Differential effects of passive immunization with somatostatin antiserum on adenohypophysial hormone secretions in starved rats.
The role of somatostatin (SRIF) on adenohypophysial hormone secretion in starved rats was reassessed by passive immunization. Because of the absence of pulsatile GH secretion in starved rats, the effects of the injection of SRIF antiserum on GH levels can be clearly demonstrated. To determine whether starvation modifies the sensitivity of the adenohypophysis to SRIF, we measured 125I-labelled iodo-N-Tyr-SRIF binding. There was no difference in the dissociation constant (Kd) nor in the maximal binding capacity (Bmax) in fed (n = 15) and starved (n = 15) animals (Kd = 0.38 +/- 0.09 (S.E.M.) and 0.45 +/- 0.09 nmol; Bmax = 204 +/- 39 and 205 +/- 30 fmol/mg protein respectively). Administration of SRIF antiserum resulted in a dose-dependent increase in plasma concentrations of GH, TSH and prolactin. The minimal effective dose of SRIF antiserum was 50 microliters for GH, 100 microliters TSH and 200 microliter for prolactin. Our results show that: starvation does not modify adenohypophysial SRIF-binding sites, in starved male rats endogenous SRIF exerts a negative control on prolactin secretion in vivo and sensitivity to endogenous SRIF seems to be different for each hypophysial cell type.


Unipolar terahertz pulse formation in a nonequilibrium plasma channel formed by an ultrashort uv laser pulse.
We perform an alternative approach to produce highly unipolar terahertz pulses. The idea is based on the nonuniform amplification of seed ultrashort carrier-envelope phase (CEP) pulses in nonequilibrium fast relaxing plasma of air or nitrogen. If the gain coefficient drops significantly within the duration of a one-cycle CEP pulse, it undergoes significant distortion where the leading edge of the pulse is amplified and the trailing tail of opposite polarity is absorbed. The obtained results involve a self-consistent solution of the second-order wave equation and kinetic Boltzmann equation for the electron velocity distribution function relaxation.


An investigation into the possible physiological roles of vascular alpha 1- and alpha 2-adrenoreceptors.
1 We have investigated the influence of chemical sympathectomy or bilateral adrenal demedullation on vasopressor responses produced by the alpha 1-adrenoreceptor agonist, phenylephrine, and the alpha 2-adrenoreceptor agonist, M-7, in pithed rats to see whether either procedure induced selective supersensitivity to either of these compounds. 5-HT, a tryptaminergic vasopressor agent, was also used to discriminate between nonspecific change in vascular responsiveness and those mediated via alpha-adrenoreceptors. 2 Adrenal demedullation caused a slight reduction in the sensitivity to all agonists. Chemical sympathectomy significantly reduced the vasopressor responses to all doses of phenylephrine, but responses to 5-HT were unchanged. In contrast there was a tendency for responses to M-7 to be greater in sympathectomized rats than in untreated rats. 3 It is concluded that circulating adrenal medullary catecholamines do not physiologically modulate vascular alpha-adrenoreceptor function. The differential effect of chemical sympathectomy on the vasopressor responses to phenylephrine and M-7 might be explained in terms of a small increase in the ratio of vascular alpha 2 : alpha 1-adrenoreceptors, that receive a noradrenergic innervation.


Primary cutaneous Langerhans cell histiocytosis in an adult.
An unusual adult case of Langerhans cell histiocytosis is presented. The case initially mimicked granuloma annulare, both clinically and histologically. The patient subsequently had development of extensive cutaneous involvement that pathologically revealed a diffuse infiltrate of CD1-positive histiocytic cells containing Langerhans granules. Extensive investigations failed to detect systemic involvement. The patient's cutaneous eruption did not respond to various therapeutic interventions, including phototherapy with oral psoralen with long-wave UV radiation in the A range (PUVA) and systemic vinblastine sulfate. Marked but temporary clinical and histologic improvement was achieved with total body electron beam radiotherapy. The nosology of this case is discussed in the context of the various histiocytic proliferative disorders.


Breast Arterial Calcification Is Not Associated with Mild Cognitive Impairment or Incident All-Cause Dementia Among Postmenopausal Women: The MINERVA Study.
Background: Since vascular risk factors are implicated in cognitive decline, and breast arterial calcification (BAC) is related to vascular risk, we postulated that BAC may be associated with cognitive impairment and dementia. Methods: We used a multiethnic cohort of 3,913 asymptomatic women 60-79 years of age recruited after mammography screening at a large health plan in 2012-2015. A BAC mass score (mg) was derived from digital mammograms. Cognitive function was measured at baseline using the Montreal Cognitive Assessment (MoCA) and incident all-cause dementia (n = 49 events; median follow-up = 5.6 years) were ascertained with validated ICD-9 and ICD-10 codes. We used cross-sectional linear regression of MoCA scores on BAC, then multinomial logistic regression predicting mild cognitive impairment not progressing to dementia and incident all-cause dementia and, finally, Cox regression of incident all-cause dementia. Results: No association by linear regression was found between MoCA scores and BAC presence in unadjusted or adjusted analysis. Women with severe (upper tertile) BAC had a MoCA score lower by 0.58 points (standard error [SE] = 0.18) relative to women with no BAC. However, this difference disappeared after multivariate adjustment. No significant associations were found in multinomial logistic regression for either BAC presence or gradation in unadjusted or adjusted analysis. No significant associations were found between BAC presence with incident all-cause dementia (fully adjusted hazard ratio = 0.74; 95% confidence interval: 0.39-1.39). Likewise, no significant association with incident all-cause dementia was noted for BAC gradation. Conclusions: Our results do not support the hypothesis that BAC presence or gradation may contribute to cognitive impairment or development of all-cause dementia.


Fostering Interdisciplinary Boundary Spanning in Health Communication: A Call for a Paradigm Shift.
Scholarship in the field of health communication is broad, with interdisciplinary contributions from researchers trained in a variety of fields including communication, nursing, medicine, pharmacy, public health, and social work. In this paper, we explore the role of "health communication boundary spanners" (HCBS), individuals whose scholarly work and academic appointment reflect dual citizenship in both the communication discipline and the health professions or public health. Using a process of critical reflective inquiry, we elucidate opportunities and challenges associated with HCBS across the spectrum of health communication in order to provide guidance for individuals pursuing boundary spanning roles and those who supervise and mentor them. This dual citizen role suggests that HCBS have unique skills, identities, perspectives, and practices that contribute new ways of being and knowing that transcend traditional disciplinary boundaries. The health communication field is evolving in response to the need to address significant healthcare and policy problems. No one discipline has the ability to single-handedly fix our current healthcare systems. Narrative data from this study illustrate the importance of seeing HCBS work beyond simply being informed by disciplinary knowledge. Rather, we suggest that adapting ways of knowing and definitions of expertise is an integral part of the solution to solving persistent health problems.


Reproducibility of urodynamic filling sensation at weekly interval in healthy volunteers and in women with detrusor overactivity.
To evaluate the reproducibility of bladder sensation during standardized filling cystometry in female volunteers and overactive bladder (OAB) patients, repeated with weekly interval. We recruited 13 female nulliparous volunteers (age 21-47) and 17 female patients with OAB between (age 18-72). They participated in three investigation periods, each separated by 7 days to assess reproducibility of sensation related to standardized cystometry. Subjects were asked to report all sensations they felt during bladder filling. The previously described pattern of sensation was reported during bladder filling in all. Consecutive sensations corresponded to statistically higher bladder volumes. Volumes, at which different sensations of bladder filling were reported, were significantly higher in controls than in OAB patients [first sensation of filling (FSF) P = 0.003, first desire to void (FDV) P < 0.0001, and strong desire to void (SDV) P < 0.0001]. The sensation/volume ratios were significantly higher in patients with OAB than in the healthy volunteers: FSF occurred at mean 46% and FDV at mean 73% of SDV in OAB patients, compared to 36% and 64% in healthy volunteers. Sensations proved highly reproducible when determined with weekly interval. Our data demonstrate that cystometric filling sensation determined in a standardized way with weekly interval is highly reproducible in healthy and in OAB patients. This finding has, in our opinion, clinical importance as it shows that the technique is reliable both for a sensory evaluation of the LUT as to study influence of treatment aimed at changing this sensation.


Calcium sulfate spinal cord scaffold: a study on degradation and fibroblast growth factor 1 loading and release.
Currently, there is no regenerative strategy for the spinal cord that is part of clinical standard of core. Current paths usually include combinations of scaffold materials and active molecules. In a recent study, a permanent dental resin scaffold for treatment of spinal cord injury was designed. The results from studies on rats were promising. However, for potential clinical use, a biodegradable scaffold material that facilitates drug delivery and the regeneration of the spinal cord needs to be developed. Also a biodegradable material is expected to allow a better evaluation of the efficacy of the surgical method. In this article, the suitability of hardened calcium sulfate cement (CSC) for use as degradable spinal cord scaffolds is investigated in bench studies and in vitro studies. Compressive strength, degradation and microstructure, and the loading capability of heparin-activated fibroblast growth factor 1 (FGF1) via soaking were evaluated. The CSC could easily be injected into the scaffold mold and the obtained scaffolds had sufficient strength to endure the loads applied during surgery. When hardened, the CSC formed a porous microstructure suitable for loading of active substances. It was shown that 10 min of FGF1 soaking was enough to obtain a sustained active FGF1 release for 20-35 days. The results showed that CSC is a promising material for spinal cord scaffold fabrication, since it is biodegradable, has sufficient strength, and allows loading and controlled release of active FGF1.


Sequential organ failure assessment score improves survival prediction for left ventricular assist device recipients in intensive care.
Preoperative risk scores facilitate patient selection, but postoperative risk scores may offer valuable information for predicting outcomes. We hypothesized that the postoperative Sequential Organ Failure Assessment (SOFA) score would predict mortality after left ventricular assist device (LVAD) implantation. We retrospectively reviewed data from 294 continuous-flow LVAD implantations performed at Mayo Clinic Rochester during 2007 to 2015. We calculated the EuroSCORE, HeartMate-II Risk Score, and RV Failure Risk Score from preoperative data and the APACHE III and Post Cardiac Surgery (POCAS) risk scores from postoperative data. Daily, maximum, and mean SOFA scores were calculated for the first 5 postoperative days. The area under receiver-operator characteristic curves (AUC) was calculated to compare the scoring systems' ability to predict 30-day, 90-day, and 1-year mortality. For the entire cohort, mortality was 5% at 30 days, 10% at 90 days, and 19% at 1 year. The Day 1 SOFA score had better discrimination for 30-day mortality (AUC 0.77) than the preoperative risk scores or the APACHE III and POCAS postoperative scores. The maximum SOFA score had the best discrimination for 30-day mortality (AUC 0.86), and the mean SOFA score had the best discrimination for 90-day mortality (AUC 0.82) and 1-year mortality (AUC 0.76). We observed that postoperative mean and maximum SOFA scores in LVAD recipients predict short-term and intermediate-term mortality better than preoperative risk scores do. However, because preoperative and postoperative risk scores each contribute unique information, they are best used in concert to predict outcomes after LVAD implantation.


Implementation science to reduce the prevalence and burden of MSK disorders following sport and exercise-related injury.
Although safety in sports and physical activity is an important prerequisite for continuing participation and maintenance of a healthy, physically active lifestyle, to date little effort has been placed upon moving evidence into preventive practice. Amongst researchers it is still often assumed that a program will disseminate itself after proven to be effective. Recently, however, there has been an increased recognition of the importance of theory-driven approaches to enhance implementation research. This manuscript aims to provide guidance for sports and physical activity injury researchers and practitioners to perform implementation research and practice. First, we will discuss the differences between research questions across the research spectrum and explain the 'drop' in effect when moving controlled evidence to a practical context. We will discuss two ways of increasing real-world effectiveness of preventive programs, i.e. through targeting the users' behaviour or through revising the intervention. Finally, we will present various implementation frameworks and tools that can guide the reader in their own efforts towards implementation practice and research.


Methoxychlor and fenvalerate induce neuronal death by reducing GluR2 expression.
GluR2, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors. Treatment of cultured rat cortical neurons with 1 or 10 µM methoxychlor and fenvalerate for 9 days selectively decreased GluR2 protein expression; the expression of other AMPA receptor subunits GluR1, GluR3, and GluR4 did not change under the same conditions. Importantly, the decreases in GluR2 protein expression were also observed on the cell surface membrane where AMPA receptors typically function. In addition, both chemicals decreased neuronal viability, which was blocked by pretreatment with 1-naphtylacetylspermine, an antagonist of GluR2-lacking AMPA receptors, and MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. These results suggest that long-term exposure to methoxychlor and fenvalerate decreases GluR2 protein expression, leading to neuronal death via overactivation of GluR2-lacking AMPA and NMDA receptors.


Beta-adrenergic blockade exacerbates sepsis-induced changes in tumor necrosis factor alpha and interleukin-6 in skeletal muscle and is associated with impaired translation initiation.
Sepsis stimulates the sympathetic nervous system. The resultant elevation in plasma catecholamines, both norepinephrine and epinephrine (Epi), might be expected to alter the expression of inflammatory cytokines, which may directly or indirectly influence muscle protein balance. The purpose of this study was twofold: (1) determine whether Epi per se increases cytokine expression in skeletal muscle, and (2) determine whether beta-adrenergic blockade alters the sepsis-induced expression of inflammatory cytokines and mediators of protein balance in skeletal muscle. In the first study, rats were infused with Epi for 2 hour to increase the circulating Epi concentration to levels seen in septic animals. In the second study, sepsis was induced by cecal ligation and puncture and a nonspecific beta-adrenergic blockade produced with a continuous infusion of propranolol (PP). Tissues were obtained 24 after induction of sepsis and analyzed for tumor necrosis factor (TNF)-alpha interleukin (IL)-1beta, IL-6 mRNA and protein content. In addition, the tissue content of insulin-like growth factor (IGF)-I and various regulators of protein synthesis were assessed. Epi acutely increased TNF-alpha IL-6 and IL-1beta mRNA content in muscle (3- to 40-fold). However, only the TNF-alpha and IL-6 protein content was increased in muscle by Epi. In the second study, beta-adrenergic blockade with PP exacerbated the sepsis-induced increase in muscle IL-6 and TNF-alpha mRNA but did not alter the increment in IL-1beta or HMGB1. Propranolol also accentuated the sepsis-induced increase in both IL-6 and TNF-alpha protein in muscle. The exaggerated muscle cytokine response in septic rats treated with PP was associated with a reduction in muscle IGF-I protein that was greater than detected in saline-infused septic rats. Finally, the combination of sepsis + PP also accentuated the sepsis-induced decrease in the phosphorylation of 4E-binding protein-1, ribosomal protein S6, and mTOR, which are key proteins controlling protein synthesis. These results demonstrate that although Epi is capable of increasing tissue cytokines in naive rats, inhibition of the beta-adrenergic effects of catecholamines exacerbates the sepsis-induced increase of selected inflammatory cytokines. This exaggerated tissue response is associated with alterations in muscle IGF-I protein and translation initiation, which would be expected to impair tissue protein synthesis.


Identification of multiple vasotocin receptor cDNAs in teleost fish: sequences, phylogenetic analysis, sites of expression, and regulation in the hypothalamus and gill in response to hyperosmotic challenge.
Vasopressin and its homolog vasotocin regulate hydromineral balance, stress responses, and social behaviors in vertebrates. In mammals, the functions of vasopressin are mediated via three classes of membrane-bound receptors: V1a-type, V1b-type and V2-type. To date, however, only a single class of vasotocin receptor has been identified in teleost fish. Here, cDNAs encoding three putative vasotocin receptors - two distinct V1a-type receptor paralogs (V1a1 and V1a2) and a previously undescribed V2-type receptor (V2) - and a single isotocin receptor were isolated and sequenced from the Amargosa pupfish (Cyprinodon nevadensis amargosae). RT-PCR revealed that mRNAs for these receptors differed in expression patterns with V1a1 mRNAs abundant in the brain, pituitary and testis, V1a2 transcripts at greatest levels in brain, heart and muscle, V2 transcripts most common in the gills, heart and kidney, and isotocin receptor mRNAs abundant in the midbrain, pituitary and gonads. In response to an acute hyperosmotic challenge, pro-vasotocin and V2 mRNA levels in the hypothalamus decreased, while transcripts of V1a1 in the hypothalamus and V1a2 in the gills increased. Partial transcripts for structurally related V2-type, as well as multiple V1a-type, receptors were also identified in other teleosts, suggesting that multiple vasotocin receptors may be present in many Actinopterygii fishes.


Assessment of chronic exposure to cigarette smoke and its change during pregnancy by segmental analysis of maternal hair nicotine.
This study aimed to investigate the association between biomarkers of fetal exposure to smoking during the whole pregnancy, nicotine in maternal and newborns hair samples, and quantitative measurement of smoking intake and exposure evaluated by maternal self-reported questionnaire. Study subjects were 150 mothers and their newborns from a hospital in Barcelona. A questionnaire including smoking habits was completed in the third trimester of pregnancy and on the day of delivery. Nicotine content was measured in two subsequent segments of maternal hair accounting for the first and last months of pregnancy, and in fetal hair. The geometric mean of nicotine concentration in maternal hair discriminated between nonexposition (3.84 and 2.80 ng/mg in distal and proximal hair segment, respectively) and exposition to cigarette smoke during pregnancy (6.06 and 4.30 ng/mg in distal and proximal hair segment, respectively) (P<0.05), and between these two classes and active smoking (14.40 and 11.08 ng/mg in distal and proximal hair segment, respectively). Maternal hair nicotine was able to differentiate levels of exposure to tobacco smoke and levels of intake. Nicotine concentration in hair from newborns did not differentiate between exposure and nonexposure to environmental tobacco smoke (ETS) in nonsmoking mothers. Finally, chronic exposure to cigarette smoke during pregnancy, assessed by maternal hair nicotine, correlated negatively with anthropometric parameters of newborns.


The effect of the duration of exposure to the electromagnetic field emitted by mobile phones on human attention.
Previous findings suggested the facilitating effect of the electromagnetic field emitted by mobile phones on human attention. This study aimed to examine the relationship between the facilitating effect and the duration of exposure to the electromagnetic field emitted by mobile phones on human attention. Seventy-eight university students were randomly assigned to either an experimental or a control group. Their performance in the administered attention tasks was compared. Participants in the experimental group performed better on one of the two measures of attention only after they had been exposed to the electromagnetic field emitted by the mobile phone for some time. The results seem to suggest that attention functions may be differentially enhanced after exposing to the electromagnetic field emitted by mobile phones. Furthermore, this transient facilitation effect might be dose dependent.


Imaging of insulinlike growth factor type 1 receptor in prostate cancer xenografts using the affibody molecule 111In-DOTA-ZIGF1R:4551.
One of the pathways leading to androgen independence in prostate cancer involves upregulation of insulinlike growth factor type 1 receptor (IGF-1R). Radionuclide imaging of IGF-1R in tumors might be used for selection of patients who would most likely benefit from IGF-1R-targeted therapy. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of IGF-1R expression in prostate cancer xenografts using a small nonimmunoglobulin-derived binding protein called an Affibody molecule. The IGF-1R-binding Z(IGF1R:4551) Affibody molecule was site-specifically conjugated with a maleimido derivative of DOTA and labeled with (111)In. The binding of radiolabeled Z(IGF1R:4551) to IGF-1R-expressing cells was evaluated in vitro and in vivo. DOTA-Z(IGF1R:4551) can be stably labeled with (111)In with preserved specific binding to IGF-1R-expressing cells in vitro. In mice, (111)In-DOTA-Z(IGF1R:4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung, and salivary gland). Receptor saturation experiments demonstrated that targeting of DU-145 prostate cancer xenografts in NMRI nu/nu mice was IGF-1R-specific. The tumor uptake was 1.1 ± 0.3 percentage injected dose per gram, and the tumor-to-blood ratio was 3.2 ± 0.2 at 8 h after injection. This study demonstrates the feasibility of in vivo targeting of IGF-1R-expressing prostate cancer xenografts using an Affibody molecule. Further development of radiolabeled Affibody molecules might provide a useful clinical tool for stratification of patients with prostate cancer for IGF-1R-targeting therapy.


Assessment of Climate-sensitive Infectious Diseases in the Federated States of Micronesia.
The health impacts of climate change are an issue of growing concern in the Pacific region. Prior to 2010, no formal, structured, evidence-based approach had been used to identify the most significant health risks posed by climate change in Pacific island countries. During 2010 and 2011, the World Health Organization supported the Federated States of Micronesia (FSM) in performing a climate change and health vulnerability and adaptation assessment. This paper summarizes the priority climate-sensitive health risks in FSM, with a focus on diarrheal disease, its link with climatic variables and the implications of climate change. The vulnerability and adaptation assessment process included a review of the literature, extensive stakeholder consultations, ranking of climate-sensitive health risks, and analysis of the available long-term data on climate and climate-sensitive infectious diseases in FSM, which involved examination of health information data from the four state hospitals in FSM between 2000 and 2010; along with each state's rainfall, temperature and El Niño-Southern Oscillation data. Generalized linear Poisson regression models were used to demonstrate associations between monthly climate variables and cases of climate-sensitive diseases at differing temporal lags. Infectious diseases were among the highest priority climate-sensitive health risks identified in FSM, particularly diarrheal diseases, vector-borne diseases and leptospirosis. Correlation with climate data demonstrated significant associations between monthly maximum temperature and monthly outpatient cases of diarrheal disease in Pohnpei and Kosrae at a lag of one month and 0 to 3 months, respectively; no such associations were observed in Chuuk or Yap. Significant correlations between disease incidence and El Niño-Southern Oscillation cycles were demonstrated in Kosrae state. Analysis of the available data demonstrated significant associations between climate variables and climate-sensitive infectious diseases. This information should prove useful in implementing health system and community adaptation strategies to avoid the most serious impacts of climate change on health in FSM.


Angiographic Dissection Patterns and Patency Outcomes After Balloon Angioplasty for Superficial Femoral Artery Disease.
To investigate the angiographic dissection patterns after balloon angioplasty for superficial femoral artery (SFA) lesions, the clinical outcome associated with each dissection pattern, and the predictive factors for severe dissection. A retrospective, multicenter analysis examined 621 patients (mean age 72.8±9.5 years; 414 men) with 748 symptomatic de novo SFA lesions treated with endovascular therapy. Vessel dissection after the initial balloon angioplasty procedure was graded into 7 types according to a modified version of the coronary artery classification types A to F. Severe vessel dissection patterns were defined as type C or higher. Nitinol stent implantation was performed in 555 (74.2%) lesions for residual stenosis >30% or flow-limiting dissection; 193 lesions (25.8%) were treated with balloon angioplasty only. To determine the clinical outcomes associated with each dissection pattern and identify predictive factors for severe dissection, 2-year follow-up data for the 193 lesions treated with balloon angioplasty only were analyzed for primary patency and clinically driven target lesion revascularization (TLR). No dissection was found in 16% (120/748) of lesions, and types A and B dissections were seen in 19% (142/748) and 23% (172/748), respectively. Dissection grades above type C were observed in 42% of cases, most frequently type D (180/748, 24%) and less often type C (37/748, 5%), type E (67/748, 9%), and type F (30/748, 4%). The bailout stent implantation rate increased according to dissection severity. At up to 2 years, the severe dissection group (types C-F) showed a significantly lower patency rate (p<0.001) and higher clinically driven TLR (p<0.001) compared to the nonsevere group (no dissection and types A and B dissections). Severe dissection was a significant risk factor for restenosis, which rose progressively from types C to F. Multivariate analysis identified a small reference vessel diameter <5 mm (p=0.001), lesion length >15 cm (p=0.001), and chronic total occlusion (p<0.001) as independent predictors of severe dissection. In subgroup analysis, vessels with a small reference diameter and TASC II C and D lesions had a higher prevalence of severe dissection. Severe dissection was found in 42% of cases after PTA. A small vessel diameter and/or TASC II C/D lesions were related to a high incidence of dissection. Severe dissection during procedures employing balloon angioplasty only could affect long-term patency.


Treatment of petroleum hydrocarbon polluted environment through bioremediation: a review.
Bioremediation play key role in the treatment of petroleum hydrocarbon contaminated environment. Exposure of petroleum hydrocarbon into the environment occurs either due to human activities or accidentally and cause environmental pollution. Petroleum hydrocarbon cause many toxic compounds which are potent immunotoxicants and carcinogenic to human being. Remedial methods for the treatment of petroleum contaminated environment include various physiochemical and biological methods. Due to the negative consequences caused by the physiochemical methods, the bioremediation technology is widely adapted and considered as one of the best technology for the treatment of petroleum contaminated environment. Bioremediation utilizes the natural ability of microorganism to degrade the hazardous compound into simpler and non hazardous form. This paper provides a review on the role of bioremediation in the treatment of petroleum contaminated environment, discuss various hazardous effects of petroleum hydrocarbon, various factors influencing biodegradation, role of various enzymes in biodegradation and genetic engineering in bioremediation.


The relationship between resistin and ghrelin levels with fibrosis in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. It is generally accepted that insulin resistance is a pathophysiological factor in the development of NAFLD. In the present study, the aim was to determine the relationship between resistin and ghrelin levels, which were found to be closely related to insulin resistance and fibrosis scores in NAFLD. A total of 40 (21 male, 19 female) NAFLD patients whose diagnosis was confirmed with biopsy and 40 (18 male, 22 female) healthy controls were included in the study. In the comparison of resistin and ghrelin levels, only resistin values were found to be significantly higher in NAFLD group while there was no significant difference in ghrelin values (respectively P < 0.05; P = 0.078). In according to the fibrosis groups there was no difference about fasting plasma glucose, insulin values, Homeostatic Measurement Assessment-Insulin Resistance measurements and also resistin and ghrelin levels. It has been understood that insulin resistance plays an important part in NAFLD. Larger studies are required that investigate the gene expression of hormones influencing insulin resistance, particularly resistin and ghrelin in order to determine their role in NAFLD.


Dicyanamide Anion-Based Ionic Liquid-Functionalized Graphene-Supported Pt Catalysts for Boosting Methanol Electrooxidation.
As an environmentally friendly energy technology, direct methanol fuel cells (DMFCs) meet the needs of sustainable development. Herein, novel dicyanamide anion-based (N(CN)2-) ionic liquid (IL)-functionalized reduced graphene oxide (rGO)-supported Pt catalysts are synthesized via a facile one-pot room temperature reduction method, which show a boost in methanol oxidation performance compared with Pt/rGO. The mass activities of the as-prepared Pt/emimN(CN)2/rGO (863.6 mA mg-1Pt) and Pt/epyN(CN)2/rGO (524.9 mA mg-1Pt) are about five and three times higher than that of Pt/rGO (178.6 mA mg-1Pt), and about six and four times higher than that of Pt/C (140.2 mA mg-1Pt), respectively. The participation of ILs significantly improves the CO poisoning resistance, stability, and activity for methanol oxidation of catalysts. The relationship between the structures and conductivities of diverse ILs and the performance of Pt catalysts are studied systematically. These findings may offer a promising prospect of ILs in DMFCs.


Comparison of Nonlinear Mixed Effects Models and Noncompartmental Approaches in Detecting Pharmacogenetic Covariates.
Genetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the pharmacokinetics (PK) of a compound under development having a nonlinear bioavailability along with genotypes for 176 single nucleotide polymorphisms (SNPs). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H1), six SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario, 200 PK data sets were simulated under the null hypothesis (no gene effect) and H1. We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others.


A rare case of squamous cell carcinoma lung with multiple locoregional recurrences and histological transformation.
A 52-year-old female nonsmoker with localized squamous cell carcinoma (T3N1M0) of lung underwent lobectomy with adjuvant chemotherapy. Two years later, the patient had her first locoregional recurrence with adenosquamous cell carcinoma, and pneumonectomy with adjuvant chemotherapy rendered her disease free. Subsequent isolated locoregional recurrence with squamous cell carcinoma 18 months later was treated with chemoradiotherapy and had a complete response. Patient yet again had locoregional recurrence after 4 years and had progressive disease despite subsequent multiple line of treatment with platinum-based chemotherapy, stereotactic body radiation therapy, and nivolumab. This case is unique in presentation due to prolonged survival with multiple line of treatment of recurrent locoregional tumor without distant metastasis and alteration in the histology of tumor during illness.


Genetic distances based on quantitative traits.
Morphological data showing continuous distributions, polygenically controlled, may be particularly useful in intergroup classification below the species level; an appropriate distance analysis based on these traits is an important tool in evolutionary biology and in plant and animal breeding.--The interpretation of morphological distances in genetic terms is not easy because simple phenotypic data may lead to biased estimates of genetic distances. Convenient estimates can be obtained whenever it is possible to breed populations according to a suitable crossing design and to derive information from genetic parameters.--A general method for determining genetic distances is proposed. The procedure of multivariate analysis of variance is extended to estimate appropriate genetic parameters (genetic effects). Not only are optimal statistical estimates of parameters obtained but also the procedure allows the measurement of genetic distances between populations as linear functions of the estimated parameters, providing an appropriate distance matrix that can be defined in terms of these parameters. The use of the T2 statistic, defined in terms of the vector of contrasts specifying the distance, permits the testing of the significance of any distance between any pair of populations that may be of interest from a genetic point of view.--A numerical example from maize diallel data is reported in order to illustrate the procedure. In particular, heterosis effects are used as the basis for estimates of genetic divergence between populations.


Coexpression of cholesterol sulfate and cytokeratin as tumor markers in well-differentiated squamous cell carcinoma of the human uterine cervix.
The expression of cholesterol sulfate (CS) is known to increase during squamous differentiation of keratinocytes and to activate the epsilon, eta, and zeta forms of protein kinase C as a signal transduction molecule for the subsequent expression of transglutaminase-1 (TG-1) and cytokeratins. To gain further insight into the regulation of cellular differentiation and tumorigenesis by CS, we examined the concentration and the potential for synthesis of CS in seven and four surgical specimens from human ovarian and uterine cervical cancer patients, respectively, and eight cell lines established from human uterine cervical cancer patients and compared them for the rate of expression of cytokeratin. CS was present in all of the uterine cervical cancer tissue specimens but only in the mucinous type of cystadenocarcinoma among ovarian cancer tissue specimens, and cytokeratin was highly expressed in the tissues with a high concentration of CS, which were classified as well-differentiated on the basis of morphological examination. Similarly, cells derived from a keratinizing type of well-differentiated cervical carcinoma demonstrated strong potential for synthesis of CS, stained positive with anti-cytokeratin antibody, and exhibited a higher specific activity of TG-1, whereas the cells without CS did not stain positive with anti-cytokeratin antibody and exhibited a lower specific activity of TG-1. These findings indicate that CS is coexpressed with TG-1 and cytokeratin in the well-differentiated types of squamous cell cancers as a tumor marker.


Reducing the duration of mechanical ventilation: three examples of change in the intensive care unit.
Mechanical ventilation is one of the most common medical therapies administered within ICUs. Similarly, the "weaning" or "liberation" of patients from mechanical ventilation is a common and extremely important task performed in ICUs and specialized ventilator units within hospitals. Various methods exist for assessing a patient's readiness to be liberated from mechanical ventilation and for conducting the weaning process. Clinicians working in ICUs frequently develop their own personal preferences regarding the best approach to weaning patients from ventilatory support. Therefore, variability in the practice of weaning patients from mechanical ventilation is frequently demonstrated, even within a single ICU. Recently, several randomized clinical trials have produced conflicting results regarding the best technique for carrying out the weaning process (e.g., spontaneous breathing trials, intermittent mandatory ventilation, pressure-support ventilation). Such conflicting findings have further illustrated the complexity of the weaning process and the difficulties in identifying the "best" medical practices for carrying out this endeavor. However, other investigations have suggested that the selection of an individual technique for weaning patients from mechanical ventilation may not be as important as employing a systematic approach to this medical process. Protocol-guided weaning of mechanical ventilation in the ICU setting, often performed by nonphysicians, has gained in acceptance as a result of these investigations. We describe the recent experiences of three ICUs which have demonstrated significant improvements in patient outcomes (e.g., shorter durations of mechanical ventilation, lower incidence of ventilator-associated pneumonia, fewer patient complications) as a result of implementing formal weaning protocols. Our hope is that these data will assist other hospitals in developing their own systematic guidelines and protocols for weaning patients from mechanical ventilation.


Failure mode classification for tumor endoprostheses: retrospective review of five institutions and a literature review.
Massive endoprostheses provide orthopaedic oncologists with many reconstructive options after tumor resection, although failure rates are high. Because the number of these procedures is limited, failure of these devices has not been studied or classified adequately. This investigation is a multicenter review of the use of segmental endoprostheses with a focus on the modes, frequency, and timing of failure. Retrospective reviews of the operative databases of five institutions identified 2174 skeletally mature patients who received a large endoprosthesis for tumor resection. Patients who had failure of the endoprosthesis were identified, and the etiology and timing of failure were noted. Similar failures were tabulated and classified on the basis of the risk of amputation and urgency of treatment. Statistical analysis was performed to identify dependent relationships among mode of failure, anatomic location, and failure timing. A literature review was performed, and similar analyses were done for these data. Five hundred and thirty-four failures were identified. Five modes of failure were identified and classified: soft-tissue failures (Type 1), aseptic loosening (Type 2), structural failures (Type 3), infection (Type 4), and tumor progression (Type 5). The most common mode of failure in this series was infection; in the literature, it was aseptic loosening. Statistical dependence was found between anatomic location and mode of failure and between mode of failure and time to failure. Significant differences were found in the incidence of failure mode Types 1, 2, 3, and 4 when polyaxial and uniaxial joints were compared. Significant dependence was also found between failure mode and anatomic location in the literature data. There are five primary modes of endoprosthetic failure, and their relative incidences are significantly different and dependent on anatomic location. Mode of failure and time to failure also show a significant dependence. Because of these relationships, cumulative reporting of segmental failures should be avoided because anatomy-specific trends will be missed. Endoprosthetic design improvements should address failure modes specific to the anatomic location.


[Heart arrest during fibro-bronchoscopic intubation in a patient with parapharyngeal space neoplasia].
A 37-year-old woman a diagnosis of squamous carcinoma of the tongue and a history of partial/hemiglossectomy with cervical lymphadenectomy and postoperative radiotherapy was scheduled for biopsy under general anesthesia given the suspicion of local recurrence. She underwent routine preparation for intubation with a fiberoptic bronchoscope with topical anesthesia of mucosal tissue without sedation. Syncope and asystole presented suddenly during intubation and external cardiopulmonary resuscitation and difficult ventilation through a face mask were necessary. She was finally intubated using a retrograde technique and recovered heartbeat after 20 minutes. No neurological sequelae were observed over the next few days. The etiologic diagnosis of this rare complication was later based on the appearance of the characteristic clinical profile of glossopharyngeal neuralgia-asystole syndrome in combination with parapharyngeal space lesion syncope syndrome; magnetic resonance findings of extensive neoplastic invasion of the space confirmed the diagnosis. Endotracheal intubation with a fiberoptic bronchoscope plays an important role in the management of the anticipated difficult airway. It is safe in the awake patient and facilitates the identification of structures, particularly when there are anatomical alterations due to neoplastic invasion, surgery, or radiotherapy. In the patient we describe, however, stimulation caused asystole.


Clinical utility of bone markers in various diseases.
Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis.


Cost savings from reduced catheter-related bloodstream infection after simulation-based education for residents in a medical intensive care unit.
Interventions to reduce preventable complications such as catheter-related bloodstream infections (CRBSI) can also decrease hospital costs. However, little is known about the cost-effectiveness of simulation-based education. The aim of this study was to estimate hospital cost savings related to a reduction in CRBSI after simulation training for residents. This was an intervention evaluation study estimating cost savings related to a simulation-based intervention in central venous catheter (CVC) insertion in the Medical Intensive Care Unit (MICU) at an urban teaching hospital. After residents completed a simulation-based mastery learning program in CVC insertion, CRBSI rates declined sharply. Case-control and regression analysis methods were used to estimate savings by comparing CRBSI rates in the year before and after the intervention. Annual savings from reduced CRBSIs were compared with the annual cost of simulation training. Approximately 9.95 CRBSIs were prevented among MICU patients with CVCs in the year after the intervention. Incremental costs attributed to each CRBSI were approximately $82,000 in 2008 dollars and 14 additional hospital days (including 12 MICU days). The annual cost of the simulation-based education was approximately $112,000. Net annual savings were thus greater than $700,000, a 7 to 1 rate of return on the simulation training intervention. A simulation-based educational intervention in CVC insertion was highly cost-effective. These results suggest that investment in simulation training can produce significant medical care cost savings.


Biomechanical analysis of cervical orthoses in flexion and extension: a comparison of cervical collars and cervical thoracic orthoses.
The analysis of current cervical collars (Aspen and Miami J collars) and cervical thoracic orthoses (CTOs) (Aspen 2-post and Aspen 4-post CTOs) in reducing cervical intervertebral and gross range of motion in flexion and extension was performed using 20 normal volunteer subjects. The gross sagittal motion of the head was measured relative to the horizon with the use of an optoelectronic motion measurement system. Simultaneous measurement of cervical intervertebral motion was performed with the use of a video fluoroscopy (VF) machine. Intervertebral motion was described as (1) the angular motion of each vertebra and (2) the translational motion of the vertebral centroid. We used surface electromyographic (EMG) signal data to compare subject efforts between the two collars and between the two CTOs. Each orthosis significantly reduced gross and intervertebral motion in flexion and extension (p < 0.05). No statistically significant differences were found between the Miami J and Aspen collars in reducing gross or intervertebral sagittal motion, except at C5-6. Both CTOs provided significantly more restriction of gross and intervertebral flexion and extension motion as compared to the two collars (p < 0.05). The Aspen 2-post CTO and 4-post CTO performed similarly in flexion, but the Aspen 4-post CTO provided significantly more restriction of extension motion (p < 0.05).


Development of an in silico stochastic 4D model of tumor growth with angiogenesis.
A stochastic computer model of tumour growth with spatial and temporal components that includes tumour angiogenesis was developed. In the current work it was used to simulate head and neck tumour growth. The model also provides the foundation for a 4D cellular radiotherapy simulation tool. The model, developed in Matlab, contains cell positions randomised in 3D space without overlap. Blood vessels are represented by strings of blood vessel units which branch outwards to achieve the desired tumour relative vascular volume. Hypoxic cells have an increased cell cycle time and become quiescent at oxygen tensions less than 1 mmHg. Necrotic cells are resorbed. A hierarchy of stem cells, transit cells and differentiated cells is considered along with differentiated cell loss. Model parameters include the relative vascular volume (2-10%), blood oxygenation (20-100 mmHg), distance from vessels to the onset of necrosis (80-300 μm) and probability for stem cells to undergo symmetric division (2%). Simulations were performed to observe the effects of hypoxia on tumour growth rate for head and neck cancers. Simulations were run on a supercomputer with eligible parts running in parallel on 12 cores. Using biologically plausible model parameters for head and neck cancers, the tumour volume doubling time varied from 45 ± 5 days (n = 3) for well oxygenated tumours to 87 ± 5 days (n = 3) for severely hypoxic tumours. The main achievements of the current model were randomised cell positions and the connected vasculature structure between the cells. These developments will also be beneficial when irradiating the simulated tumours using Monte Carlo track structure methods.


Stability of the effect of silencing fibronectin type III domain-protein 1 (FN3D1) gene on Anopheles arabiensis reared under different breeding site conditions.
Malaria vector mosquitoes acquire midgut microbiota primarily from their habitat. The homeostasis of these microbial communities plays an essential role in the mosquito longevity, the most essential factor in the mosquito vectorial capacity. Our recent study revealed that silencing genes involved in regulation of the midgut homeostasis including FN3D1, FN3D3 and GPRGr9 reduced the survival of female adult Anopheles arabiensis mosquitoes. In the present study, we investigate the stability of the gene silencing efficiency of mosquitoes reared in three different breeding conditions representing distinct larval habitat types: town brick pits in Jimma, flood pools in the rural land of Asendabo and roadside pools in Wolkite. First-instar larvae of An. arabiensis mosquitoes were reared separately using water collected from the three breeding sites. The resulting adult females were micro-injected with dsRNA targeting the FN3D1 gene (AARA003032) and their survival was monitored. Control mosquitoes were injected with dsRNA Lacz. In addition, the load of midgut microbiota of these mosquitoes was determined using flow cytometry. Survival of naïve adult female mosquitoes differed between the three sites. Mosquitoes reared using water collected from brick pits and flood pools survived longer than mosquitoes reared using water collected from roadside. However, the FN3D1 gene silencing effect on survival did not differ between the three sites. The present study revealed that the efficacy of FN3D1 gene silencing is not affected by variation in the larval habitat. Thus, silencing this gene has potential for application throughout sub-Saharan Africa.


["Multimedia symposium wares". An enrichment of medical and graduate education?].
The continual development of the internet has supported the spread of surgical knowledge by electronic means. High quality products have to be offered from a software as well as a contents point of view. The question as to whether these new media and their contents have a real value for efficient and motivating use in medical education needed to be answered by first assessing a quality profile for the development of surgical educational modules which were then evaluated on the basis of so-called "symposia ware". First, the reactions and opinions of physicians at 47 universities were assessed by a standardized questionnaire concerning their demands on multimedia teaching/learning modules. Several different aspects of technique, content, presentation, didactics and background knowledge were analyzed. In a second step, their opinions were evaluated concerning two applications (symposia implemented on CD-ROM as a slideshow with original slides and audio) with surgical and gastroenterological contents by standardized questionnaire. Questions concerning personal background such as educational status and experience with computers, e-mail and the internet on one hand and the CD-ROM itself concerning content, relevance for daily clinical work and continuing medical education as well as the quality of the application on the other hand, were evaluated using marks (1 = best, 6 = worst). A total of 320 physicians participated in the first part of the interview. Of these, 93% were equipped with computers in hospital as well as privately. The Internet was used by 90% of them. The majority declined a full text presentation as well as the application of scroll fields. The participants rather favored the integration of text, pictures, animations and videos. Furthermore, 95% demanded the provision on the internet. Thirty-seven colleagues in their 5th (1-11) year of training were interviewed, and of those, 27 were working in a surgical department and 10 in a medical department. Individual computer knowledge was rated with a median of 3. This revealed that 60% were equipped with computers in hospital as well as at home, the remaining 40% had computers either in hospital or at home. All participants used the internet. In total, 57% had experience with "Symposia ware". The rating of the "Symposia ware" itself was positive. Relevance and applicability of a slideshow for imparting knowledge were rated with a median of 2. This showed that 81% would buy the CD-ROM in principle, and 89% would spent up to 50 EUR. Quality, language, content and user-friendliness were all rated 2. Physicians frequently use computers and the internet. All this indicates a high degree of acceptance of electronic teaching/learning modules in medical education. A uniform structure of contents as well as a platform-independent, web-based presentation is appreciated. To enhance illustration, a picture and video-oriented visualization should be chosen. Overall, "symposia ware" is rated positively. It should cost no more than 50 EUR and it represents a valuable source of information for physicians.


Strategies for in vivo imaging of enzyme activity: an overview and recent advances.
Imaging of enzyme activity in living subjects promises many applications in both basic and translational researches from helping elucidate the enzyme function and mechanism in biology to better disease detection and monitoring, but the complexity and dynamics of enzymatic reactions in living systems present unique challenges for probe design. This critical review examines the approaches in recent literature to in vivo imaging of the activity of a variety of enzyme targets with an emphasis on the chemical perspective of probe design, structure and function. Strategies for designing enzyme-activated probes based on a variety of molecular scaffolds including small molecules, organic and inorganic nanoparticles, and genetically encoded proteins for commonly used molecular imaging modalities--whole body optical (fluorescence, bioluminescence) imaging, magnetic resonance imaging, and radionuclide-based tomographic imaging, are critically evaluated. Recent advances in combining multiple modalities to imaging enzyme activity in living subjects are also highlighted (255 references).


Recombinant or Standard-Dose Influenza Vaccine in Adults under 65 Years of Age.
Quadrivalent recombinant influenza vaccines contain three times the amount of hemagglutinin protein as standard-dose egg-based vaccines, and the recombinant formulation is not susceptible to antigenic drift during manufacturing. Data are needed on the relative effectiveness of recombinant vaccines as compared with standard-dose vaccines against influenza-related outcomes in adults under the age of 65 years. In this cluster-randomized observational study, Kaiser Permanente Northern California facilities routinely administered either a high-dose recombinant influenza vaccine (Flublok Quadrivalent) or one of two standard-dose influenza vaccines during the 2018-2019 and 2019-2020 influenza seasons to adults 50 to 64 years of age (primary age group) and 18 to 49 years of age. Each facility alternated weekly between the two vaccine formulations. The primary outcome was influenza (A or B) confirmed by polymerase-chain-reaction (PCR) testing. Secondary outcomes included influenza A, influenza B, and influenza-related hospitalization outcomes. We used Cox regression analysis to estimate the hazard ratio of the recombinant vaccine as compared with the standard-dose vaccines against each outcome. We calculated the relative vaccine effectiveness as 1 minus the hazard ratio. The study population included 1,630,328 vaccinees between the ages of 18 and 64 years (632,962 in the recombinant-vaccine group and 997,366 in the standard-dose group). During this study period, 1386 cases of PCR-confirmed influenza were diagnosed in the recombinant-vaccine group and 2435 cases in the standard-dose group. Among the participants who were 50 to 64 years of age, 559 participants (2.00 cases per 1000) tested positive for influenza in the recombinant-vaccine group as compared with 925 participants (2.34 cases per 1000) in the standard-dose group (relative vaccine effectiveness, 15.3%; 95% confidence interval [CI], 5.9 to 23.8; P = 0.002). In the same age group, the relative vaccine effectiveness against influenza A was 15.7% (95% CI, 6.0 to 24.5; P = 0.002). The recombinant vaccine was not significantly more protective against influenza-related hospitalization than were the standard-dose vaccines. The high-dose recombinant vaccine conferred more protection against PCR-confirmed influenza than an egg-based standard-dose vaccine among adults between the ages of 50 and 64 years. (Funded by Sanofi; ClinicalTrials.gov number, NCT03694392.).


Atrial natriuretic peptide in human essential hypertension.
We measured the circulating levels of atrial natriuretic peptide (ANP) in 62 patients with untreated uncomplicated essential hypertension and in 30 normotensive subjects. In the hypertensive patients, mean systolic and diastolic blood pressures were 148 and 101 mm Hg, respectively, and the mean heart rate was 73 beats/min. ANP concentrations were not elevated in the hypertensive group but were actually decreased slightly over those of the control group (27.4 +/- 1.8 pg/ml versus 35.3 +/- 2.4 pg/ml [P less than 0.02]). No relationship was found between ANP levels and diastolic blood pressure, plasma renin activity, urinary sodium excretion, or serum creatinine level. In 8 of the 62 patients with essential hypertension, 6 weeks of treatment with a dihydropyridine calcium channel blocker, nitrendipine, significantly reduced plasma ANP levels from 28.6 +/- 4.3 pg/ml to 18.7 +/- 1.8 pg/ml (P less than 0.05). In 17 additional patients treated with the hypotensive agent ketanserin, ANP levels were not significantly reduced after treatment. Thus, this study demonstrates that circulating plasma ANP levels are not increased but are slightly decreased in patients with uncomplicated essential hypertension in comparison with normotensive subjects. Furthermore, antihypertensive treatment with a calcium channel antagonist reduced plasma levels of ANP.


Vaginocervical stimulation of Ewes induces the rapid formation of a new bond with an alien young without interfering with a previous bond.
Ewes form a selective olfactory memory for their lambs after 2 hr of mother-young interaction following parturition. Mothers will subsequently reject any strange lamb at suckling. The present study investigated whether artificial vaginocervical stimulation (VCS) allows the formation of a selective bond with an unfamiliar lamb and whether it interferes with the maintenance of the bond formed with the familiar lamb. At 2 hr postpartum, mothers were separated from their familiar lamb after having formed a selective bond with it and were given 10 min of mechanical VCS. In the "VCS + lamb" group (n = 24) an unfamiliar lamb was left with the ewe for 2 hr whereas in the "VCS no lamb" group (n = 26) the mother was left alone for the same period of time. Ewes of the "no VCS" group (n = 14) did not receive any VCS. In the majority of animals of the "VCS + lamb" group (23/24) VCS induced a complete acceptance of the unfamiliar lamb without any disruption of the bond previously formed with the familiar lamb. VCS or 2 hr of separation did not disrupt the maintenance of the selective bond initially formed with the familiar lamb since all the ewes of the "VCS no lamb" and "no VCS" groups accepted it at suckling.


Observation of transition-state vibrational thresholds in the rate of dissociation of ketene.
Rate constants for the dissociation of highly vibrationally excited ketene (CH(2)CO) have been measured at the threshold for the production of CH(2)((3)B(1)) and CO((1)Sigma(+)). The rate constant increases in a stepwise manner with increasing energy, consistent with the long-standing premise that the rate of a unimolecular reaction is controlled by flux through quantized transition-state thresholds. The data give the energies of the torsional and C-C-O bending vibrations of the transition state.


Social climate perception and depression of patients and staff in a chronic hemodialysis unit.
This socioecological study investigates the relationship of depression and social climate perception of patients (N = 59) and staff N = 18) in a chronic hemodialysis unit. The Beck Depression Inventory (BDI) and Moos Ward Atmosphere Scale (WAS) Form C revised for dialysis are used for measurement. Patients and staff are found to have significantly dissonant perception of the unit. Patients perceive the environment more negatively than the staff. Depressed patients correlate with Low WAS scores (p less than .03) indicating that depression influences social climate perception. Depressed patient BDI items are correlated with WAS items via a series of Pearson correlation coefficients for a perceptual profile. Discussion is made as to the dysfunctional affects of dissonance, depression, staff denial and withdrawal. Further studies on altering the social ecology of dialysis units as a method for reducing depression and staff turnover rates are called for.


Efficacy and safety of oral tibolone 1.25 or 2.5 mg/day vs. placebo in postmenopausal women.
tibolone at usual doses of 2.5 mg/day in postmenopausal women has been shown to improve climacteric complaints, without affecting endometrial thickness and lipid profile or blood glucose. However, the potentially similar efficacy, but better tolerability, of a low dose of this drug (1.25 mg) has never been established. 162 healthy, non-obese, post-menopausal women, aged 40-65 years, with an intact uterus were enrolled in a national, single centre, randomised, double blind, placebo controlled, parallel group trial. After 1 week of runin, patients were treated for 24 weeks with placebo, tibolone 1.25 mg or 2.5 mg/day. During the study laboratory tests, endometrial ultrasound scans and mammography were performed. Occurrence of menopausal signs and symptoms, including vaginal bleeding, and quality of sexual life were also checked. in the 120 patients terminating the study without major protocol violations, climacteric symptoms were similarly improved by tibolone 1.25 and 2.5 mg (78% and 90% reduction at week 24 for hot flushes, 36% and 34% for sweating episodes and 44% and 51% for vaginal dryness), but not by placebo. Benefits occurred earlier in the group treated with tibolone 2.5 mg. Quality of sexual life was almost invariably improved by tibolone as compared to placebo, but improvement occurred earlier in the tibolone 1.25 mg group. Severity of vaginal bleeding was not different between placebo and active treatment groups, except at week 12 when was higher. At the end of treatment vaginal bleeding occurred in 15% of patients treated with placebo, 14% treated with tibolone 1.25 mg and 12% treated with tibolone 2.5 mg. Endometrial thickness and breast density were not changed by treatment, as well as FSH, 17-beta-estradiol, total cholesterol, HDL and LDL cholesterol, triglycerides and blood glucose. Adverse events were reported by 14.7%, 26.7% and 24.4% of patients treated with placebo, tibolone 1.25 mg and tibolone 2.5 mg/day, respectively. tibolone at doses of 1.25 or 2.5 mg/day given for 24 weeks to postmenopausal women displayed similar efficacy and safety profiles, though were more effective than placebo. Tibolone 1.25 mg induced a more gradual relief from climacteric symptoms and a more prompt improvement of sexual function.


Hemoglobin induces binding of several extracellular matrix proteins to Candida albicans. Identification of a common receptor for fibronectin, fibrinogen, and laminin.
Host infection by the pathogenic fungus Candida albicans is initiated by adhesion and mediated by binding to several host extracellular matrix proteins. Previously, we demonstrated that hemoglobin supplemented into a chemically defined medium significantly and specifically induced fibronectin binding to C. albicans. We now report that hemoglobin also induces binding of laminin, fibrinogen, and type IV collagen but not of thrombospondin-1 or type I collagen. The binding of each protein was inhibited by the respective unlabeled ligand in a concentration-dependent manner. Fibrinogen inhibited the binding of radiolabeled fibronectin, laminin, and fibrinogen with similar IC50 values, suggesting that a single promiscuous receptor recognizes these three proteins. Competitive binding studies indicated that a second class of receptor binds specifically to laminin. Growth of C. albicans in the presence of hemoglobin also increased cell adhesion to immobilized fibronectin, laminin, fibrinogen, and type IV collagen but not to thrombospondin-1 or type I collagen. Exposure to hemoglobin induced increased or de novo expression of several surface proteins on C. albicans. One of these proteins with a molecular weight of 55,000 recognized fibronectin, based on ligand protection and affinity chromatography on immobilized fibronectin. Thus, hemoglobin induces both promiscuous and specific receptors for extracellular matrix proteins and, therefore, may regulate matrix adhesion during dissemination of C. albicans infections.


Tobacco components induce alterations in keratinocyte lipid membrane fluidity and inhibit cell proliferation in culture.
Guinea pig epidermal keratinocytes were harvested and grown in vitro (20). The cells were treated with polyphenolic compounds, acetate/shikimate aromatics, that are ubiquitous in plants. In addition, the cells were exposed to tobacco glycoprotein (TGP), a plant-derived substance prepared from cured tobacco (19). All of the polyphenolic compounds enhanced the attachment of cells to a defined substratum and inhibited cell proliferation. Tobacco glycoprotein (TGP), rutin conjugates and ellagic acid inhibited cell spreading and enhanced the apparent microviscosity of keratinocyte membrane lipids. These data suggest that the use of these compounds may be associated with alterations in cytoskeletal architecture and membrane fluid dynamics that might result in clinical alterations characterized by whitening of mucosae.


The Effect of Preoperative Carbohydrate Intake on Length of Stay and Postoperative Recovery Following Laparoscopic Living Donor Nephrectomy.
Enhanced Recovery After Surgery (ERAS) protocols are applied in many surgical procedures and often involve preoperative carbohydrate intake. Research surrounding the utility of ERAS in living donor nephrectomy is limited. The objective of this study was to identify whether living kidney donors who received preoperative oral carbohydrates experienced a difference in length of hospital stay (LOS), duration of time required to resume regular oral food and fluid intake, and incidence of gastrointestinal (GI) complications following laparoscopic nephrectomy compared to historical control donors who underwent preoperative fasting. This study was a retrospective analysis of data from adult subjects at one transplant center who underwent laparoscopic living donor nephrectomy. A total of 55 ERAS subjects who received preoperative carbohydrates and 93 historical control subjects who underwent preoperative fasting were included in the final analysis. The following variables were compared between groups: LOS, time to tolerating a regular oral diet postoperatively, time to meeting 50% of estimated fluid needs by oral intake postoperatively, and incidence of postoperative GI complications. No significant differences between the ERAS and historical control groups in age, weight, body mass index, sex distribution, or estimated fluid needs were identified. Both groups consisted of predominantly female subjects. ERAS subjects experienced a shorter LOS (2.8 days versus 3.9 days, P < .001), time to tolerating a regular oral diet (36.5 hours versus 68.2 hours, P < .001), and time to meeting 50% of estimated fluid needs (25.3 hours versus 44.6 hours, P < .001) after laparoscopic nephrectomy compared to historical control subjects. No significant difference between groups in the incidence of postoperative GI complications (nausea, vomiting, or ileus) was identified. Our findings demonstrate the advantages of ERAS in living kidney donors undergoing laparoscopic nephrectomy and support ERAS implementation within this patient population.


Classification of protein sequences by means of irredundant patterns.
The classification of protein sequences using string algorithms provides valuable insights for protein function prediction. Several methods, based on a variety of different patterns, have been previously proposed. Almost all string-based approaches discover patterns that are not "independent, " and therefore the associated scores overcount, a multiple number of times, the contribution of patterns that cover the same region of a sequence. In this paper we use a class of patterns, called irredundant, that is specifically designed to address this issue. Loosely speaking the set of irredundant patterns is the smallest class of "independent" patterns that can describe all common patterns in two sequences, thus they avoid overcounting. We present a novel discriminative method, called Irredundant Class, based on the statistics of irredundant patterns combined with the power of support vector machines. Tests on benchmark data show that Irredundant Class outperforms most of the string algorithms previously proposed, and it achieves results as good as current state-of-the-art methods. Moreover the footprints of the most discriminative irredundant patterns can be used to guide the identification of functional regions in protein sequences.


Concept Development of "Nursing Presence": Application of Schwartz-Barcott and Kim's Hybrid Model.
Although nursing presence is a foundation for professional nursing practice and has known positive outcomes such as patient satisfaction and recovery; it is not well known. The ambiguity surrounding how to define nursing presence has challenged its evaluation and education. Therefore, in an attempt to discover attributes of this underdeveloped concept and studying it in a new context, concept development is essential. The purpose of this study was to clarify the concept of nursing presence through concept development, to produce a tentative definition of this subjective concept in clinical practice. Concept development was carried out using Schwartz-Barcott and Kim's hybrid model including, theoretical, fieldwork and final analysis phases. First, 29 related articles available on the databases from 1990-2015 were reviewed and analyzed. Then, 22 interviews were conducted with 19 participants, followed with inductive content analysis. At last, an overall definition was performed. Nursing presence can be explained as co-constructed interaction identified by deliberate focus, task-oriented/patient-oriented relationship, accountability, clarification, and ubiquitous participation. Nursing presence requires clinical competence, self-actualization, reciprocating openness, and conducive working environment. Worthwhile communications, balance/recovery, and growth and transcendence are the main consequences of this concept. Co-constructed interaction underscored the value of the nursing presence as an integral component of caring with humanistic and patient-centered approaches. The findings could help clinical nurses have a better understanding of the nursing presence. Findings also can improve educators' and managers' knowledge for developing and conducting appropriate education strategies and caring activities to facilitate the promotion of nursing presence.


Synthesis of new multivalent metal ion functionalized mesoporous silica and studies of their enhanced antimicrobial and cytotoxicity activities.
In the present study, we have reported the synthesis of a transition metal (Me = Ti, V, and Pd) incorporated into MCM-41 mesoporous molecular sieves (Si/Me = 20) synthesized by the sol-gel method. Their physicochemical properties were studied in detail by standard techniques like low angle powder X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDXS), transmission electron microscopy (TEM), N2 adsorption/desorption studies, and thermogravimetric-differential thermal (TG-DTA) analysis and spectral studies like Fourier transform infrared spectroscopic analysis (FT-IR), diffuse reflectance ultraviolet-visible spectroscopic analysis (UV-Visible-DRS), and X-ray photoelectron spectroscopy (XPS). The XRD patterns prove that the material's phase identity is the same irrespective of metal incorporation. SEM displayed the uniform shape and size of the nanoparticles. The presence of elements such as Ti, V, Pd, Si and O in respective materials is revealed using the EDXS analysis. Around 30% weight loss arose upon calcination from room temperature to 800 °C. BET surface area analysis presented that the parent materials have a high surface area (1024 m2 g-1) which was reduced upon metal incorporation. FT-IR analysis exhibited the framework vibrations of the synthesised materials. UV-Visible-DRS analysis indicated the presence of tetrahedrally coordinated transition metal ions. The multivalent-metal-ion-functionalized mesoporous materials showed significant enhancement in potent antimicrobial and anticancer activity. The antimicrobial activity is because of its low lipophilicity, which no longer allows the materials to enter via the lipid membrane. Thus, the new materials neither obstruct the metal-binding sites nor inhibit the growth of microbe enzymes. Further, the results show that the transition metal ion-containing mesoporous materials possessing good anticancer activity arising from their excessive surface area to volume ratio provided appropriate association with a tumour cell due to the direct penetration of mesoporous materials into the cell wall, causing membrane damage and cell death.


Worth the Tears .
I walk into work thinking about her. The last time I walked through these doors, I wondered if I would ever see her again. Today, I wondered if she would be there when I walked through the halls. As I start my day, I begin to inquire about her. Is she still here? Is she still alive? How is she? They tell me she is still here, in body, but she's really gone. Any minute could be her last. I go about my busy day, tending to my patients and their needs. She begins to slip from my mind in the craziness of the day. Later in the day, someone comes to find me and says, "She's yours to take care of until the end of your shift." I slowly walk down the hallway, dreading what I will see. .


Synthetic Melanin E-Ink.
Extensive efforts have been devoted to the development of surfactant-free electronic ink (E-ink) with excellent display resolution for high-definition resolution display. Herein, we report the use of polydopamine-based synthetic melanin, a class of functional nanoparticles with similar chemical compositions and physical properties to those of naturally occurring melanin, as a new E-ink material. It was found that such E-ink displays could achieve ultrahigh resolution (>10 000 ppi) and low power consumption (operation voltage of only 1 V) in aqueous solutions. Interestingly, simple oxidation of synthetic melanin nanoparticles enables the generation of intrinsic fluorescence, allowing further development of fluorescent E-ink displays with nanoscale resolution. We describe these bioinspired materials in an initial proof-of-concept study and propose that synthetic melanin nanoparticles will be suitable for electronic nanoinks with a potential wide range of applications in molecular patterning and fluorescence bioimaging.


Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks.
Acetylsalicylic acid (ASA) in combination with metoclopramide has been frequently used in clinical trials in the acute treatment of migraine attacks. Recently the efficacy of a new high buffered formulation of 1000 mg effervescent ASA without metoclopramide compared to placebo has been shown. To further confirm the efficacy of this new formulation in comparison with a triptan and a nonsteroidal anti-inflammatory drug (ibuprofen) a three-fold crossover, double-blind, randomized trial with 312 patients was conducted in Germany, Italy and Spain. Effervescent ASA (1000 mg) was compared to encapsulated sumatriptan (50 mg), ibuprofen (400 mg) and placebo. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (primary endpoint) was 52.5% for ASA, 60.2% for ibuprofen, 55.8% for sumatriptan and 30.6% for placebo. All active treatments were superior to placebo (P < 0.0001), whereas active treatments were not statistically different. The number of patients who were pain-free at 2 h was 27.1%, 33.2%, 37.1% and 12.6% for those treated with ASA, ibuprofen, sumatriptan or placebo, respectively. The difference between ASA and sumatriptan was statistically significant (P = 0.025). With respect to other secondary efficacy criteria and accompanying symptoms no statistically significant differences between ASA and ibuprofen or sumatriptan were found. Drug-related adverse events were reported in 4.1%, 5.7%, 6.6% and 4.5% of patients treated with ASA, ibuprofen sumatriptan or placebo. This study showed that 1000 mg effervescent ASA is as effective as 50 mg sumatriptan and 400 mg ibuprofen in the treatment of migraine attacks regarding headache relief from moderate/severe to mild/no pain at 2 h. Regarding pain-free at 2 h sumatriptan was most effective.


Managing the transition to capitation.
Although most experts believe that capitation and financial risk-sharing among providers will become key components of the U.S. healthcare system, providers may not feel the full effect of this shift for several years. In the interim, providers must operate under an activity-based payment system that rewards them for the volume of patients seen, while preparing for the transition to a fixed, per-capita payment system that will reward them for the efficiency with which services are provided. Preparation for the move to capitation will involve implementation of the systems necessary to negotiate managed care contracts, enhance quality and efficiency, and take responsibility for the health of a defined population.


Follicular Dendritic Cell Sarcoma of the Thyroid Gland in a Patient with Preexisting Hashimoto's Thyroiditis: A Rare Case Report with a Literature Review.
Thyroid follicular dendritic cell sarcoma (FDCS) is an extremely rare malignancy that originates from follicular dendritic cells of the thyroid germinal centers. To the best of our knowledge, there are only 4 reported cases of thyroid FDCS in the English literature. Herein, we present the fifth case of FDCS of the thyroid gland. A 63-year-old woman presented with a painless midline neck mass, enlarging for the last 4 months. Physical examination revealed a 6-cm nonmobile, firm, multinodular thyroid mass with palpable cervical lymphadenopathy. Due to high suspicion for thyroid malignancy, the patient underwent total thyroidectomy with bilateral modified radical neck dissection. Histologic evaluations revealed sheets of storiform eosinophilic tumoral cells with prominent nucleoli containing multinucleated giant cells, and subsequent immunohistochemistry showed immunoreactivity for CD4, CD21, CD35, CD45 (LCA), and CD68. The patient was started on 6 cycles of doxorubicin, ifosfamide, and radiotherapy. She has had monthly thyroid ultrasonography and contrast-enhanced thoracoabdominal CT scan every 3 months for detecting potential recurrence and/or metastasis screening. Fortunately, 8 months after the operation, the patient is alive without any signs of local or distant metastasis.


Sampling framework for accurate curvature estimation in discrete surfaces.
Accurate curvature estimation in discrete surfaces is an important problem with numerous applications. Curvature is an indicator of ridges and can be used in applications such as shape analysis and recognition, object segmentation, adaptive smoothing, anisotropic fairing of irregular meshes, and anisotropic texture mapping. In this paper, a new framework is proposed for accurate curvature estimation in discrete surfaces. The proposed framework is based on a local directional curve sampling of the surface where the sampling frequency can be controlled. This local model has a large number of degrees of freedoms compared with known techniques and, so, can better represent the local geometry. The proposed framework is quantitatively evaluated and compared with common techniques for surface curvature estimation. In order to perform an unbiased evaluation in which smoothing effects are factored out, we use a set of randomly generated Bezier surface patches for which the curvature values can be analytically computed. It is demonstrated that, through the establishment of sampling conditions, the error in estimations obtained by the proposed framework is smaller and that the proposed framework is less sensitive to low sampling density, sampling irregularities, and sampling noise.


Racial phenotypes in moyamoya disease: a comparative analysis of clinical presentation and natural history in a single multiethnic cohort of 250 hemispheres.
The authors aimed to determine whether differences exist in presentation and natural history when comparing Asian patients with moyamoya disease (MMD) to those of other ethnicities in North America. A database of 137 patients with MMD presenting to their institution between 1994 and 2015 was reviewed. Baseline characteristics and outcome variables, including stroke and functional outcome, were compared between Asian and non-Asian patients. Unadjusted Kaplan-Meier survival analysis and adjusted Cox regression models were used to compare stroke-free survival and stroke hazard after diagnosis among hemispheres of both racial groups. The analysis was stratified by age group, and censoring was performed until last follow-up or at the time of surgery. Because the relative rate of stroke changed between Asian and non-Asian adults after 1.5 years of follow-up, a time-segmented analysis focusing on the period 1.5 years after diagnosis was performed. The cohort comprised 23% (31/137) Asian and 77% (106/137) non-Asian patients with MMD with a bimodal age distribution. Non-Asian patients had a higher prevalence of increased BMI (p = 0.02) and smoking (p = 0.04). Among patients who presented with stroke (n = 90), hemorrhage was significantly more common among Asians (p = 0.02). The natural history analysis included 250 hemispheres: 67 pediatric and 183 adult hemispheres. The overall mean follow-up duration since diagnosis was 3.3 years. Among adults, Asian patients had a higher incidence of stroke (8.0 per 100 person-years vs 3.0 per 100 person-years) over a mean follow-up of 3.3 years, but results were not statistically significant (p = 0.45). In the period beginning 1.5 years after diagnosis, Asian adults had a significantly higher hazard of stroke over a mean follow-up of 7.7 years, while controlling for sex, hypertension, and stroke before diagnosis (hazard ratio 8.8, p = 0.02). Among pediatric patients, Asians also had a higher stroke incidence (10.0 per 100 person-years vs 3.5 per 100 person-years) over a mean follow-up of 3.2 years; however, results did not reach statistical significance (p = 0.40). Functional outcome was similar between both ethnic groups at last follow-up (p = 0.57). This study suggests a comparatively more progressive course of MMD in Asians. Further studies are required to fully characterize the phenotypic distinctions between different races and underlying pathophysiological mechanisms.


Measuring the characteristic topography of brain stiffness with magnetic resonance elastography.
To develop a reliable magnetic resonance elastography (MRE)-based method for measuring regional brain stiffness. First, simulation studies were used to demonstrate how stiffness measurements can be biased by changes in brain morphometry, such as those due to atrophy. Adaptive postprocessing methods were created that significantly reduce the spatial extent of edge artifacts and eliminate atrophy-related bias. Second, a pipeline for regional brain stiffness measurement was developed and evaluated for test-retest reliability in 10 healthy control subjects. This technique indicates high test-retest repeatability with a typical coefficient of variation of less than 1% for global brain stiffness and less than 2% for the lobes of the brain and the cerebellum. Furthermore, this study reveals that the brain possesses a characteristic topography of mechanical properties, and also that lobar stiffness measurements tend to correlate with one another within an individual. The methods presented in this work are resistant to noise- and edge-related biases that are common in the field of brain MRE, demonstrate high test-retest reliability, and provide independent regional stiffness measurements. This pipeline will allow future investigations to measure changes to the brain's mechanical properties and how they relate to the characteristic topographies that are typical of many neurologic diseases.


The efficiency of Taxonomic Sufficiency for identification of spatial patterns at different scales in transitional waters.
Taxonomic Sufficiency (TS), the use of coarser taxonomic resolution in monitoring plans, has been receiving increasing attention in last years. A comprehensive dataset of macrobenthos from 18 Italian lagoons in a range of different latitude, typology, salinity and surface area, was analysed in order to test the efficiency of TS, in terms of correlation between patterns at level of species and patterns resulting from different levels of taxonomic aggregation. First, TS was applied on a range of univariate indices, providing complementary information on macrobenthic community, in order to test the efficiency, in a contest of different taxonomic composition, and different number of lower taxa belonging to the same higher taxon in each lagoon. Then, TS was applied on multivariate analyses, in order to test whether the efficiency changes between two different scales: local (comparison of sites nested within each lagoon) and regional (comparison among lagoons), and with different data transformation. The patterns resulting from univariate indices and multivariate analyses, at both local and regional scales, were retained till family level, despite the different levels of taxonomic composition and different number of lower taxa belonging to the same higher taxon of different lagoons. Nevertheless, the correlation values among matrices and the effect of data transformation differed between regional and local scales. Our results support the efficiency of TS until family level, but at the same time underline the need of scale- and region-specific baseline knowledge prior application of TS in lagoons.


Strategies combining total and percent free prostate specific antigen for detecting prostate cancer: a prospective evaluation.
Determining total prostate specific antigen (PSA) in plasma can often identify men who are subsequently diagnosed with prostate cancer. However, excess false-positives create large financial and psychological burdens in prostate cancer screening. The percent free PSA is lower when prostate cancer is present, although to our knowledge no large prospective analyses to date have evaluated whether adding testing for free PSA may decrease false-positives, while maintaining or perhaps improving the detection of potentially curable tumors. We measured total and percent free PSA in banked plasma samples from the Physicians' Health Study in 430 men who were later diagnosed with prostate cancer and 1,642 age matched controls who were not diagnosed with prostate cancer during a 12-year observation period. We calculated the number of cancers detected and the number of false-positives for various strategies of combined free and total PSA levels, and compared them to the use of total PSA alone. Total PSA with a cutoff of 4 ng./ml. detected 149 cases but also yielded 144 false-positives. A strategy that applied percent free PSA to men with total PSA 4 to 10 ng./ml. detected 133 to 140 cancers and decreased false-positives to 83 of 117 depending on the percent free PSA cutoff used. As the percent free PSA cutoff was lowered from 25% to 20%, additional undetected cancers did not occur until year 9 of followup and the 20% cutoff decreased false-positives and, thus, potential negative biopsies, by 42%. Percent free PSA was superior to total PSA for discriminating cases from controls within the total PSA range of 4 to 10 or 3 to 10 ng./ml. (p <0.0001). A percent free PSA cutoff of 20% in men with total PSA 3 to 10 ng./ml. detected 10% more cancers with 12.5% fewer false-positives than the conventional strategy of total PSA greater than 4 ng./ml. Cancers missed by combined total and free PSA testing had longer intervals between blood sampling and diagnosis, and a greater likelihood of later diagnosis at an organ confined stage. These results demonstrate that in a prospective setting with long-term followup free PSA strategies can be identified that decrease unnecessary biopsies, while preserving or even improving cancer detection. Thus, total and free PSA can be combined without the need to weigh subjectively the trade-offs and relative costs of false-negative and false-positive results.


Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV- and HIV+ subjects.
Hematogenous dissemination of Mycobacterium tuberculosis (M. tb) occurs during both primary and reactivated tuberculosis (TB). Although hematogenous dissemination occurs in non-HIV TB patients, in ∼80% of these patients, TB manifests exclusively as pulmonary disease. In contrast, extrapulmonary, disseminated, and/or miliary TB is seen in 60-70% of HIV-infected TB patients, suggesting that hematogenous dissemination is likely more common in HIV+ patients. To understand M. tb adaptation to the blood environment during bacteremia, we have studied the transcriptome of M. tb replicating in human whole blood. To investigate if M. tb discriminates between the hematogenous environments of immunocompetent and immunodeficient individuals, we compared the M. tb transcriptional profiles during replication in blood from HIV- and HIV+ donors. Our results demonstrate that M. tb survives and replicates in blood from both HIV- and HIV+ donors and enhances its virulence/pathogenic potential in the hematogenous environment. The M. tb blood-specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, potential evasion of immune surveillance, and enhanced expression of important virulence factors that drive active M. tb infection and dissemination. These changes are accentuated during bacterial replication in blood from HIV+ patients. Furthermore, the expression of ESAT-6, which participates in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood, especially during growth in blood from HIV+ patients. Preliminary experiments also demonstrate that ESAT-6 promotes HIV replication in U1 cells. These studies provide evidence, for the first time, that during bacteremia, M. tb can adapt to the blood environment by modifying its transcriptome in a manner indicative of an enhanced-virulence phenotype that favors active infection. Additionally, transcriptional modifications in HIV+ blood may further accentuate M. tb virulence and drive both M. tb and HIV infection.


Serum calcium-decreasing factor, caldecrin, inhibits osteoclast differentiation by suppression of NFATc1 activity.
Caldecrin/chymotrypsin C is a novel secretory-type serine protease that was originally isolated as a serum calcium-decreasing factor from the pancreas. Previously, we reported that caldecrin suppressed the bone-resorbing activity of rabbit mature osteoclasts (Tomomura, A., Yamada, H., Fujimoto, K., Inaba, A., and Katoh, S. (2001) FEBS Lett. 508, 454-458). Here, we investigated the effects of caldecrin on mouse osteoclast differentiation induced by macrophage-colony stimulating factor and the receptor activator of NF-kappaB ligand (RANKL) from the monocyte/macrophage cell lineage of bone marrow cells. Wild-type and protease-deficient mutant caldecrin dose-dependently inhibited RANKL-stimulated tartrate-resistant acid phosphatase-positive osteoclast formation from bone marrow cells. Caldecrin did not affect macrophage colony formation from monocyte/macrophage lineage cells or osteoclast progenitor generation in cultures of bone marrow cells. Caldecrin inhibited accumulation of the RANKL-stimulated nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) mRNA in bone marrow cells, which is a key transcription factor for the differentiation of osteoclasts. Caldecrin also suppressed RANKL-induced differentiation of the RAW264.7 monocyte/macrophage cell line into osteoclasts. Caldecrin reduced the transcriptional activity of NFATc1 in RAW264.7 cells, whereas those of NF-kappaB and c-Fos, which are also transcription factors involved in osteoclast differentiation, were unaffected. Caldecrin inhibited RANKL-stimulated nuclear translocation of NFATc1 and the activity of the calcium/calmodulin-dependent phosphatase, calcineurin. Caldecrin inhibited phospholipase Cgamma1-mediated Ca(2+) oscillation evoked by RANKL stimulation. RANKL-stimulated phosphorylation of spleen tyrosine kinase (Syk) was also attenuated by caldecrin. Taken together, these results indicate that caldecrin inhibits osteoclastogenesis, without its protease activity, by preventing a phospholipase Cgamma1-mediated Ca(2+)oscillation-calcineurin-NFATc1 pathway.


Tyrosine confounds oxidative electrochemical detection of nitric oxide.
We report evidence that a porphyrinic microsensor for detection of nitric oxide (NO) also detects biologically relevant concentrations of tyrosine (Tyr) in dog brain. Tyr is oxidized by this sensor at the same potential as NO, and the sensitivity for NO and Tyr are of the same order of magnitude. The interference from Tyr is of importance because 1) Tyr is abundant and 2) there is a concentration gradient of Tyr across the blood-brain barrier that can lead to unpredictable results if disturbed by ischemia or hypoxia. The knowledge of this interference is important for the interpretation of results obtained with this sensor and for the design of future studies.