung tissue and a classification on the segmented area into diagnostic classes. Feedback to the MD will be given in the form of marked regions in the images that appear to be different from the norm of healthy tissue. We are currently working on a small set of training images with marked and annotated regions but a larger set of images for the evaluation of our algorithm is in work. For this reason, the article does currently not contain much quantitative evaluation.For several tasks we use existing open source software such as Weka and itk. This allows an easy reproduction of the search results.


Enhancing the incorporation of Sn in vapor-liquid-solid GeSn nanowires by modulation of the droplet composition.
We report on the influence of the liquid droplet composition on the Sn incorporation in GeSn nanowires (NWs) grown by the vapor-liquid-solid (VLS) mechanism with different catalysts. The variation of the NW growth rate and morphology with the growth temperature is investigated and 400 °C is identified as the best temperature to grow the longest untapered NWs with a growth rate of 520 nm min-1. When GeSn NWs are grown with pure Au droplets, we observe a core-shell like structure with a low Sn concentration of less than 2% in the NW core regardless of the growth temperature. We then investigate the impact of adding different fractions of Ag, Al, Ga and Si to Au catalyst on the incorporation of Sn. A significant improvement of Sn incorporation up to 9% is obtained using 75:25 Au-Al catalyst, with a high degree of spatial homogeneity across the NW volume. Thermodynamic model based on the energy minimization at the solid-liquid interface is developed, showing a good correlation with the data. These results can be useful for obtaining technologically important GeSn material with a high Sn content and, more generally, for tuning the composition of VLS NWs in other material systems.


Controlled exposure to particulate matter from urban street air is associated with decreased vasodilation and heart rate variability in overweight and older adults.
Exposure to particulate matter (PM) is generally associated with elevated risk of cardiovascular morbidity and mortality. Elderly and obese subjects may be particularly susceptible, although short-term effects are poorly described. Sixty healthy subjects (25 males, 35 females, age 55 to 83 years, body mass index>25 kg/m2) were included in a cross-over study with 5 hours of exposure to particle- or sham-filtered air from a busy street using an exposure-chamber. The sham- versus particle-filtered air had average particle number concentrations of ~23.000 versus ~1800/cm3 and PM2.5 levels of 24 versus 3 μg/m3, respectively. The PM contained similar fractions of elemental and black carbon (~20-25%) in both exposure scenarios. Reactive hyperemia and nitroglycerin-induced vasodilation in finger arteries and heart rate variability (HRV) measured within 1 h after exposure were primary outcomes. Potential explanatory mechanistic variables included markers of oxidative stress (ascorbate/dehydroascorbate, nitric oxide-production cofactor tetrahydrobiopterin and its oxidation product dihydrobiopterin) and inflammation markers (C-reactive protein and leukocyte differential counts). Nitroglycerin-induced vasodilation was reduced by 12% [95% confidence interval: -22%; -1.0%] following PM exposure, whereas hyperemia-induced vasodilation was reduced by 5% [95% confidence interval: -11.6%; 1.6%]. Moreover, HRV measurements showed that the high and low frequency domains were significantly decreased and increased, respectively. Redox and inflammatory status did not change significantly based on the above measures. This study indicates that exposure to real-life levels of PM from urban street air impairs the vasomotor function and HRV in overweight middle-aged and elderly adults, although this could not be explained by changes in inflammation, oxidative stress or nitric oxide-cofactors.


External validation of the Simplified PADUA REnal (SPARE) nephrometry system in predicting surgical outcomes after partial nephrectomy.
Pentafecta is a major goal in the era of partial nephrectomy (PN). Simplified PADUA REnal (SPARE) nephrometry system was developed to evaluate the complexity of tumor. However, the predictive ability in pentafecta of SPARE system is yet to be determined. The aim of this study was to externally validate the applicability of SPARE nephrometry system in predicting pentafecta achievement after partial nephrectomy, and to examine inter-observer concordance. We retrospectively reviewed data of 207 consecutive patients who underwent PN between January 2012 and August 2018 at a tertiary referral center. We obtained SPARE, R.E.N.A.L., and PADUA scores and evaluated correlations among the nephrometries and surgical outcomes including pentafecta by Spearman test. Logistic regression analysis was used to identify independent predictors of pentafecta outcomes. We compared the nephrometries to determine the predictive ability of achieving pentafecta using receiver operating characteristic curve analysis. Fleiss' generalized kappa was used to assessed interobserver variation in the SPARE system. Based on the SPARE system, 120, 74, and 13 patients were stratified into low-risk, intermediate-risk, and high-risk groups, respectively. Regarding the individual components of pentafecta, there were significant differences in the complication rate (p = 0.03), ischemia time (p < 0.001), and percent change of eGFR (p < 0.001) among the three risk groups. In addition, higher tumor complexity was significantly associated with a lower achievement rate of pentafecta (p = 0.01). In Spearman correlation tests, SPARE nephrometry was correlated with ischemia time (ρ:0.37, p < 0.001), operative time (ρ:0.28, p < 0.001), complication rate (ρ:0.34, p < 0.001), percent change of eGFR (ρ:0.34, p < 0.001), and progression of chronic kidney disease stage (ρ:0.17, p = 0.02). Multivariate analysis revealed that SPARE significantly affected pentafecta (OR: 0.67, p < 0.001). In ROC curve analysis, SPARE showed fair predictive ability in the achievement pentafecta (AUC: 0.71). The predictive ability of pentafecta was similar between nephrometries (SPARE vs. R.E.N.A.L., p = 0.78; SPARE vs. PADUA, p = 0.66). The interobserver concordance of SPARE was excellent (Kappa: 0.82, p = 0.03). SPARE system was a predictive factor of surgical outcomes after PN. This refined nephrometry had similar predictive abilities for pentafecta achievement compared with R.E.N.A.L. and PADUA.


Simple and accurate quantitative analysis of 20 anti-tuberculosis drugs in human plasma using liquid chromatography-electrospray ionization-tandem mass spectrometry.
A simple and accurate liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method for the quantitation of 20 anti-tuberculosis (anti-TB) drugs in human plasma, was developed as a tool for therapeutic drug monitoring. Two protein precipitation methods were adopted; one using methanol containing 0.13N HCl, for precipitation of amikacin, kanamycin, streptomycin and pyrazinamide, and the other using acetonitrile, for precipitation of preamoxicillin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, p-aminosalicylic acid (PAS), prothionamide, rifabutin, rifampin and roxithromycin. Separation was performed either on an HILIC silica column or a reversed-phase dC18 column, with a gradient elution. Detection was carried out in multiple reaction-monitoring (MRM) mode. The calibration curves were linear over a 50-fold concentration range, with correlation coefficients (r) greater than 0.9969 for all anti-TB drugs. The intra- and inter-day precision was less than 14.3%, and the accuracy ranged between 84.8 and 113.0%. The developed method was successfully applied to the identification and quantitation of anti-TB drugs in patients with multi-drug resistant TB.


MRI artifact simulation for clinically relevant MRI sequences for guidance of prostate HDR brachytherapy.
For the purpose of magnetic resonance imaging (MRI) guidance of prostate high-dose-rate (HDR) brachytherapy, this paper presents a study on the potential of clinically relevant MRI sequences to facilitate tracking or localization of brachytherapy devices (HDR source/titanium needle), and which could simultaneously be used to visualize the anatomy. The tracking or localization involves simulation of the MRI artifact in combination with a template matching algorithm. Simulations of the MRI artifacts induced by an HDR brachytherapy source and a titanium needle were implemented for four types of sequences: spoiled gradient echo, spin echo, balanced steady-state free precession (bSSFP) and bSSFP with spectral attenuated inversion recovery (SPAIR) fat suppression. A phantom study was conducted in which mentioned sequences (in 2D) as well as the volumetric MRI sequences of the current clinical scan protocol were applied to obtain the induced MRI artifacts for an HDR source and a titanium needle. Localization of the objects was performed by a phase correlation based template matching algorithm. The simulated images demonstrated high correspondences with the acquired MR images, and allowed localization of the objects. A comparison between the object positions obtained for all applied MRI sequences showed deviations (from the average position) of 0.2-0.3 mm, proving that all MRI sequences were suitable for localization of the objects, irrespective of their 2D or volumetric nature. This study demonstrated that the MRI artifact induced by an HDR source or a titanium needle could be simulated for the four investigated types of MRI sequences (spoiled gradient echo, spin echo, bSSFP and bSSFP-SPAIR), valuable for real-time object localization in clinical practice. This leads to more flexibility in the choice of MRI sequences for guidance of HDR brachytherapy, as they are suitable for both object localization and anatomy visualization.


[Mobile cardiac electrical center: a new concept and mathematical modeling].
A method for determination of the cardiac electric center on the basis of noninvasive multichannel measurements and multipole description of the cardioelectric potential is proposed. The method provides a more accurate and stable spatial location of the cardioelectric generator as compared to other methods (in particular, those based on minimization of the quadrupole potential). The position of the electric center is a useful characteristic for topical diagnosis of the electrophysiological state and function of the heart. Using mathematical models, the dependence of the position of the electric center, determined by the method presented, on the configuration and spatial position of the cardiogenerator is illustrated.


Vibrio cholerae O139 requires neither capsule nor LPS O side chain to grow inside Acanthamoeba castellanii.
Vibrio cholerae, the causative agent of cholera, has the ability to grow and survive in the aquatic free-living amoeba Acanthamoeba castellanii. The aim of the present study was to examine the ability of the clinical isolate V. cholerae O139 MO10 to grow in A. castellanii and to determine the effect of the bacterial capsule and LPS O side chain on intracellular growth. Results from co-cultivation, viable counts, a gentamicin assay, electron microscopy and statistical analysis showed that the association of V. cholerae O139 MO10 with A. castellanii did not inhibit growth of the amoeba, and enhanced growth and survival of V. cholerae O139 MO10 occurred. The wild-type V. cholerae O139 MO10 and a capsule mutant or capsule/LPS double mutant grew inside A. castellanii. Neither the capsule nor the LPS O side chain of V. cholerae O139 was found to play an important role in the interaction with A. castellanii, disclosing the ability of V. cholerae to multiply and survive inside A. castellanii, as well as the role of A. castellanii as an environmental host for V. cholerae.


Antimalarial effects of rifampin in Plasmodium vivax malaria.
The antimalarial effects of rifampin in 60 adults with Plasmodium vivax malaria were assessed. There were three treatment groups: rifampin (20 and 15 mg/kg of body weight per day for 1 and 4 days, respectively; n = 5); rifampin followed by primaquine (15 mg of base per day for 14 days; n = 25), and chloroquine (25 mg of base per kg over 3 days) followed by primaquine (n = 30). All patients were hospitalized till clearance of fever and parasites, and 45 patients stayed in the hospital for 1 month. Despite initial clearance of fever in all patients and a > or = 6-fold reduction in parasitemia per 48-h life cycle, rifampin alone was not effective: all five patients had subsequent R2-like parasitological responses. All patients treated with rifampin-primaquine cleared both fever and parasitemia, but the therapeutic responses were slower than those following treatment with chloroquine-primaquine. Final fever clearance times were significantly longer (mean [standard deviation] = 43 [35] versus 27 [19] h; P = 0.046), and the parasite clearance times (to 50 and 90% of admission parasite counts and to a level undetectable in a peripheral blood smear) were also significantly greater (P = 0.053 to < 0.001). However, reappearance of infection occurred in only one patient treated with rifampin-primaquine. The results of this study suggest that rifampin at the usual therapeutic doses has partial activity against blood stages of P. vivax in humans but that used alone it is insufficient for cure. Rifampin might therefore be of value in combination antimalarial therapy.


Antibodies and antigen expression in human melanoma detected by the immune adherence test.
By means of a modified immune adherence (IA) technique, sera from melanoma patients were tested for the presence of antimelanoma antibodies. In total 13/73 sera tested showed a positive IA reaction of which 4/6 sera showed a positive reaction in the autologous situation. Sera from 33 patients with other tumors, 7 patients with non-neoplastic diseases and 50 healthy individuals did not show any IA reactivity towards melanoma cells. The reaction seemed to be selectively directed against tumor-associated antigens (TAA) on melanoma cells. No correlation with the stage of the disease could be found. Longitudinal studies indicated that conversions in antibody activity did not correlate with the clinical state of the patients. There was also no correlation with the corresponding in vitro data obtained in cell-mediated immunity tests. Cell lines and short-term cultures originating from tumors from different melanoma patients shared a common antigenicity. The expression of TAA on cells from a melanoma cell line fluctuated significantly during prolonged culture. The expression of TAA was influenced by the culture conditions and the growth state of the cells. A relation between TAA-expression and cell cycle phase was demonstrated.


Leukocyte expression profiles reveal gene sets with prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy.
Among patients with intractable epilepsy, the most commonly performed surgical procedure is craniotomy for amygdalohippocampectomy (AH). Stereotactic laser amygdalohippocampotomy (SLAH) has also been recently employed as a minimally invasive treatment for intractable temporal lobe epilepsy (TLE). Among patients treated with AH and SLAH approximately 65% and 54% of patients become seizure-free, respectively. Therefore, selection criteria for surgical candidates with improved prognostic value for post-operative seizure-free outcome are greatly needed. In this study, we perform RNA sequencing (RNA-Seq) on whole blood leukocyte samples taken from 16 patients with intractable TLE prior to SLAH to test the hypothesis that pre-operative leukocyte RNA expression profiles are prognostic for post-operative seizure outcome. Multidimensional scaling analysis of the RNA expression data indicated separate clustering of patients with seizure free (SF) and non-seizure-free (NSF) outcomes. Differential expression (DE) analysis performed on SF versus NSF groups revealed 24 significantly differentially expressed genes (≥2.0-fold change, p-value < 0.05, FDR <0.05). Network and pathway analyses identified differential activation of pathways involved in lipid metabolism, morphology of oligodendrocytes, inflammatory response, and development of astrocytes. These results suggest that pre-operative leukocyte expression profiles have prognostic value for seizure outcome following SLAH.


The shivering response in animals and man.
The physiological response to body cooling may be regarded as a homeostatic response embracing the concept of negative feedback. The metabolic response to falling body temperature is normally both appropriate and adequate. However, there are reports of inadequate or absent responses to body cooling and of non-febrile animals shivering at elevated body temperature. The reasons for these paradoxical findings are not fully understood, particularly since the controller of body temperature receives the largest proportion of its thermal afferent information from temperature sensors located within the body core. During anaesthesia and certain phases of sleep the shivering response to hypothermia may be impaired. It also appears that other factors such as the rate of cooling and disturbances of the circadian machinery (altered light conditions, phase shifting of activity patterns) may be of importance. These factors are relevant for people working in the arctic, especially since many of them are shift workers.


Earlier arterial switch operation improves outcomes and reduces costs for neonates with transposition of the great arteries.
This study sought to examine the impact of surgical timing on major morbidity and hospital reimbursement for late preterm and term infants with dextrotransposition of the great arteries (d-TGA). Neonatal arterial switch operation is the standard of care for d-TGA. Little is known about the effects of age at operation on clinical outcomes or costs for these neonates. We conducted a retrospective cohort study of infants at ≥36 weeks' gestation, with d-TGA, with or without ventricular septal defects, admitted to our institution at 5 days of age or younger, between January 1, 2003 and October 1, 2012. Children with other cardiac abnormalities or other major comorbid conditions were excluded. Univariable and multivariable analyses were performed to determine the effects of age at operation on major morbidity and hospital reimbursement. A total of 140 infants met inclusion criteria. Reimbursement data were available for them through January 1, 2012 (n = 128). The mortality rate was 1.4% (n = 2). Twenty percent (n = 28) experienced a major morbidity. The median costs were $60,000, in 2012 dollars (range: $25,000 to $549,000). The median age at operation was 5 days (range: 1 to 12 days). For every day later that surgery was performed, beyond day of life 3, the odds of major morbidity increased by 47% (range: 23% to 66%, p < 0.001) and costs increased by 8% (range: 5% to 11%, p < 0.001), after considering the effects of sex, birth weight, gestational age, year at which surgery was performed, transfer, weekend admission, insurance, surgeon, septostomy, bypass and cross-clamp times, and the presence of ventricular septal defects or abnormal coronary anatomy. Delay of neonatal arterial switch operation beyond 3 days is significantly associated with increased morbidity and healthcare costs.


Tracheobronchial and esophageal foreign bodies in the pediatric population.
A foreign body lodged in the aerodigestive tract of a child often poses a difficult medical problem. Experience with the diagnosis and removal of these foreign bodies is presented in this retrospective review. The description by a witness of the actual ingestion frequently provided the key to diagnosis. Rigid endoscopy remains a safe technique for foreign body extraction with a low resultant morbidity and mortality. Organic matter comprises the majority of bronchial foreign bodies (70%) while coins are the predominant finding (80%) in the esophagus.


Uterus Allo-Transplantation in a Swine Model: Long-Term Graft Survival and Reproductive Function.
BACKGROUND The present study examined the feasibility and safety of allogeneic uterus transplantation (UTx) from a living donor and assessed long-term graft survival and the resumption of reproductive function in a swine model. MATERIAL AND METHODS Ten female miniature swine with regular menstrual cycles were used; the animals were either donors or recipients (n=5) depending on the sibling. Retrieval surgery included uterus and uterine arteries together with the anterior branches of the internal iliacs from the living donor; the vaginal canal was cut. After the back-table had been prepared, bilateral internal iliac arteries were anastomosed end-to-side with the external iliac arteries. The transplanted uterus was evaluated based on the arterial blood flow by transabdominal ultrasonography and observed by secondary laparotomy after surgery; estrus recovery was stimulated by mating with a male, and artificial embryo transfer was performed in healing swine. RESULTS All 5 pigs revealed successful surgery without any surgical complications, injuries to other organs, or unanticipated vascular injury. All recipients survived for >3 months after the surgery, except pig 5, which died due to uterus necrosis 3 days post-surgery. A 100% surgical success rate and 80% long-term survival rate of the receptor were observed. Pig 2 had temporary estrus resumed, and the artificial embryo was transplanted 3 months after surgery; however, apparent gestation was not found by ultrasonography. CONCLUSIONS This study evaluated the safety and feasibility of the technology of allogeneic UTx, which was performed only by transplant uterine artery system from living-donor surgery in a swine model. Laboratory animals can show long-term survival and resumed estrous after UTx, which can be monitored by ultrasonography to assess the arterial blood flow of the grafted uterus.


[Risk factors for fibrinoid reaction after posterior chamber lens implantation--a retrospective study].
Previous ocular diseases (e.g. herpetic keratouveitis), glaucoma, previous ocular surgery and surgery longer than normal turned out to be the main risk factors for a fibrinoid reaction after an extracapsular cataract extraction with posterior chamber lens implantation in patients of the Universitäts-Augenklinik Düsseldorf between June 1989 and March 1990. This result was obtained from a retrospective study of the medical records. No special risks could be concluded neither from the presence of general diseases (e.g. diabetes mellitus, consumptive basic diseases), immuno-suppressive treatment, constitutional factors, nor from age, sex, operative method nor from the surgeon. Preoperative antiexsudative prophylactic treatment is suggested for patients with one or more risk factor.


Transcriptomic analysis of the heat stress response for a commercial baker's yeast Saccharomyces cerevisiae.
The aim of this study is to explore the effects of heat stresses on global gene expression profiles and to identify the candidate genes for the heat stress response in commercial baker's yeast (Saccharomyces cerevisiae) by using microarray technology and comparative statistical data analyses. The data from all hybridizations and array normalization were analyzed using the GeneSpringGX 12.1 (Agilent) and the R 2.15.2 program language. In the analysis, all required statistical methods were performed comparatively. For the normalization step, among alternatives, the RMA (Robust Microarray Analysis) results were used. To determine differentially expressed genes under heat stress treatments, the fold-change and the hypothesis testing approaches were executed under various cut-off values via different multiple testing procedures then the up/down regulated probes were functionally categorized via the PAMSAM clustering. The results of the analysis concluded that the transcriptome changes under the heat shock. Moreover, the temperature-shift stress treatments show that the number of differentially up-regulated genes among the heat shock proteins and transcription factors changed significantly. Finally, the change in temperature is one of the important environmental conditions affecting propagation and industrial application of baker's yeast. This study statistically analyzes this affect via one-channel microarray data.


Antimalarial diterpenoids from Vitex rotundifolia: Isolation, structure elucidation, and in vitro antiplasmodial activity.
Vitex rotundifolia is an important medicinal plant frequently employed in traditional medicines for the treatment of various ailments. Although this plant species has been under exploration for its constituents by various research groups including our own group, no reports were found regarding the antimalarial potential of this plant or of its purified phytochemicals. Phytochemical investigation of this plant yielded three new (1-3) and five known (4-8) diterpenoids. These compounds were purified by modern chromatographic techniques and their structures were determined by advanced spectroscopic techniques such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The in vitro antiplasmodial activities were encouraging, as compounds 2, 6, and 8 were found to have significant IC50 values of 1.2, 1.3 and 11.0 µM, respectively against Plasmodium falciparum.


Biomarkers of Response to Smoking Cessation Pharmacotherapies: Progress to Date.
For the past 30 years, research examining predictors of successful smoking cessation treatment response has focused primarily on clinical variables, such as levels of tobacco dependence, craving, and self-efficacy. However, recent research has begun to determine biomarkers (such as genotype, nicotine and metabolite levels, and brain imaging findings) that may have utility in predicting smoking cessation. For genotype, genes associated with nicotinic acetylcholine receptors (nAChRs) and related proteins have been found to predict response to first-line medications (e.g. nicotine replacement therapy [NRT], bupropion, or varenicline) or quitting over time without a controlled treatment trial. For nicotine and metabolite levels, function of the cytochrome P450 2A6 liver enzyme, which can be assessed with the nicotine metabolite ratio or via genotype, has been found to predict response, with slow nicotine metabolizers having less severe nicotine dependence and a greater likelihood of quitting with NRT than normal metabolizers. For brain imaging, decreased activation of brain regions associated with emotion regulation and increased connectivity in emotion regulation networks, increased responsiveness to pleasant cues, and altered activation with the Stroop effect have been found in smokers who quit with the first-line medications listed above or counseling. In addition, our group recently demonstrated that lower pre-treatment brain nAChR density is associated with a greater chance of quitting smoking with NRT or placebo. Several of these studies found that specific biomarkers may provide additional information for predicting response beyond subjective symptom or rating scale measures, thereby giving an initial indication that biomarkers may, in the future, be useful for guiding smoking cessation treatment intensity, duration, and type.


Adaptation to a limiting element involves mitigation of multiple elemental imbalances.
About 20 elements underlie biology and thus constrain biomass production. Recent systems-level observations indicate that altered supply of one element impacts the processing of most elements encompassing an organism (i.e. ionome). Little is known about the evolutionary tendencies of ionomes as populations adapt to distinct biogeochemical environments. We evolved the bacterium Serratia marcescens under five conditions (i.e. low carbon, nitrogen, phosphorus, iron or manganese) that limited the yield of the ancestor compared with replete medium, and measured the concentrations and use efficiency of these five, and five other elements. Both physiological responses of the ancestor, as well as evolutionary responses of descendants to experimental environments involved changes in the content and use efficiencies of the limiting element, and several others. Differences in coefficients of variation in elemental contents based on biological functions were evident, with those involved in biochemical building (C, N, P, S) varying least, followed by biochemical balance (Ca, K, Mg, Na), and biochemical catalysis (Fe, Mn). Finally, descendants evolved to mitigate elemental imbalances evident in the ancestor in response to limiting conditions. Understanding the tendencies of such ionomic responses will be useful to better forecast biological responses to geochemical changes.


THE CONCENTRATION EFFECT IN NITELLA.
A METHOD DISTINGUISHING BETWEEN THE CONCENTRATION EFFECT DUE TO THE CELL WALL AND THAT DUE TO THE PROTOPLASM IS DESCRIBED: the importance of this lies in the fact that if the protoplasm shows a concentration effect one or both ions of the salt must tend to enter its outer surface. Studies on the concentration effect of KCl with living protoplasm of Nitella show that when P.D. is plotted as ordinates and the logarithm of concentration as abscissae the graph is not the straight line demanded in the ideal case by theory but has less slope and is somewhat concave to the axis of the abscissae. With a variety of salts the dilute solution is positive, which indicates that the cation has a greater mobility in the protoplasm than the anion or that the partition coefficient of the cation (A(c)) increases faster than that of the anion (A(a)) as the concentration increases. If the result depended on the partition coefficients we should say that when A(c) / A(a) increases with concentration the dilute solution is positive. When A(c) / A(a) decreases as the concentration increases the dilute solution is negative. In either case the increase in concentration may be accompanied by an increase or by a decrease in the relative amount of salt taken up. Theoretically therefore there need be no relation between the sign of the dilute solution and the relative amount of salt taken up with increasing concentration. Hypothetical diagrams of the electrical conditions in the cell are given. If we define the chemical effect as the P.D. observed in leading off at two points with equivalent concentrations of different salts we may say that the chemical effect of the protoplasm is very much greater than that of the cell wall.


Treatment of Acute Otitis Media in the Pediatric Emergency Department.
Over-treatment of acute otitis media (AOM) with antibiotics is common, and poses a high burden on health-care systems. Records of children 6-36 months of age with AOM visiting a university-affiliated pediatric emergency department between 2014 and 2016 were reviewed for the treatment given: watchful waiting versus antibiotics. If antibiotics were prescribed, the type and duration were recorded. We evaluated appropriate and inappropriate treatment rates of eligible AOM cases, in respect to the local guidelines, which encourage watchful waiting in most mild-moderate cases. Out of 1493 AOM visits, 863 (57.8%) were boys, with a median age of 14.9 months (interquartile range, 9-19). The overall pre-visit antibiotic rate was 24.1%, but among those children examined by a physician, this rate was 95.2%. Amoxicillin was the most common antibiotic, administered in 66.3% of the cases. Only 21 children (5.8%) had been treated with antibiotics for ≥7 days before their visit, and were considered as treatment failure. Antibiotic therapy upon discharge was recorded in 1394/1449 visits (96.2%), again with amoxicillin as the most common antibiotic therapy, in 80.8% of the cases. In these visits, the average duration of antibiotic treatment was 8.29 days. Appropriateness of treatment (watchful waiting or antibiotics) could be analyzed in 1134 visits; 20.9% were considered as inappropriate. Of them, 98.3% were prescribed with the wrong antibiotic type and duration. Adherence rate to the local guidelines treatment recommendations for uncomplicated AOM was high, as measured by whether appropriate treatment was given and type and duration of antibiotics.


Delivering nanomedicine to solid tumors.
Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.


Discontinuation of statin therapy and clinical outcome after ischemic stroke.
The majority of patients with previous ischemic stroke are expected to benefit significantly from long-term statin therapy. However, discontinuation of medication therapy frequently occurs in clinical practice. The aim of this study was to assess the impact of discontinued statin therapy on clinical outcome in patients discharged after an acute ischemic stroke. The study population included 631 consecutive stroke survivors (322 men and 309 women; mean+/-SD age, 70.2+/-7.6 years) without clinical evidence of coronary heart disease. All patients were discharged on statin therapy and were followed up for 12 months after the acute ischemic stroke. Within 12 months from discharge, 246 patients (38.9%) discontinued statin therapy; the mean time from discharge to statin discontinuation was 48.6+/-54.9 days (median time, 30 days; interquartile range, 18 to 55 days). During follow-up, 116 patients died (1-year probability of death=0.18; 95% CI, 0.15 to 0.21). Multivariate analysis demonstrated that after adjustment for all confounders and interactions, statin therapy discontinuation (hazard ratio=2.78; 95% CI, 1.96 to 3.72; P=0.003) was an independent predictor of all-cause 1-year mortality. A large number of patients discontinue their use of statins early after acute stroke. Moreover, patients discontinuing statins have a significantly increased mortality during the first year after the acute cerebrovascular event. These findings suggest that patient care should be improved during the transition from a hospital setting to outpatient primary care.


Holistic approach to analysis of medical data: vulvar cancer.
This paper continues the series of studies introducing holistic approach to analysis of clinical data. Namely, besides the information regarding his/her disease, each hospitalized cancer patient also provides the variety of data regarding his/her psychological, cultural, social, economical, genetic, constitutional and medical background. The aim of this study was to introduce a holistic approach to analysis of medical data, in this case clinical data regarding cancer of the vulva. Such approach requires the collection of data regarding different aspects of the cancer patients, and after the satisfactory sample size is obtained (which should be at least five times greater than the number of examined patient characteristics), the performance of factor analysis. In this study, the authors have processed the data regarding 25 characteristics of all 755 vulvar cancer patients treated between 1938 and 1990 at the Department for Gynecological Oncology of the University Hospital for Gynecology and Obstetrics, Zagreb, Croatia. In factor analysis, the principal components were rotated after the initial extraction (the authors recommended the use of oblimin rotation) in order to obtain better ground for interpretation of the obtained results. The next step in this approach was the stepwise exclusion of characteristics with smallest commonality according to Kaiser-Meyer-Olkin criteria, and retaining the characteristics and components with the most significant impact on the explained system variance. When the number of principal components and initial analyzed characteristics was reduced to 3-4 and 7-10, respectively, the ultimate interpretations and conclusions were made. This approach outlined some clusters of correlations between medical data which are difficult to identify using other statistical procedures, primarily the impacts of various socioeconomic and hereditary-constitutional variables on overall survival.


The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions.
Gastric cancer grows under a hypoxic environment. HIF-1α is known to play an important role in controlling the production of reactive oxygen species (ROS) in the mitochondria under hypoxic conditions. We previously established HIF-1α knockdown (KD) cells and control (SC) cells in the 58As9 gastric cancer cell line. In this study, we revealed that KD cells, but not SC cells, induced apoptosis under conditions of hypoxia (1% O2) due to excessive production of ROS. A quantitative RT-PCR analysis demonstrated that the expressions of ten genes, which are involved in the control mechanisms of ROS (including the Warburg effect, mitophagy, electron transport chain [ETC] modification and ROS scavenging), were regulated by HIF-1α. Moreover, the promotion of glucose uptake by glucose plus insulin (GI) treatment enhanced the apoptotic effect, which was accompanied by further ROS production in hypoxic KD cells. A Western blot analysis showed that the membranous expression of GLUT1 in KD cells was elevated by glucose and/or insulin treatments, indicating that the GI-induced glucose uptake is mediated by the increased translocation of GLUT1 on the cell membrane. Finally, the anti-tumor effect of HIF-1α knockdown (KD) plus GI was evaluated using a tumor xenograft model, where a hypoxic environment naturally exists. As a result, the GI treatment strongly inhibited the growth of the KD tumors whereby cell apoptosis was highly induced in comparison to the control treatment. In contrast, the growth of the SC tumors expressing HIF-1α was not affected by the GI treatment. Taken together, the results suggest that HIF-1α inhibition plus GI may be an ideal therapy, because the apoptosis due to the destruction of ROS homeostasis is specifically induced in gastric cancer that grows under a hypoxic environment, but not in the normal tissue under the aerobic conditions.


Biological and abiological sulfur reduction at high temperatures.
Reduction of elemental sulfur was studied in the presence and absencè of thermophilic sulfur-reducing bacteria, at temperatures ranging from 65 to 110 degrees C, in anoxic artificial seawater media. Above 80 degrees C, significant amounts of sulfide were produced abiologically at linear rates, presumably by the disproportionation of sulfur. These rates increased with increasing temperature and pH and were enhanced by yeast extract. In the same medium, the sulfur respiration of two recent thermophilic isolates, a eubacterium and an archaebacterium, resulted in sulfide production at exponential rates. Although not essential for growth, sulfur increased the cell yield in both strains up to fourfold. It is suggested that sulfur respiration is favored at high temperatures and that this process is not limited to archaebacteria, but is shared by other extreme thermophiles.


Clinical, serologic, and cross-challenge response and virus isolation in cattle infected with three bovine dermatotropic herpesviruses.
The relationship of 3 dermatotropic bovine herpes-viruses (bovine mamillitis herpesvirus, dermatotropic bovine herpesvirus, and Allerton virus) was investigated; special emphasis was on the clinical response and the development of complement-fixation and precipitating antibodies in cattle. The immune respnse in steers was determined throughout the disease and after challenge exposure of the steers with 1 of the other 2 herpesviruses. Blood samples and sections of skin were collected intermittently from infected animals and examined for presence of virus.


[The iberoamerican scientific production in nutritional sciences: the indexation in PubMed and Google Scholar].
Analyze by bibliometric technique, the Iberoamerican scientific literature related to the nutritional sciences and retrieved on main search engines with free access through Internet (PubMed and Google Scholar). Bibliometric analysis of scientific production recovered in the different selected search tools. The data were obtained by applying to each of them, a composed search equation according to the scheme: Population (neoplasms), Intervention (nutritional status), Outcome (quality of life). 789 references were reviewed, 604 of those were papers published in 277 journals, presenting 20 or more references: Supportive Care in Cancer 27 (4.47%; CI 95% 2.82-6.12) and Clinical Nutrition 20 (3.31%; CI 95% 1.88-4.74). Mean age of documents: 8.08 ± 6.40 (CI 95% 7.63-8.53), median 6 years (Burton Kleber Index), maximum 34 years and Price Index of 43.90%. The predominant geographical distribution among the authors was American, while the articles were written primarily in English. Dispersion of literature (Bradford Law): core (1st tertile), 22 journals (7.94%; CI 95% 4.76-11.13) with 202 articles published (33.44%; CI 95% 29.68-37.21). Statistics related to the impact factor of the core: mean 4.033 ± 4.022 and maximum 18,038 (Journal of Clinical Oncology). The studied thematic continues in force according to the current indicators, with a dominance of English as language of publication and United States filiation. The most referenced journals matching with high Impact publications on nutritional sciences and oncology. Highlighting the presence of an Iberoamerican journal (Nutrición Hospitalaria) with a clear international vocation.


Biliary manometry in dogs. Influence of selective electrostimulation of the right and left vagus nerves.
Acute biliary manometry was performed in 10 dogs during operation. The sphincter of Oddi was a high-pressure zone with phasic activity. No active contractions were observed either in the common bile duct or in the gallbladder. Electrostimulation of the right and left thoracic vagal branches increased bile flow, decreased the activity of the sphincter of Oddi and gallbladder pressure. Stimulation of the right vagus gave a more complex response as the initial inhibition of the activity of the sphincter of Oddi was followed by an increased motor activity. Intra-arterial cholecystokinin injection increased bile flow, inhibited the activity of the sphincter of Oddi, whereas gallbladder pressure remained unchanged.


Genomic footprints of dryland stress adaptation in Egyptian fat-tail sheep and their divergence from East African and western Asia cohorts.
African indigenous sheep are classified as fat-tail, thin-tail and fat-rump hair sheep. The fat-tail are well adapted to dryland environments, but little is known on their genome profiles. We analyzed patterns of genomic variation by genotyping, with the Ovine SNP50K microarray, 394 individuals from five populations of fat-tail sheep from a desert environment in Egypt. Comparative inferences with other East African and western Asia fat-tail and European sheep, reveal at least two phylogeographically distinct genepools of fat-tail sheep in Africa that differ from the European genepool, suggesting separate evolutionary and breeding history. We identified 24 candidate selection sweep regions, spanning 172 potentially novel and known genes, which are enriched with genes underpinning dryland adaptation physiology. In particular, we found selection sweeps spanning genes and/or pathways associated with metabolism; response to stress, ultraviolet radiation, oxidative stress and DNA damage repair; activation of immune response; regulation of reproduction, organ function and development, body size and morphology, skin and hair pigmentation, and keratinization. Our findings provide insights on the complexity of genome architecture regarding dryland stress adaptation in the fat-tail sheep and showcase the indigenous stocks as appropriate genotypes for adaptation planning to sustain livestock production and human livelihoods, under future climates.


Origin and Spread of HIV-1 Subtype B Among Heterosexual Individuals in Bulgaria.
Human immunodeficiency virus (HIV) was originally introduced in Bulgaria through heterosexual transmission (HET) and later transferred to other vulnerable groups along with numerous more recent introductions from outside Bulgaria. To define the diversity, origins, and dynamics of the HIV-1 subtypes prevalent in HET population in Bulgaria, we applied phylogenetic and phylodynamic analyses using polymerase (pol) sequences from HET individuals to infer the spatiotemporal evolutionary history of the HIV-1 epidemic in this population in Bulgaria. High genetic diversity was found, including 13 different HIV-1 subtypes: 45.7% subtype B, 19.9% CRF01_AE, 7.5% CRF02_AG, 7.5% sub-subtypes A1 and A6, 7.1% subtype C, 5.3% subtype F1, 4.0% URFs, 1.2% CRF05_DF, 0.6% subtype G, 0.3% CRF04_cpx, 0.3% CRF29_BF, 0.3% CRF14_BG, and 0.3% subtype H. The estimated root of the subtype B in the phylogenetic tree dated back to the year 1980 largely due to multiple introductions of subtype B from outside the country. Several significant clades have been identified highlighting six different main epidemic entrances of subtype B dating from 1989 to 2007. The Bayesian skyline plot showed two different exponential growth periods starting in the 1980s to 1990 followed by a constant phase up to about 2008, with another exponential growth period from 2008 to the year 2012. The migration analysis identified dynamic pattern of gene flow and demonstrated that many HET probably acquired the infection abroad (14.6%), while only (6.6%) of non-HET were infected outside country. The phylogenetic analysis showed an intermixing between sequences from Bulgarians with sequences from other countries, suggesting different HIV introduction in this country followed by the internal spread through local transmission networks.


Retinal hemorrhage and vacuum extraction delivery.
The purpose of this prospective study was to investigate whether there is an increased risk of retinal hemorrhage in those infants delivered with the assistance of the silastic vacuum extractor from mothers who were low-risk and who had normal labors. Ocular fundi of 38 term newborns (19 vacuum assisted deliveries, 19 spontaneous deliveries) were examined for retinal hemorrhage within 72 hours after delivery. The overall frequency of retinal hemorrhage was 21.1%, 31.6% with the vacuum extractor and 10.5% with a spontaneous delivery. The mode of delivery did influence the number of infants with hemorrhages in each category, however this was only statistically significant in primiparous patients. The prognostic significance of the degree of retinal hemorrhage was not assessed.


Organic cation/carnitine transporter OCTN2 (Slc22a5) is responsible for carnitine transport across apical membranes of small intestinal epithelial cells in mouse.
The organic cation/carnitine transporter OCTN2 is responsible for renal tubular reabsorption of its endogenous substrate, carnitine, although its physiological role in small intestine remains controversial. Here we present direct evidence for a predominant role of OCTN2 in small intestinal absorption of carnitine based on experiments with juvenile visceral steatosis (jvs) mice, which have a hereditary deficiency of the octn2 gene. Uptake of carnitine, assessed with an Ussing-type chamber system, from the apical surface of the small intestine was saturable and higher than that from the basal surface in wild-type mice, whereas carnitine uptake having these characteristics was almost absent in jvs mice. Saturable uptake of carnitine was also confirmed in isolated enterocytes obtained from wild-type mice, and the Km value obtained (approximately 20 microM) was close to that reported for carnitine uptake by human embryonic kidney 293 cells stably expressing mouse OCTN2 (Slc22a5). The carnitine uptake by enterocytes was decreased in the presence of various types of organic cations, and this inhibition profile was similar to that of mouse OCTN2, whereas uptake of carnitine was quite small and unsaturable in enterocytes obtained from jvs mice. Immunohistochemical and immunoprecipitation analyses suggested colocalization of OCTN2 with PDZK1, an adaptor protein that functionally regulates OCTN2. Immunoelectron microscopy visualized both OCTN2 and PDZK1 in microvilli of absorptive epithelial cells. These findings indicate that OCTN2 is predominantly responsible for the uptake of carnitine from the apical surface of mouse small intestinal epithelial cells, and it may therefore be a promising target for oral delivery of therapeutic agents that are OCTN2 substrates.


[Concentration of neuron- and non-neuron-specific enolase isoenzymes in different structures of the brains of mentally healthy subjects and schizophrenic patients].
Using immunoenzymic assays, the authors studied concentrations of two isoforms of the glycolytic enzyme enolase (neurospecific, NSE, and non-neurospecific, NNE) in different structures of the postmortem brain in mentally normal people (n = 15) and in schizophrenics (n = 9). In schizophrenic patients NSE concentrations were increased by 70% (p less than 0.001) in the sensory cortex and reduced by the same magnitude in the thalamus. Insignificant changes in their levels (by 15-20%, p less than 0.05) were also discovered in the temporal cortex (elevation), lymbic cortex and the hippocampus (decrease). Cerebral values of NNE in schizophrenic patients were virtually unaltered; a certain augmentation was detected only in the hippocampus. It is supposed that marked changes in NSE concentrations in the sensory cortex and in the thalamus are probably related to the pathological processes occurring in the neural tissue in schizophrenia.


Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study.
Early response to induction chemotherapy is used in current European guidelines to evaluate the efficacy of chemotherapy and subsequently to adapt treatment in pediatric patients with rhabdomyosarcoma (RMS). However, existing literature on the prognostic value of early radiologic response on survival is contradictory; here the prognostic value is analyzed with data from the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor 95 (MMT-95) study. This study examined 432 Intergroup Rhabdomyosarcoma Study Grouping III (macroscopic residue) patients enrolled in the SIOP MMT-95 study with a response assessment after 3 courses of chemotherapy (a 2-dimensional assessment). Patients with progressive disease (PD) after 3 courses of chemotherapy were excluded (n = 7). Failure-free survival (FFS) and overall survival (OS), calculated with the Kaplan-Meier method, were compared for 3 groups (complete response [CR]/partial response [PR], objective response [OR], and no response [NR]). The prognostic impact of early response was assessed through the calculation of Cox proportional hazards. After 3 courses of chemotherapy, 85.2% of the patients had CR/PR, 8.6% had OR, and 6.3% had NR. For all patients, the 5-year FFS and OS rates were 60% (95% confidence interval [CI], 56%-65%) and 74% (95% CI, 70%-78%), respectively. However, a Cox proportional hazards regression analysis revealed no significant difference in FFS or OS between the response groups. The adjusted hazard ratios for an OR and NR were 1.09 (95% CI, 0.63-1.88) and 0.81 (95% CI, 0.39-1.67), respectively, for FFS and 0.91 (95% CI, 0.47-1.76) and 1.27 (95% CI, 0.61-2.64), respectively, for OS. No evidence was found for the idea that early radiologic response to chemotherapy is prognostic for survival for patients with RMS. Treatment adaptation based on early response (except for patients with PD) should, therefore, no longer be incorporated into future studies. Cancer 2018;124:1016-24. © 2017 American Cancer Society.


Methylated DNA Markers of Esophageal Squamous Cancer and Dysplasia: An International Study.
Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.


Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats.
Heavy episodic drinking early in adolescence is associated with increased risk of addiction and other stress-related disorders later in life. This suggests that adolescent alcohol abuse is an early marker of innate vulnerability and/or binge exposure impacts the developing brain to increase vulnerability to these disorders in adulthood. Animal models are ideal for clarifying the relationship between adolescent and adult alcohol abuse, but we show that methods of involuntary alcohol exposure are not effective. We describe an operant model that uses multiple bouts of intermittent access to sweetened alcohol to elicit voluntary binge alcohol drinking early in adolescence (~postnatal days 28-42) in genetically heterogeneous male Wistar rats. We next examined the effects of adolescent binge drinking on alcohol drinking and anxiety-like behavior in dependent and non-dependent adult rats, and counted corticotropin-releasing factor (CRF) cell in the lateral portion of the central amygdala (CeA), a region that contributes to regulation of anxiety- and alcohol-related behaviors. Adolescent binge drinking did not alter alcohol drinking under baseline drinking conditions in adulthood. However, alcohol-dependent and non-dependent adult rats with a history of adolescent alcohol binge drinking did exhibit increased alcohol drinking when access to alcohol was intermittent. Adult rats that binged alcohol during adolescence exhibited increased exploration on the open arms of the elevated plus maze (possibly indicating either decreased anxiety or increased impulsivity), an effect that was reversed by a history of alcohol dependence during adulthood. Finally, CRF cell counts were reduced in the lateral CeA of rats with adolescent alcohol binge history, suggesting semi-permanent changes in the limbic stress peptide system with this treatment. These data suggest that voluntary binge drinking during early adolescence produces long-lasting neural and behavioral effects with implications for anxiety and alcohol use disorders.


Aqueous Proton Transportation in Graphene-Based Nanochannels.
Graphene oxide (GO) has been unveiled to exhibit high proton conductivity in a humidified or aqueous environment, making it a promising candidate to construct proton conduction nanochannels. In this work, we systematically investigate how the confinement effect and surface chemistry influence the proton transportation behavior in graphene-based nanochannels via extensive ReaxFF MD simulations. Graphene (GE), graphane (GA), and hydroxygraphane (HG) sheets were employed to mimic the graphitic and functionalized region of GO and construct nanochannels with different interlayer distances. We find that confined water molecules are stratified and their orientation is influenced by the surface chemistry, thus impacting the distribution of protons. Surface chemistry makes the compression of the hydrogen-bond network induced by the confinement effect more variable. The hydrogen-bond network between GE slabs is crushed by extreme confinement and ultrafast proton transportation behavior mainly achieved via vehicle mechanism. Meanwhile, the hydrogen-bond network and solvation structure can be kept more complete with the existence of functional groups. The hydrogen bonds formed with surface functional groups impede the transportation of water molecules but allow more Grotthuss hopping of protons to different extents. Our work clarified the proton transportation mechanism in graphene-based nanochannels with different interlayer distances and surface chemistry and can guide the future design of proton conduction devices such as proton exchange membranes.


[The effect of immersion baths on the length of childbirth labor].
The objectives of this experimental, randomized, controlled trial study were to evaluate the effect of immersion baths on the length of the first stage of childbirth labor and on the frequency and length of the uterine contractions. Data were collected in a philanthropic public maternity hospital of the city of São Paulo whose month average is 1,100 births. The sample was comprised of 108 women in labor--54 in the control group and 54 in the experimental group that had immersion baths. The results showed that immersion baths did not have any influence on the length of labor and on the frequency of uterine contractions. However, the length of contractions was statistically shorter in the experimental group (experimental 41.9 versus control 44.6 min). The conclusion was that immersion baths are an alternative for the woman's comfort during labor, since it provides relief to her without interfering on the labor progression or jeopardizing the baby.


Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.
Mutations within the mtrR gene are commonly found amongst multidrug resistant clinical isolates of Neisseria gonorrhoeae, which has been labelled a superbug by the Centers for Disease Control and Prevention. These mutations appear to contribute to antibiotic resistance by interfering with the ability of MtrR to bind to and repress expression of its target genes, which include the mtrCDE multidrug efflux transporter genes and the rpoH oxidative stress response sigma factor gene. However, the DNA-recognition mechanism of MtrR and the consensus sequence within these operators to which MtrR binds has remained unknown. In this work, we report the crystal structures of MtrR bound to the mtrCDE and rpoH operators, which reveal a conserved, but degenerate, DNA consensus binding site 5'-MCRTRCRN4YGYAYGK-3'. We complement our structural data with a comprehensive mutational analysis of key MtrR-DNA contacts to reveal their importance for MtrR-DNA binding both in vitro and in vivo. Furthermore, we model and generate common clinical mutations of MtrR to provide plausible biochemical explanations for the contribution of these mutations to multidrug resistance in N. gonorrhoeae. Collectively, our findings unveil key biological mechanisms underlying the global stress responses of N. gonorrhoeae.


Changes in Motor, Cognitive, and Behavioral Symptoms in Parkinson's Disease and Mild Cognitive Impairment During the COVID-19 Lockdown.
Objective: The effects of the COVID-19 lockdown on subjects with prodromal phases of dementia are unknown. The aim of this study was to evaluate the motor, cognitive, and behavioral changes during the COVID-19 lockdown in Italy in patients with Parkinson's disease (PD) with and without mild cognitive impairment (PD-MCI and PD-NC) and in patients with MCI not associated with PD (MCInoPD). Methods: A total of 34 patients with PD-NC, 31 PD-MCI, and 31 MCInoPD and their caregivers were interviewed 10 weeks after the COVID-19 lockdown in Italy, and changes in cognitive, behavioral, and motor symptoms were examined. Modified standardized scales, including the Neuropsychiatric Inventory (NPI) and the Movement Disorder Society, Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I and II, were administered. Multivariate logistic regression was used to evaluate associated covariates by comparing PD-NC vs. PD-MCI and MCInoPD vs. PD-MCI. Results: All groups showed a worsening of cognitive (39.6%), pre-existing (37.5%), and new (26%) behavioral symptoms, and motor symptoms (35.4%) during the COVID-19 lockdown, resulting in an increased caregiver burden in 26% of cases. After multivariate analysis, PD-MCI was significantly and positively associated with the IADL lost during quarantine (OR 3.9, CI 1.61-9.58), when compared to PD-NC. In the analysis of MCInoPD vs. PD-MCI, the latter showed a statistically significant worsening of motor symptoms than MCInoPD (OR 7.4, CI 1.09-45.44). Regarding NPI items, nighttime behaviors statistically differed in MCInoPD vs. PD-MCI (16.1% vs. 48.4%, p = 0.007). MDS-UPDRS parts I and II revealed that PD-MCI showed a significantly higher frequency of cognitive impairment (p = 0.034), fatigue (p = 0.036), and speech (p = 0.013) than PD-NC. On the contrary, PD-MCI showed significantly higher frequencies in several MDS-UPDRS items compared to MCInoPD, particularly regarding pain (p = 0.001), turning in bed (p = 0.006), getting out of bed (p = 0.001), and walking and balance (p = 0.003). Conclusion: The COVID-19 quarantine is associated with the worsening of cognitive, behavioral, and motor symptoms in subjects with PD and MCI, particularly in PD-MCI. There is a need to implement specific strategies to contain the effects of quarantine in patients with PD and cognitive impairment and their caregivers.


Patients Can Accurately Perform Their Own Rapid HIV Point-of-Care Test in the Emergency Department.
The objective of this study was to evaluate the feasibility, acceptability, and accuracy of having emergency department (ED) patients perform a rapid, point-of-care (POC) self-test for HIV before routine HIV testing. Patients aged 18 to 65 years were recruited to perform a rapid POC HIV oral fluid at The Johns Hopkins ED in conjunction with the standard-of-care HIV POC test. Acceptability and ease of use were assessed by a questionnaire. A total of 259 patients were approached for testing, and 249 (96.1%) consented to perform a self POC HIV test. Of patients performing a self-test, 100% had concordant results with those obtained by the health care worker. Four females (1.6%) were newly identified as HIV positive. Median participant age was 41 years, and 58% of patients were female; 83% were African American, and 16% were white. Overall, greater than 90% of patients reported trust of the test results, ease of testing, and willingness to test again. Approximately 35% of patients indicated they would pay up to a maximum price of $30 for testing. Overall, 46.9% of patients preferred self-testing, and 39.5% preferred health care professional testing. Regarding preferred location for testing, 51.0% preferred home self-testing, 39.5% preferred clinic/ED self-testing (P > 0.05), and 9.5% had no preference. A significant proportion of patients offered POC testing in the ED agreed to perform a self-HIV test. Patients' results were concordant with those obtained by the health care worker; 1.6% were HIV positive. The majority of participants believed the veracity of their results. A greater number of patients preferred self-testing.


Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice.
Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by gastrointestinal hamartomatous polyposis associated with mucocutaneous pigmentation. Germ-line mutations of the gene encoding LKB1 (STK11), a serine/threonine kinase, are identified in most PJS patients. To investigate the role of LKB1 in the PJS phenotypes, we introduced a germ-line mutation in the mouse Lkb1 gene by homologous recombination in mouse embryonic stem cells. In most Lkb1 (+/-) mice >20 weeks of age, hamartomatous polyps developed in the glandular stomach, often in the pyloric region. Small intestinal hamartomas also developed in approximately one-third of the Lkb1 (+/-) mice >50 weeks of age. A genomic PCR and sequence analysis showed that all hamartomas retained both the wild-type and targeted Lkb1 alleles, indicating that allelic loss of the wild-type Lkb1 was not the cause of polyp formation. Moreover, the LKB1 protein level was not reduced in hamartomatous polyps compared with that in the Lkb1 (+/-) normal gastric mucosa. In addition, the remaining allele showed neither missense mutations in the coding sequence nor produced truncated LKB1 in the hamartoma. Taken together, these data suggest that the wild-type Lkb1 is expressed in the hamartoma at the haploid amount. Accordingly, the gastrointestinal hamartomas appear to develop because of the Lkb1 haploinsufficiency. Although additional genetic events may be critical in hamartoma and adenocarcinoma development, these data strongly suggest that the initiation of polyposis is not the result of loss of heterozygosity in Lkb1.


Personalized pathway enrichment map of putative cancer genes from next generation sequencing data.
Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data. In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation. We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems.


Hot brines on los roques, Venezuela.
Solar heating of dense natural brines to 47 degrees C has been observed in a small lagoon in the Venezuelan Antilles and in an artificial brine reservoir in New York State. Calculations indicate that approximately 90 percent of the solar energy can be trapped in the brine by a combination of refraction and absorption. Brine ponds should be considered as solar energy collectors.


Splintless orthognathic surgery: a novel technique using patient-specific implants (PSI).
In the past few years, advances in three-dimensional imaging have conducted to breakthrough in the diagnosis, treatment planning and result assessment in orthognathic surgery. Hereby error-prone and time-consuming planning steps, like model surgery and transfer of the face bow, can be eluded. Numerous positioning devices, in order to transfer the three-dimensional treatment plan to the intraoperative site, have been described. Nevertheless the use of positioning devices and intraoperative splints are failure-prone and time-consuming steps, which have to be performed during the operation and during general anesthesia of the patient. We describe a novel time-sparing and failsafe technique using patient-specific implants (PSI) as positioning guides and concurrently as rigid fixation of the maxilla in the planned position. This technique avoids elaborate positioning and removal of manufactured positioning devices and allows maxillary positioning without the use of occlusal splints.


Mechanisms of Resistance to the Contact-Dependent Bacteriocin CdzC/D in Caulobacter crescentus.
The Cdz bacteriocin system allows the aquatic oligotrophic bacterium Caulobacter crescentus to kill closely related species in a contact-dependent manner. The toxin, which aggregates on the surfaces of producer cells, is composed of two small hydrophobic proteins, CdzC and CdzD, each bearing an extended glycine-zipper motif, that together induce inner membrane depolarization and kill target cells. To further characterize the mechanism of Cdz delivery and toxicity, we screened for mutations that render a target strain resistant to Cdz-mediated killing. These mutations mapped to four loci, including a TonB-dependent receptor, a three-gene operon (named zerRAB for zipper envelope resistance), and perA (for pentapeptide envelope resistance). Mutations in the zerRAB locus led to its overproduction and to potential changes in cell envelope composition, which may diminish the susceptibility of cells to Cdz toxins. The perA gene is also required to maintain a normal cell envelope, but our screen identified mutations that confer resistance to Cdz toxins without substantially affecting the cell envelope functions of PerA. We demonstrate that PerA, which encodes a pentapeptide repeat protein predicted to form a quadrilateral β-helix, localizes primarily to the outer membrane of cells, where it may serve as a receptor for the Cdz toxins. Collectively, these results provide new insights into the function and mechanisms of an atypical, contact-dependent bacteriocin system.IMPORTANCE Bacteriocins are commonly used by bacteria to kill neighboring cells that compete for resources. Although most bacteriocins are secreted, the aquatic, oligotrophic bacterium Caulobacter crescentus produces a two-peptide bacteriocin, CdzC/D, that remains attached to the outer membranes of cells, enabling contact-dependent killing of cells lacking the immunity protein CdzI. The receptor for CdzC/D has not previously been reported. Here, we describe a genetic screen for mutations that confer resistance to CdzC/D. One locus identified, perA, encodes a pentapeptide repeat protein that resides in the outer membrane of target cells, where it may act as the direct receptor for CdzC/D. Collectively, our results provide new insight into bacteriocin function and diversity.


A Comparison of Robotically Assisted Microsurgery versus Manual Microsurgery in Challenging Situations.
Microsurgery can be challenging secondary to orientation of the vessels, accessibility, or depth of the wound. Robotically assisted microsurgery reduces tremors and improves visualization and may improve the quality of anastomosis compared with traditional microsurgery. The purpose of this study was to compare robotically assisted microsurgery to traditional microsurgery in technically challenging situations with respect to time of anastomosis, quality of anastomosis, and Objective Structured Assessment of Technical Skills. Two investigators with no prior surgery or microsurgery experience performed 160 anastomoses on artificial microvessels after undergoing standardized traditional and robotically assisted microsurgery courses. Five different exposure groups were created with depths of 0, 10, and 20 cm and sidewall angles of 20 and 30 degrees. A comparison of 80 manual with 80 robotically assisted microsurgery anastomoses in different exposure groups was undertaken. The modified Objective Structured Assessment of Technical Skills scoring system, duration per anastomosis, and a subjective comfort scale were evaluated. In the most difficult exposure, Objective Structured Assessment of Technical Skills scores were similar in both groups (p = 0.98), the duration was higher in the manual group (p = 0.004), and the subjective comfort rating was higher in the robotically assisted microsurgery group (p < 0.001). In the easiest (0-cm depth, flat) exposure, Objective Structured Assessment of Technical Skills scores were higher in the manual group (p = 0.018) and the duration was longer in the robotically assisted microsurgery group (p = 0.008). Manual surgery was superior to robotically assisted microsurgery in technically easy exposures. In difficult exposures (greater depth and lower sidewall angles), however, robotically assisted microsurgery had a shorter surgery time and a higher comfort rating, with Objective Structured Assessment of Technical Skills scores similar to those assessing traditional microsurgery. Therapeutic, V.


Credentialing of vertebral stereotactic ablative body radiotherapy in a multi-centre trial.
Stereotactic ablative body radiotherapy (SABR) in multi-centre trials requires rigorous quality assurance to ensure safe and consistent treatment for all trial participants. We report results of vertebral SABR dosimetry credentialing for the ALTG/TROG NIVORAD trial. Centres with a previous SABR site visit performed axial film measurement of the benchmarking vertebral plan in a local phantom and submitted radiochromic film images for analysis. Remaining centres had on-site review of SABR processes and axial film measurement of the vertebral benchmarking plan. Films were analysed for dosimetric and positional accuracy: gamma analysis (>90% passing 2%/2mm/10% threshold) and ≤ 1 mm positional accuracy at target-cord interface was required. 19 centres were credentialed; 11 had on-site measurement. Delivery devices included linear accelerator, TomoTherapy and CyberKnife systems. Five centres did not achieve 90% gamma passing rate. Of these, three were out of tolerance (OOT) in low (<5Gy) dose regions and > 80% passing rate and deemed acceptable. Two were OOT over the full dose range: one elected not to remeasure; the other also had positional discrepancy greater than 1 mm and repeat measurement with a new plan was in tolerance. The original OOT was attributed to inappropriate MLC constraints. All centres delivered planned target-cord dose gradient within 1 mm. Credentialing measurements for vertebral SABR in a multi-centre trial showed although the majority of centres delivered accurate vertebral SABR, there is high value in independent audit measurements. One centre with inappropriate MLC settings was detected, which may have resulted in delivery of clinically unacceptable vertebral SABR plans.