The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.
This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF). Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2-30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP ( 2007 ) and BEIR VII (NRC/NAS 2006 ).


A Brief Report of Transformation From NSCLC to SCLC: Molecular and Therapeutic Characteristics.
Histologic transformation from NSCLC to SCLC is a mechanism of resistance in EGFR-mutant tumors but is also occasionally observed in nonmutated NSCLC. We performed a multicenter retrospective collection of cases presenting between 2005 and 2017. The objectives were to analyze survival data and to define epidemiologic, clinical, treatment and histomolecular characteristics at both the time of diagnosis of NSCLC and of SCLC. Forty-eight EGFR-mutant NSCLC and 13 non-EGFR-mutant cases were registered. Most EGFR-mutant tumors retained the same EGFR mutation after transformation. The median time to SCLC transformation was shorter in the EGFR-mutant group than in non-EFGR mutants (16 months versus 26 months (p = 0.01)). Both tumors were responsive to platinum etoposide regimens (45% partial response for the EGFR-mutant group versus 40% for non-EFGR mutants). The median overall survival rates were 28 months in the EGFR-mutant group versus 37 months in the non-EFGR-mutant group, respectively. After transformation, the median overall survival was 9 months in the non-EGFR-mutant group versus 10 months in the EGFR-mutant group. Transformation into SCLC seems to occur more quickly in EGFR mutated tumors; however, once the tumor is transformed its survival and response to treatment seems comparable to that of classical SCLC.


Testing the hypothesis that system y(+)L accounts for high- and low-transport phenotypes in chicken erythrocytes using L-leucine as substrate.
Experiments were carried out to test the hypothesis that system y(+)L accounts for the high (HT) and low (LT) amino-acid transport phenotypes in chicken erythrocytes and to explain the different effect of selective breeding on lysine and leucine fluxes. L: -Leucine transport was characterized in individuals which had been separated into two groups (HT and LT) according to their capacity to transport L: -lysine across the erythrocyte membrane. Whereas lysine influx (1 muM: ) in the two groups differed by 32-fold (HT/LT), leucine influx was not significantly different. Average rates (nmol/ L cells/ min) were: 227 (HT) and 7.0 (LT) for L: -lysine, and 8.9 (HT) and 7.1 (LT) for L: -leucine. The differential ability of L: -lysine and L: -leucine fluxes to discriminate between the HT and LT phenotypes was shown to be consistent with the interactions of these substrates with system y(+)L and to vary depending on the conditions of the assay. It is shown that the two phenotypes can be clearly discriminated by measuring L: -leucine influx in the presence of Li(+). These results support the hypothesis that the HT and LT phenotypes reflect alterations in the function of system y(+)L and illustrate that the choice of the appropriate substrate and medium composition must be carefully considered when investigating the consequences of either experimental or natural alterations of broad-scope transporters.


Automated detection of activity onset after postictal generalized EEG suppression.
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. If timely assessment of SUDEP risk can be made, early interventions for optimized treatments might be provided. One of the biomarkers being investigated for SUDEP risk assessment is postictal generalized EEG suppression [postictal generalized EEG suppression (PGES)]. For example, prolonged PGES has been found to be associated with a higher risk for SUDEP. Accurate characterization of PGES requires correct identification of the end of PGES, which is often complicated due to signal noise and artifacts, and has been reported to be a difficult task even for trained clinical professionals. In this work we present a method for automatic detection of the end of PGES using multi-channel EEG recordings, thus enabling the downstream task of SUDEP risk assessment by PGES characterization. We address the detection of the end of PGES as a classification problem. Given a short EEG snippet, a trained model classifies whether it consists of the end of PGES or not. Scalp EEG recordings from a total of 134 patients with epilepsy are used for training a random forest based classification model. Various time-series based features are used to characterize the EEG signal for the classification task. The features that we have used are computationally inexpensive, making it suitable for real-time implementations and low-power solutions. The reference labels for classification are based on annotations by trained clinicians identifying the end of PGES in an EEG recording. We evaluated our classification model on an independent test dataset from 34 epileptic patients and obtained an AUreceiver operating characteristic (ROC) (area under the curve) of 0.84. We found that inclusion of multiple EEG channels is important for better classification results, possibly owing to the generalized nature of PGES. Of among the channels included in our analysis, the central EEG channels were found to provide the best discriminative representation for the detection of the end of PGES. Accurate detection of the end of PGES is important for PGES characterization and SUDEP risk assessment. In this work, we showed that it is feasible to automatically detect the end of PGES-otherwise difficult to detect due to EEG noise and artifacts-using time-series features derived from multi-channel EEG recordings. In future work, we will explore deep learning based models for improved detection and investigate the downstream task of PGES characterization for SUDEP risk assessment.


Impact of respiratory syncytial virus: the nurse's perspective.
Respiratory syncytial virus (RSV) is a highly contagious virus, and is the major cause of lower respiratory tract infections in infants and toddlers worldwide. RSV infection poses serious health risks to young children during the first 2 years of life. Several infant populations have been classified as high risk, and additional risk factors are known to increase the likelihood of severe RSV infection. Treatment for active RSV infection is limited to the symptoms of infection rather than the underlying cause; therefore, it is critical to reduce the transmission of RSV. As nurses, we highlight the importance of educating healthcare professionals, both in the hospital and community settings, as well as parents and other caregivers about the risks and outcomes associated with RSV infection, and necessary measures to decrease the risk of infection. We also highlight the importance of the successful identification of those children who are at high risk of RSV infection. RSV prophylaxis (RSVP) with palivizumab has been shown to improve clinical outcome in infants who are considered high risk compared with those who have not received RSVP. The failure of healthcare staff and primary caregivers to protect children against an RSV infection can have lasting detrimental effects on the health and lives of affected children and their families.


Solitary Fibrous Tumour: A Single Institution Retrospective Study and Further Validation of a Prognostic Risk Assessment System.
Solitary fibrous tumour (SFT) is a rare mesenchymal-derived neoplasm that can arise in any anatomical location in the body. SFT rarely metastasises, but aggressive behaviour is seen in a minority of cases, and relapses can occur several years after treatment. It would be a clinical advantage if high-risk patients could be identified before treatment. We retrospectively analysed a population-based cohort of SFT to describe treatment, outcome, prognostic factors and to further validate a previously published risk assessment tool (D-score) based on age, tumour size and mitotic index. Seventy-two patients diagnosed with SFT in the Central, North and Southern Denmark regions between 1979 and 2013 were included in the study. For patients with localised disease at the time of diagnosis (n = 64) the 5 and 10 year overall survival was 86% (95% confidence interval 74-92) and 65% (95% confidence interval 50-78), respectively. Seventeen of 62 patients (27%) who were in remission after radical treatment developed recurrence with either local or distant disease. The 5 year recurrence-free survival was 83% (95% confidence interval 70-90) and the 10 year was 69% (95% confidence interval 53-81). The 5 year local recurrence-free survival was 96% (95% confidence interval 86-99) and the 10 year was 92% (95% confidence interval 76-96). The median time to both overall recurrence and local recurrence was 4.3 years. Metastatic or inoperable SFT had a poor prognosis with a median overall survival of 8.4 months (range 3.6-26.4) and a 5 year overall survival of 11% (95% confidence interval 2-30). A further validation of a risk assessment tool (D-score) confirmed that patients classified as high-risk had a significantly decreased overall survival, with a hazard ratio of 3.7 (95% confidence interval 1.1-12.3). This study showed that our management and outcome were comparable with other published studies describing SFT and confirmed the value of the D-score as a risk assessment tool. Because of late recurrences, long-term (e.g. 10 years) follow-up for moderate- and high-risk patients is recommended.


Validation of analytical conditions for determination of polycyclic aromatic hydrocarbons in roasted coffee by gas chromatography-mass spectrometry.
Polycyclic aromatic hydrocarbons (PAHs) are of significant interest due to their genotoxicity in humans. PAHs quantification in coffee is complex since some of its compounds interfere in the chromatographic analysis, which hinders the reliable determination of the PAHs. Analytical conditions for the ultrasound extraction, purification and quantification of 16 PAHs in roasted coffee were studied. The better extraction efficiency of benzo[a]pyrene (68%) from ground-roasted coffee was achieved with a solvent ratio of Hex:MC (9:1 v/v) and three extraction periods of 20 min, followed by alkaline saponification and purification of the extracts. The detection limits were 0.85-39.32 ng mL(-1), and the quantification limits from 2.84 to 131.05 ng mL(-1), obtained for fluoranthene and chrysene, respectively. The extraction was effective for most of the analytes, with recoveries of 39.8% dibenzo[ah]anthracene and 69.0% benzo[b]fluoranthene. For coffee roasted in a spouted bed reactor, the summation of the 16 PAHs ranged from 3.5 to 16.4 μg kg(-1).


Proteoform Identification and Quantification Using Intact Protein Database Search Engine ProteinGoggle.
Proteomics studies the proteome of organisms, especially proteins that are differentially expressed under certain physiological or pathological conditions; qualitative identification of protein sequences and posttranslational modifications (PTMs) and their positions can help us systematically understand the structure and function of proteoforms. With the development and relative popularity of soft ionization technology (such as electrospray ionization technology) and high mass measurement accuracy and high-resolution mass spectrometers (such as orbitrap), the mass spectrometry (MS) characterization of complete proteins (the so-called top-down proteomics) has become possible and has gradually become popular. Corresponding database search engines and protein identification bioinformatics tools have also been greatly developed. This chapter provides a brief overview of intact protein database search algorithm "isotopic mass-to-charge ratio and envelope fingerprinting" and search engine ProteinGoggle.


Localization of beta power decrease as measure for lateralization in pre-surgical language mapping with magnetoencephalography, compared with functional magnetic resonance imaging and validated by Wada test.
Objective: Atypical patterns of language lateralization due to early reorganizational processes constitute a challenge in the pre-surgical evaluation of patients with pharmaco-resistant epilepsy. There is no consensus on an optimal analysis method used for the identification of language dominance in MEG. This study examines the concordance between MEG source localization of beta power desynchronization and fMRI with regard to lateralization and localization of expressive and receptive language areas using a visual verb generation task. Methods: Twenty-five patients with pharmaco-resistant epilepsy, including six patients with atypical language lateralization, and ten right-handed controls obtained MEG and fMRI language assessment. Fourteen patients additionally underwent the Wada test. We analyzed MEG beta power desynchronization in sensor (controls) and source space (patients and controls). Beta power decrease between 13 and 35 Hz was localized applying Dynamic Imaging of Coherent Sources Beamformer technique. Statistical inferences were grounded on cluster-based permutation testing for single subjects. Results: Event-related desynchronization of beta power in MEG was seen within the language-dominant frontal and temporal lobe and within the premotor cortex. Our analysis pipeline consistently yielded left language dominance with high laterality indices in controls. Language lateralization in MEG and Wada test agreed in all 14 patients for inferior frontal, temporal and parietal language areas (Cohen's Kappa = 1, p < 0.001). fMRI agreed with Wada test in 12 out of 14 cases (85.7%) for Broca's area (Cohen's Kappa = 0.71, p = 0.024), while the agreement for temporal and temporo-parietal language areas were non-significant. Concordance between MEG and fMRI laterality indices was highest within the inferior frontal gyrus, with an agreement in 19/24 cases (79.2%), and non-significant for Wernicke's area. Spatial agreement between fMRI and MEG varied considerably between subjects and brain regions with the lowest Euclidean distances within the inferior frontal region of interest. Conclusion: Localizing the desynchronization of MEG beta power using a verb generation task is a promising tool for the identification of language dominance in the pre-surgical evaluation of epilepsy patients. The overall agreement between MEG and fMRI was lower than expected and might be attributed to differences within the baseline condition. A larger sample size and an adjustment of the experimental designs are needed to draw further conclusions.


Dermatitis artefacta in a child.
The high visibility of dermatologic diseases and their easy accessibility make the skin a primary and direct target for dysfunctional behaviors. Self-harm tendencies can frequently be expressed through dermatologic lesions, and dermatitis artefacta falls within this clinical frame. The occurrence of this cutaneous manifestation in children is very rare, with a peak of greater frequency in adolescence. We describe the characteristics of a multidisciplinary intervention-dermatologic and psychologic. Our pediatric patient displays a dermatologic picture that has no etiologic confirmation. The source of this disorder must therefore be found in socio-relational difficulties within the family and school environments, which lead the patient to self-harm behaviors that have a high communication value.


Cd induced biphasic response in soil alkaline phosphatase and changed soil bacterial community composition: The role of background Cd contamination and time as additional factors.
Hormesis is an intriguing phenomenon characterized by low-dose stimulation and high-dose inhibition. The hormetic phenomena have been frequently reported in the past decades, but the researches on the biphasic responses of soil enzymes are still limited. The main objective of this study is to explore dose response of alkaline phosphatase (ALP) to Cd (0, 0.003, 0.03, 0.3, 3.0 and 30 mg/kg) in the presence of different levels of background Cd contamination (bulk soil with no added Cd, BS; low background Cd, LB; medium background Cd, MB; and high background Cd, HB). ALP activity at 0.003-0.3 mg Cd/kg was 13-39% higher than that of the control (0 mg Cd/kg) for HB after 7 d. Similarly, the enzyme activities at 0.003-0.03 mg Cd/kg were 2-25% and 14-17% higher than those of the controls for MB and HB after 60 d. After 90 d, ALP activities at 0.3-3.0 mg Cd/kg increased by 11-17% for LB. The dose-response curves had the shape of an inverted U, showing biphasic responses at days 7 (HB), 60 (MB and HB) and 90 (LB). After 60 days of exposure, total operational taxonomic units (OTU) numbers and unique species exposed to Cd stress displayed hormetic-response curve for MB. The relative abundances of Agrobacterium, Salinimicrobiums, Bacilllus, and Oceanobacillus displayed significantly positive correlations with ALP activity. This suggested that bacterial communities potentially contribute to ALP's hormesis. This study further provides new insights into the ecological mechanisms of pollutant-induced hormesis, and substantially contributes to the ecological risk assessment of Cd pollution.


A giant ureteric calculus successfully removed by mini-endoscopic combined intrarenal surgery: A case report.
Giant ureteric calculi are extreme rare and associated with a subsequent decline in the function of the affected kidney. We report the case of a 58-year-old male with a huge opaque ureteral calculus found during a routine medical check-up. Computed tomography revealed an 11 × 12 × 67 mm3 ureteral stone at the right proximal ureter with mild hydronephrosis. The patient was treated successfully by mini-endoscopic combined intrarenal surgery, and the entire stone was retrieved. The patient recovered fully without additional complications.


Herpes virus inhibitory substances from Hypericum connatum Lam., a plant used in southern Brazil to treat oral lesions.
Hypericum connatum (Guttiferae) is used in southern Brazil in the treatment of lesions in the mouth, often related to acute herpetic gingivo-stomatitis. The chemical investigation of the plant revealed the presence of phloroglucinol derivatives and flavonoids. From the n-hexane extract of the aerial parts a phloroglucinol derivative, hyperbrasilol B, was isolated, while the methanolic extract afforded four flavonoids: amentoflavone, hyperoside, guaijaverine and luteoforol. The crude methanolic extract and fractions (n-hexane, dichloromethane and methanol) as well as the isolated compounds were tested for antiviral activity against herpes simplex viruses (HSV). Among the tested samples, luteoforol was the most active inhibiting the cytopathic effect (CPE) and reducing the viral titer of HSV-1 DNA viral strains KOS and VR733 (ATCC).


Clearance rate of intravenously administered lipid in postoperative patients.
Elimination rate (K) of intravenously given triglyceride was studied in seventeen patients who underwent elective abdominal operations, and levels of adrenaline, noradrenaline, insulin and blood sugar were simultaneously measured, as stress-indices. All these indices, except for the insulin/blood sugar ratio, increased post-operatively. The postoperative K value increased significantly in comparison with the preoperative value. There was no significant correlation between K value and any of the stress-indices. These results suggest that the initial catabolism of the lipid emulsion triglyceride is enhanced by surgical stress.


Liquid chromatography coupled with tandem mass spectrometry for the bioanalysis of proteins in drug development: practical considerations in assay development and validation.
In recent years, there has been increasing interest in using LC-MS/MS to measure protein drugs (biotherapeutics) in plasma/serum to support pharmacokinetic/toxicokinetic (PK/TK) studies. A number of strategies have been proposed to quantify different types of protein drug candidates in biological matrices. However, the application of LC-MS/MS in biotherapeutics is still very limited in regulated bioanalysis due to practical challenges. In this manuscript, we propose a "data-dependent" approach for the LC-MS/MS support of protein drug candidates, focusing on operational aspects. We have developed and validated a fast, simple and reliable LC-MS/MS method to quantify a protein drug candidate in mouse serum. This method can fit into our current workflow for routine small molecule LC-MS/MS assays with an overall sample preparation time of less than two hours. The method has been demonstrated to be accurate, precise and rugged, and it has been successfully applied to analyze samples from toxicology studies. The results were verified using a ligand binding assay and tested by standard-addition sample reanalysis. In addition, general recommendations for developing and validating an LC-MS/MS assay based on surrogate peptide(s) of protein drug candidates are also proposed for regulated bioanalysis.


Inhibition by the antilipogenic antibiotic cerulenin of thrombin-induced activation of human platelets.
Upon incubation with an antibiotic cerulenin, human platelets lost their abilities to aggregate and to release serotonin or ATP in response to various stimuli such as thrombin, ADP, collagen and platelet activating factor. The loss of activities was dependent on both incubation time and cerulenin concentrations. As judged by 14C-serotonin release, concentrations of cerulenin required for the half-maximal inhibition of thrombin-induced activation were 5-10 and 70 micrograms/ml in the incubation for 120 min at 37 degrees C for washed platelets and those in platelet rich plasma, respectively. The cerulenin treatment also resulted in a significant inhibition of 14C-acetate incorporation into the lipid fraction of platelets, suggesting that de novo synthesis of fatty acids was inhibited by the treatment. No release of lactate dehydrogenase activity nor morphological changes in platelet structure was detected upon cerulenin treatment. When effects of cerulenin on intracellular Ca2+ concentration were examined, mobilization of intracellular Ca2+ by thrombin was significantly depressed in the cerulenin-treated platelets as judged by Fura2, Quin2 or chlortetracycline fluorescence. Since the influx of external Ca2+ is not essential to the thrombin-induced platelet activation (Rink, T. J. et al. FEBS Lett. 148 21-26, 1982), the results suggest that cerulenin-treatments affect the platelet function through the inhibition of intracellular Ca2+ mobilization.


Perfluoroalkyl substances exposure and immunity, allergic response, infection, and asthma in children: review of epidemiologic studies.
Increased exposure to perfluoroalkyl substances (PFAS) potentially affects infant and childhood health through immunosuppression. Given rapidly evolving research on PFAS, it is important to comprehensively examine the impact of PFAS exposure among the pediatric population as new research becomes available due to potential fragility of the developing immune system. This review assessed the effects of PFAS fetal, infant and childhood exposures upon the development of immune function during early life stages. Researchers completed a literature review, searching PubMed for human studies published since 2010 for PFAS and health outcomes among infants and children. Included articles incorporated key search terms in the title or abstract; non-research reports and non-English papers were excluded. The search identified 518 studies for possible inclusion. Following hands-on review, 34 were determined relevant. Subsequent analyses found 8 additional relevant articles, totaling 42 studies. Major immune-related sequelae from PFAS exposures on infant and child health outcomes documented in recent literature include:• Strong indication of immunosuppression, with diminished childhood antibody response to vaccination, particularly with PFOA, PFOS and PFHxS exposures.• Some indication of increased risks of childhood infectious diseases/infections, particularly from PFOS exposures.• Limited indication of an effect of PFAS exposure on allergic reactions/allergen specific IgE antibodies.• Limited indication of an effect of PFAS exposure on atopic dermatitis (AD).• Limited indication of an effect of PFAS exposure on asthma and lung function. This review summarizes recent findings of PFAS effects on infant and childhood immune health. Evidence of immunosuppression, diminished vaccine efficacy, and increased risk of infections, allergies, asthma and AD were described following in utero, infant, and early childhood PFAS exposures. Further investigation is warranted to characterize PFAS exposure pathways and potential modes of action in relation to PFAS effects on the developing immune system. Incontrovertible proof of PFAS immunotoxic effects could optimally be obtained by a large prospective study cohort of mothers and children from infancy through school-age. Regular assessments of circulating antibodies and response to infant and childhood vaccines during growth years could prove invaluable.


Associations between anxiety disorders and diet quality in a Swiss cohort study.
Anxiety disorders are common in the general population and can have a major impact on a person's behavior. These disorders may also affect shopping and cooking habits, which may lead to a less healthy diet. Thus, we aimed to assess whether any current anxiety disorder or current specific anxiety disorders were associated with diet quality. Data of 6392 observations of 3993 participants were retrieved from 2 data waves of a population-based prospective cohort study conducted in an urban area in Switzerland. To assess the associations of anxiety status with diet quality measured by the Alternate Healthy Eating Index (AHEI), we performed cross-sectional multilevel random-effects linear regression analyses, which accounted for potential repeated participation and a series of potential confounders. We observed an association between the presence of any current anxiety disorder and lower diet quality. For the most conclusive model, the AHEI was 1.2 points lower among those with current anxiety disorders compared to those participants with no anxiety disorder (p = 0.016). When specific anxiety disorders were included separately into the model, panic disorder was associated with lower diet quality in the fully adjusted model (p = 0.037). Our findings of reduced diet quality in people with any current anxiety disorder suggest that practical support is needed when it comes to buying and processing food. This might be systematically addressed in psychotherapy and external interdisciplinary support (e.g. occupational therapy and dietary counselling) should be involved. However, further data is needed to strengthen the findings of the present study.


Hamilton rating scale for depression-24 (HAM-D24) as a novel predictor for diabetic microvascular complications in type 2 diabetes mellitus patients.
The study was designed to investigate whether the hamilton rating scale for depression (24-items) (HAM-D24) can be used to predict the diabetic microvascular complications in type 2 diabetes mellitus (T2DM) patients. 288 hospitalized patients with T2DM were enrolled. Their diabetic microvascular complications including diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy and diabetic foot as well as demographic, clinical data, blood samples and echocardiography were documented. All the enrolled patients received HAM-D24 evaluation. The HAM-D24 score and incidence of depression in T2DM patients with each diabetic microvascular complication were significantly higher than those in T2DM patients without each diabetic microvascular complication. After the adjustment of use of insulin and hypoglycemic drug, duration of T2DM, mean platelet volume, creatinine, albumin, fasting glucose, glycosylated hemoglobin type A1C, left ventricular ejection fraction, respectively, HAM-D24 score was still significantly associated with diabetic microvascular complications (OR = 1.188-1.281, all P < 0.001). The AUC of HAM-D24 score for the prediction of diabetic microvascular complication was 0.832 (0.761-0.902). 15 points of HAM-D24 score was considered as the optimal cutoff with the sensitivity of 0.778 and specificity of 0.785. In summary, HAM-D24 score may be used as a novel predictor of diabetic microvascular complications in T2DM patients.


Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases.
Mast cells and eosinophils are the key cells in the early and late stages of allergic inflammation. There is increasing evidence that angiogenesis plays an important role both in the development of inflammation and in the pathophysiology of tissue remodeling during allergic disorders. In this review we provide recent data showing a link between allergy and angiogenesis and some possible mechanisms through which vascular endothelial growth factor and the immune system can interact. We discuss the multifaceted roles of mast cells and eosinophils in tissue remodeling and angiogenesis during allergic diseases and whether these cells can be both source and target cells for pro-angiogenic mediators.


Exploring new-graduate physiotherapists' preparedness for, and experiences working within, Australian acute hospital settings.
New-graduate physiotherapists experience a steep learning curve when transitioning from student to clinician. The acute hospital setting is known to present unique challenges for health clinicians, however, the preparedness of new-graduate physiotherapists for working within this setting remains unclear. The aim of this study was to investigate new-graduate physiotherapists' experiences of working in acute hospital settings and their perceptions toward how their pre-professional training prepared them for this setting. A qualitative study with a general inductive approach was used. Semi-structured interviews with new-graduate physiotherapists working in acute hospital settings were undertaken (n = 14). Interview data were subject to thematic analysis. Four themes were generated from the data: 1) multifactorial and high-pressure nature; 2) managing relationships; 3) realizing responsibility; and 4) constructing realistic experiences. The acute hospital setting presents unique obstacles and additional challenges when transitioning from student to clinician. New-graduates value the role of pre-professional training in their preparation for this context, however, new-graduates reflected on being sheltered from some areas of practice as students. Recommendations are suggested for education providers to adapt pre-professional training, and for employers to implement workplace strategies, which may support new-graduate physiotherapists in the acute hospital setting.


Sticky situations: key components that control bacterial surface attachment.
The formation of bacterial biofilms is initiated by cells transitioning from the free-swimming mode of growth to a surface. This review is aimed at highlighting the common themes that have emerged in recent research regarding the key components, signals, and cues that aid in the transition and those involved in establishing a more permanent surface association during initial attachment.


Excitant amino acid projections from rat amygdala and thalamus to nucleus accumbens.
High affinity uptake of D-[3H]aspartate, [3H]choline and [3H]GABA was examined in synaptosomal-containing preparations of rat nucleus accumbens septi 7 to 10 days after unilateral or bilateral N-methyl-D-aspartate lesions confined to the parataenial nucleus of the thalamus or the basolateral nucleus of the amygdala. Uptake of both D-[3H]aspartate and [3H]choline was significantly reduced (11% and 14% less than control, respectively) by unilateral lesion of the thalamus, whereas [3H]GABA uptake was unaffected. Bilateral thalamic lesions significantly reduced D-[3H]aspartate uptake (11% less than control) into homogenates of the nucleus accumbens, whilst [3H]GABA uptake was unaltered. D-[3H]aspartate uptake was significantly reduced (26% less than control) following unilateral lesion of the amygdala, whereas both [3H]GABA and [3H]choline uptake were unaffected. Bilateral amygdaloid lesions significantly increased D-[3H]aspartate uptake (39% greater than control), whilst uptake of [3H]GABA was not affected. The results implicate glutamate and/or aspartate as putative neurotransmitters in afferent projections from the basolateral amygdala and the parataenial thalamus to the nucleus accumbens. Thalamic afferents to the nucleus accumbens may also utilize acetylcholine as their transmitter.


Clinical features, treatment and prognosis of MuSK antibody-associated myasthenia gravis in Northwest China: a single-centre retrospective cohort study.
To summarize the clinical characteristics of patients with muscle-specific kinase antibody-associated myasthenia gravis (MuSK-MG) and to evaluate the therapeutic responses to different treatment regimes. Eighteen MuSK-MG patients admitted in our department between October 2017 and September 2020 were included. Clinical parameters were collected and the responses to different immunosuppressive drugs were assessed by MGFA Postintervention Status (MGFA-PIS). Meanwhile, the correlation between QMG scores and MuSK antibody titers were analyzed and MuSK antibody (MuSK-ab) titers were compared before and after therapy based on different immunosuppressive treatment regimes. Female predominance (ratio of females to males, 15:3) was evident in the study population, with the average onset age of (40.28 ± 18.57) years and the median disease course of 30.50 months (interquartile range [IQR], 17.50-44.75 months). Ocular manifestation was the most common onset symptom (11/18; 61.11%), and mild symmetrical ptosis was most frequent. Bulbar symptoms had the highest incidence of 88.89% over the entire disease course. Abnormal responses to RNS test were recorded most frequently on the musculus deltoideus (83.33%). All patients were treated with prednisone (Pred) alone or plus azathioprine (AZA), tacrolimus (TAC) or low-dose rituximab (RTX), and 17 (94.44%) of them achieved a favorable outcome defined as minimal manifestation (MM) or better. In general, an obvious positive correlation between QMG score and MuSK-ab titer (r = 0.710, P < 0.001) were found in all patients. A more significant reduction of MuSK-ab titers was observed in patients receiving TAC or RTX plus Pred than those receiving AZA plus Pred. The prominent clinical manifestations of ocular and bulbar muscles involvements, together with abnormal RNS response mostly recorded on the musculus deltoideus and better efficacy associated with TAC or low-dose RTX plus Pred, provide a more exhaustive picture of MuSK-MG, particularly in Northwest China.


[Detection of Aedes (Stegomyia) albopictus skus. Mosquitoes in the Russian Federation].
Aedes (Stegomyia) albopictus Skus. mosquitoes were for the first time collected in the Bolshoi Sochi region in the Russian Federetion. 16 females and 1 male were morphologically and genetically identified as Ae. albopictus and Aedes aegypti, respectively.


Variation in surface marking of superior epigastric vessels. A guide to safe laparoscopic port insertion.
This study aimed to map surface markings of the superior epigastric artery, to provide safe landmarks for the placement of trochars in laparoscopic surgery. Seventeen cadavers were dissected and surface anatomy of the superior epigastric artery was defined at two levels: the xiphoid process, and midway between the xiphoid process and umbilicus. Safe sites for insertion of ports were determined in cadavers by dissecting and locating the main trunks of the superior epigastric artery. At the level of the xiphoid process, the distance from the midline ranged from 3.9cm to 4.8cm with a mean of 4.3cm (SD +/- 0.2cm) while midway between the xiphoid process and umbilicus, the distance of the superior epigastric artery from the midline ranged from 4 to 7.5cm, with a mean of 5.7cm (SD +/- 0.7cm). In this area the artery is vulnerable to damage, hence it can be declared as a danger zone.


Loss of homeostatic strain alters mechanostat "set point" of tendon cells in vitro.
Tendon cells respond to mechanical loads. The character (anabolic or catabolic) and sensitivity of this response is determined by the mechanostat set point of the cell, which is governed by the cytoskeleton and its interaction with the extracellular matrix. To determine if loss of cytoskeletal tension following stress deprivation decreases the mechanoresponsiveness of tendon cells, we cultured rat tail tendons under stress-deprived conditions for 48 hours and then cyclically loaded them for 24 hours at 1%, 3%, or 6% strain at 0.17 Hz. Stress deprivation upregulated MMP-13 mRNA expression and caused progressive loss of cell-matrix contact compared to fresh controls. The application of 1% strain to fresh tendons for 24 hours inhibited MMP-13 mRNA expression compared to stress-deprived tendons over the same period. However, when tendons were stress-deprived for 48 hours and then subjected to the same loading regime, the inhibition of MMP-13 mRNA expression was decreased. In stress-deprived tendons, it was necessary to increase the strain magnitude to 3% to achieve the same level of MMP-13 mRNA inhibition seen in fresh tendons exercised at 1% strain. The data suggest loss of cytoskeletal tension alters the mechanostat set point and decreases the mechanoresponsiveness of tendon cells.


TheCellMap.org: A Web-Accessible Database for Visualizing and Mining the Global Yeast Genetic Interaction Network.
Providing access to quantitative genomic data is key to ensure large-scale data validation and promote new discoveries. TheCellMap.org serves as a central repository for storing and analyzing quantitative genetic interaction data produced by genome-scale Synthetic Genetic Array (SGA) experiments with the budding yeast Saccharomyces cerevisiae In particular, TheCellMap.org allows users to easily access, visualize, explore, and functionally annotate genetic interactions, or to extract and reorganize subnetworks, using data-driven network layouts in an intuitive and interactive manner.


A randomized trial to increase physical activity among native elders.
Physical inactivity is common among older populations and American Indians. Our objective was to compare two methods for increasing physical activity and walking among American Indian elders. We conducted a two arm randomized trial to increase physical activity in 125 American Indians aged 50-74 years at the Seattle Indian Health Board in 2005. Participants were randomized into either an activity monitoring (N=63) or activity monitoring with a pedometer (N=62) arm over a six-week period. Outcomes included self-reported physical activity and well-being, and the 6-min walk test. There were no group differences in self-reported physical activities and well-being. The 6-min walk test yielded no between-group differences. All participants increased the frequency of leisure walking (p<0.01), frequency of all exercise-related activities (p<0.01), frequency of moderate-intensity exercise activities (p<0.01), and improved weekly caloric expenditure for all exercise activities (p<0.05) by the end of the trial. Pedometers did not confer enhanced performance on the physical activity outcomes beyond those achieved through self-monitoring. Physical activity can be promoted among at-risk groups in a brief, inexpensive manner in primary care. Exercise prescription and culturally relevant enhancement strategies may optimize physical activity outcomes for elder American Indians.


Poorly Differentiated Neuroendocrine Tumors.
Poorly differentiated neuroendocrine carcinomas of the gastrointestinal tract are rare and limited data are available to guide treatment. These tumors have been treated akin to small cell lung cancer given the histologic similarities. Their pathology is complex. Over the last decade, these tumors are shown as likely a distinct disease entity that is more heterogeneous than accounted for by the current classification system. This article discusses the epidemiology, prognosis, clinical presentation and pathologic nuances and provides a review of the existing clinical data in poorly differentiated neuroendocrine carcinomas and small cell lung cancers.


Opposite effects of naloxone on substance P-induced changes in brain DOPA synthesis and in locomotor activity in rats.
Intracerebroventricular injection of substance P (SP) enhanced the synthesis of dopamine and noradrenaline (measured as increase in DOPA formation after inhibition of the aromatic L-amino-acid decarboxylase) in rat brain. These biochemical effects were blocked in most brain regions by pretreatment with naloxone. SP also induced vasodilation, salivation and increased locomotor activity. These effects were not antagonized, but, in the case of locomotor activity, potentiated by naloxone. The data suggest the existence of specific SP-containing neuronal pathways for behavior, which pathways are not related to those regulating the synthesis of brain catecholamines.


Nesting holes and food supply in relation to forest bird densities on islands and mainland.
Bird densities were estimated on 41 small islands and two mainland plots at a South Swedish lake both in 1976 and 1983. In the latter year, three additional plots were also censused. The ratio between combined densities of hole-nesting birds on the mainland and on islands was 3:1 both in plots without and with nest boxes. In plots with boxes combined densities of hole-nesting birds doubled compared with control plots. This increase was caused by a tenfold increase of pied flycatcher Ficedula hypoleuca. Territories of this species were on average established about a week later on the islands compared with the mainland. Furthermore, 50% of the males on the islands did not attract a female. Densities of great tit Parus major, marsh tit Parus palustris and nuthatch Sitta europaea were unaffected by increased nesthole availability. For P. major this result contrasts with those in other studies.The density of chaffinch Fringilla coelebs in habitats with similar height and vertical structure was two times higher on the islands compared to the mainland. On the islands the density was the same on islands with only one pair and on those with two or more pairs. In spring, there were no significant differences between islands and the mainland in the proportion of leaves with insect feeding traces. The proportion of Salix leaves with feeding traces increased with island size, but this was not so for Alnus and Betula leaves. In late summer, the proportion of leaves with feeding traces were halved inside a plot with nest boxes and hence increased bird densities compared to a nearby control plot. This result was the same along the lake shore and about 150 m away from the shore.The discussion centers on the effect of man on the food-and nest site-availability of hole-nesting birds, food limitation of insectivorous birds and density compensation on islands.


Combined-modality treatment for isolated recurrences of breast carcinoma: update on 30 years of experience at the University of Texas M.D. Anderson Cancer Center and assessment of prognostic factors.
In three prospective, single-arm studies, the authors previously showed an improved outcome for anthracycline-naïve patients with isolated sites of recurrent breast carcinoma (BC) who were treated with doxorubicin-based chemotherapy after local therapy (surgery and/or radiotherapy). In the current report, the initial results are presented from a Phase II trial of docetaxel (100 mg/m(2) every 21 days for 6 cycles) given after local therapy for recurrent BC (Stage IV BC with no evidence of clinically measurable disease) in patients who received prior adjuvant anthracycline-based chemotherapy, and the authors provide an update of the 3 previous studies. An analysis of prognostic factors for these patients also is presented. Eligibility criteria for all studies included histologic proof of recurrent BC that had been resected and/or irradiated with curative intent. Survival was calculated using the Kaplan-Meier method. Univariate survival analyses were performed to test for associations between patient characteristics and outcome (log-rank test). Cox proportional hazards models were used to determine the multivariable correlations between patient characteristics and outcome. The median follow-up for the docetaxel-based trial (n = 26 patients) was 45 months. Early outcomes for this study are promising. The median disease-free survival (DFS) was 44 months, and the 3-year DFS and overall survival (OS) rates were 58% and 87%, respectively. In the 3 doxorubicin-based studies, the median follow-up was 121.5 months for all living patients, and the estimated 20-year DFS and OS rates were both 26%. On multivariable analysis of patients from all 4 studies, the only significant prognostic factor for DFS and OS (P = 0.0006) was the number of involved axillary lymph nodes at initial diagnosis. A proportion of patients with isolated BC recurrences achieved prolonged DFS with combined-modality treatment. Patients who receive anthracycline-based chemotherapy at primary diagnosis may benefit from local treatment followed by docetaxel-based chemotherapy for isolated recurrences. The only significant independent prognostic factor was the number of involved axillary lymph nodes at initial diagnosis.


Hormonal changes during flower development in floral tissues of Lilium.
Much effort has been focussed on better understanding the key signals that modulate floral senescence. Although ethylene is one of the most important regulators of floral senescence in several species, Lilium flowers show low sensitivity to ethylene; thus their senescence may be regulated by other hormones. In this study we have examined how (1) endogenous levels of hormones in various floral tissues (outer and inner tepals, androecium and gynoecium) vary throughout flower development, (2) endogenous levels of hormones in such tissues change in cut versus intact flowers at anthesis, and (3) spray applications of abscisic acid and pyrabactin alter flower longevity. Results show that floral tissues behave differently in their hormonal changes during flower development. Cytokinin and auxin levels mostly increased in tepals prior to anthesis and decreased later during senescence. In contrast, levels of abscisic acid increased during senescence, but only in outer tepals and the gynoecium, and during the latest stages. In addition, cut flowers at anthesis differed from intact flowers in the levels of abscisic acid and auxins in outer tepals, salicylic acid in inner tepals, cytokinins, gibberellins and jasmonic acid in the androecium, and abscisic acid and salicylic acid in the gynoecium, thus showing a clear differential response between floral tissues. Furthermore, spray applications of abscisic acid and pyrabactin in combination accelerated the latest stages of tepal senescence, yet only when flower senescence was delayed with Promalin. It is concluded that (1) floral tissues differentially respond in their endogenous variations of hormones during flower development, (2) cut flowers have drastic changes in the hormonal balance not only of outer and inner tepals but also of androecium and gynoecium, and (3) abscisic acid may accelerate the progression of tepal senescence in Lilium.


What predicts successful nonoperative management with botulinum toxin for anal fissure?
Botulinum toxin has been established as a non-surgical alternative for chronic anal fissures. There is a paucity of data regarding which patients benefit most from this intervention. We retrospectively collected data from all cases of chronic anal fissures treated with botulinum toxin over seven years to identify predictors of success. Non-responders were defined as any subsequent surgery or reporting satisfaction as poor or fair. Of 91 patients, 60% (n = 55) were responders and 26% (n = 25) underwent subsequent surgery. There were significantly more females among responders (78% vs. 55%, p = 0.02). A higher body mass index tended towards significance among non-responders (30 ± 7 vs. 27 ± 6, p = 0.08). High satisfaction at the first visit was associated with no subsequent surgery (18% vs. 45%, p = 0.002). Botulinum toxin can be successfully used to treat anal fissures in a majority of patients. Primary predictors of success were female sex, satisfaction at the first post-procedure visit and there was a tendency towards a lower body mass index.


Albuterol responsiveness in infants with respiratory failure caused by respiratory syncytial virus infection.
To assess the bronchodilator effect of inhaled albuterol in the acute stage of severe respiratory syncytial virus (RSV) infection. Prospective, nonrandomized study of previously healthy infants who underwent intubation and whose lungs were ventilated because of respiratory failure caused by RSV infection. Ten infants with an endotracheal tube in place and without lung disease were matched for age and weight and served as normal control subjects. Lung function tests, including respiratory mechanics by single-breath occlusion, small airway function by forced deflation, and lung volumes by nitrogen washout, were performed before and after inhalation of 900 micrograms albuterol by metered dose inhaler. Bronchodilator response was defined as a change of more than twice the coefficient of variation of repeated baseline measurements. Twenty-three infants (mean +/- SE age = 4.2 +/- 1.1 months) were studied, of whom 20 (87%) had obstructive small airway disease, and 3 (13%) had exclusively restrictive lung function profiles. Ten of the infants with obstructive disease (50%) did not benefit from albuterol, and 9 (45%) had small but significant improvements in lung function. Deterioration of lung function was documented in 1 patient after albuterol inhalation. Inhaled albuterol is of limited value as a bronchodilator in infants with RSV-induced respiratory failure and should be discontinued if a beneficial response cannot be observed.


Antibody-dependent enhancement (ADE) of dengue virus: Identification of the key amino acid that is vital in DENV vaccine research.
The antibody-dependent enhancement (ADE) of dengue virus (DENV) has critically restricted vaccine development. Prior research suggested pr4 as the probable ADE epitope of DENV. Chimeric DENV was constructed by replacing the DENV pr4 gene with the corresponding Japanese encephalitis virus (JEV) gene to determine whether it can reduce ADE activities. An alanine scanning method and bioinformatics analysis were utilized to identify the amino acid of pr4 that was crucial as an ADE epitope. Chimeric virus reduced ADE and virulence. The amino acids at the following locations on the mutant peptides showed significantly reduced binding ability to prM antibody: pr4.5 (position 5 - leucine), pr4.6 (position 6 - leucine), pr4.7 (position 7 - phenyalanine) and pr4.16 (position 16 - cysteine). The four amino acids had formed a pocket-like structure, which could increase the possibility of binding to an antibody. ADE activities could be reduced by replacing the DENV pr4 gene with the corresponding JEV gene. Leucine at position 5, leucine at position 6, phenyalanine at position 7 and cysteine at position 16 were the key amino acid sites in the ADE response of DENV. The occurrence of ADE can potentially be reduced by the replacement of key amino acids, hence highlighting its possible contribution to dengue vaccine design, paving a way for future vaccine research.


[Ophthalmological alterations at the initial diagnosis of HIV infection].
Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV), is one of the most important infectious causes of death in the twentieth and twenty-first centuries. Ocular manifestations can appear in particular when the CD4 cell count is low. This article presents a case report of a 38-year-old homosexual man in whom HIV microangiopathy retinopathy syndrome (MAPS) was found during the assessment of the initial HIV diagnosis. Typical findings in MAPS are conjunctival and retinal vessel abnormalities, cotton wool spots as well as intraretinal hemorrhages. Loss of vision is a rare complication but MAPS shows an impairment of the immune status and is also associated with a higher mortality.


Transgenic mouse mammary tumor virus superantigen expression prevents viral infection.
Endogenous mouse mammary tumor virus (MMTV) proviruses have recently been shown to cosegregate genetically with the minor lymphocyte-stimulating loci, also termed self-superantigens. The antigenic activity has been localized to the open reading frame (ORF) protein encoded in the long terminal repeat of MMTV. We show here that unlike their nontransgenic littermates, transgenic mice expressing high levels of an ORF protein derived from the C3H exogenous MMTV specifically delete their V beta 14+ T cells and do not become infected with this virus when it is present in their mother's milk. Thus, it appears that MMTV utilizes cells of the immune system in its infection pathway, and mice that retain endogenous MMTVs should be immune to infection by exogenous virus. These results offer possible new approaches to anti-viral therapy or immunization.


Effects of water and carboxylic acid monomer on polymerization of HEMA in the presence of N-phenylglycine.
This research was designed to study the effect of water or carboxylic acid monomer on the polymerization of 2-hydroxyethyl methacrylate (HEMA) in order to understand the bonding mechanism of dentin bonding systems using N-phenylglycine (NPG). The polymerization of HEMA in the presence of NPG was studied by adding various amounts of water and/or 4-(2-methacryloyloxyethoxycarbonyl) phthalic acid (4-MET) and evaluated using differential scanning calorimetry (DSC). The addition of water promoted the polymerization of HEMA. Polymerization was further promoted through the addition of 4-MET as a carboxylic acid monomer. Polymerization was promoted at the molar ratio of 4-MET to NPG of 1.0-7.0. Moisture on the dentin surface could contribute to improving bond strength in dentin bonding systems using NPG by promoting polymerization at the dentin interface.


Cleavages along {110} in bcc iron emit dislocations from the curved crack fronts.
Body-centered-cubic (bcc) transition metals, such as [Formula: see text]-Fe and W, cleave along the {100} plane, even though the surface energy is the lowest along the {110} plane. To unravel the mechanism of this odd response, large-scale atomistic simulations of curved cleavage cracks of [Formula: see text]-Fe were conducted in association with stress intensity factor analyses of straight crack fronts using an interatomic potential created by an artificial neural network technique. The study provides novel findings: Dislocations are emitted from the crack fronts along the {110} cleavage plane, and this phenomenon explains why the {100} plane can be the cleavage plane. However, the simple straight crack-front analyses did not yield the same conclusion. It is suggested that atomistic modeling, at sufficiently large scales to capture the inherent complexities of materials using highly accurate potentials, is necessary to correctly predict the mechanical strength. The method adopted in this study is generally applicable to the cleavage problem of bcc transition metals and alloys.


Anti-tumor activity of N-thiolated beta-lactam antibiotics.
An ongoing strategy for cancer treatment is selective induction of apoptosis in cancer over normal cells. N-thiolated beta-lactams were found to induce DNA damage, growth arrest and apoptosis in cultured human cancer cells. However, whether these compounds have a similar effect in vivo has not been studied. We report here that treatment with the beta-lactam L-1 caused a significant inhibition of tumor growth in a breast cancer xenograft mouse model, associated with induction of DNA damage and apoptosis in vivo. These results suggest that the synthetic antibiotic N-thiolated beta-lactams hold great potential to be developed as novel anti-cancer drugs.


CCl4-hepatotoxicity in the Mongolian gerbil: influence of monooxygenase system induction.
The effects of chlordecone (CD), mirex or phenobarbital (PB) treatment of male Mongolian gerbils on CCl4-hepatotoxicity were determined. These monooxygenase inducers did not potentiate CCl4-hepatotoxicity in the gerbil although phenobarbital and CD are known potentiators in the rat. The control gerbil was more sensitive to CCl4-hepotoxicity than the control rat as reflected in loss of cytochrome (cyt) P-450 and increases in SGOT and SGPT. In addition, CCl4 treatment of the control gerbils resulted in significant reductions in cyt b5 and NADPH-cyt P-450 levels, a phenomenon not observed in the rat.


CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol--potential role(s) for estrogen signaling.
CYP7B1, a cytochrome P450 enzyme, metabolizes several steroids involved in hormonal signaling including 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an estrogen receptor agonist, and dehydroepiandrosterone, a precursor for sex hormones. Previous studies have suggested that CYP7B1-dependent metabolism involving dehydroepiandrosterone or 3beta-Adiol may play an important role for estrogen receptor beta-mediated signaling. However, conflicting data are reported regarding the influence of different CYP7B1-related steroids on estrogen receptor beta activation. In the present study, we investigated CYP7B1-mediated conversions of dehydroepiandrosterone and 3beta-Adiol in porcine microsomes and human kidney cells. As part of these studies, we compared the effects of 3beta-Adiol (a CYP7B1 substrate) and 7alpha-hydroxy-dehydroepiandrosterone (a CYP7B1 product) on estrogen receptor beta activation. The data obtained indicated that 3beta-Adiol is a more efficient activator, thus lending support to the notion that CYP7B1 catalysis may decrease estrogen receptor beta activation. Our data on metabolism indicate that the efficiencies of CYP7B1-mediated hydroxylations of dehydroepiandrosterone and 3beta-Adiol are very similar. The enzyme catalyzed both reactions at a similar rate and the K(cat)/K(m) values were in the same order of magnitude. A high dehydroepiandrosterone/3beta-Adiol ratio in the incubation mixtures, similar to the ratio of these steroids in many human tissues, strongly suppressed CYP7B1-mediated 3beta-Adiol metabolism. As the efficiencies of CYP7B1-mediated hydroxylation of dehydroepiandrosterone and 3beta-Adiol are similar, we propose that varying steroid concentrations may be the most important factor determining the rate of CYP7B1-mediated metabolism of dehydroepiandrosterone or 3beta-Adiol. Consequently, tissue-specific steroid concentrations may have a strong impact on CYP7B1-dependent catalysis and thus on the levels of different CYP7B1-related steroids that can influence estrogen receptor beta signaling.


[Identification of microorganisms related to chronic rhinosinusitis in adult patients with variable common immunodeficiency].
The prevalence of chronic rhinosinusitis in adult patients with common variable immunodeficiency (CVID) is 52%. The patients with CVID show higher incidence of chronic rhinosinusitis, which is an inflammatory disease that affects the lining of one or more paranasal sinuses and nasal cavity. To identify the microorganisms in the middle meatus secretion obtained by endoscopy associated with chronic rhinosinusitis in adult patients with common variable immunodeficiency (CVID). A descriptive, cross-sectional study, which included adult patients with CVID, from whom a sample endoscopic middle meatus secretion from both nostrils was obtained and sent to culture for aerobic, anaerobic bacteria and fungi. Informed consent of all patients was obtained. 29 patients were studied: 18 women and 11 men with a mean age of 40±13 years. The results were: 2 samples showed no microbial growth, 24 showed growth of aerobic bacteria, 3 cases had fungal growth without development of anaerobic bacteria. Our results show that the most common microorganisms associated with CSR in adult patients are: Moraxella catarrhalis, Staphylococcus, Sphingomonas paucimobilis and Citrobacter koseri, and associated fungal agents were: Candida albicans and Aspergillus fumigatus.


In vitro effects of cytosolic inhibitor and opiates on the binding of [3H]oestradiol to nuclear type II binding sites of rat uterus and hypothalamus.
The effect of cytosolic ultrafiltrates prepared from intact rat uteri, brain hemispheres and hypothalami and of some opiate analogues on oestradiol binding to nuclear type II sites in rat uterus and hypothalamus was studied. Opiate binding in nuclear fraction of rat uteri was also evaluated. Both uterine and hypothalamic low affinity nuclear oestradiol binding was inhibited by filtrate from uteri, while only hypothalamic nuclear binding was decreased in presence of hypothalamic filtrate. Filtrate from brain was ineffective on nuclear oestradiol binding of the studied tissues. Concentration dependent inhibition of uterine nuclear oestradiol binding could be demonstrated by some opiate analogues in vitro. Specific low affinity nuclear binding of opiate antagonist naloxone and agonist dihydromorphine was observed in rat uteri which could be inhibited by uterine filtrate and oestradiol but not by hypothalamic filtrate or other steroids. Present findings support the probable intracellular interplay of opiates and oestradiol action and suggest that cytosolic inhibitor factor might be involved.


The myristoylated amino-terminus of an Arabidopsis calcium-dependent protein kinase mediates plasma membrane localization.
Calcium-dependent protein kinases (CDPK) are a major group of calcium-stimulated kinases found in plants and some protists. Many CDPKs are membrane-associated, presumably because of lipid modifications at their amino termini. We investigated the subcellular location and myristoylation of AtCPK5, a member of the Arabidopsis CDPK family. Most AtCPK5 was associated with the plasma membrane as demonstrated by two-phase fractionation of plant microsomes and by in vivo detection of AtCPK5-GFP fusion proteins. AtCPK5 was a substrate for plant N-myristoyltransferase and myristoylation was prevented by converting the glycine at the proposed site of myristate attachment to alanine (G2A). In transgenic plants, a G2A mutation completely abolished AtCPK5 membrane association, indicating that myristoylation was essential for membrane binding. The first sixteen amino acids of AtCPK5 were sufficient to direct plasma membrane localization. In addition, differentially phosphorylated forms of AtCPK5 were detected both in planta and after expression of AtCPK5 in a cell-free plant extract. Our results demonstrate that AtCPK5 is myristoylated at its amino terminus and that myristoylation is required for membrane binding.


Reversal of prostaglandin E2 effect on adrenal catecholamine release after hypophysectomy.
Prostaglandin E2 induced increased catecholamine release in vitro from adrenals of hypophysectomized rats, while in adrenals of intact rats catecholamine release was suppressed by prostaglandin E2.


Effect of indapamide on an experimental model of cerebral ischemia in hypertensive rats.
This study quantified the immediate general hemodynamic events following the bilateral carotid ligation-induced cerebral ischemia in normotensive and spontaneously hypertensive rats. The influence of treatment with indapamide was evaluated. In normotensive rats, hemodynamic values remained unchanged during the 10 minutes following the carotid ligation. In spontaneously hypertensive rats, arterial pressure values immediately and significantly (p less than 0.01) increased, up to 50 percent during the 10 minutes following the carotid ligation. Heart rate was unchanged. Indapamide at a short-term 3 mg/kg intraperitoneally, chosen in order to give a minimal (nonsignificant) antihypertensive effect in spontaneously hypertensive rats, significantly (p less than 0.01) reduced the bilateral carotid ligation-induced vasopressor response, whereas heart rate remained unchanged. The results presented here show that in spontaneously hypertensive rats, but not in normotensive rats, bilateral common carotid ligation induces an immediate and strong increase in arterial pressure values. These results compare with the previously described differences in cerebral ischemia-induced disorders in normotensive and hypertensive rats. Finally, indapamide, an antihypertensive agent that decreases vascular reactivity, significantly inhibits the carotid ligation-induced vasopressive response in hypertensive rats.


Testosterone prevents castration-induced reduction in peripheral benzodiazepine receptors in Cowper's gland and adrenal.
The effect of surgical castration of adult male Sprague-Dawley rats on peripheral and central benzodiazepine (BZ) receptors was studied. Following removal of the testes, a significant decrease in the density of peripheral BZ receptors (PBR) was observed in Cowper's glands (71%; P less than 0.005) and the adrenal (31%; P less than 0.01), but not in the heart. Administration of testosterone acetate (TA) prevented castration-induced PBR depletion. Orchiectomy per se, as well as TA administration to castrated rats, had no effect on central or peripheral BZ receptors in whole brain without the cerebellum. These results indicate the regulatory role of testosterone in the regulation of PBR in Cowper's glands and adrenal.


Larvicidal composite alginate hydrogel combined with a Pickering emulsion of essential oil.
Sulfonated cellulose nanocrystals (S-CNCs) can be used to encapsulate thyme white essential oil (EO) that is volatile and immiscible with water. S-CNCs form a Pickering emulsion (PE) with EOs and the micron-scale PEs are embedded in sodium alginate (SA) to form macroscale hydrogel beads. The incorporation of PEs with SA is confirmed with FTIR, XRD, SEM and confocal microscopic characterizations and the release behavior is monitored to understand the time-dependent biological activity of the EOs. The larvicidal performance of the SA-PE composite hydrogel beads is investigated with Aedes albopictus (Skuse) larvae. The larvicidal activity is higher for SA/PE hydrogel beads prepared at 0.5 % CaCl2 than 0.75 or 1.0 % CaCl2 due to their higher release rate.


Primary Care Considerations for the Baseball Athlete.
To summarize current guidance and best practices surrounding non-orthopedic medical concerns in baseball. Discussion of COVID19-related practice changes pertaining to the prevention and screening of communicable respiratory illness, concussion protocol updates, the enhanced role of a multi-disciplinary team of mental health professionals. Prevention, appropriate screening, and early identification remain cornerstones of effective primary care both within the general population as well as for the baseball athlete.


Immune response and gene polymorphism profiles in Crohn's disease and ulcerative colitis.
Polymorphisms in genes linked to the innate and adaptive immune response may be involved in inflammatory bowel disease pathogenesis. Our aim was to investigate associations among IL1B-511, IL1B-31, IL1RN, TNFA-307, TLR-2, TLR-4, IL2-330, NOD2 G908R, NOD2 L1007fsinsC polymorphisms and both Crohn's disease (CD) and ulcerative colitis (UC) in a Brazilian population. We studied 43 patients with CD, 42 with UC, and 541 blood donors. Polymorphisms were evaluated by PCR, PCR-CTPP, or PCR-RFLP. Data were analyzed in multivariate models adjusting for confounding factors. IL1RN VNTR (P = 0.00, odds ratio [OR] = 2.43, 95% confidence interval [CI] = 1.50-3.90), as well as TNFA-307 polymorphic allele (P = 0.05, OR = 1.70, 95% CI = 1.00-2.94) were associated with UC. Both NOD2 mutations (G908R, P = 0.02, OR = 6.83, 95% CI = 1.62-25.45, and L1007fsinsC, P = 0.00, OR = 20.00, 95% CI = 3.21-124.69) were associated with CD. Our analyses showed positive associations between proinflammatory polymorphisms at IL1RN and TNFA-307 loci and UC, as well as polymorphisms in the NOD2 gene and CD. These results highlight the importance of different genetic profiles associated with CD and UC.


Origin of reactive oxygen species in erythrocytes infected with Plasmodium falciparum.
Oxidative radicals are demonstrably produced in malaria-infected erythrocytes. In order to verify the biochemical origin of these radicals, erythrocyte lysate was brought to acid pH to mimic the environment of the parasite food vacuole into which host cell cytosol is transferred during parasite feeding. Oxyhemoglobin, but not deoxyhemoglobin, is rapidly converted to methemoglobin at rates which decline with increasing pH. The rate of conversion is further increased in the presence of the catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and the extent of inhibition of the lysate catalase increases upon acidification, implying that H2O2 is thus produced by the spontaneous dismutation of superoxide radicals generated during methemoglobin formation. Intact Plasmodium falciparum trophozoite-infected human red blood cells (TRBC) were shown to produce H2O2 and OH radicals about twice as much as normal erythrocytes, as evidenced by the inhibition of endogenous catalase activity in the presence of 3-AT and the degradation of deoxyribose, respectively. Increased H2O2 levels and catalase activity were found in both host cell and parasite compartments. No increase in H2O2 production over that observed in uninfected erythrocytes could be detected at the ring stage when host cell digestion is absent. H2O2 and OH radicals production in TRBC was considerably reduced when digestion of host cell cytosol was inhibited either by antiproteases (which reduce the proteolysis of imported catalase) or by its alkalinization with NH4Cl (which reduce methemoglobin formation). These results suggest that reactive oxygen species are produced in the parasite's food vacuole during the digestion of host cell cytosol, and are able to egress from the parasite to the host cell compartment.


Hearing-related quality of life outcomes for Singaporean children using hearing aids or cochlear implants.
The Children Using Hearing Devices Quality of Life Questionnaire (CuHDQOL) is a new parent-administered hearing-specific questionnaire for children fitted with hearing devices. The aim of this study was to assess outcomes for hearing-impaired children in Singapore using this measure, as well as to examine its applicability for use in a clinical setting. The CuHDQOL has 26 items, uses a recall period of 1 month, and is divided into three sections: parental perspectives and expectations (eight items), impact on the family (eight items) and hearing-related quality of life (QOL) of the child (10 items). Responses are made on a 5-point Likert scale, and transformed to a score from 0-100. Twenty-two parents of children with hearing aids and 14 parents of children with cochlear implants completed the CuHDQOL. The mean total CuHDQOL scores was 62/100 for the children using hearing aids and 53/100 for children with cochlear implants. Scores for the children using hearing aids were higher across all subscales, with a linear regression showing this to be significant for the parental perspectives and expectations subscale (B=-10.58, P=0.041). Analyses of Variance showed that both the 'Parent Perspective and Expectations' and the 'Hearing-related QOL' subscales were significantly higher than the 'Impact on Family' subscale for both groups (P≤0.003). The CuHDQOL was found to be a simple, efficient questionnaire that could easily be incorporated into clinical practice to provide a more holistic evaluation of a child's outcomes post intervention, and/or to monitor their progress over time.


Physicochemical characterization and antioxidant activity of sulphated polysaccharides derived from Porphyra haitanensis.
This study was designed to fully characterize Porphyra haitanensis polysaccharides, and to evaluate their antioxidant activity. The polysaccharides primarily contained galactose and 3,6-anhydrogalactose in a molar ratio of 1.2:1.0, respectively and sulfate content about 3.8%. The molecular weight of polysaccharides is 2.5 × 105 Da. Scanning electron microscopy and atomic force microscopy of the polysaccharides pointed towards an irregular network with more or less hexagonal and a few rectangular pores. The chemical structure was confirmed through Fourier transform infrared spectroscopy, and 1D and 2D nuclear magnetic resonance structural characterization wherein → 4-3,6-anhydro-α-L-galactopyranose-(1 → 3)-β-D-galactopyranose segments. The extracted polysaccharides revealed relatively high 2, 2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity (53.16% at 2 mg/mL), moderate 2,2-diphenyl-1-picrylhydrazyl radical scavenging efficacy (34.63% at 2 mg/mL), and low hydroxyl radical scavenging potential (23.80% at 2 mg/mL). Further purification of these polysaccharides, hence, is advised for their potential role as antioxidants in the food, pharmaceutical and cosmeceutical industry.


Identification of haptoglobin as an endogenous inhibitor of prostaglandin H synthase in the cytosol fraction of primary cells from sheep vesicular glands.
It was shown that cytosol of primary sheep vesicular gland cells inhibits peroxidase activity of prostaglandin H synthase (PGHS). The degree of the enzyme inactivation depends on cytosol concentration. It was established that cytosol contains glycoprotein haptoglobin that is one of the cytosol basic components responsible for its property to inhibit PGHS. Haptoglobin is supposed to participate in endogenous regulation of PGHS activity in sheep vesicular glands.


Pressure injury prevention practice in Australian intensive care units: A national cross-sectional survey.
Pressure injury (PI) is an ongoing problem for patients in intensive care units (ICUs). The aim of this study was to explore the nature and extent of PI prevention practices in Australian adult ICUs. An Australian multicentre, cross-sectional study was conducted via telephone interview using a structured survey instrument comprising six categories: workplace demographics, patient assessment, PI prevention strategies, medical devices, skin hygiene, and other health service strategies. Publicly funded adult ICUs, accredited with the College of Intensive Care Medicine, were surveyed. Data were analysed using descriptive statistics and chi-square tests for independence to explore associations according to geographical location. Of the 75 eligible ICUs, 70 responded (93% response rate). PI was considered problematic in two-thirds (68%) of all ICUs. Common PI prevention strategies included risk assessment and visual skin assessment conducted within at least 6 h of admission (70% and 73%, respectively), a structured repositioning regimen (90%), use of barrier products to protect the skin (94%), sacrum or heel prophylactic multilayered silicone foam dressings (88%), regular PI chart audits (96%), and PI quality improvement projects (90%). PI prevention rounding and safety huddles were used in 37% of ICUs, and 31% undertook PI research. Although most ICUs were supported by a facility-wide skin integrity service, it was more common in metropolitan ICUs than in rural and regional ICUs (p < 0.001). Conversely, there was greater involvement of occupational therapists in PI prevention in rural or regional ICUs than in metropolitan ICUs (p = 0.026). This is the first study to provide a comprehensive description of PI prevention practices in Australian ICUs. Findings demonstrate that PI prevention practices, although nuanced in some areas to geographical location, are used in multiple and varied ways across ICUs.


Serotonin and 5-hydroxyindoleacetic acid concentrations in individual hypothalamic nuclei and other brain areas of rat.
Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were measured in individual nuclei of rat hypothalamus and other brain areas using HPLC with electrochemical detection. 5-HIAA levels were first demonstrated in hypothalamic and some discrete brain areas. The 5-HIAA/5-HT ratio was highest in the n. caudatus putamen, high in the n. ventromedialis and lowest in the n. suprachiasmaticus.


Toward a broader concept of societal value: family spillovers in Alzheimer's disease.
Recognizing that the "healthcare sector perspective" can be too limited in some situations, the National Institute of Health and Care Excellence (NICE), Institute for Clinical and Economic Review (ICER), and the U.S. Second Panel on Cost-Effectiveness in Health and Medicine all recommend a "societal" perspective in "reference case" cost-effectiveness analyses (CEAs). Although costs of informal caregiving are sometimes included in the CEAs of Alzheimer's Disease (AD) drugs, the benefits and disutility to family members, referred to as "family spillovers" by the U.S. Second Panel, are usually omitted. We estimate that the aggregate cost of family spillovers could be substantial in the USA-on the order of USD 57 billion or over 10 percent of the total economic burden of AD in 2020. Incorporation of family spillovers in AD value frameworks and HTAs is important for comprehensively defining, rewarding, and providing high-value care in AD.


Allogeneic stem cell transplantation in acute myeloid leukemia: a risk-adapted approach.
Allogeneic hematopoietic stem cell transplantation (alloSCT) is nowadays most frequently applied in patients with acute myeloid leukemia (AML). It combines chemoradiotherapy with immunotherapy, also known as the graft-versus-leukemia (GVL) effect. While it effectively reduces the relapse rate in patients, transplanted in remission, non-relapse mortality (NRM) may counterbalance that beneficial effect. As a result, alloSCT is generally associated with a modest gain in overall survival. Therefore, alloSCT may especially be applied in patients with a relatively high risk of relapse and a relatively low risk of NRM. Here, we discuss how recent findings that have identified and validated specific prognostic factors may affect our decision making for which category of AML-patients alloSCT may especially be indicated.


Genetics and senescence. I. Age-related changes in activity and exploration in three inbred strains of mice.
Exploratory, locomotor and ambulatory activities were measured in nine independent groups of three inbred strains of mice (BALB/cBy, C57BL/6J and DBA/2J), at three different ages (150 days, 400 days and 750 days). The results show that for two of the three variables, the age-related changes present different patterns as a function of strain. The genetic and/or environmental correlates of the reactivity to aging may thus depend on the behavioral trait under study.


Phenolics, nutrition and insect herbivory in some garrigue and maquis plant species.
Garrigue plant species growing on a calcareous substrate in southern France had higher foliar N levels than the same species growing on a relatively lower nutrient siliceous substrate (maquis). However maquis species had significantly higher foliar levels of P, more water, higher phenolic concentrations and larger leaf areas. The cumulative amount of insect damage on garrigue and maquis plants was similar, presumably due to different nutritional "advantages" in each case. Soil fertilization signifincantly elevated N levels in Q. coccifera, increased total leaf areas, decreased condensed tannin levels, and these leaves showed significantly more insect damage. Some effects of burning on Q. coccifera are also described. In these shrublands, fertilization may render leaf material more nutritional for herbivores by increasing nitrogen content and decreasing condensed tannin concentration, although very heavy grazing pressure may increase levels of leaf phenolics.


Mutation and sex in a competitive world.
How do deleterious mutations interact to affect fitness? The answer to this question has substantial implications for a variety of important problems in population biology, including the evolution of sex, the rate of adaptation and the conservation of small populations. Here we analyse a mathematical model of competition for food in which deleterious mutations affect competitive ability. We show that, if individuals usually compete in small groups, then competition can easily lead to a type of genetic interaction known as synergistic epistasis. This means that a deleterious mutation is most damaging in a genome that already has many other deleterious mutations. We also show that competition in small groups can produce a large advantage for sexual populations, both in mean fitness and in ability to resist invasion by asexual lineages. One implication of our findings is that experimental efforts to demonstrate synergistic epistasis may not succeed unless the experiments are redesigned to make them much more naturalistic.


Attitudes towards mental illness in the Athens area: implications for community mental health intervention.
Attitudes towards mental illness were measured in a probability sample of 1574 male and female adults, residents of two boroughs in the greater Athens area before the development of community mental health services in the area. The objective of this study was to identify the components of these attitudes, taking into account the fact that public opinions about mental illness influence the utilization of community mental health services and the level of reintegration of the mentally disabled into society. The instrument used to measure attitudinal dimensions was the Cohen and Struening Opinion about Mental Illness (O.M.I.) scale. Factor analysis revealed five attitude dimensions: social discrimination, social restriction, social care, integration, and etiology. Among the socio-demographic variables age, education, occupational status and place of residence up to 18 years of age affected the factors mainly, reflecting social discrimination and restriction. O.M.I. factor scores underlying the need for social care and reintegration of the mentally ill into society were found to be socially invariant, implying the need for social care and more humane treatment methods for mental patients. Certain population groups responded with rejection or suspicion and considerable fear of the mentally ill, indicating the necessity for the planning of appropriate community mental health intervention programs parallel to the development of community mental health services and psychiatric reforms in Greece.


Efficacy of aminocaproic acid in the control of bleeding after total knee and hip arthroplasty: A systematic review and meta-analysis.
To assess the effectiveness and safety of intravenous aminocaproic acid for blood management after total knee and hip arthroplasty. Electronic databases: PubMed (1950.1-2018.8), EMBASE (1974.1-2018.8), the Cochrane Central Register of Controlled Trials (CENTRAL, 2017.10), Web of Science (1950.1-2018.8), and CNKI (1980.1-2018.8) were systematically searched for clinical controlled trials comparing intravenous aminocaproic acid and placebo after joint arthroplasties. Heterogeneity was assessed using the chi-square test and I-square statistic. The meta-analysis was performed using STATA 12.0 (College Station, TX). Six studies with 756 patients were included. Our meta-analysis revealed that there were significant differences between aminocaproic acid and placebo in terms of total blood loss (SMD = -0.673, 95% CI: -0.825 to -0.520, P <.001), hemoglobin reduction (SMD = -0.689, 95% CI: -0.961 to -0.418, P <.001), drain output (SMD = -2.162, 95% CI: -2.678 to -1.646, P <.001) and transfusion rates (RD = -0.210, 95% CI: -0.280 to -0.141, P <.001). Aminocaproic acid results in a significant reduction of total blood loss, postoperative hemoglobin decline and transfusion requirement in patients undergoing arthroplasties. Due to the limited quality of the evidence currently available, the results of our meta-analysis should be treated with caution.


Treating Early-Stage CKD With New Medication Therapies: Results of a CKD Patient Survey Informing the 2020 NKF-FDA Scientific Workshop on Clinical Trial Considerations for Developing Treatments for Early Stages of Common, Chronic Kidney Diseases.
With a growing number of medications and therapies available to treat chronic kidney disease (CKD), risk-versus-benefit discussions are increasingly critical. Balancing risks and benefits requires assessing patients' understanding of these, as well as incorporating patient preferences and tolerance for side effects into shared decision making. A 26-question online survey was sent to people in the National Kidney Foundation patient email list and posted on associated social media pages to assess the respondents' willingness and comfort with taking preventative medications during earlier-stage CKD to inform a December 2020 scientific workshop co-sponsored by the National Kidney Foundation and the US Food and Drug Administration on clinical trial considerations in developing treatments for individuals with early stages of CKD. Online survey of CKD patients, including broad demographic data and responses to risk-benefit scenarios, with surveys emailed to 20,249 people not identified as currently receiving kidney replacement therapy. Survey results are presented as descriptive data. Of 1,029 respondents, 45 self-identified as at risk for CKD, 566 had CKD, 267 had received kidney transplants, 51 were receiving dialysis, and 100 replied other or did not answer. Respondents reported being willing to assume some risk with the goal of preventing the progression of CKD, with a greater willingness to assume risk and treatment burdens the closer they came to late-stage disease. Clinician recommendations regarding kidney therapies and clinician willingness to work with patients to address any side effects were important in respondents' willingness to initiate and persevere with a new medication. Approximately 10% response rate with limited data on respondents. Risk-versus-benefit discussions appear key to patients and their care partners making well-informed decisions about taking a new medication that may or may not help the progression of their kidney disease. Future tools and strategies are needed to facilitate informed discussions of treatment in early-stage kidney disease.


Weevil pgrp-lb prevents endosymbiont TCT dissemination and chronic host systemic immune activation.
Long-term intracellular symbiosis (or endosymbiosis) is widely distributed across invertebrates and is recognized as a major driving force in evolution. However, the maintenance of immune homeostasis in organisms chronically infected with mutualistic bacteria is a challenging task, and little is known about the molecular processes that limit endosymbiont immunogenicity and host inflammation. Here, we investigated peptidoglycan recognition protein (PGRP)-encoding genes in the cereal weevil Sitophilus zeamais's association with Sodalis pierantonius endosymbiont. We discovered that weevil pgrp-lb generates three transcripts via alternative splicing and differential regulation. A secreted isoform is expressed in insect tissues under pathogenic conditions through activation of the PGRP-LC receptor of the immune deficiency pathway. In addition, cytosolic and transmembrane isoforms are permanently produced within endosymbiont-bearing organ, the bacteriome, in a PGRP-LC-independent manner. Bacteriome isoforms specifically cleave the tracheal cytotoxin (TCT), a peptidoglycan monomer released by endosymbionts. pgrp-lb silencing by RNAi results in TCT escape from the bacteriome to other insect tissues, where it chronically activates the host systemic immunity through PGRP-LC. While such immune deregulations did not impact endosymbiont load, they did negatively affect host physiology, as attested by a diminished sexual maturation of adult weevils. Whereas pgrp-lb was first described in pathogenic interactions, this work shows that, in an endosymbiosis context, specific bacteriome isoforms have evolved, allowing endosymbiont TCT scavenging and preventing chronic endosymbiont-induced immune responses, thus promoting host homeostasis.


Real-World Outcomes of Acute Ischemic Stroke Treatment with Intravenous Thrombolysis: A Systematic Review and Meta-Analysis.
Evidence from outside the typical clinical research setting, such as the real-world setting, complements evidence coming from randomized controlled trials. The purpose of this study was to evaluate all available evidence from the real-world observational trials about long-term outcomes of treatment with intravenous (IV) recombinant tissue-type plasminogen activator (rt-PA) compared with not treated with IV rt-PA (non-rt-PA) in patients with acute ischemic stroke. We searched PubMed and Embase until March 1, 2018 for observational studies reporting matched or adjusted results comparing IV rt-PA versus non-rt-PA in patients with acute ischemic stroke. Outcomes assessed included all-cause mortality, hospital readmission rates, and independence rates. Hazard ratios with 95% confidence intervals were used as a measure of comparing between patients treated with IV rt-PA and non-rt-PA. Six observational trials with 16,399 participants were identified. The use of IV rt-PA in acute ischemic stroke patients was associated with a lower risk of mortality (hazard ratio .61; 95% confidence interval, .52-.70; P < .00001), and there was no heterogeneity across trials. There was no evidence of an effect on hospital readmission rates and independence rates. IV rt-PA is associated with reduced long-term mortality in acute ischemic stroke patients.


A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial.
This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC). Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25-30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS). A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively. FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.


Cellular and molecular pharmacology of 4'-epidoxorubicin in HeLa cells. Comparison with its parent drug, doxorubicin.
The effects on cellular DNA and cytotoxicity produced by doxorubicin (Dx) and its epimer 4'-epidoxorubicin (4'E-Dx) were investigated in cultured HeLa cells. 4'E-Dx was 2.3 times more cytotoxic than Dx after 1 h of treatment, but the two anthracyclines were equally cytotoxic on longer-term (24 h) drug exposure. The different kinetics of cell lethality were related to pharmacodynamic differences between the two drugs. In fact, cellular uptake and efflux rates of 4'E-Dx were faster than those of Dx on 1 h of drug exposure but similar after 24 h of treatment. 4'E-Dx caused more protein-concealed strand breaks in DNA (single and double) than did Dx, despite a lower potency for free-radical formation. The degree of strand breakage by 4'E-Dx was not a linear function of exposure time and, in fact, the rate of strand-break induction declined continuously with time. In contrast, Dx caused an almost linear increase in DNA single-strand breaks with time during 1 h of drug exposure; this was apparently due to its slower uptake. There was little repair of the DNA single-strand breaks produced by Dx upon postincubation for 5 h in a drug-free medium, whereas DNA lesions caused by 4'E-Dx were removed with a t1/2 of about 1.7 h. These findings underline the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytotoxic and DNA-damaging effects.


Wagner-Nelson method for analysing the atypical double-peaked [13CO2] excretion curve in the [13C]-octanoate gastric emptying breath test in humans.
1. In the [(13)C]-octanoic acid breath test, the time versus pulmonary [(13)CO(2)] excretion rate curve is analysed using mathematical curve-fitting techniques to calculate gastric emptying parameters. Thus, the goodness-of-fit highly influences the accuracy of the breath test. However, a double-peaked [(13)CO(2)] excretion curve, which occasionally develops owing to the presence of an interval of quiescent gastric emptying (the plateau phase), is likely to be fitted poorly. 2. In pharmacokinetics, the Wagner-Nelson method has been used to describe precisely the absorption kinetics of orally administered drugs and its reliability is independent of the nature of gastric emptying. A recent study has shown the potential of the Wagner-Nelson method to generate a realistic gastric emptying flow curve from [(13)CO(2)] excretion data. In the present report, we have demonstrated that the Wagner-Nelson method can visualize the plateau emptying phase responsible for the cases of double peaks. 3. Wagner-Nelson analysis applied to the breath test described precisely the characteristic emptying pattern of the two emptying phases being interrupted by the plateau phase. Conventional analysis for the breath test failed to detect the plateau phase. 4. The Wagner-Nelson method is a useful tool for analysing atypical double-peaking [(13)CO(2)] excretion curves.


The impact of recently excavated dredge pits on coastal hypoxia in the northern Gulf of Mexico shelf.
Large volumes of sand are needed in order to combat coastal land loss due to global sea-level rise for restoration of barrier island systems and beaches undergoing rapid erosion and submergence. The sediment required for such projects often originates from dredging of sand deposits on the adjacent shelf. Two dredge pits, with contrasting geology and located at varying distances from the Mississippi River Delta in the northern Gulf of Mexico shelf were sampled during spring and summer. Samples were also collected concurrently from surrounding continental shelf stations that are subject to seasonal hypoxia every summer. The bottom water dissolved O2 inside the dredge pits were found to be consistently hypoxic or near hypoxic throughout both seasons, with high sediment O2 consumption (SOC) rates of 23.7 to 51.8 mmol m-2 d-1 in spring and 34.3 to 51.3 mmol m-2 d-1 in summer. In contrast, control stations immediately outside the dredge pits showed lower SOC rates ranging between 6.3 and 35.9 mmol m-2 d-1. The SOC rates of the surrounding continental shelf subjected to annual seasonal hypoxia ranged between 25.7 and 59.6 mmol m-2 d-1 indicating that the dredge pits experienced similar high rates of SOC. Our results suggest that sluggish water circulation inside these topographic depressions coupled with higher SOC rates does result in persistent low bottom O2 conditions inside these dredge pits well beyond the duration of the seasonal hypoxia period in this region. This is the first study to provide insight on the impacts of dredge pits to surrounding hypoxia in this region which is critical as future dredging operations are expected to increase worldwide with projected sea-level rise.