Comparison of three multiplex PCR assays for the detection of respiratory viral infections: evaluation of xTAG respiratory virus panel fast assay, RespiFinder 19 assay and RespiFinder SMART 22 assay.
A broad spectrum of pathogens is causative for respiratory tract infections, but symptoms are mostly similar. Therefore, the identification of the causative viruses and bacteria is only feasible using multiplex PCR or several monoplex PCR tests in parallel. The analytical sensitivity of three multiplex PCR assays, RespiFinder-19, RespiFinder-SMART-22 and xTAG-Respiratory-Virus-Panel-Fast-Assay (RVP), were compared to monoplex real-time PCR with quantified standardized control material. All assays include the most common respiratory pathogens. To compare the analytical sensitivity of the multiplex assays, samples were inoculated with 13 different quantified viruses in the range of 10(1) to 10(5) copies/ml. Concordant results were received for rhinovirus, whereas the RVP detected influenzavirus, RSV and hMPV more frequently in low concentrations. The RespiFinder-19 and the RespiFinder-SMART-22 showed a higher analytical sensitivity for adenoviruses and coronaviruses, whereas the RVP was incapable to detect adenovirus and coronavirus in concentrations of 10(4) copies/ml. The RespiFinder-19 and RespiFinder-SMART-22A did not detect influenzaviruses (104 copies/ml) and RSV (10(3) copies/ml). The detection of all 13 viruses in one sample was only achieved using monoplex PCR. To analyze possible competitive amplification reactions between the different viruses, samples were further inoculated with only 4 different viruses in one sample. Compared to the detection of 13 viruses in parallel, only a few differences were found.The incidence of respiratory viruses was compared in tracheal secretion (TS) samples (n = 100) of mechanically ventilated patients in winter (n = 50) and summer (n = 50). In winter, respiratory viruses were detected in 32 TS samples (64%) by RespiFinder-19, whereas the detection rate with RVP was only 22%. The most frequent viruses were adenovirus (32%) and PIV-2 (20%). Multiple infections were detected in 16 TS samples (32%) by RespiFinder-19. Fewer infections were found in summer (RespiFinder-19: 20%; RVP: 6%). All positive results were verified using monoplex PCR. Multiplex PCR tests have a broad spectrum of pathogens to test at a time. Analysis of multiple inoculated samples revealed a different focus of the detected virus types by the three assays. Analysis of clinical samples showed a high concordance of detected viruses by the RespiFinder-19 compared to monoplex tests.


Software- and TDM-Guided Dosing of Meropenem Promises High Rates of Target Attainment in Critically Ill Patients.
Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The optimal dosing strategy for beta-lactams in critically ill patients, particularly in septic patients, is an ongoing matter of discussion. This retrospective study aimed to evaluate the success of software-guided empiric meropenem dosing (CADDy, Calculator to Approximate Drug-Dosing in Dialysis) with subsequent routine meropenem measurements and expert clinical pharmacological interpretations. Adequate therapeutic drug exposure was defined as concentrations of 8-16 mg/L, whereas concentrations of 16-24 mg/L were defined as moderately high and concentrations >24 mg/L as potentially harmful. A total of 91 patients received meropenem as a continuous infusion (229 serum concentrations), of whom 60% achieved 8-16 mg/L, 23% achieved 16-24 mg/L, and 10% achieved unnecessarily high and potentially harmful meropenem concentrations >24 mg/L in the first 48 h using the dosing software. No patient showed concentrations <2 mg/L using the dosing software in the first 48 h. With a subsequent TDM-guided dose adjustment, therapeutic drug exposure was significantly (p ≤ 0.05) enhanced to 70%. No patient had meropenem concentrations >24 mg/L with TDM-guided dose adjustments. The combined use of dosing software and consecutive TDM promised a high rate of adequate therapeutic drug exposures of meropenem in patients with sepsis and septic shock.


Response of primary leptomeningeal melanoma to intrathecal recombinant interleukin-2. A case report.
Primary leptomeningeal melanomas are rare tumors that originate in the leptomeninges and are associated with a poor prognosis and no response to radiation and chemotherapy. These tumors rarely metastasize outside the central nervous system. Recombinant interleukin-2-(rIL-2) is a cytokine that activates natural killer cells and lymphokine-activated killer cells, augments their antitumor effects, and recruits and activates cytotoxic T lymphocytes. We have hypothesized that rIL-2 may prolong disease free survival in a patient with primary leptomeningeal melanoma. The patient was treated with intrathecal rIL-2 via lumbar puncture daily for 5 days, the weekly for 5 weeks. To investigate whether rIL-2 induced a favorable clinical response, the following parameters were monitored: survival, neurologic status, cerebrospinal fluid (CSF) analysis, visual fields, and magnetic resonance imaging (MRI) of the lumbosacral spine. The patient is still alive and disease free 15 months after receiving rIL-2, and his neurologic status remains unchanged. The CFS glucose concentration, undetectable prior to therapy, has become normal. Repeated cytologic examinations of CSF were negative for malignant cells. The visual field examinations have remained unchanged. MRI scans of the lumbosacral spine have shown the development of arachnoiditis, but no recurrence of the mass lesion. The tumor response in this patient, as measured by remarkable disease free survival and normalization of the CSF glucose concentration, illustrates the potential benefits of intrathecal rIL-2 in the treatment of patients with this otherwise rapidly fatal disease.


A review of instruments to assess illness representations in patients with rheumatic diseases.
Critical appraisal of instruments to assess illness representations in rheumatology. A first search (MEDLINE, EMBASE, PsycINFO) identified articles describing development of instruments assessing illness representations. A second search identified articles applying them in rheumatology. Appraisal was performed using checklists. Five instruments were identified: the Illness Perception Questionnaire (IPQ), the Revised Illness Perception Questionnaire (IPQ-R), the Illness Cognition Questionnaire (ICQ), the Implicit Models of Illness Questionnaire (IMIQ) and the Meaning of Illness Questionnaire (MIQ). The number of items varied from 18 to 70. Internal consistency was good. Construct validity was moderate to good for all instruments, but was not tested for the IMIQ. Predictive validity was assessed for the ICQ and IPQ and was low to moderate. Sensitivity to change was tested for ICQ and was good. Applications in rheumatology are increasing. Significant relationships with different outcomes and additional evidence for predictive validity were found. Five instruments that assess illness representations can be used in rheumatology. The number of subscales and items vary. The ICQ and IPQ are most extensively validated and have been most frequently applied in rheumatology. Illness representations have relevant associations with self-report and objective outcomes. They should be considered when exploring health in rheumatology.


Developing erosion models for integrated coastal zone management: a case study of The New Caledonia west coast.
The tropical climate and human pressures (mining industry, forest fires) cause significant sediment inputs into the New Caledonia lagoon and are a major cause of degradation of the fringing reefs. The erosion process is spatially characterized on the west coast of New Caledonia to assess potential sediment inputs in the marine area. This paper describes the methodologies that are used to map soil sensitivity to erosion using remote sensing and a geographic information system tool. A cognitive approach, multi-criteria evaluation model and Universal Soil Loss Equation are implemented. This article compares the relevance of each model in order to spatialize and quantify potential erosion at catchment basin scale. These types of studies provide valuable results for focusing on areas subject to erosion and serve as a decision-making tool for the minimization of lagoon vulnerability to the natural and human dynamics on the level of the catchment basins.


Management of genetic epilepsies: From empirical treatment to precision medicine.
Despite the over 20 antiepileptic drugs (AEDs) now licensed for epilepsy treatment, seizures can be effectively controlled in about ∼70% of patients. Thus, epilepsy treatment is still challenging in about one third of patients and this may lead to a severe medically, physically, and socially disabling condition. However, there is clear evidence of heterogeneity of response to existing AEDs and a significant unmet need for effective intervention. A number of studies have shown that polymorphisms may influence the poor or inadequate therapeutic response as well as the occurrence of adverse effects. In addition, the new frontier of genomic technologies, including chromosome microarrays and next-generation sequencing, improved our understanding of the genetic architecture of epilepsies. Recent findings in some genetic epilepsy syndromes provide insights into mechanisms of epileptogenesis, unrevealing the role of a number of genes with different functions, such as ion channels, proteins associated to the vesical synaptic cycle or involved in energy metabolism. The rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis are revolutionizing the practice and it is a fact that for some monogenic epilepsies the molecular confirmation may influence the choice of the treatment. Moreover, the novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized (or precision) medicine.


Battlefield pain management: A view of 17 years in Israel Defense Forces.
Pain control in trauma is an integral part of treatment in combat casualty care (CCC). More soldiers injured on the battlefield will need analgesics for pain than those who will need lifesaving interventions (LSI). It has been shown that early treatment of pain improves outcomes after traumatic injury, whereas inadequate treatment leads to higher rates of PTSD. The purpose of this article is to report the Israel Defense Forces Medical Corps (IDF-MC) experience with point of injury (POI) use of analgesia. All cases documented in the IDF Trauma Registry (ITR) between January 1997 and December 2014 were examined. All cases of POI pain medications were extracted. Data collection included mechanism of injury, wound distribution, pain medication administered, mortality, and provider type. Of 8,576 patients, 1,056 (12.3%) patients who had at least one documented pain management treatment were included in this study. Demographics of the study population included 94.2% men and 5.8% women with a median age of 21 years. Injury mechanisms included 40.3% blast injuries (n = 426) and 29% gunshot injuries (306). Of 1,513 injured body regions reported, 52% (787) were extremity wounds (upper and lower), 23% (353) were truncal wounds, and 17.7% (268) were head and neck injuries. A total of 1,469 episodes of analgesic treatment were reported. The most common types of analgesics were morphine (74.7%, 1,097 episodes), ketamine (9.6%, 141 episodes), and fentanyl (13.6%, 200 episodes). Of the patients, 39% (413) received more than one type of analgesic. In 90.5% of cases, analgesia was administered by a physician or a paramedic. Over the span of the study period (1997-2014), types of analgesics given by providers at POI had changed, as fentanyl was introduced to providers. A total of 801 LSIs were performed on 379 (35.9%) patients receiving analgesia, and no adverse events were found in any of the casualties. Most casualties at POI did not receive any analgesics while on the battlefield. The most common analgesics administered at POI were opioids and the most common route of administration was intravenously. This study provides evidence that over time analgesic administration has gained acceptance and has been more common place on the battlefield. Increasingly, more casualties are receiving pain management treatment early in CCC along with LSIs. We hope that this shift will impact CCC by reducing PTSD and overall morbidity resulting from inadequate management of acute pain.


Protective efficacy of inactivated reverse genetics based equine influenza vaccine candidate adjuvanted with MontanideTM Pet Gel in murine model.
Equine influenza is a leading cause for respiratory illness in equines. Major control measures involve vaccination which requires continuous harmonization owing to antigenic drift. The present study focused on assessing the protective efficacy of an inactivated recombinant equine influenza virus (rgEIV) vaccine candidate adjuvanted with MontanideTM Pet Gel in murine model. The rgEIV was generated using reverse genetics by incorporating HA and NA segments from EIV/H3N8, clade 2-Florida sublineage in an A/WSN/33 /H1N1 backbone and inactivated by formalin. The vaccine was prepared by mixing inactivated rgEIV with MontanideTM Pet Gel adjuvant followed by intranasal inoculation into BALB/c mice intranasally. The immune responses and protective efficacy of the vaccine was evaluated by measurement of antibody titer, immunoglobulin subtyping, cytokines, clinical signs and pathological lesions after immunization and challenge with wild EIV. Serology and cytokine expression pattern indicated that the vaccine activated mixed Th1- and Th2-like responses of vaccine. Booster immunization stimulated strong antibody responses (HAI titre: 192 ± 28.6) at 42 days post immunization and the predominant antibody subtype was IgG1. Upregulation of interferon (IFN)-gamma, interleukin (IL)-12 and IL-2 levels indicates effective induction of Th1 type response. We found that vaccination has protected mice against equine influenza virus challenge as adjudged through a lack of nonappearance of visible clinical signs of disease, no loss of body weight loss, reduced pathology in the lungs and markedly reduced virus shedding from the respiratory tract. Therefore, we conclude that recombinant EIV vaccine candidate adjuvanted with MontanideTM Pet Gel could aid in quick harmonization of the vaccines through replacement of HA and NA genes for control of EIV outbreaks.


Purification of adenylosuccinate lyase from rat skeletal muscle by a novel affinity column. Stabilization of the enzyme, and effects of anions and fluoro analogues of the substrate.
Adenylosuccinate lyase from rat skeletal muscle was purified to apparent homogeneity by a combination of ion-exchange chromatography and affinity chromatography on agarose containing covalently bound adenylophosphonopropionate. The purified enzyme is stable when stored in 20% glycerol at -70 degrees C, and can be thawed and re-frozen with minimal loss of activity. Adenylosuccinate lyase has a specific activity of 11 mumol/min per mg of protein at 25 degrees C. Its subunit Mr is 52,000, by SDS/polyacrylamide-gel electrophoresis, and its apparent native Mr is approx. 200,000, by gel filtration. The purified enzyme has Km values for adenylosuccinate and 4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide (SAICAR) of 1.5 microM and approximately 1 microM respectively, in Hepes/KOH buffer, pH 7.4. Several monoanions and dianions activate the enzyme at low concentration; several of these inhibit the enzyme at high concentrations. Fluoro analogues of adenylosuccinate and SAICAR were synthesized by using highly purified adenylosuccinate synthase and SAICAR synthase respectively, and erythro-beta-fluoroaspartate in place of aspartate. Both analogues are competitive inhibitors of adenylosuccinate lyase in both of the reactions catalysed by the enzyme, with Ki values well below the Km values for the two substrates.


Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial.
Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study. This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete. Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred. Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future. Merck Sharp & Dohme.


Validity of Cognitive Tests for Non-human Animals: Pitfalls and Prospects.
Comparative psychology assesses cognitive abilities and capacities of non-human animals and humans. Based on performance differences and similarities in various species in cognitive tests, it is inferred how their minds work and reconstructed how cognition might have evolved. Critically, such species comparisons are only valid and meaningful if the tasks truly capture individual and inter-specific variation in cognitive abilities rather than contextual variables that might affect task performance. Unlike in human test psychology, however, cognitive tasks for non-human primates (and most other animals) have been rarely evaluated regarding their measurement validity. We review recent studies that address how non-cognitive factors affect performance in a set of commonly used cognitive tasks, and if cognitive tests truly measure individual variation in cognitive abilities. We find that individual differences in emotional and motivational factors primarily affect performance via attention. Hence, it is crucial to systematically control for attention during cognitive tasks to obtain valid and reliable results. Aspects of test design, however, can also have a substantial effect on cognitive performance. We conclude that non-cognitive factors are a minor source of measurement error if acknowledged and properly controlled for. It is essential, however, to validate and eventually re-design several primate cognition tasks in order to ascertain that they capture the cognitive abilities they were designed to measure. This will provide a more solid base for future cognitive comparisons within primates but also across a wider range of non-human animal species.


Oral and parenteral immunization of chickens (Gallus gallus) against West Nile virus with recombinant envelope protein.
West Nile virus (WNV) causes morbidity and mortality in humans, horses, and in more than 315 bird species in North America. Currently approved WNV vaccines are designed for parenteral administration and, as yet, no effectiveoral WNV vaccines have been developed. WNV envelope (E) protein is a highly antigenic protein that elicits the majority ofvirus-neutralizing antibodies during a WNV immune response. Leghorn chickens were given three vaccinations (each 2 wk apart) of E proteinorally (20 microg or 100 microg/dose), of E protein intramuscularly (IM, 20 microg/dose), or of adjuvant only (control group) followed by a WNV challenge. Viremias were measured post-WNV infection, and three new enzyme-linked immunosorbent assays were developed for quantifying IgM, IgY, and IgA-mediated immune response of birds following WNV infection. WNV viremia levelswere significantly lower in the IM group than in both oral groups and the control group. Total WNV E protein-specific IgY production w assignificantly greater, and WNV nonstructural 1-specific IgY w as significantly less, in the IM group compared to all other treatment groups.The results of this study indicate that IM vaccination of chickens with E protein is protective against WNV infection and results in a significantly different antibody production profile as compared to both orally vaccinated and nonvaccinated birds.


Differential response of cultured human normal and tumor cells to trace element-induced resistance to the alkylating agent melphalan.
Previous studies using cultured Chinese hamster cells indicated that pretreatment of the cells with the trace elements copper, selenium, and/or zinc resulted in increased survival of the metal-induced cultures following subsequent exposure to mono- and bifunctional alkylating agents. To ascertain whether a comparable protective response could be activated in human-derived material, a series of human normal and tumor cells was treated with these trace elements and later challenged with the alkylating agent melphalan, prior to determination of the surviving fraction via colony formation. Normal human cells derived from either newborn infants or adults exhibited an increase in survival of 7- to 9-fold when pretreated with zinc alone that increased to approximately 16-fold when these normal cells were induced with all three trace elements. In contrast, comparable pretreatment of tumor cell populations resulted in an increase in survival of 1.7-fold or less, with most types of tumors exhibiting no induced protection. These observations describing a differential inducibility of normal and tumor cells raise the possibility of a novel approach for selectively sparing normal tissue in patients undergoing treatment with alkylating agents. Possible ramifications to cancer chemotherapy are discussed.


Sites of action of testosterone and estradiol on longitudinal bone growth.
In this study the mechanisms by which sex steroids influence body growth were investigated. The effect of different doses of testosterone propionate on longitudinal bone growth and body weight gain was studied in a) gonadectomized male rats, b) gonadohypophysectomized male rats, and c) gonadohypophysectomized male rats given replacement therapy with bovine growth hormone (bGH). The effect of different doses of estradiol benzoate on the same growth parameters was studied in female rats divided into the same experimental groups as the males. Accumulated longitudinal bone growth was determined using oxytetracycline as an intravital marker. Testosterone caused a dose-dependent increase in longitudinal bone growth in gonadectomized male rats. In contrast, testosterone exerted no significant increase in longitudinal bone growth in gonadohypophysectomized male rats with and without bGH replacement therapy. Treatment with estrogen inhibited longitudinal bone growth and body weight gain. The inhibitory effect of estradiol was approximately the same in gonadohypophysectomized female rats given bGH replacement therapy as in gonadectomized female rats. The results suggest that testosterone exerts its stimulatory effect on body growth mainly by modulating hypothalamopituitary functions, e.g., by altering the secretory pattern of GH. On the other hand, it seems that changes in the hypothalamopituitary functions are less significant for the inhibitory effect of estradiol on body growth. It is concluded from this study that the sites of action for estrogen and testosterone in modulating body growth in the rat are different.


Phosphatidylinositol 3-kinase, protein kinase B and ribosomal S6 kinases in the stimulation of thyroid epithelial cell proliferation by cAMP and growth factors in the presence of insulin.
The proliferation of most normal cells depends on the co-operation of several growth factors and hormones, each with a specific role, but the key events involved in the action of each necessary stimulant remain largely uncharacterized. In the present study, the pathways involved in the mechanism(s) of co-operation have been investigated in primary cultures of dog thyroid epithelial cells. In this physiologically relevant system, thyroid stimulating hormone (TSH) acting through cAMP, epidermal growth factor (EGF) and phorbol esters (such as PMA) induce DNA synthesis. Their effect requires stimulation of the insulin-like growth factor-1 (IGF-1) receptor by either IGF-1 or insulin, which are not themselves mitogenic agents. In contrast, hepatocyte growth factor (HGF) is itself fully mitogenic. The results of the study demonstrate that cAMP, EGF, HGF and PMA stimulate p70 ribosomal S6 kinase (p70 S6 kinase). However, insulin/IGF-1 also stimulate p70 S6 kinase. Thus stimulation of p70 S6 kinase might be necessary, but is certainly not sufficient, for the induction of DNA synthesis and is not specific for any stimulated pathway. In contrast, phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (PKB) activation by insulin and HGF is strong and sustained, whereas it is weak and transient with EGF and absent in the presence of TSH or PMA. These findings suggest that: (i) stimulation of PI 3-kinases and/or PKB is not involved in the cAMP-dependent pathways leading to thyrocyte proliferation, or in the action of PMA, (ii) the stimulation of the PI 3-kinase/PKB pathway may account for the permissive action of insulin/IGF-1 in the proliferation of these cells, and (iii) the stimulation of this pathway by HGF may explain why this agent does not require insulin or IGF-1 for its mitogenic action.


Primary Care Utilization and Cardiovascular Screening in Adult Survivors of Childhood Cancer.
Cardiovascular disease is the leading noncancer cause of premature death among survivors of childhood cancer. Adult survivors of childhood cancer are largely managed by primary care practitioners (PCPs), and health care utilization patterns related to cardiovascular screening are not well described. To examine screening and health care utilization among survivors of childhood cancer at high risk for cardiovascular complications. This multicenter cross-sectional study included participants enrolled in a randomized clinical trial from 2017 to 2021. Abstracted documentation of participants' cancer history, cardiotoxic treatment exposures, and survivorship care plans were obtained from participants' PCPs spanning 2 years preceding trial enrollment. Participants were members of the Childhood Cancer Survivor Study cohort at elevated risk for ischemic heart disease or heart failure, enrolled in a randomized trial focused on improving cardiovascular risk factor control. Data were analyzed from November 2022 to July 2023. Outcomes of interest were numbers of PCP and specialist visits, cardiovascular risk factors (hypertension, dyslipidemia, and diabetes), risk factor screening, and cardiac testing. Multivariable logistic regression assessed characteristics associated with up-to-date cardiac testing at enrollment. Of 347 enrolled participants, 293 (84.4%) had evaluable medical records (median [range] age, 39.9 [21.5-65.0] years; 149 [50.9%] male) and were included in analyses. At baseline, 238 participants (81.2%) had a documented PCP encounter; 241 participants (82.3%) had undergone blood pressure screening, 179 participants (61.1%) had undergone lipid testing, and 193 participants (65.9%) had undergone diabetes screening. A total of 63 participants (21.5%) had echocardiography completed or planned. Only 198 participants (67.6%) had records referencing a cancer history. PCP documentation of prior cardiotoxic exposures was low compared with known exposures, including radiation therapy (103 participants [35.2%] vs 203 participants [69.3%]; P < .001) and anthracycline chemotherapy (27 participants [9.2%] vs 222 participants [75.8%]; P = .008). Few records referenced a need for cancer-related late effects surveillance (95 records [32.4%]). Independent factors associated with cardiac screening included documentation of increased cardiovascular disease risk (odds ratio [OR], 11.94; 95% CI, 3.37-42.31), a late-effects surveillance plan (OR, 3.92; 95% CI, 1.69-9.11), and existing cardiovascular risk factors (OR per each additional factor, 2.09; 95% CI, 1.32-3.31). This cross-sectional study of adult survivors of childhood cancer at increased risk of cardiovascular disease found low adherence to recommended cardiac testing and documentation of risk for these individuals. Improving accuracy of reporting of survivors' exposures and risks within the medical record may improve screening.


Nutrition in Surgery: An Orthopaedic Perspective.
➤ Malnutrition is common among subsets of patients undergoing orthopaedic surgery and is associated with an increased risk of postoperative complications.➤ Serum proteins, in particular, albumin, may be used in the evaluation of nutritional status.➤ Anthropometric measurements and surveys also play a role in the evaluation of nutritional status.➤ Increased energy and nutrient requirements due to surgical procedures necessitate increased caloric and protein intake in the perioperative period, which may be achieved through diet or supplementation.➤ Evidence supports the use of protein-calorie, amino acid, and immunonutrition supplements. Vitamin D supplementation is an area of further consideration.➤ Diet restriction, activity alterations, pharmacotherapy, and bariatric surgery are all safe, effective approaches to weight loss, although the optimal timing and magnitude of preoperative weight loss require further investigation.


Allylation reactions of aldehydes with allylboronates in aqueous media: unique reactivity and selectivity that are only observed in the presence of water.
Zn(OH)2-catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the α-addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B-to-Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates (6a-6d) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2-dimethyl-1,3-propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)2 and achiral ligand 4d in aqueous media to afford the corresponding syn-adducts in high yields with high diastereoselectivities. In all cases, the α-addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9. Based on the X-ray structure of the Zn-9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated.


Cadherin-defined segments and parasagittal cell ribbons in the developing chicken cerebellum.
In the developing chicken cerebellar cortex, three cadherins (Cad6B, Cad7, and R-cadherin) are expressed in distinct parasagittal segments that are separated from each other by ribbons of migrating interneurons and granule cells which express R-cadherin and Cad7, respectively. The segment/ribbon pattern is respected by the expression of other types of molecules, such as engrailed-2 and SC1/BEN/DM-GRASP. The cadherin-defined segments contain young Purkinje cells which are connected to underlying nuclear zones expressing the same cadherin, thereby forming parasagittal cortico-nuclear zones of topographically organized connections. In addition, R-cadherin-positive mossy fiber terminals display a periodic pattern in the internal granular layer. In this layer, Cad7 and R-cadherin are associated with synaptic complexes. These results suggest that cadherins play a pivotal role in the formation of functional cerebellar architecture by providing a three-dimensional scaffold of adhesive information.


Breakdown of supersaturation barrier links protein folding to amyloid formation.
The thermodynamic hypothesis of protein folding, known as the "Anfinsen's dogma" states that the native structure of a protein represents a free energy minimum determined by the amino acid sequence. However, inconsistent with the Anfinsen's dogma, globular proteins can misfold to form amyloid fibrils, which are ordered aggregates associated with diseases such as Alzheimer's and Parkinson's diseases. Here, we present a general concept for the link between folding and misfolding. We tested the accessibility of the amyloid state for various proteins upon heating and agitation. Many of them showed Anfinsen-like reversible unfolding upon heating, but formed amyloid fibrils upon agitation at high temperatures. We show that folding and amyloid formation are separated by the supersaturation barrier of a protein. Its breakdown is required to shift the protein to the amyloid pathway. Thus, the breakdown of supersaturation links the Anfinsen's intramolecular folding universe and the intermolecular misfolding universe.


Situation Awareness-Oriented Patient Monitoring with Visual Patient Technology: A Qualitative Review of the Primary Research.
Visual Patient technology is a situation awareness-oriented visualization technology that translates numerical and waveform patient monitoring data into a new user-centered visual language. Vital sign values are converted into colors, shapes, and rhythmic movements-a language humans can easily perceive and interpret-on a patient avatar model in real time. In this review, we summarize the current state of the research on the Visual Patient, including the technology, its history, and its scientific context. We also provide a summary of our primary research and a brief overview of research work on similar user-centered visualizations in medicine. In several computer-based studies under various experimental conditions, Visual Patient transferred more information per unit time, increased perceived diagnostic certainty, and lowered perceived workload. Eye tracking showed the technology worked because of the way it synthesizes and transforms vital sign information into new and logical forms corresponding to the real phenomena. The technology could be particularly useful for improving situation awareness in settings with high cognitive demand or when users must make quick decisions. This comprehensive review of Visual Patient research is the foundation for an evaluation of the technology in clinical applications, starting with a high-fidelity simulation study in early 2020.


[Child neuropsychology in the next millennium].
The progress made in recent decades in neuropsychology has meant a major advance in the recognition of sub-types of various disorders of nervous development. Recognition of symptomatology by means of a fragmental study of the components of all the different systems for obtaining information brings to light new therapeutic options. The different neuropsychological tests are used to study not only the final development of a particular ability but also how this has been achieved. Study of the type of mistakes made by each child permits recognition of the neuro-cognitive profile used. Cognitive rehabilitation of different processes presenting in infancy and adolescence offers the possibility of acquiring an alternative system of learning to minimize or substitute for deficiency. This is possible in cases affecting secondary or tertiary processing areas. The recognition of alternative routines, used to overcome specific disorders of nervous system development, makes one reflect on the way in which information is acquired, processed and produced by the brain and the possibility of generating auxiliary strategies for processing, even in healthy brains, so that perhaps options will be available in the case of future lesions (aphasia, Alzheimer's disease, etc.).


Exchange Bias in Nanostructures: An Update.
Exchange bias (EB) is a unidirectional anisotropy occurring in exchange-coupled ferromagnetic/antiferromagnetic systems, such as thin films, core-shell particles, or nanostructures. In addition to a horizontal shift of the hysteresis loop, defining the exchange bias, asymmetric loops and even vertical shifts can often be found. While the effect is used in hard disk read heads and several spintronics applications, its origin is still not fully understood. Especially in nanostructures with their additional shape anisotropies, interesting and often unexpected effects can occur. Here, we provide an overview of the most recent experimental findings and theoretical models of exchange bias in nanostructures from different materials.


Calcified Thrombus in Right Atrium: Rare but Treatable Complication of Long-term Indwelling Central Venous Catheter.
Catheter-related central thrombosis is a rare complication of long-term central line. We describe the case of an asymptomatic boy who was diagnosed a calcified thrombus in right atrium eight years after the removal of a long-term central venous device. Although the most appropriate therapeutic approach for managing floating right heart thrombi remains to be determined, surgical removal is an effective and safe procedure for calcified long-standing thrombus and it is to be preferred in elective conditions especially in young asymptomatic patients without hemodynamic involvement, that are at low risk of surgery-related morbidity and mortality.


Cyclic nucleotides and gap-junctional permeability.
1. The role of cAMP on cell-to-cell diffusion of Lucifer Yellow was investigated. It was found that dB-cAMP or isoproterenol increases the junctional permeability appreciably in dog's atrium muscle. 2. This effect which occurs within 85 min seems to be related to an increase in unit channel permeability. Chronic treatment of animals with ephedrine enhances the junctional permeability in vivo. 3. The results support the view that cAMP plays a short-term and long-term regulatory role on junctional permeability.


Axial current generation from electric field: chiral electric separation effect.
We study a relativistic plasma containing charged chiral fermions in an external electric field. We show that with the presence of both vector and axial charge densities, the electric field can induce an axial current along its direction and thus cause chirality separation. We call it the chiral electric separation effect (CESE). On a very general basis, we argue that the strength of CESE is proportional to μ(V)μ(A) with μ(V) and μ(A) the chemical potentials for vector charge and axial charge. We then explicitly calculate this CESE conductivity coefficient in thermal QED at leading-log order. The CESE can manifest a new gapless wave mode propagating along the electric field. Potential observable effects of CESE in heavy-ion collisions are also discussed.


Technical feasibility of liver transplantation without cold storage.
The success of liver transplantation (LT) is accompanied by an increased need for organs. The wider use of older donors and marginal organs with risk factors such as steatosis has lead to a new interest to improve the outcome with marginal organs. We herewith report a novel technique for LT with in situ preparation and immediate warm-ischemia liver transplantation (WI-LT). The aim of our study was to demonstrate the technical feasibility and report the transplant course. Six patients underwent WI-LT at our institution. Hepatectomies during procurement and LT were both performed in parallel by different surgical teams. Technical factors and postoperative allograft function were analyzed. All six WI-LTs were performed without intraoperative complications with a mean warm-ischemia time (WIT) of 29.0 min. No patient developed primary non-function or required retransplantation. Mean alanine aminotransferase (194.0 ± 170.4 U/l) and aspartate aminotransferase (316.3 ± 222.1 U/l) values on the first postoperative day were low, indicating a low ischemia/reperfusion injury and an excellent liver function. These results demonstrate that WI-LT is a safe and technically feasible approach for LT with possibly reduced IRI and an excellent postoperative allograft quality. WI-LT may therefore be considered in individual patients especially with extended criteria donors to eventually improve postoperative allograft quality.


Malignant potential of homozygous and heterozygous complete moles.
There are two main mechanisms of origin for complete hydatidiform mole: (a) fertilization of an empty egg by a haploid sperm followed by duplication (monospermic mole); and (b) fertilization of such an egg by two haploid spermatozoa (dispermic mole). The former is inevitably homozygous (homozygous mole), whereas the latter may be heterozygous for a given genetic marker (heterozygous mole). A recent cytogenetic study showed that three cases of choriocarcinoma were undoubtedly heterozygous, which prompted us to compare the incidence of postmolar sequelae between patients with homozygous moles and those with heterozygous moles. Making use of chromosomal heteromorphisms and human lymphocyte antigen and phosphoglucuromutase 1 polymorphisms, we established the androgenetic origin of a complete mole in 49 of 56 cases. Homozygosity was confirmed in 21 moles, and heterozygosity was confirmed in five. Three of five patients with heterozygous moles developed postmolar trophoblastic disease, whereas none of the 21 patients with homozygous moles suffered postmolar trophoblastic disease except one who showed signs of degenerating residual trophoblasts. Consistent with this observation is the fact that all of the four destructive moles studied here were of dispermic origin. Thus, heterozygous moles seem to have a higher malignant potential than do homozygous moles.


Predicting outcome and complications in the surgical treatment of adult scoliosis.
prospective, multicenter. To determine if models for predicting outcome and complications in the setting of adult deformity surgery can be constructed. A classification of adult spinal deformity has been established. The latter categorizes patients radiographically and ties to disability as well as most likely treatment approach. Classification by radiographs alone is insufficient to guide treatment and models for predicting outcome are necessary to establish algorithms. This is a longitudinal study of adult patients with spinal deformity. All subjects were drawn from a prospective multicenter database. Baseline, 1-year and 2-year radiographic and health related quality of life measures were obtained (SRS, ODI, SF-12). Any peri- or postoperative complications were tabulated. Binary and logistic regressions were applied to create models of outcome and complications. Predictive models of reaching a minimal clinically important difference had an area under the ROC curve above 0.82 and correct classification from 75% to 81%. Development of a complication was correctly classified in 71% of cases. Patients most likely to reach threshold improvement through surgery: older, lower apex deformity, greater disability, higher deformity score by classification. Patients most likely to develop complications: high sagittal balance grade and fusion to sacrum. By applying the classification of adult deformity and considering baseline health status, models for predicting outcome can be established. Further work will refine these models and permit clinical validation. This effort will help establish reliable clinical models such that treatment algorithms can be established for the challenging patients suffering from adult spinal deformity.


Sarcocornia neei as an Indicator of Environmental Pollution: A Comparative Study in Coastal Wetlands of Central Chile.
Being adapted to saline environments, halophytes are plant species that have received considerable attention due to their ability to cope with environmental stress factors, such as high concentrations of soluble salts and heavy metals. In this work, we focused on determining if the Sarcocornia neei (S. neei) plant can be considered as an indicator of heavy metal pollution in soil. This was done by analyzing the concentration of cadmium (Cd), lead (Pb), copper (Cu), and arsenic (As) in plants and soil sampled from two wetlands in the central zone of Chile: a wetland contaminated by industrial activities and a wetland protected by the Chilean government. In addition, 14 fertility parameters (pH, electrical conductivity, organic matter, nitrogen (N), phosphorus (P), potassium (K), sodium (Na), Pb, calcium (Ca), magnesium (Mg), Manganese (Mn), zinc (Zn), iron (Fe), and boron (B)) were analyzed for soil samples in both wetlands. This was done to differentiate between available elements and contamination by heavy metals. Plant and soil samples in the contaminated wetland exhibited significantly higher heavy metal concentrations in comparison to samples analyzed from the protected wetland. This indicates that the S. neei plant can be further researched as an indicator of heavy metal pollution in saline soils and possibly for phytoremediation purposes.


Automated location invariant animal detection in camera trap images using publicly available data sources.
A time-consuming challenge faced by camera trap practitioners is the extraction of meaningful data from images to inform ecological management. An increasingly popular solution is automated image classification software. However, most solutions are not sufficiently robust to be deployed on a large scale due to lack of location invariance when transferring models between sites. This prevents optimal use of ecological data resulting in significant expenditure of time and resources to annotate and retrain deep learning models.We present a method ecologists can use to develop optimized location invariant camera trap object detectors by (a) evaluating publicly available image datasets characterized by high intradataset variability in training deep learning models for camera trap object detection and (b) using small subsets of camera trap images to optimize models for high accuracy domain-specific applications.We collected and annotated three datasets of images of striped hyena, rhinoceros, and pigs, from the image-sharing websites FlickR and iNaturalist (FiN), to train three object detection models. We compared the performance of these models to that of three models trained on the Wildlife Conservation Society and Camera CATalogue datasets, when tested on out-of-sample Snapshot Serengeti datasets. We then increased FiN model robustness by infusing small subsets of camera trap images into training.In all experiments, the mean Average Precision (mAP) of the FiN trained models was significantly higher (82.33%-88.59%) than that achieved by the models trained only on camera trap datasets (38.5%-66.74%). Infusion further improved mAP by 1.78%-32.08%.Ecologists can use FiN images for training deep learning object detection solutions for camera trap image processing to develop location invariant, robust, out-of-the-box software. Models can be further optimized by infusion of 5%-10% camera trap images into training data. This would allow AI technologies to be deployed on a large scale in ecological applications. Datasets and code related to this study are open source and available on this repository: https://doi.org/10.5061/dryad.1c59zw3tx.


Potential Energy Surfaces of HN(CH)SX:CO2 for X = F, Cl, NC, CN, CCH, and H: N···C Tetrel Bonds and O···S Chalcogen Bonds.
MP2/aug'-cc-pVTZ calculations have been performed in search of complexes, molecules, and transition structures on the HN(CH)SX:CO2 potential energy surfaces, for X = F, Cl, NC, CN, CCH, and H. Complexes stabilized by traditional N···C tetrel bonds and O···S chalcogen bonds exist on all surfaces and are bound relative to the isolated monomers. Molecules stabilized by an N-C covalent bond and an O···S chalcogen bond are found when X = F, Cl, and NC, but only the HN(CH)SF:CO2 molecule is bound. The binding energies of these complexes correlate with the O-S distance but not with the N-C distance. Binding energies of complexes rotated by 90° about the N···C tetrel bond and by 90° about the O···S chalcogen bond provide estimates of these bond energies. Charge-transfer energies across tetrel and chalcogen bonds correlate with the N-C and O-S distances, respectively. As a function of the N-C distance, equation-of-motion coupled cluster singles and doubles spin-spin coupling constants 1tJ(N-C) for complexes and transition structures and 1J(N-C) for molecules describe the evolution of the N···C tetrel bonds in the complexes and transition structures to N-C covalent bonds in the molecules. The O···S chalcogen bond gains some covalency in the transition structures and again in the molecules but does not become a covalent bond.


[The molecular-weight characteristics of the bacterial lectins and humus components in soil].
A method has been developed to determine the molecular-weight distribution of biologically active substances: bacterial lectins and soil humus compounds. The method based on the simultaneous centrifugation of samples and molecular weight standards in the density gradient of NaCl solutions or combined gradient of NaCl and CsCl solutions permits analysing biologically active substances: lectins, proteins, polysaccharides, protein-polysaccharide complexes, humus compounds in the interval of molecular weight of 13.7 kappa [symbol: see text] a to 2000 kappa [symbol: see text] a. The use of this method in the soil researches makes it possible to study the dynamics of change of molecular parameters of the soil organic matter depending on agrotechnical methods as well as to determine transformation regularities of microbial polysaccharides.


Massilia namucuonensis sp. nov., isolated from a soil sample.
A Gram-staining-negative, rod-shaped and non-spore-forming bacterium, designated strain 333-1-0411(T), was isolated from a soil sample collected from Namucuo, Tibet Autonomous Region, China and characterized in a taxonomic study using a polyphasic approach. The major fatty acid components of strain 333-1-0411(T) were summed feature 3 (C(16 : 1)ω7c and/or C(16 : 1)ω6c) and C(16 : 0); its major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. Q-8 was the dominant ubiquinone, and the G+C content of the genomic DNA was 66.7 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain 333-1-0411(T) fell within the evolutionary radiation encompassed by the genus Massilia. The 16S rRNA gene sequence similarities between strain 333-1-0411(T) and recognized species of the genus Massilia ranged from 95.4 % to 97.2 %, and the most closely related strains were Massilia flava Y9(T) (97.2 %) and Massilia albidiflava 45(T) (97.0 %). However, the DNA-DNA relatedness values between strain 333-1-0411(T) and M. flava Y9(T) and M. albidiflava 45(T) were 20.2 % and 27.2 %, respectively. Based on the phenotypic, chemotaxonomic and phylogenetic properties, strain 333-1-0411(T) is considered to represent a novel species of the genus Massilia, for which the name Massilia namucuonensis sp. nov. is proposed. The type strain is 333-1-0411(T) (= CGMCC 1.11014(T) = DSM 25159(T)).


Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues.
The proto-oncogene c-myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis and that has also been found to be deregulated in several forms of human and experimental tumors. We have shown that forced expression of c-myc in epithelial tissues of transgenic mice (K5-Myc) resulted in keratinocyte hyperproliferation and the development of spontaneous tumors in the skin and oral cavity. Although a number of genes involved in cancer development are regulated by c-myc, the actual mechanisms leading to Myc-induced neoplasia are not known. Among the genes regulated by Myc is the cyclin-dependent kinase 4 (CDK4) gene. Interestingly, previous studies from our laboratory showed that the overexpression of CDK4 led to keratinocyte hyperproliferation, although no spontaneous tumor development was observed. Thus, we tested the hypothesis that CDK4 may be one of the critical downstream genes involved in Myc carcinogenesis. Our results showed that CDK4 inhibition in K5-Myc transgenic mice resulted in the complete inhibition of tumor development, suggesting that CDK4 is a critical mediator of tumor formation induced by deregulated Myc. Furthermore, a lack of CDK4 expression resulted in marked decreases in epidermal thickness and keratinocyte proliferation compared to the results obtained for K5-Myc littermates. Biochemical analysis of the K5-Myc epidermis showed that CDK4 mediates the proliferative activities of Myc by sequestering p21Cip1 and p27Kip1 and thereby indirectly activating CDK2 kinase activity. These results show that CDK4 mediates the proliferative and oncogenic activities of Myc in vivo through a mechanism that involves the sequestration of specific CDK inhibitors.


Non-adherence to anti-tuberculosis treatment and determinant factors among patients with tuberculosis in northwest Ethiopia.
Non-adherence to anti tuberculosis treatment is one of the crucial challenges in improving tuberculosis cure-rates and reducing further healthcare costs. The poor adherence to anti-tuberculosis treatment among patients with tuberculosis is a major problem in Ethiopia. Hence, this study assessed level of non-adherence to anti-tuberculosis therapy and associated factors among patients with tuberculosis in northwest Ethiopia. An institution based cross-sectional survey was conducted among tuberculosis patients who were following anti-tuberculosis treatment in North Gondar zone from February 20--March 30, 2013. Data were collected by trained data collectors using a structured and pre-tested questionnaire. Data were entered to EPI INFO version 3.5.3 and analyzed using statistical package for social sciences (SPSS) version 20. Multiple logistic regressions were fitted to identify associations and to control potential confounding variables. Odds ratio (OR) with 95% confidence interval was calculated and p-values<0.05 were considered statistically significant. A total of 280 tuberculosis patients were interviewed; 55.7% were males and nearly three quarters (72.5%) were urban dwellers. The overall non-adherence for the last one month and the last four days before the survey were 10% and 13.6% respectively. Non-adherence was high if the patients had forgetfulness (AOR 7.04, 95% CI 1.40-35.13), is on the continuation phase of chemotherapy (AOR: 6.95, 95% CI 1.81-26.73), had symptoms of tuberculosis during the interview (AOR: 4.29, 95% CI 1.53-12.03), and had co-infection with HIV (AOR: 4.06, 95% CI 1.70-9.70). Non-adherence to anti-tuberculosis treatment was high. Forgetfulness, being in the continuation phases of chemotherapy, having symptoms of tuberculosis during the interview, and co-infected with HIV were significantly associated with non-adherence to anti-tuberculosis therapy. Special attention on adherence counseling should be given to symptomatic patients, TB/HIV co-infected patients, and those in the continuation phase of the tuberculosis therapy.


Alpha-galactosidase of the marine bacterium Pseudoalteromonas sp. KMM 701.
An alpha-galactosidase that inactivates the group specificity of B erythrocytes (group III) of human blood and does not affect A erythrocytes (group II) was isolated from the marine bacterium Pseudoalteromonas sp. KMM 701. The enzyme preparation did not contain lectin, hemolytic, sialidase, endoglycanase, or glycosidase activities. The enzyme is stable at 20 degreesC for 24 h, has pH optimum for catalysis within the range of 6.7-7.7, and is stable to high concentrations of NaCl. It is 4-fold more efficient than the alpha-galactosidase from green coffee beans. At pH 7.0 the Km for p-nitrophenyl-alpha-D-galactopyranoside is 0.29 mM. The molecular weight of the enzyme determined by gel-filtration is 195 +/- 5 kD. The alpha-galactosidase is denatured by urea and guanidine hydrochloride. Its activity does not depend on the presence of metal ions. It contains a sulfhydryl group essential for its catalytic activity.


Patterns and correlates of self-reported racial discrimination among Australian Aboriginal and Torres Strait Islander adults, 2008-09: analysis of national survey data.
There is now considerable evidence that racism is a pernicious and enduring social problem with a wide range of detrimental outcomes for individuals, communities and societies. Although indigenous people worldwide are subjected to high levels of racism, there is a paucity of population-based, quantitative data about the factors associated with their reporting of racial discrimination, about the settings in which such discrimination takes place, and about the frequency with which it is experienced. Such information is essential in efforts to reduce both exposure to racism among indigenous people and the harms associated with such exposure. Weighted data on self-reported racial discrimination from over 7,000 Indigenous Australian adults participating in the 2008-09 National Aboriginal and Torres Strait Islander Survey, a nationally representative survey conducted by the Australian Bureau of Statistics, were analysed by socioeconomic, demographic and cultural factors. More than one in four respondents (27%) reported experiencing racial discrimination in the past year. Racial discrimination was most commonly reported in public (41% of those reporting any racial discrimination), legal (40%) and work (30%) settings. Among those reporting any racial discrimination, about 40% experienced this discrimination most or all of the time (as opposed to a little or some of the time) in at least one setting. Reporting of racial discrimination peaked in the 35-44 year age group and then declined. Higher reporting of racial discrimination was associated with removal from family, low trust, unemployment, having a university degree, and indicators of cultural identity and participation. Lower reporting of racial discrimination was associated with home ownership, remote residence and having relatively few Indigenous friends. These data indicate that racial discrimination is commonly experienced across a wide variety of settings, with public, legal and work settings identified as particularly salient. The observed relationships, while not necessarily causal, help to build a detailed picture of self-reported racial discrimination experienced by Indigenous people in contemporary Australia, providing important evidence to inform anti-racism policy.


Visual gravitational motion and the vestibular system in humans.
The visual system is poorly sensitive to arbitrary accelerations, but accurately detects the effects of gravity on a target motion. Here we review behavioral and neuroimaging data about the neural mechanisms for dealing with object motion and egomotion under gravity. The results from several experiments show that the visual estimates of a target motion under gravity depend on the combination of a prior of gravity effects with on-line visual signals on target position and velocity. These estimates are affected by vestibular inputs, and are encoded in a visual-vestibular network whose core regions lie within or around the Sylvian fissure, and are represented by the posterior insula/retroinsula/temporo-parietal junction. This network responds both to target motions coherent with gravity and to vestibular caloric stimulation in human fMRI studies. Transient inactivation of the temporo-parietal junction selectively disrupts the interception of targets accelerated by gravity.


Hyperpolarized MRI - An Update and Future Perspectives.
In recent years, hyperpolarized 13C magnetic resonance spectroscopic (MRS) imaging has emerged as a complementary metabolic imaging approach. Hyperpolarization via dissolution dynamic nuclear polarization is a technique that enhances the MR signal of 13C-enriched molecules by a factor of > 104, enabling detection downstream metabolites in a variety of intracellular metabolic pathways. The aim of the present review is to provide the reader with an update on hyperpolarized 13C MRS imaging and to assess the future clinical potential of the technology. Several carbon-based probes have been used in hyperpolarized studies. However, the first and most widely used 13C-probe in clinical studies is [1-13C]pyruvate. In this probe, the enrichment of 13C is performed at the first carbon position as the only modification. Hyperpolarized [1-13C]pyruvate MRS imaging can detect intracellular production of [1-13C]lactate and 13C-bicarbonate non-invasively and in real time without the use of ionizing radiation. Thus, by probing the balance between oxidative and glycolytic metabolism, hyperpolarized [1-13C]pyruvate MRS imaging can image the Warburg effect in malignant tumors and detect the hallmarks of ischemia or viability in the myocardium. An increasing number of clinical studies have demonstrated that clinical hyperpolarized 13C MRS imaging is not only possible, but also it provides metabolic information that was previously inaccessible by non-invasive techniques. Although the technology is still in its infancy and several technical improvements are warranted, it is of paramount importance that nuclear medicine physicians gain knowledge of the possibilities and pitfalls of the technique. Hyperpolarized 13C MRS imaging may become an integrated feature in combined metabolic imaging of the future.


Structural basis of human transcription-DNA repair coupling.
Transcription-coupled DNA repair removes bulky DNA lesions from the genome1,2 and protects cells against ultraviolet (UV) irradiation3. Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA and UV-stimulated scaffold protein A (UVSSA)3. Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published3,4 data, the structures provide a model for transcription-repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, ECTCR, uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA.


Cu(II)-azide polynuclear complexes of Cu4 building clusters with Schiff-base co-ligands: synthesis, structures, magnetic behavior and DFT studies.
Three new copper-azido complexes [Cu(4)(N(3))(8)(L(1))(2)](n) (1), [Cu(4)(N(3))(6)(L(2))(2)(H(2)O)(2)] (2), and [Cu(4)(N(3))(6)(L(3))(2)](n) (3) [L(1) is the imine resulting from the condensation of pyridine-2-carboxaldehyde with N-methylethylenediamine, HL(2) and HL(3) are the condensation products of 2-hydroxy-3-methoxybenzaldehyde with N,N-diethylethylenediamine and N-ethylethylenediamine respectively] have been synthesized by using 0.5 molar equivalents of the Schiff base ligands with Cu(NO(3))(2)·3H(2)O and an excess of NaN(3). Single crystal X-ray structures show that the basic unit of these complexes contains very similar Cu(II)(4) building blocks. While 1 and 3 have overall 1D structures, 2 forms discrete tetranuclear clusters due to blocking of two coordination sites on the tetranuclear cluster by water molecules. Magnetic susceptibility measurements over a wide range of temperatures exhibit the presence of both antiferromagnetic and ferromagnetic exchanges within the tetranuclear unit structures. Density functional theory calculations (using B3LYP functional and two different basis sets) have been performed on the complexes 1-3 to provide a qualitative theoretical interpretation of their overall magnetic behavior.


Introduction of the American Academy of Facial Plastic and Reconstructive Surgery FACE TO FACE Database.
The American Academy of Facial Plastic and Reconstructive Surgery FACE TO FACE database was created to gather and organize patient data primarily from international humanitarian surgical mission trips, as well as local humanitarian initiatives. Similar to cloud-based Electronic Medical Records, this web-based user-generated database allows for more accurate tracking of provider and patient information and outcomes, regardless of site, and is useful when coordinating follow-up care for patients. The database is particularly useful on international mission trips as there are often different surgeons who may provide care to patients on subsequent missions, and patients who may visit more than 1 mission site. Ultimately, by pooling data across multiples sites and over time, the database has the potential to be a useful resource for population-based studies and outcome data analysis. The objective of this paper is to delineate the process involved in creating the AAFPRS FACE TO FACE database, to assess its functional utility, to draw comparisons to electronic medical records systems that are now widely implemented, and to explain the specific benefits and disadvantages of the use of the database as it was implemented on recent international surgical mission trips.


Recurrent laryngeal nerve management in thyroid surgery: consequences of routine visualization, application of intermittent, standardized and continuous nerve monitoring.
The objective is to compare the consequences of routine visualization (RV) and the application of intermitted (I-IONM), standardized (S-IONM), and continuous monitoring (C-IONM) of recurrent laryngeal nerve (RLN) management. RV includes that 698 RLNs managed solely with visual identification. In a second period 777, RLNs were handled by the I-IONM. The third period 768 RLNs monitoring was performed according to the standards. C-IONM via VN stimulation included 626 RLNs. The following issues were analyzed and compared per each period study: RLN identification rate, branching detection, assessment of NRLN, intraoperative recognizable nerve damage, stage thyroidectomy rate, transient or definitive lesions, bilateral nerve palsy, and recovery time. Significance for nerve identification rate was achieved (p = 0.03) when the statistical analysis was applied between RV vs. S-IONM and C-IONM. Extralaryngeal bifurcation was identified in 21, 44, 43, and 46 of RLN dissected, respectively, per period (p = 0.005). The incidence of paralysis in identified and unidentified RLN was 3.8 % (107/2806) and 82 % (52/63), respectively. Rates of temporary/permanent RLNP were 16.7/1.7, 5/1.1, 4.5/1, and 3.1/0 % per period study, respectively (p = 0.07). Recognizable intraoperatively nerve damage was, respectively, 15, 45, 100, and 100 % for period study (p = 0.03). The recovery of injured nerves was significantly faster in C-IONM group. S-IONM and C-IONM cumulate 40-stage procedures. The standardized technique, guidelines adherences, and C-IONM allowed to (1) increase RLN identification; (2) reduce the severity of injuries in terms of (a) reset bilateral RLNP, (b) faster recovery time, and


Design of a 3D prosthesis of the big toe for amputees due to diabetes mellitus type II and finite element analysis.
At present the percentage of people suffering from type II diabetes mellitus continues to increase. One of the consequences of this disease is the reduction of blood flow in the feet and legs, which could hinder the healing of a sore, in such a way that if a patient with this condition is not treated in time, gangrene can be generated, which could cause the amputation of the first toe, this would affect the gait process, which will not be carried out properly. There are foot prostheses focused on the functionality of the first toe; however, there are no prostheses focused on the specific design of the big toe. Therefore, this work aims to design a prosthesis for the first toe capable of improving gait, likewise a finite element analysis was carried out to ensure that the proposed design is capable of resisting up to a certain body weight. After carrying out the finite element analysis, the maximum and minimum values of displacement and equivalent force are observed with respect to the external forces to which the designed part is subjected.


RARα and RARγ reciprocally control K5+ progenitor cell expansion in developing salivary glands.
Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RARα and RARγ have opposing effects on K5+ cell cycle progression and cell distribution. RARα negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RARγ is necessary but not sufficient to positively maintain K5+ cells, as agonism of RARγ alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RARα agonism and RARγ inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RARα may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool. RARα and RARγ reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.


The TRIPLE PHD FINGERS proteins are required for SWI/SNF complex-mediated +1 nucleosome positioning and transcription start site determination in Arabidopsis.
Eukaryotes have evolved multiple ATP-dependent chromatin remodelers to shape the nucleosome landscape. We recently uncovered an evolutionarily conserved SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler complex in plants reminiscent of the mammalian BAF subclass, which specifically incorporates the MINUSCULE (MINU) catalytic subunits and the TRIPLE PHD FINGERS (TPF) signature subunits. Here we report experimental evidence that establishes the functional relevance of TPF proteins for the complex activity. Our results show that depletion of TPF triggers similar pleiotropic phenotypes and molecular defects to those found in minu mutants. Moreover, we report the genomic location of MINU2 and TPF proteins as representative members of this SWI/SNF complex and their impact on nucleosome positioning and transcription. These analyses unravel the binding of the complex to thousands of genes where it modulates the position of the +1 nucleosome. These targets tend to produce 5'-shifted transcripts in the tpf and minu mutants pointing to the participation of the complex in alternative transcription start site usage. Interestingly, there is a remarkable correlation between +1 nucleosome shift and 5' transcript length change suggesting their functional connection. In summary, this study unravels the function of a plant SWI/SNF complex involved in +1 nucleosome positioning and transcription start site determination.


New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome.
Although many children with idiopathic nephrotic syndrome (INS) respond initially to steroid therapy, repeated courses for patients with relapses often cause significant steroid toxicity. Patients with frequent relapses who develop steroid dependency thus require alternative treatment. The first such options have been considered to be cyclophosphamide or levamisole, although the latter is no longer available in many countries. There is also an increasing body of data indicating that mycophenolic acid (MPA) may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and often used after cytotoxic treatment, but long-term treatment with these agents is necessary, raising concerns of a possible accumulation of side effects. Some patients show a tendency to relapse even on such maintenance regimens, and some even have a refractory course that creates a medical dilemma. For this situation, recent data indicate that monoclonal antibodies directed to B-cells (e.g. rituximab) may have some effect and that such drugs may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to steroid treatment need genetic testing and a renal biopsy since focal segmental glomerulosclerosis (FSGS) may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors, mainly in the form of cyclosporine, but tacrolimus has also come into recent favor. Some studies have found cytotoxic treatment, especially intravenous cyclophosphamide, to be effective in steroid resistant nephrotic syndrome, but it seems to be inferior to calcineurin inhibitors. MPA and rituximab have also been used in children with primary FSGS, but the response seems to be inferior to that in patients with steroid sensitive nephrotic syndrome. Taken together, INS in both steroid-sensitive and steroid-resistant patients is a potentially complicated disorder, and despite a wide arsenal of immunological interventions, some patients have a treatment refractory course. Prospective studies or at least standardized treatment for complicated cases is urgently needed.


Pharmacological and dietary prevention for colorectal cancer.
Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. People at higher risk are those individuals with a family history of CRC and familial adenomatous polyposis. Prevention and screening are two milestones for this disease. The aim of this study is to evaluate the chemopreventive role of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase 2 inhibitors, some micronutrients (folic acid, calcium, selenium, antioxidants) and probiotics. The studies on aspiring reported promising results, but it is debatable whether aspirin should be used as chemoprevention, because of its side effects and because of poor efficacy evident in subjects at high risk. Similar results were reported for other non-aspirin NSAIDs, such as sulindac and celecoxib, which the potential adverse effects limit their use. Selenium role in prevention of various types of cancer as well as in colon adenomas are often inconclusive or controversial. Several studies suggested that calcium may have a possible chemopreventive effect on colon adenomas and CRC, although contrasting results are reported for the latter. A recent meta-analysis including 13 randomized trial suggested that folic acid supplementation had not a chemiopreventive action on CRC. Several studies investigated the association between antioxidants, administered alone or in combination, and CRC risk, both among general and at risk population, but only few of them supported statistically significant results. The results of this literature review showed an unclear role in CRC prevention of both pharmacological and dietary intervention. Despite several options are available to prevent colon cancer, it is challenging to identify a correct strategy to prevent CRC through pharmacological and dietary intervention due to the long latency of cancer promotion and development. Since some of the drugs investigated may have uncertain individual effects, it can be suggested to potentiate such effects by adding them together.


Prospective Evaluation of ResistancePlus MG, a New Multiplex Quantitative PCR Assay for Detection of Mycoplasma genitalium and Macrolide Resistance.
Mycoplasma genitalium is a significant pathogen for which first-line treatment is becoming less effective due to increased resistance to macrolides. As conventional culture and antimicrobial susceptibility testing is not feasible for routine detection of this pathogen, molecular markers such as detection of mutations in the 23S rRNA gene have been described to predict resistance. Recently, a novel multiplex quantitative PCR (qPCR) assay, ResistancePlus MG, has been described for the simultaneous detection of Mycoplasma genitalium and macrolide resistance. In the current study, the clinical performance of the assay was evaluated on 1,089 consecutive urine and anogenital swab samples in symptomatic and asymptomatic male and female patients. Overall, 6.0% were positive for M. genitalium, with 63.1% having macrolide resistance-associated mutations. Compared to the laboratory-validated qPCR method targeting the 16S rRNA gene and Sanger sequencing to determine 23S rRNA mutations, the sensitivity and specificity of M. genitalium detection were 98.5% and 100% and for detection of macrolide resistance mutations were 100.0% and 96.2%, respectively. This assay offers a considerable advantage in clinical settings for M. genitalium testing by making the results of macrolide resistance and mutation analyses simultaneously available, which is increasingly important with escalating macrolide resistance.


Admission rates and costs associated with emergency presentation of urolithiasis: analysis of the Nationwide Emergency Department Sample 2006-2009.
We sought to examine a large nationwide (United States) sample of emergency department (ED) visits to determine data related to utilization and costs of care for urolithiasis in this setting. Nationwide Emergency Department Sample was analyzed from 2006 to 2009. All patients presenting to the ED with a diagnosis of upper tract urolithiasis were analyzed. Admission rates and total cost were compared by region, hospital type, and payer type. Numbers are weighted estimates that are designed to approximate the total national rate. An average of 1.2 million patients per year were identified with the diagnosis of urolithiasis out of 120 million visits to the ED annually. Overall average rate of admission was 19.21%. Admission rates were highest in the Northeast (24.88%), among teaching hospitals (22.27%), and among Medicare patients (42.04%). The lowest admission rates were noted for self-pay patients (9.76%) and nonmetropolitan hospitals (13.49%). The smallest increases in costs over time were noted in the Northeast. Total costs were least in nonmetropolitan hospitals; however, more patients were transferred to other hospitals. When assessing hospital ownership status, private for-profit hospitals had similar admission rates compared with private not-for-profit hospitals (16.6% vs 15.9%); however, costs were 64% and 48% higher for ED and inpatient admission costs, respectively. Presentation of urolithiasis to the ED is common, and is associated with significant costs to the medical system, which are increasing over time. Costs and rates of admission differ by region, payer type, and hospital type, which may allow us to identify the causes for cost discrepancies and areas to improve efficiency of care delivery.


Molecular cloning of ovine connexin44 and temporal expression of gap junction proteins in a lens cell culture.
The lens plasma membranes of several mammalian species have been shown to contain three different connexin proteins. The goal of this study was to clone the sheep homologue of rat connexin46 identified as sheep connexin44 and to determine the temporal changes in the expression of the three sheep connexin proteins in a lens primary cell culture system. A sheep genomic library was screened with a rat lens connexin46 cDNA probe. Lens junctional protein and mRNA levels were determined in a sheep primary cell culture system by Western and Northern blot analyses, respectively. Sheep connexin44, the homologue of rat lens connexin46, was identified as a single-copy gene with a predicted molecular weight of 43,989 Daltons that is contained within a single exon. Northern blot analysis detected a 2.2-kb connexin44 transcript in RNA isolated from lens but not that isolated from heart, kidney, liver, or lung. During the in vitro differentiation of lens epithelial cells from 5 to 20 days in culture, connexin43 mRNA levels declined approximately 75%, whereas connexin49 RNA levels increased approximately 24 fold. The 40% decrease in the level of connexin43 protein and the 21-fold increase in the level of connexin49 protein did not directly correlate with the changes in mRNA levels encoding these proteins during this same period. Although detectable, the amount of connexin44 mRNA and protein remained low throughout the 20-day period during which lens cells were grown in culture. Neither mRNA nor protein encoding MP20 or MP26 transcripts could be detected in even the oldest 20-day lens cultures. Steady state mRNA levels of sheep connexin43 and connexin49 do not appear to be the only factor regulating the expression of these genes during in vitro differentiation of lens cells in culture. Although a decreased level of expression of connexin43 was accompanied by an increased level of expression of connexin49 over the 20-day period in culture, connexin44 mRNA and protein levels remained low throughout this 20-day period. Overall, these results suggest that these junctional proteins have a unique temporal pattern of expression during differentiation, and this lens primary cell culture system provides a valuable tool to better understand this process.


Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA.
The recent discovery of genomic 5-hydroxymethylcytosine (hmC) and mutations affecting the respective Tet hydroxylases in leukemia raises fundamental questions about this epigenetic modification. We present a sensitive method for fast quantification of genomic hmC based on specific transfer of radiolabeled glucose to hmC by a purified glucosyltransferase. We determined hmC levels in various adult tissues and differentiating embryonic stem cells and show a correlation with differential expression of tet genes.


Spinal extradural angiolipoma.
We report a case of spinal angiolipoma, causing paraplegia in a 38-year-old pregnant female. The tumour was excised and the patient made remarkable recovery. The role of pregnancy and its associated hormonal profiles on tumour growth is discussed.


Integrating HIV Preexposure Prophylaxis (PrEP) Into Routine Preventive Health Care to Avoid Exacerbating Disparities.
More than 3 decades since its emergence in the United States, HIV continues to spread and disproportionately affect socially marginalized groups. Preexposure prophylaxis (PrEP), a highly effective prevention strategy federally approved since 2012, could fundamentally alter the course of the epidemic. However, PrEP's potential has not been fully realized, in part because health care providers have been slow to adopt PrEP in clinical practice and have been selective in their discussion of PrEP with patients. This nonstandardized approach has constrained PrEP access. PrEP access has not only been inadequate but also inequitable, with several groups in high need showing lower rates of uptake than do their socially privileged counterparts. Recognizing these early warning signs that current approaches to PrEP implementation could exacerbate existing HIV disparities, we call on health professionals to integrate PrEP into routine preventive health care for adult patients-particularly in primary care, reproductive health, and behavioral health settings. Drawing on the empirical literature, we present 4 arguments for why doing so would improve access and access equity, and we conclude that the benefits clearly outweigh the challenges.


Renal sodium reabsorption, oxygen consumption, and gamma-glutamyltransferase excretion in the postischemic rat kidney.
The effect of 30 min of renal artery occlusion on renal sodium reabsorption, oxygen consumption, and brush border integrity was studied in the immediate 1-h reflow period. Rats were studied using clearance and renal extraction measurements. Glomerular filtration rate and renal plasma flow were measured over four consecutive 15-min periods; renal venous samples were drawn via an indwelling catheter. Renal oxygen consumption (QO2) was calculated from renal blood flow, corrected for urine flow, and from blood oxygen content measured with a fuel cell analyzer. Brush border integrity was assessed by the excretion of the brush border marker enzyme gamma-glutamyltransferase as well as by morphologic observation. Ischemia induced a 10-fold rise in fractional sodium excretion in the initial 0- to 15-min period, rose to 20-fold during the subsequent two periods, 15-45 min, and then returned to the initial reflow period level. The progressive deterioration of renal function with reflow could not be attributed to an increase in the filtered Na+ load. Rather, Na+ reabsorption appeared to be related to the presence of intact brush borders at 0-15 min, their removal from the luminal surface between 15 and 45 min, and their return at 60 min of reflow. Renal QO2 was coupled to Na+ reabsorption in the initial 15-min and final 45- to 60-min reflow periods. However QO2 was significantly increased over the control level at 30-45 min of reflow. The results point to a significant role of brush border uptake in the development of functional impairment following renal ischemia and suggest that the associated rise in renal O2 consumption may be coupled to the reparation of this organelle.


Anticholinesterase, Antioxidant, Antiaflatoxigenic Activities of Ten Edible Wild Plants from Ordu Area, Turkey.
Turkey has highly rich floras of medicinal and aromatic plants because of having various climate conditions in different regions. One of these regions is Middle Black Sea Region, especially Ordu Province. Extracts of 10 edible plants (Arum maculatum L., Hypericum orientale L., Ornithogalum sigmoideum Freyn et Sint., Silene vulgaris Garcke var. macrocarpa, Plantago lanceolata L., Achillea millefolium L. subsp. pannonica, Rumex crispus L., Rumex acetosella L., Capsella bursa-pastoris L., Coronopus squamatus Asch.), grown in Ordu, Turkey, were prepared with different solvents (hexane, ethanol and water, separately) and their anticholinestrase and antiaflatoxigenic activities were evaluated. Additionally, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the extracts were assayed. The ethanol extract of R. acetosella exhibited the highest antioxidant activity (A0.5 value of 25.31 µg/mL, for CUPRAC activity; IC50 value of 23.73 µg/mL, for ABTS activity). The hexane extract of C. bursa-pastoris showed the strongest inhibition against AChE enzyme with IC50 value of 7.24 µg/mL, and the hexane extract of A. millefolium subsp. pannonica had the highest BChE activity with IC50 value of 6.40 µg/mL. The ethanol extract of P. lanceolata exhibited the strongest inhibition against aflatoxin with 88% inhibition.


Herpes simplex virus infections of the newborn.
Herpes simplex virus (HSV) infections are fortunately quite rare in the neonatal population. Nevertheless, due to their life-threatening nature and the tremendous damage that surviving infants can incur, neonatal HSV is actually considered in a differential diagnosis relatively commonly. The availability of safe and effective antiviral therapy for the management of neonatal HSV also can accelerate a clinician's decision to consider HSV as the cause of a neonate's disease presentation, and then to obtain appropriate diagnostic studies and empirically institute antiviral treatment. Decisions on whether to continue antiviral therapy for a full course are predicated on the appropriate interpretation of these diagnostic studies as they subsequently are reported to the treating physician. For HSV-infected neonates, the duration of parenteral acyclovir therapy ranges from 14 to 21 days, depending on the extent of disease. Use of subsequent oral suppressive antiviral therapy is under investigation in randomized controlled trials, and at this time cannot be routinely recommended. This article will summarize the current state of neonatal HSV disease presentation, diagnosis, and management.


Epigenetic patterns associated with the immune dysregulation that accompanies psychosocial distress.
The molecular basis for psychosocial-distress mediated immune-dysregulation is not well understood. The purpose of this study was to determine whether peripheral blood mononuclear cell (PBMC) epigenetic pattern associates with this form of immune dysregulation. Women newly diagnosed with early stage breast cancer were enrolled into the study and psychosocial, immunological and epigenetic assessments were made at diagnosis and four months later, after completion of cancer treatment. At diagnosis women reported increased perceived stress, anxiety, and mood disturbance and the PBMC of these women exhibited reduced natural killer cell activity and reduced production of interferon gamma, which contrasted with results, obtained after completion of treatment. At the epigenetic level, a PBMC subset derived from women at diagnosis exhibited a distinct epigenetic pattern, with reduced nuclear acetylation of histone residues H4-K8 and H4-K12, as well as reduced phosphorylation of H3-S10, when compared to similar cells derived after the completion of treatment. Natural killer cell activity and interferon-gamma production were associated with nuclear acetylation and phosphorylation status of these histone residues. These findings demonstrate associations among nuclear epigenetic pattern and the immune dysregulation that accompanies psychosocial distress.


Effects of superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis on the cerebrospinal fluid gas tensions and pH in hemodynamically compromised patients.
This study was aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after STA-MCA anastomosis for occlusive carotid artery diseases to investigate its direct effects on the ischemic brain. This study included 9 patients who underwent STA-MCA anastomosis on the basis of CBF studies. About 1 mL of CSF was collected before and after bypass procedures, and CSF pH, CSF PO2, and CSF PCO2 were measured with a blood gas analyzer. As the controls, the CSF was collected from 6 patients during surgery for unruptured cerebral aneurysm. CSF PO2 and CSF PCO2 were expressed as the ratio to PaO2 and PaCO2, respectively. Before bypass procedure, CSF PO2/PaO2 was 0.88 ± 0.16, being lower than the controls (1.10 ± 0.09; P = 0.005). CSF PCO2/PaCO2 was 0.93 ± 0.13, being higher than the controls (0.84 ± 0.06; P = 0.039). Ipsilateral-to-contralateral CBF ratio had a positive correlation with CSF PO2/PaO2 (P = 0.0028) but a negative correlation with the CSF PCO2/PaCO2 (P = 0.0045). STA-MCA anastomosis increased CSF pH from 7.402 ± 0.133 to 7.504 ± 0.126 (P = 0.0011) and CSF PO2/PaO2 from 0.88 ± 0.16 to 1.05 ± 0.26 (P = 0.018) but decreased CSF PCO2/PaCO2 from 0.93 ± 0.13 to 0.70 ± 0.17 (P = 0.0006). The severity of cerebral ischemia before surgery is intensely reflected in the gas tensions and pH of the CSF. STA-MCA anastomosis carries dramatic effects on CSF gas tensions and pH in hemodynamically compromised patients. CSF would be a valuable surrogate biomarker to monitor the severity of cerebral ischemia.


Bicelle size modulates the rate of bacteriorhodopsin folding.
The conformational equilibria of integral membrane proteins have proven extremely difficult to characterize within native lipid bilayers. To circumvent technical issues, investigations of the structure and stability of α-helical membrane proteins are often carried out in mixed micelle or bicelle solvents that mimic the membrane and facilitate measurements of reversible folding. Under these conditions, the energetics of membrane protein folding are typically proportional to the mole fraction of an anionic detergent in the micelle. However, investigations of the folding and unfolding of bacteriorhodopsin (bR) surprisingly revealed that the folding rate is also highly sensitive to the bulk molar concentration of lipids and detergents. We show here that this rate enhancement coincides with changes in bicelle size and suggest this effect arises through restriction of the conformational search space during folding. In conjunction with previous mutagenic studies, these results provide additional evidence that a topological search limits the rate of bR folding. Furthermore, this finding provides insights into the manner by which micellar and bicellar environments influence the conformational stability of polytopic membrane proteins.


Modulatory roles of microRNAs in the regulation of different signalling pathways in large bowel cancer stem cells.
There are emerging data to suggest that microRNAs (miRNAs) have significant roles in regulating the function of normal cells and cancer stem cells (CSCs). This review aims to analyse the roles of miRNAs in the regulation of colon CSCs through their interaction with various signalling pathways. Studies showed a large number of miRNAs that are reported to be deregulated in colon CSCs. However, few of the studies available were able to outline the function of miRNAs in colon CSCs and uncover their signalling pathways. From those miRNAs, which are better described, miR-21 followed by miR-34, miR-200 and miR-215 are the most reported miRNAs to have roles in colon CSC regulation. In particular, miRNAs have been reported to regulate the stemness features of colon CSCs mainly via Wnt/B-catenin and Notch signalling pathways. Additionally, miRNAs have been reported to act on processes involving CSCs through cell cycle regulation genes and epithelial-mesenchymal transition. The relative paucity of data available on the significance of miRNAs in CSCs means that new studies will be of great importance to determine their roles and to identify the signalling pathways through which they operate. Such studies may in future guide further research to target these genes for more effective cancer treatment. miRNAs were shown to regulate the function of cancer stem cells in large bowel cancer by targeting a few key signalling pathways in cells.


Genetic variation in Staphylococcus aureus surface and immune evasion genes is lineage associated: implications for vaccine design and host-pathogen interactions.
S. aureus is a coloniser and pathogen of humans and mammals. Whole genome sequences of 58 strains of S. aureus in the public domain and data from multi-strain microarrays were compared to assess variation in the sequence of proteins known or putatively interacting with host. These included 24 surface proteins implicated in adhesion (ClfA, ClfB, Cna, Eap, Ebh, EbpS, FnBPA, FnBPB, IsaB, IsdA, IsdB, IsdH, SasB, SasC, SasD, SasF, SasG, SasH, SasK, SdrC, SdrD, SdrE, Spa and SraP) and 13 secreted proteins implicated in immune response evasion (Coa, Ecb, Efb, Emp, EsaC, EsxA, EssC, FLIPr, FLIPr like, Sbi, SCIN-B, SCIN-C, VWbp) located on the stable core genome. Many surface protein genes were missing or truncated, unlike immune evasion genes, and several distinct variants were identified. Domain variants were lineage specific. Unrelated lineages often possess the same sequence variant domains proving that horizontal transfer and recombination has contributed to their evolution. Surprisingly, sequenced strains from four animal S. aureus strains had surface and immune evasion proteins remarkably similar to those found in human strains, yet putative targets of these proteins vary substantially between different hosts. This suggests these proteins are not essential for virulence. However, the most variant protein domains were the putative functional regions and there is biological evidence that variants can be functional, arguing they do play a role. Surface and immune evasion genes are candidates for S. aureus vaccines, and their distribution and functionality is key. Vaccines should contain cocktails of antigens representing all variants or they will not protect against naturally occurring S. aureus populations.