The Experiences of Children with Primary Immunodeficiency Who Receive Immunoglobulin Subcutaneously Instead of Intravenously.
Children with primary immunodeficiency disorder have begun receiving subcutaneous immunoglobulin (SCIg) instead of intravenous immunoglobulin (IVIg). So, we aim to explore the experiences of primary immunodeficiency children with regard to receiving SCIg instead of IVIg. We adopted a phenomenological approach in 2022 in Turkey using semi-structured interviews. We recruited 15 participants using the purposive sampling method. The main theme was the sweetness and bitterness of living with SCIg. The first subtheme was sweetness (sense of freedom, having a normal life, saving time, ease of use, and feeling better). The second subtheme was bitterness (worries about taking responsibility for injection, impaired body image due to abdominal edema, and minimal tolerable complications). The results show these children had more sweet experiences than bitter ones. Being flexible in choosing a method, teaching patients to apply it correctly, and providing enough time to cope are as reasons for this.


Rhabdomyolysis and myoglobinuria following single induction dose of propofol in a dog.
To report a case of rhabdomyolysis and myoglobinuria following single induction dose of propofol in a dog. A 5-year-old intact male Shih-Tzu dog was presented for pigmenturia occurring a few hours following anesthesia for comprehensive oral health assessment and treatment. After premedication with IV diazepam (0.5 mg/kg), anesthesia was induced with IV propofol (4 mg/kg) and maintained with isoflurane vaporized in oxygen. A few hours following recovery from anesthesia, the dog developed rhabdomyolysis and myoglobinuria associated with increased serum alanine aminotransferase and C-reactive protein concentrations, as well as mild hypokalemia and euglycemic glycosuria. Approximately 48 hours after IV fluid therapy, the dog was clinically normal, and myoglobinuria progressively resolved. This is the first case description of rhabdomyolysis and myoglobinuria following a single dose of injectable propofol.


Internationally educated health professionals and the challenge of workforce distribution.
Internationally educated health professionals (IEHPs) have always been an important part of the Canadian health workforce. A particularly important aspect related to the role of IEHPs is their distribution across different sectors of the healthcare system and various geographical regions. Several provinces and territories have implemented strategies that restrict the initial practice of IEHPs to areas that have long-standing workforce shortages. While the outcomes of these approaches are mixed, some evidence suggests that IEHPs remain in place only as long as their contractual requirements stipulate. However, studies also indicate that IEHPs are increasingly practising in care settings that are perceived to be less attractive by their Canadian-trained counterparts. Whether the contribution of IEHPs is framed in terms of short- or long-term sustainable solutions, their role will continue to be an important component of health service across Canada.


[The evaluation of fat and muscles of the arm in the nutritional study in pre-school children in Madrid].
The objective of this study was to evaluate the body composition of the pre-school children in the city of Madrid as a part of their nutritional evaluation. Seven hundred and three healthy children of both sexes were studied by means of a cross-sectional sample. The children, between 2 and 6 years of age, attended nursery schools in the city of Madrid. The study evaluated the arm muscle and fat areas through an anthropometric assessment. After measuring the triceps skinfold and the arm circumference, we obtained the arm muscle circumference, the arm area, and the arm muscle and fat areas. Once all data were gathered, they were statistically evaluated. The parameters studied reveal a normal distribution in the population in question. The mean values of muscle and fat areas were normal in relationship to age.


Hexose metabolism in pancreatic islets. Inhibition of hexokinase.
In islet homogenates, hexokinase-like activity (Km 0.05 mM; Vmax. 1.5 pmol/min per islet) accounts for the major fraction of glucose phosphorylation. Yet the rate of glycolysis in intact islets incubated at low glucose concentrations (e.g. 1.7 mM) sufficient to saturate hexokinase only represents a minor fraction of the glycolytic rate observed at higher glucose concentrations. This apparent discrepancy between enzymic and metabolic data may be attributable, in part at least, to inhibition of hexokinase in intact islets. Hexokinase, which is present in both islet and purified B-cell homogenates, is indeed inhibited by glucose 6-phosphate (Ki 0.13 mM) and glucose 1,6-bisphosphate (Ki approx. 0.2 mM), but not by fructose 2,6-bisphosphate. In intact islets, the steady-state content of glucose 6-phosphate (0.26-0.79 pmol/islet) and glucose 1,6-bisphosphate (5-48 fmol/islet) increases, in a biphasic manner, at increasing concentrations of extracellular glucose (up to 27.8 mM). From these measurements and the intracellular space of the islets, it was estimated that the rate of glucose phosphorylation as catalysed by hexokinase represents, in intact islets, no more than 12-24% of its value in islet homogenates.


Development and Evaluation of Innovative and Practical Table-top Exercises Based on a Real Mass-Casualty Incident.
The aim of this work was to develop a table-top exercise (TTX) program for mass-casualty incident (MCI) response based on a real incident to evaluate the program. The TTX program was developed based on the 8 TTX design steps. Convenience sampling was adopted to recruit recently graduated physicians in China. After the TTX training, the participants completed a self-designed questionnaire, as well as the Simulation Design Scale (SDS) and Educational Practices in Simulation Scale (EPSS). In total, 148 valid questionnaires were collected. The difficulty score of the TTX program was 3.69 ± 0.8. The participants evaluated the program highly, with a score of 4.72 ± 0.54 out of 5. Both the SDS and the EPSS had average scores higher than 4.5. Guided reflection/feedback (M = 4.68, SD = 0.41) and fidelity (M =4.66, SD = 0.57) were the 2 highest-rated SDS subscales. For the EPSS, diverse ways of learning and collaboration were the 2 highest-rated subscales. Multivariate stepwise regression analysis showed that the participants' evaluations of the TTX training course were related to the EPSS score, the difficulty rating, the evaluation of the instructional props, and the degree of participant involvement (F = 24.385, P < 0.001). A TTX program for MCIs was developed based on the 2014 Shanghai New Year Crush. The TTX kit is practical and sophisticated, and it provides an effective strategy for MCI training.


Prevalence of Achilles and patellar tendinopathy and their association to intratendinous changes in adolescent athletes.
Achilles (AT) and patellar tendons (PT) are commonly affected by tendinopathy in adult athletes but prevalence of symptoms and morphological changes in adolescents is unclear. The study aimed to determine prevalence of tendinopathy and intratendinous changes in ATs and PTs of adolescent athletes. A total of 760 adolescent athletes (13.0 ± 1.9 years; 160 ± 13 cm; 50 ± 14 kg) were examined. History, local clinical examination, and longitudinal Doppler ultrasound analysis for both ATs and PTs were performed including identification of intratendinous echoic changes and vascularization. Diagnosis of tendinopathy was complied clinically in case of positive history of tendon pain and tendon pain on palpation. Achilles tendinopathy was diagnosed in 1.8% and patellar tendinopathy in 5.8%. Vascularizations were visible in 3.0% of ATs and 11.4% of PTs, hypoechogenicities in 0.7% and 3.2% as well as hyperechogenicities in 0% and 0.3%, respectively. Vascularizations and hypoechogenicities were statistically significantly more often in males than in females (P ≤ 0.02). Subjects with patellar tendinopathy had higher prevalence of structural intratendinous changes than those without PT symptoms (P ≤ 0.001). In adolescent athletes, patellar tendinopathy is three times more frequent compared with Achilles tendinopathy. Longitudinal studies are necessary to investigate physiological or pathological origin of vascularizations and its predictive value in development of tendinopathy.


Direct Neuronal Reprogramming of Common Marmoset Fibroblasts by ASCL1, microRNA-9/9*, and microRNA-124 Overexpression.
The common marmoset (Callithrix jacchus) has attracted considerable attention, especially in the biomedical science and neuroscience research fields, because of its potential to recapitulate the complex and multidimensional phenotypes of human diseases, and several neurodegenerative transgenic models have been reported. However, there remain several issues as (i) it takes years to generate late-onset disease models, and (ii) the onset age and severity of phenotypes can vary among individuals due to differences in genetic background. In the present study, we established an efficient and rapid direct neuronal induction method (induced neurons; iNs) from embryonic and adult marmoset fibroblasts to investigate cellular-level phenotypes in the marmoset brain in vitro. We overexpressed reprogramming effectors, i.e., microRNA-9/9*, microRNA-124, and Achaete-Scute family bHLH transcription factor 1, in fibroblasts with a small molecule cocktail that facilitates neuronal induction. The resultant iNs from embryonic and adult marmoset fibroblasts showed neuronal characteristics within two weeks, including neuron-specific gene expression and spontaneous neuronal activity. As directly reprogrammed neurons have been shown to model neurodegenerative disorders, the neuronal reprogramming of marmoset fibroblasts may offer new tools for investigating neurological phenotypes associated with disease progression in non-human primate neurological disease models.


Population history, phylogeography, and conservation genetics of the last Neotropical mega-herbivore, the lowland tapir (Tapirus terrestris).
Understanding the forces that shaped Neotropical diversity is central issue to explain tropical biodiversity and inform conservation action; yet few studies have examined large, widespread species. Lowland tapir (Tapirus terrrestris, Perissodactyla, Tapiridae) is the largest Neotropical herbivore whose ancestors arrived in South America during the Great American Biotic Interchange. A Pleistocene diversification is inferred for the genus Tapirus from the fossil record, but only two species survived the Pleistocene megafauna extinction. Here, we investigate the history of lowland tapir as revealed by variation at the mitochondrial gene Cytochrome b, compare it to the fossil data, and explore mechanisms that could have shaped the observed structure of current populations. Separate methodological approaches found mutually exclusive divergence times for lowland tapir, either in the late or in the early Pleistocene, although a late Pleistocene divergence is more in tune with the fossil record. Bayesian analysis favored mountain tapir (T. pinchaque) paraphyly in relation to lowland tapir over reciprocal monophyly, corroborating the inferences from the fossil data these species are sister taxa. A coalescent-based analysis rejected a null hypothesis of allopatric divergence, suggesting a complex history. Based on the geographic distribution of haplotypes we propose (i) a central role for western Amazonia in tapir diversification, with a key role of the ecological gradient along the transition between Andean subcloud forests and Amazon lowland forest, and (ii) that the Amazon river acted as an barrier to gene flow. Finally, the branching patterns and estimates based on nucleotide diversity indicate a population expansion after the Last Glacial Maximum. This study is the first examining lowland tapir phylogeography. Climatic events at the end of the Pleistocene, parapatric speciation, divergence along the Andean foothill, and role of the Amazon river, have similarly shaped the history of other taxa. Nevertheless further work with additional samples and loci is needed to improve our initial assessment. From a conservation perspective, we did not find a correspondence between genetic structure in lowland tapir and ecogeographic regions proposed to define conservation priorities in the Neotropics. This discrepancy sheds doubt into this scheme's ability to generate effective conservation planning for vagile species.


Star clusters, self-interacting dark matter halos, and black hole cusps: The fluid conduction model and its extension to general relativity.
We adopt the fluid conduction approximation to study the evolution of spherical star clusters and self-interacting dark matter (SIDM) halos. We also explore the formation and dynamical impact of density cusps that arise in both systems due to the presence of a massive, central black hole. The large N-body, self-gravitating systems we treat are "weakly collisional": the mean free time between star or SIDM particle collisions is much longer than their characteristic crossing (dynamical) time scale, but shorter than the system lifetime. The fluid conduction model reliably tracks the "gravothermal catastrophe" in star clusters and SIDM halos without black holes. For a star cluster with a massive, central black hole, this approximation reproduces the familiar Bahcall-Wolf quasistatic density cusp for the stars bound to the black hole and shows how the cusp halts the "gravothermal catastrophe" and causes the cluster to re-expand. An SIDM halo with an initial black hole central density spike that matches onto to an exterior NFW profile relaxes to a core-halo structure with a central density cusp determined by the velocity dependence of the SIDM interaction cross section. The success and relative simplicity of the fluid conduction approach in evolving such "weakly collisional," quasiequilibrium Newtonian systems motivates its extension to relativistic systems. We present a general relativistic extension here.


A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.
Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. ACTRN12609000294257.


Prognostication with point-of-care echocardiography during cardiac arrest: A systematic review.
To conduct a prognostic factor systematic review on point-of-care echocardiography during cardiac arrest to predict clinical outcomes in adults with non-traumatic cardiac arrest in any setting. We conducted this review per PRISMA guidelines and registered with PROSPERO (ID pending). We searched Medline, EMBASE, Web of Science, CINAHL, and the Cochrane Library on September 6, 2019. Two investigators screened titles and abstracts, extracted data, and assessed risks of bias using the Quality in Prognosis Studies (QUIPS) template. We estimated prognostic test performance (sensitivity and specificity) and measures of association (odds ratio). Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology evaluated the certainty of evidence. In total, 15 studies were included. We found wide variation across studies in the definition of 'cardiac motion' and timing of sonographic assessment. Most studies were hindered by high risks of bias from prognostic factor measurement, outcome measurement, and lack of adjustment for other prognostic factors. Ultimately, heterogeneity and risk of bias precluded meta-analyses. We tabulated ranges of prognostic test performance and measures of association for 5 different combinations of definitions of 'cardiac motion' and sonographic timing, as well as other miscellaneous sonographic findings. Overall certainty of this evidence is very low. The evidence for using point-of-care echocardiography as a prognostic tool for clinical outcomes during cardiac arrest is of very low certainty and is hampered by multiple risks of bias. No sonographic finding had sufficient and/or consistent sensitivity for any clinical outcome to be used as sole criterion to terminate resuscitation.


Covalently functionalized nanotubes as nanometre-sized probes in chemistry and biology.
Carbon nanotubes combine a range of properties that make them well suited for use as probe tips in applications such as atomic force microscopy (AFM). Their high aspect ratio, for example, opens up the possibility of probing the deep crevices that occur in microelectronic circuits, and the small effective radius of nanotube tips significantly improves the lateral resolution beyond what can be achieved using commercial silicon tips. Another characteristic feature of nanotubes is their ability to buckle elastically, which makes them very robust while limiting the maximum force that is applied to delicate organic and biological samples. Earlier investigations into the performance of nanotubes as scanning probe microscopy tips have focused on topographical imaging, but a potentially more significant issue is the question of whether nanotubes can be modified to create probes that can sense and manipulate matter at the molecular level. Here we demonstrate that nanotube tips with the capability of chemical and biological discrimination can be created with acidic functionality and by coupling basic or hydrophobic functionalities or biomolecular probes to the carboxyl groups that are present at the open tip ends. We have used these modified nanotubes as AFM tips to titrate the acid and base groups, to image patterned samples based on molecular interactions, and to measure the binding force between single protein-ligand pairs. As carboxyl groups are readily derivatized by a variety of reactions, the preparation of a wide range of functionalized nanotube tips should be possible, thus creating molecular probes with potential applications in many areas of chemistry and biology.


Monomers through trimers of large tumor antigen bind in region I and monomers through tetramers bind in region II of simian virus 40 origin of replication DNA as stable structures in solution.
Large tumor (T) antigen and its bound multimeric states are positioned by scanning transmission electron microscopy (STEM) within a few base pairs at control sequences of the simian virus 40 DNA origin of replication region. Proximal and distal edge positions for each multimer group match the end positions of previously mapped fragments protected from DNase cleavage. Since chance correspondence is shown to be extremely unlikely, STEM mass measurements, obtained concurrently with STEM map positions, indicate that the DNase fragments arise from bound monomers, dimers, trimers, and tetramers in binding region II and monomers, dimers, and trimers in binding region I. Simultaneous binding of seven monomer-equivalent masses is observed, three in region I and four in region II, with an ordered and interpretable mass distribution in the plane of the foil. Although this observation does not prove that the six G-A-G-G-C and one T-A-G-G-C sequences, similarly distributed, function as recognition sequences for T-antigen monomer, it provides strong support for such a model. The stable existence in solution of low-and intermediate-mass structures, observed at lower T-antigen concentrations, suggests a role as assembly intermediates.


Quality of informed consent for invasive procedures in central Saudi Arabia.
Informed consent is considered the most important step in clinical interventions. The aims of this study were (1) to assess the quality of informed consent for invasive procedures with regard to consent process and information given about risks and alternative treatments, and (2) to determine patients' attitude toward informed consent at King Abdulaziz Medical City, Riyadh, Saudi Arabia. A cross-sectional study was conducted of 162 adult patients in different wards after undergoing surgery or invasive procedures within 1-2 days of signing the informed consent, using a previously validated interview questionnaire. Data on patients' characteristics, type of invasive procedure, and some informed consent-related issues were collected. Multiple linear regression analysis was used to identify the predictors of the percentage mean score of quality of informed consent, and significance was considered at P ≤ 0.05. The quality of informed consent was generally poor (% mean score = 50.98 ± 17.49). About two-thirds of patients were told during the informed consent process that they have to sign merely as routine, 48% thought that if they refused the treatment plan they would lose the interest of the treating physician to help them, 42% thought that by saying no they would lose the good relationship with their physician, and 42.6% were not interested in having a copy of the informed consent document. Significantly higher quality was predicted when the physicians were the ones who explained the informed consent (t = 4.15, P < 0.001) and when informed consent was explained to younger patients (t = 2.754, P = 0.007). The overall attitude of the patients toward the process of informed consent was satisfactory (% mean score = 76.31 ± 7.63). The results suggest either that patients are not aware of their rights or that physician paternalism is practiced in Saudi Arabia. Cultural barriers should not be an argument to diminish the role of informed consent. Further studies should focus on how the value of autonomy can be appreciated in the Saudi culture.


Reculturing of cells from primary CFU-C colonies.
This study was aimed at investigating whether cells of CFU-C derived colonies could form secondary colonies. Bone marrow cultures of volumes of agar medium between 25 microliter and 75 microliter contained in glass capillaries were stimulated with mouse lung-conditioned medium (MLCM) containing granulocyte/macrophage colony-stimulating factor (GM-CSF). Agar gels with colonies of up to greater than or equal to 20 were blown out into identical culture medium, completely dispersed on a whirl-mix to single cell suspensions, and used for establishing secondary agar cultures. In these secondary cultures considerable numbers of secondary granulocytic, mixed granulocytic/macrophage and macrophage colonies as well as numerous clusters arose. In contrast, when single colonies were recultured, only few secondary cell aggregates were formed. When primary cultures containing up to greater than or equal to 20 cell aggregates were used for serial reculture at intermittent intervals of 3 and 4 days, a 2-7-fold increase of colony-forming cells was found in tertiary cultures as was monitored by 7 day colony counts. And by use of different kinds of CSF-containing media, an over 4-fold increase of secondary over primary colonies was obtained with bovine lung-conditioned medium (BLCM) in primary and L-cell-conditioned medium (LCCM) in secondary 7 day cultures. Primary capillary cultures were found to be devoid of CFU-S. Also, setting up bone marrow cultures in petri dishes and stimulating with MLCM, growth of primary as well as secondary colonies was obtained. The results indicate some self-renewal potential of CFU-C in vitro.


The cytoskeleton and cytomusculature in embryogenesis--an overview.
The role of microfilaments and microtubules comprising the cytoskeleton and cytomusculature in embryonic development is discussed. The cytomusculature, as microfilaments, is evident in both the unfertilized and fertilized egg and probably plays a role in sperm incorporation, cortical contractions, and cytokinesis. The cytoskeleton, in the form of microtubules, appears after fertilization in the form of the sperm aster and the mitotic apparatus. The cytoskeleton and cytomusculature play a decisive role in shape changes of individual cells responsible for gastrulation, neurulation, and morphogenesis of other epithelial sheets. Several developmental defects, such as spina bifida, may be related to malfunctioning of the cytoskeleton or cytomusculature. The putative role of microfilaments and microtubules in cell shape changes during embryogenesis can best be, at least initially, inferred from careful ultrastructural observations.


Use of the C-scan in evaluation of peripheral lymphedema.
The C-(cutaneous)-scan constitutes a simple way to evaluate the status of the lymphatic system of swollen and apparently normal extremities. We have termed the procedure C-scan because this expression emphasizes the injection of the radiotracer into the cutis. Only one scintiscan, which takes approximately 15 minutes, is performed 3 hours after injection, in contrast to other investigative procedures including standard lymphangioscintigraphy, which utilize multiple scannings that unnecessarily prolong the duration of the study. The C-scan method is semi-quantitative and distinguishes pathologic conditions of the lymphatic system by means of whole body scintigraphy and by measuring the radioactivity in specific regions of interest rather than by examining solely differences in delay of transport. Both a qualitative image and a quantitative assessment are thereby produced. The C-scan is performed using a general purpose gamma camera in line to a multiprocessor computer system. Scinti-scanning is performed 3 hours after an intracutaneous injection of 20 MBq of Tc99m nanocolloid (Solco) distally into the dorsum of the extremity. The image obtained is divided into regions of interest and the radioactivity in these regions is calculated as the percentage of the total radioactivity counted. The C-scan is easy to perform and can be repeated if necessary every 2 days. The effects of various treatments of lymphedema, either nonoperative or operative, can be assessed short-term, and examples are provided. In conjunction with limb volume measurements, the C-scan gives an accurate impression of changes in the lymphedematous extremity before, during, and after treatment. Applications of this imaging technique are shown after combined "decongestive" physiotherapy, lymph-venous anastomosis, ablative (debulking) surgery, liposuction, and thermotherapy.


Changes in the cell size of Brevundimonas diminuta using different growth agitation rates.
Brevundimonas diminuta (ATCC 19146) is a standard organism for validation of sterilizing-grade membrane filters. Cell size is critical for the determination of retention characteristics of 0.2 micron rated membrane filters. In this study, cell size changes of B. diminuta cultured under different physiologic states and variable agitations at 50, 100 and 200 rpm were measured by a particle size analyzer and scanning electron microscope (SEM). The smallest cells were obtained at initial stationary phase in saline lactose broth (SLB) as a shaking culture at 50 rpm. Cells grown under agitation at 50, 100 and 200 rpm showed an increase of specific growth rate (mu), about 2.9, 3.6 and 3.6 fold, respectively, compared to the non-agitated cells in SLB media. These results suggested that the cell size decreased proportionally with increase of the specific growth rate (mu) in SLB. These size changes were associated with penetration through a 0.2 micron rated cellulose acetate filter. A scale-down filtration system was developed and performed bacterial challenge test and bubble point test with cells cultured in SLB. Cells grown under agitation conditions in SLB were not retained by 0.2 micron rated membrane filter.


Exploring the Link Between Mentoring and Intangible Outcomes of Entrepreneurship: The Mediating Role of Self-Efficacy and Moderating Effects of Gender.
Entrepreneurship education is increasingly becoming a focal strategy for promoting entrepreneurship, particularly to foster entrepreneurial intentions and startups. However, learning and support are equally important after startup for novice entrepreneurs to gain a good level of confidence to manage their business and achieve the desired outcomes. Using a sample of 189 young self-employed individuals in Uganda, this study examines the differential impact of mentoring and self-efficacy on the achievement of intangible outcomes of entrepreneurship including satisfaction of need for autonomy, work satisfaction and the intention to stay in self-employment. We found self-efficacy to mediate the effects of mentoring on these intangible outcomes. In addition, the results showed substantial gender differences. Whereas women's satisfaction of the need for autonomy and intention to stay in self-employment were strongly associated with the direct effects of mentoring, their male counterparts seemed to benefit more if mentoring resulted in increased self-efficacy. Overall, our findings suggest that whereas mentoring improves the competence of small business owners and consequently achievement of superior outcomes, mentoring should also focus on boosting self-efficacy which in turn is essential for the application of the entrepreneurial competencies.


Complex malformation (Ruggieri-Happle) phenotype with "cutis tricolor" in a 10-year-old girl.
The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. It is currently regarded as a twin-spotting phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far: (a) as an isolated skin manifestation; (b) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (c) as a distinct phenotype [cutis tricolor parvimaculata]; (d) in association with other (e.g., vascular) skin disturbances. We report a novel case of cutis tricolor in a 10-year-old girl who had dysmorphic facial features [alike those seen in cases with syndromic (RHS) cutis tricolor], overall overgrowth [weight, length, and head circumference were >90th percentile; there was increased bone age], mild cognitive delay (current IQ=55), behavioural disturbances, febrile seizures and (later) partial complex epilepsy (currently under good control), and skeletal defects [i.e., posterior scalloping of the lumbar vertebrae]. We discuss the main similarities and differences between the various phenotypes in the spectrum of cutis tricolor and with other conditions sharing features with the present case.


Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion.
Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.


[Effect of urea on the mechanism of percutaneous permeation].
The influence of urea on the percutaneous permeation under different conditions of application and on the epidermal effectiveness of 5-fluorouracil (FU) as an example for water-soluble agents is reported. The proceedings of permeation of FU are accelerated by admixture of, or pretreatment with, urea and by increasing the hydration of the horny layer by pretreatment with NaCl. The effectiveness of FU on the epidermis is increased simultaneously. However, the permeation rate of FU is decreased by pretreatment with HTH as an example of a stabilized urea emulsion; on the other hand, the most favourable therapeutic effect is demonstrable. Therefore, the permeation of an agent may be both enhanced and inhibited by different modes of urea application. These findings appear to be important for both the optimization of topical treatment and the industrial medicine's point of view.


[Is the needs-based planning mechanism effectively needs-based? An analysis of the regional distribution of outpatient care providers].
Since the 1990s licenses for opening a medical practice in Germany are granted based on a needs-based planning system which regulates the regional allocation of physicians in primary care. This study aims at an analysis of the distribution of physicians (and hence the effects of the planning system) with regard to the overarching objective of primary care supply: the safeguarding of "needs-based and evenly distributed health care provision" (Section 70 para 1 German Social Code V). The need for health care provision of each German district (or region) and the actual number of physicians in the respective area are compared using a concentration analysis. For this purpose, the local health-care need was approximated in a model based on the morbidity predictors age and sex and by combining data on the local population structure with the age- and sex-specific frequency of physician consultations (according to data of the GEK sickness fund). The concentration index then measures the degree of regional inequity in the distribution of outpatient care. The results of the analysis demonstrate an inequitable regional distribution between medical needs of the local population and the existing outpatient health care provider capacities. These regional disparities in needs-adjusted supply densities are particularly large for -outpatient secondary care physicians and psychotherapists, even when taking into account the care provision of urban physicians for peri-urban areas as well as the adequacy of longer travel times to specialists. One major reason for these inequities is the design of today's physician planning mechanism which mainly conserves a suboptimal status quo of the past. The initiated reforms of the planning mechanism should progress and be further deepened. Especially today's quota-based allocation of practice licenses requires fundamental changes taking into account the relevant factors approximating local health care needs, re-assessing the adequate spatial planning level and expanding opportunities for introducing innovative and more flexible health care services models.


Encysted corneal contact lens presenting as an eyelid mass.
A 57-year-old woman presented with a 10 by 10 mm movable eyelid mass which had been present for 8 months before examination by me. Diagnostic exploration of the eyelid was performed, and a cyst containing a hard corneal contact lens was discovered. Further history obtained after surgery revealed that the patient had lost her contact lens approximately 4 years prior to the surgical exploration.


Intraabdominal follicular dendritic cell sarcoma: a report of three cases and review of the literature.
Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from follicular dendritic cells in lymphoid follicles. FDCS has been increasingly reported in recent years. However, data on FDCS are mostly based on single case reports or case series and its natural history and standard treatment are not clear. To increase the understanding of this rare disease, we report our experience of three cases of FDCS with an analysis of the morphological and immunophenotypic characteristics, clinical course, treatment options and response to treatment. In addition, we reviewed the literature on FDCS.


Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by a persistent elevation of pulmonary artery pressure accompanied by right ventricular hypertrophy (RVH). The current treatment for pulmonary hypertension is limited and only provides symptomatic relief due to unknown cause and pathogenesis of the disease. Both vasoconstriction and structural remodeling (enhanced proliferation of vascular smooth muscle cell) of the pulmonary arteries contribute to the progressive course of PAH, irrespective of different underlying causes. The exact molecular mechanism of PAH, however, is not fully understood. The purpose of this review is to provide recent advances in the mechanistic investigation of PAH. Specifically, this review focuses on nitric oxide, oxidative stress and inflammation and how these factors contribute to the development and progression of PAH. This review also discusses recent and potential therapeutic advancements for the treatment of PAH.


Caudal Lumbar Disc Herniations Are More Likely to Require Surgery for Symptom Resolution.
Retrospective study. We examined the impact that location of a lumbar disc herniation has on the likelihood that a patient will require surgery after at least 6 weeks of nonoperative management. Using ICD-10 codes M51.26 and M51.27, we identified patients at a single academic institution from 2015 to 2016 who received a diagnosis of primary lumbar radicular pain, had magnetic resonance imaging confirming a lumbar disc herniation, and underwent at least 6 weeks of nonoperative management. Patients experiencing symptoms suggesting cauda equina syndrome or progressive motor deficits were excluded. Five hundred patients met inclusion/exclusion criteria. Twenty-nine (5.8%) had L3-L4 herniations, 245 (49.0%) had L4-L5 herniations, and 226 (45.2%) had L5-S1 herniations. Overall, 451 (90.2%) patients did not undergo surgery within 1 year of diagnosis. Nonsurgical patients had an average herniation size occupying 31.2% of the canal, compared with 31.5% in patients who underwent surgery. While herniation size, age, sex, and race failed to demonstrate a statistical association with the likelihood for surgery, location of disc herniation demonstrated a strong association. L3-L4 and L4-L5 herniations had odds ratios of 0.19 and 0.45, respectively, relative to L5-S1 herniations (P = .0047). Patients were more than twice as likely to require a surgery on an L5-S1 herniation in comparison with an L4-L5 herniation (P < .05). L3-L4 herniations rarely required surgery. Patients with caudal lumbar disc herniations were more likely to require surgery after at least 6 weeks of conservative management than those with disc herniations in the mid-lumbar spine.


ATP-dependent silver transport across the basolateral membrane of rainbow trout gills.
Silver has been shown to be extremely toxic to freshwater teleosts, acting to inhibit Na(+) uptake at the gills, due to the inactivation of branchial Na(+)/K(+)-ATPase activity. However, the gills are also a route by which silver may enter the fish. Therefore, this study focuses on the mechanism of transport of this nonessential metal across the basolateral membrane of the gill cell, using basolateral membrane vesicles (BLMV) prepared from the gills of freshwater rainbow trout. Uptake of silver by BLMV was via a carrier-mediated process, which was ATP-dependent, reached equilibium over time, and followed Michaelis-Menten kinetics, with maximal transport capacity (V(max)) of 14.3 +/- 5.5 (SE) nmol mg membrane protein(-1) min(-1) and an affinity (K(m)) of 62.6 +/- 43.7 microM, and was inhibited by 100 microM sodium orthovanadate (Na(3)VO(4)). The ionophore monensin (10 microM) released transported silver from the BLMV. Acylphosphate intermediates, of a 104 kDa size, were formed from the BLMV preparations in the presence of ATP plus Ag. These results demonstrate that there is a P-type ATPase present in the basolateral membrane of the gills of rainbow trout that can actively transport silver, a process which will remove this heavy metal from its site of toxic action, the gill.


Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation.
Multipotent mesenchymal stromal cells (MSC) have immunomodulatory effects. The aim of this study was to demonstrate safety and feasibility of MSC transfusion in pediatric patients who had undergone allogeneic stem cell transplantation from MMFD, MUD, MMUD and MSD. Patients with posttransplant complications based on deregulated immune effector cells who may benefit from an immunomodulatory effect of MSC had been selected. MSC were isolated from the hematopoietic stem cell donors in five cases and from a third party parental donor in two cases. We transfused ex vivo-expanded MSC in 11 doses into seven pediatric patients. Cell doses were escalated based on availability from 0.4x10(6) to 3.0x10(6) per kg bodyweight No adverse effects were detected with a maximum follow-up of 29 months. One out of three patients showed slight improvement of chronic GVHD. Two patients with severe acute GvHD did not progress to cGvHD. One patient received MSC to stabilize graft function after secondary haploidentical transplantation. One patient recovered from trilineage failure due to severe hemophagocytosis. This is the first case of a pediatric patient treated with MSC for trilineage failure after haploidentical stem cell transplantation from her father. We report the first series of 11 transfusions of expanded MSC in pediatric patients with immunological complications after allogeneic transplantation. Transfusion of MSC was safe and encouraging improvements in some patients were observed.


Prepartum application of internal teat sealant or intramammary amoxicillin on dairy heifers: Effect on udder health, survival, and performance.
Intramammary infusion of antimicrobials (IA) and application of an internal teat sealant (ITS) at the end of the lactation is a common strategy to prevent and treat intramammary infections during the dry period. In heifers, precalving IA has been reported to improve udder health and milk quality; however, the effect of ITS in heifers housed in freestall barns is still unknown. The objective of this study was to investigate the effect of prepartum application of ITS or IA on udder health of dairy heifers. A total of 886 heifers were randomly allocated into 1 of 4 treatment groups when they were 245 ± 3 d pregnant. Control heifers (CON) did not receive any treatment. Heifers in the ITS group received the application of ITS containing 2.6 g of bismuth subnitrate. Animals in the IA group received intramammary administration of 62.5 mg of amoxicillin. Heifers in IA+ITS group received intramammary administration of amoxicillin followed by ITS application. The follow-up period was 270 d in milk (DIM). Clinical mastitis was diagnosed and treated by trained farm personnel throughout the study period. Composite milk somatic cell counts (SCC) were determined monthly for the first 9 mo of lactation by Dairy Herd Improvement Association. Subclinical mastitis was defined as a cow having a SCC >200,000 cells/mL for at least 1 test day and not diagnosed with clinical mastitis during the study period. At 7 ± 3 DIM, composite milk samples were collected for bacteriological analysis for a subset of the study animals. The presence of pathogens in milk at 7 ± 3 DIM was more frequently detected in the CON heifers compared with animals enrolled in the treatment groups. Heifers in IA+ITS group had a decreased incidence of clinical mastitis compared with CON heifers (12.9 vs. 21.4%). Additionally, the incidence of subclinical mastitis was decreased for IA+ITS heifers compared with CON counterparts (20.1 vs. 43.8%). During the first 9 mo of lactation, IA and IA+ITS heifers had lower SCC linear scores compared with ITS and CON counterparts. Although IA+ITS treatment successfully improved udder health, it did not result in better milk yield, fertility, and survivability. In conclusion, ITS alone was not effective in improving udder health; however, the combination of ITS and IA decreased the incidence of clinical and subclinical mastitis during the first 9 mo of lactation. Additionally, IA+ITS had a long-term effect on the SCC linear score throughout the study period.


Lenticular cytoprotection. Part 1: the role of hypoxia inducible factors-1α and -2α and vascular endothelial growth factor in lens epithelial cell survival in hypoxia.
The prosurvival signaling cascades that mediate the unique ability of human lens epithelial cells to survive in their naturally hypoxic environment are not well defined. Hypoxia induces the synthesis of the hypoxia inducible factor HIF-1α that in turn, plays a crucial role in modulating a downstream survival scheme, where vascular endothelial growth factor (VEGF) also plays a major role. To date, no published reports in the lens literature attest to the expression and functionality of HIF-2α and the role it might play in regulating VEGF expression. The aim of this study was to identify the functional expression of the hypoxia inducible factors HIF-1α and HIF-2α and establish their role in regulating VEGF expression. Furthermore, we demonstrate a link between sustained VEGF expression and the ability of the hypoxic human lens epithelial cell to thrive in low oxygen conditions and resist mitochondrial membrane permeability transition (also referred to as lenticular cytoprotection). Hypoxia inducible factor translation inhibitors were used to demonstrate the role of HIF-1α and HIF-2α and the simultaneous expression of both hypoxic inducible factors to determine their role in regulating VEGF expression. Axitinib, which inhibits lenticular cell autophosphorylation of its VEGF receptor, was employed to demonstrate a role for the VEGF-VEGFR2 receptor complex in regulating Bcl-2 expression. Specific antisera and western blot analysis were used to detect the protein levels of HIF-1α and HIF-2α, as well as the proapoptotic protein, BAX and the prosurvival protein, Bcl-2. VEGF levels were analyzed with enzyme-linked immunosorbent assay (ELISA). The potentiometric dye, 5,5',6,6'-tetrachloro1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide, was used to determine the effect of the inhibitors on mitochondrial membrane permeability transition. Cultured human lens epithelial cells (HLE-B3) maintained under hypoxic condition (1% oxygen) displayed consistent accumulation of VEGF throughout the 72 h incubation period. Using hypoxia inducible factor translation inhibitors targeting HIF-1α or HIF-2α, the specific inhibition of each protein did not diminish VEGF synthesis. The combined inhibition of HIF-1α and HIF-2α expression, using a double hypoxia inducible factor translation inhibitor, markedly decreased the level of VEGF. The inhibition of VEGF synthesis was associated with a profound deficiency in the level of the prosurvival protein, Bcl-2. Axitinib also prevented the VEGF-mediated expression of Bcl-2. The loss of VEGF coupled with the decrease in intracellular Bcl-2 correlated with marked mitochondrial depolarization, an early predictor of cellular apoptosis. Our data support a model in which the sustained synthesis of VEGF in human lens epithelial cells, maintained under hypoxic condition, is regulated by a compensatory inter-relationship between HIF-1α and HIF-2α. VEGF acts as a prosurvival factor in hypoxic lens epithelial cells by maintaining consistent expression of the prosurvival protein Bcl-2, which likely prevents the translocation of cytosolic BAX to the outer mitochondrial membrane, thus preventing the initiation of mitochondrial depolarization.


Punishment Attacks in Post-Ceasefire Northern Ireland: An Emergency Department Perspective.
Northern Ireland (NI) has been in a post-conflict state for over twenty years. However, injuries sustained during paramilitary Punishment Attacks (PA) remain a common hospital presentation. The aim of this study was to compare the current province-wide frequency and cost with data collected from the same unit in 1994, the end of the so called, "Troubles". A ten month retrospective emergency chart analysis from all assault and gunshot wound (GSW) attendances to the Emergency Department, Royal Victoria Hospital Belfast (RVH) in 2012 was carried out. Age, sex, injury type, treatment outcome and associated cost of PA was documented. During the study period we recorded a total of thirty two PAs. Twenty seven were the result of gunshot wounds (GSWs), while five were assaults (punishment beatings). Seventeen required admission for definitive management. Nine cases required orthopaedic intervention, two required plastic surgery, two required maxillofacial input and one case required vascular surgery. All but two of those involved were male. Mean age of individuals admitted was 27.47. Total cost of patients both admitted and managed in the Emergency Department (ED) amounted to £91,362. On comparison with 1994, there are more PA presentations. Due to changing wound characteristics and evolving management overall cost is however less.


Chlorotyrosine exerts renal effects and antagonizes renal and gastric responses to atrial natriuretic peptide.
3-Chloro-L-tyrosine (3CT) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. In vivo inhibition of tyrosine hydroxylase results in lower catecholamine levels. 3CT (0.5 mg/kg), administered as a bolus i.v. to anesthetized uninephrectomized rats, elicited increases of 72% and 44% in urinary sodium concentration and volume, respectively, whereas a dose of 1 mg/kg caused increases of 27% and 29%. 3CT, 1 mg/kg, resulted in a 2-fold increase in plasma aldosterone (ALD); 0.5 mg/kg was without significant effect. At a dose of 1 mg/kg 3CT significantly antagonized the renal effects of atrial natriuretic peptide (ANP) (1.5 micrograms kg-1 min-1 by intrarenal infusion), expressed as an enhanced excretion of urine volume (102 +/- 14 vs. 70 +/- 11 microliters/min) and sodium (16.1 +/- 1.8 vs. 11.5 +/- 1.7 microEq/min) and increased osmolar clearance (171 +/- 12 vs. 144 +/- 13 microliters/min). A dose of 0.5 mg/kg of 3CT did not produce these same responses to ANP. The increased urine flow caused by 3CT may reflect reduced norepinephrine synthesis. The inverse dose-effect relationship of 3CT on urine flow rate may result from concomitant depletion of dopamine (DA) and elevated circulating ALD. The antagonism of 3CT on responses to ANP is not at the receptor level, because 3CT did not compete for [125I] ANP binding or inhibit ANP-stimulated guanylate cyclase in kidney cell membranes. It was proposed that the reduced basal sympathetic and renal DA tone, together with the elevated ALD level, account for this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)


Benchmarking the Performance of the ReaxFF Reactive Force Field on Hydrogen Combustion Systems.
A thorough understanding of the kinetics and dynamics of combusting mixtures is of considerable interest, especially in regimes beyond the reach of current experimental validation. The ReaxFF reactive force field method has provided a way to simulate large-scale systems of hydrogen combustion via a parametrized potential that can simulate bond breaking. This modeling approach has been applied to hydrogen combustion, as well as myriad other reactive chemical systems. In this work, we benchmark the performance of several common parametrizations of this potential against higher-level quantum mechanical (QM) approaches. We demonstrate instances where these parametrizations of the ReaxFF potential fail both quantitatively and qualitatively to describe reactive events relevant for hydrogen combustion systems.


Increased access to medical care: the impact on health.
Many federally financed programs have been launched to improve the access of the poor to medical care, under the assumption that this will improve their health. The effectiveness of these programs, however, has generally been measured by increased utilization rather than by improved health. The few studies which have considered health status have shown small or negative effects. Here, data are presented from a project which provided fully prepaid care to near poor families through existing sources in the community. A group of 748 enrollees was found to report worse health on four of five health indicators after one year of enrollment in the program; further, they appeared sicker on all five measures than a group without free medical care. It is suggested: 1) that the impact of health programs on the health of a population is a complex and poorly understood issue; and 2) that increasing access to health care may not be an effective way to improve health.


Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2.
Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome.


The International Sexual Health And Reproductive Health Survey (I-SHARE-1): A Multi-Country Analysis of Adults from 30 Countries Prior to and During the Initial COVID-19 Wave.
The COVID-19 pandemic forced billions of people to shelter in place, altering social and sexual relationships worldwide. In many settings, COVID-19 threatened already precarious health services. However, there is limited evidence to date about changes to sexual and reproductive health (SRH) during the initial wave of COVID-19 disease. To address this gap, our team organized a multi-country, cross-sectional online survey as part of a global consortium. Consortium research teams conducted online surveys in 30 countries. Sampling methods included convenience, online panels, and population-representative. Primary outcomes included sexual behaviors, partner violence, and SRH service utilization, and we compared three months prior to and three months after policy measures to mitigate COVID-19. We used established indicators and analyses pre-specified in our protocol. We conducted meta-analyses for primary outcomes and graded the certainty of the evidence using Cochrane methods. Descriptive analyses included 22,724 individuals in 25 countries. Five additional countries with sample sizes <200 were included in descriptive meta-analyses. Respondents were mean age 34 years; most identified as women (15160; 66.7%), cis-gender (19432; 86.6%) and heterosexual (16592; 77.9%). Among 4546 respondents with casual partners, condom use stayed the same for 3374 (74.4%) people and 640 (14.1%) people reported a decline. Fewer respondents reported physical or sexual partner violence during COVID-19 measures (1063/15144, 7.0%) compared to the period before COVID-19 measures (1469/15887, 9.3%). COVID-19 measures impeded access to condoms (933/10790, 8.7%), contraceptives (610/8175, 7.5%), and HIV/STI testing (750/1965, 30.7%). Pooled estimates from meta-analysis indicate during COVID-19 measures, 32.3% (95% CI 23.9-42.1) of people needing HIV/STI testing had hindered access, 4.4% (95% CI 3.4-5.4) experienced partner violence, and 5.8% (95% CI 5.4-8.2) decreased casual partner condom use (moderate certainty of evidence for each outcome). Meta-analysis findings were robust in sensitivity analyses that examined country income level, sample size, and sampling strategy. Open science methods are feasible to organize research studies as part of emergency responses. The initial COVID-19 wave impacted SRH behaviors and access to services across diverse global settings.


'Near-miss' or 'near-myth' for sudden infant death syndrome? Clinical observations on 57 infants.
A clinical approach to infants who may have 'nearly missed' Sudden Infant Death Syndrome (SIDS) is suggested as appropriate whether or not the eventual conclusion is that there is no connection between these surviving infants and those who die of SIDS. A non-restrictive investigative approach has been applied to 57 infants with episodes causing similar levels of alarm and recourse to medical aid but not exclusively having documented apnoea or need for cardiopulmonary resuscitation. Similarities among patients in past history, recent minor symptoms, modes of presentation and positive investigations support the concept that they may show a common response to a variety of pathophysiologic stresses. Epidemiological similarities to SIDS cases support the suggestion that SIDS may be the end-stage inadequate response to such stresses. Future studies should address the reasons for 'inappropriate' collapse, its treatment and prevention and be alert to any resultant effect upon the incidence of SIDS or further evidence of a link between the conditions.


[Possibilities of enteral correction of posthemorrhagic disorders depending on the absorption function of the small intestine].
Physiologic and morphologic research on animals in chronic experiment shows that depression of small intestine absorption function takes place during the first hour after hemorrhage of 30-40 ml/kg for 30-50% of animals and after hemorrhage of 50 ml/kg for 100% animals. This excludes except the possibility of efficient post-hemorrhage hypovolemia enteral correction without additional treatment. Enteral correction appears to be sufficient to preserve animal's life, being applied in 30 minutes after the hemorrhage of 30-40 ml/kg or in 90 minutes after the hemorrhage of 20 ml/kg.


Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms.
Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While molecular mechanisms of how CTLs kill their targets are relatively well understood we still lack solid quantitative understanding of the kinetics and efficiency at which CTLs kill their targets in different conditions. Collagen-fibrin gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study the cytotoxicity in vitro. Budhu et al. [1] systematically varied the number of peptide (SIINFEKL)- pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured remaining targets at different times after target and CTL co-inoculation into collagen-fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data we found that this simple "exponential-growth-mass-action-killing" model does not precisely fit the data. However, determining the best fit model proved difficult because the best performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations ( E ≤ 10 7 cell/ml) the model in which tumors grow exponentially and CTLs suppress tumor's growth non-lytically and kill tumors according to the mass-action law (SiGMA model) fitted the data with best quality. Results of power analysis suggested that longer experiments (∼ 3 - 4 days) with 4 measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow to discriminate between alternative models. Taken together, our results suggest that interactions between tumors and CTLs in collagen-fibrin gels are more complex than a simple exponential-growth- mass-action killing model and provide support for the hypothesis that CTLs impact on tumors may go beyond direct cytotoxicity.


Framing the EU as Common Project vs. Common Heritage: Effects on Attitudes Towards the EU Deepening and Widening.
The present study investigated the effects of framing the European Union (EU) as a common project vs. a common heritage on participants' attitude towards EU integration (Experiment 1) and EU enlargement (Experiment 2). An additional aim was exploring whether the different frames affected the strength of identification with the EU, and if the framing effect on attitudes was mediated by participants' identification with the EU and/or by their message evaluation (Experiment 3). Results showed that a common project-based frame was more effective than a common heritage-based frame in promoting positive attitude toward EU integration and enlargement, as well as participants' identification with the EU, which mediated the framing effect on both attitudes; the mediation of participants' message evaluation was not significant. The procedure of the last experiment was replicated on a British sample (Experiment 4), showing a similar pattern of results.


Inter- and intra-specific variation in hair cortisol concentrations of Neotropical bats.
Quantifying hair cortisol has become popular in wildlife ecology for its practical advantages for evaluating stress. Before hair cortisol levels can be reliably interpreted, however, it is key to first understand the intrinsic factors explaining intra- and inter-specific variation. Bats are an ecologically diverse group of mammals that allow studying such variation. Given that many bat species are threatened or have declining populations in parts of their range, minimally invasive tools for monitoring colony health and identifying cryptic stressors are needed to efficiently direct conservation efforts. Here we describe intra- and inter-specific sources of variation in hair cortisol levels in 18 Neotropical bat species from Belize and Mexico. We found that fecundity is an important ecological trait explaining inter-specific variation in bat hair cortisol. Other ecological variables such as colony size, roost durability and basal metabolic rate did not explain hair cortisol variation among species. At the individual level, females exhibited higher hair cortisol levels than males and the effect of body mass varied among species. Overall, our findings help validate and accurately apply hair cortisol as a monitoring tool in free-ranging bats.


Appraising the quality standard underpinning international clinical practice guidelines for the selection and care of vascular access devices: a systematic review of reviews.
Catheter-related bloodstream infections are one of the most important adverse events for patients. Evidence-based practice embraces interventions to prevent and reduce catheter-related bloodstream infections in patients. At present, a growing number of guidelines exist worldwide. The purpose of the study was to assess clinical practice guidelines for peripheral and central venous access device care and prevention of related complications. Systematic review of clinical practice guidelines: We conducted a search of the literature published from 2005 to 2018 using Medline/PubMed, Embase, CINAHL, Ovid, ScienceDirect, Scopus and Web of Science. We also evaluated grey literature sources and websites of organisations that compiled or produced guidelines. Guideline quality was assessed with the Appraisal of Guidelines for Research and Evaluation, Second Edition tool by three independent reviewers. Cohen's kappa coefficient was used to evaluate the concordance between reviewers. We included seven guidelines in the evaluation. The concordance between observers was substantial, K=0.6364 (95% CI 0.0247 to 1.2259). We identified seven international guidelines, which scored poorly on crucial domains such as applicability (medium 39%), stakeholder involvement (medium 65%) and methodological rigour (medium 67%). Guidelines by Spanish Health Ministry and UK National Institute for Health and Care Excellence presented the highest quality. It is crucial to critically evaluate the validity and reliability of clinical practice guidelines so the best, most context-specific document is selected. Such choice is a necessary prior step to encourage and support health organisations to transfer research results to clinical practice. The gaps identified in our study may explain the suboptimal clinical impact of guidelines. Such low adoption may be mitigated with the use of implementation guides accompanying clinical documents.


Ixodes ricinus and Its Endosymbiont Midichloria mitochondrii: A Comparative Proteomic Analysis of Salivary Glands and Ovaries.
Hard ticks are hematophagous arthropods that act as vectors of numerous pathogenic microorganisms of high relevance in human and veterinary medicine. Ixodes ricinus is one of the most important tick species in Europe, due to its role of vector of pathogenic bacteria such as Borrelia burgdorferi and Anaplasma phagocytophilum, of viruses such as tick borne encephalitis virus and of protozoans as Babesia spp. In addition to these pathogens, I. ricinus harbors a symbiotic bacterium, Midichloria mitochondrii. This is the dominant bacteria associated to I. ricinus, but its biological role is not yet understood. Most M. mitochondrii symbionts are localized in the tick ovaries, and they are transmitted to the progeny. M. mitochondrii bacteria have however also been detected in the salivary glands and saliva of I. ricinus, as well as in the blood of vertebrate hosts of the tick, prompting the hypothesis of an infectious role of this bacterium. To investigate, from a proteomic point of view, the tick I. ricinus and its symbiont, we generated the protein profile of the ovary tissue (OT) and of salivary glands (SG) of adult females of this tick species. To compare the OT and SG profiles, 2-DE profiling followed by LC-MS/MS protein identification were performed. We detected 21 spots showing significant differences in the relative abundance between the OT and SG, ten of which showed 4- to 18-fold increase/decrease in density. This work allowed to establish a method to characterize the proteome of I. ricinus, and to detect multiple proteins that exhibit a differential expression profile in OT and SG. Additionally, we were able to use an immunoproteomic approach to detect a protein from the symbiont. Finally, the method here developed will pave the way for future studies on the proteomics of I. ricinus, with the goals of better understanding the biology of this vector and of its symbiont M. mitochondrii.


Differences between medical school and PGY1 learning outcomes: An explanation for new graduates not being "work ready"?
Background: Widespread concerns about new medical graduates' 'work readiness' may reflect, in part, differences in mandatory learning outcomes for medical students and new medical graduates.Purpose: To examine differences between required medical student and PGY1 (first year resident) training program outcomes, and the nature and magnitude of these differences.Method: Comparison, systematic identification and thematic analysis of differences between the graduate outcomes in the Australian Medical Council Standards for the Assessment and Accreditation of Primary Medical Programs and those in the New Zealand Curriculum Framework for Prevocational Training.Results: The relationship between these outcome statements were categorized as: essentially similar; continuity; partial discontinuity; and complete discontinuity of learning trajectory. Areas requiring substantial new learning may reflect medical schools' focus on individual student performance, and on learning and assessments based on single episodes of often uncomplicated illness. This contrasted with a post-graduate focus on integrated health care delivery by teams and management of complex illnesses over the whole patient care journey.Conclusions: Characterizing these marked differences between pre-graduate and postgraduate standards, within a trajectory of learning, explains some of the difficulties in students' preparation for work readiness. These could inform learning interventions to support new graduates' professional development to ensure patient safety. Development and revision of accreditation standards should include formal review against the expectations of the preceding and succeeding phases of learning.


Effects of race and ethnicity on the incidence of venous thromboembolism.
Although there is strong evidence that the prevalence of venous thrombo-embolism (VTE) varies significantly among different ethnic/racial groups, the genetic, physiologic and/or clinical basis for these differences remain largely undefined. African-American patients have a significantly higher rate of incident VTE, particularly following exposure to a provoking risk factor such as surgery, medical illness, trauma, etc. In addition, African-Americans are more likely to be diagnosed with pulmonary embolism (PE) than deep-vein thrombosis (DVT) compared to Caucasian and other racial groups. On the other extreme, Asians/Pacific Islanders have a 70% lower prevalence of VTE and this is true for both idiopathic VTE and provoked, or 'secondary', VTE. Hispanics have a significantly lower prevalence of VTE compared to Caucasians, but higher than Asians/Pacific Islanders. The incidence of recurrent VTE varies depending on gender, type of thromboembolic event and race. Further research is needed in order to determine the fundamental differences between racial/ethnic groups that explain the observed differences in the prevalence of VTE. Race/ethnicity should be considered an important factor in the risk-stratification of patients with suspected VTE or patients at some risk for developing VTE.


Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression.
Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing "helpless" behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing "resilient" behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.


The G23 and G25 genes of temperate mycobacteriophage L1 are essential for the transcription of its late genes.
Two lysis-defective but DNA synthesis non-defective temperature-sensitive (ts) mutants of mycobacteriophage L1, L1G23ts23 and L1G25ts889 were found to be defective also in phage-specific RNA synthesis in the late period of their growth at 42 degrees C, each to the extent of 50% of that at 32 degrees C. The double mutant, L1G23ts23G25ts889 showed the ts defect in phage RNA synthesis that was nearly additive of those shown individually by the two single-mutant parents. Both G23 and G25 were shown to start functioning sometimes between 30 and 45 min after infection but the former gene might be dispensable after 45 min, while the latter was not. Northern analysis also shows that at 42 degrees C, L1G23ts23 affects RNA synthesis more strongly than L1G25ts889 from L1 DNA segments that serve as the template for late gene transcription. Among the 21 virion and 12 non-virion late proteins synthesized by L1, L1G23ts23 is defective in the synthesis of at least 9 virion and all of non-virion proteins at 42 degrees C. In contrast, L1G25ts889 is completely defective in synthesis of all the 33 late proteins. Possible roles of G23 and G25 in the positive regulation of transcription of different sets of late genes of L1 have been discussed.


[Primary pericardial mesothelioma: a clinicopathological analysis of 7 cases].
Primary pericardial mesotheliona is a clinical rarity. 7 cases were reported in this paper. There were no typical clinical symptoms and signs. It could not be diagnosed simply with chest film, ECG or echocardiagram and was usually misdiagnosed as constritive pericarditis, tuberculous pericarditis etc. In order to make correct diagnosis, some investigative diagnose methods such as pathological examination of pericardial fluid and pericardial biopsy, Gallium-67 scintigraphy, Ber-EP4 antibody and immunohistochemical procedures should be employed.


[Occupational exposure of the anesthesiologist to nitrous oxide and halothane. Control measures].
Anesthetic gas spillage does occur in the operating room. Anesthesiologists and other operating room personnel are likely exposed to health hazards caused by chronic exposure to anesthetic gases and vapours. The aim of the present study is to elucidate the possible relationship between the chronic exposure to anesthetic gases and their adverse effects on the health. Present data, while controversial, do not establish a cause-effect relationship. Nevertheless, until solid data refutes the existence of a health hazard for operating room personnel, the anesthesiologist must try to reduce the anesthetic contamination level, with preventive and technical measures.


Gap junctions in Turing-type periodic feather pattern formation.
Periodic patterning requires coordinated cell-cell interactions at the tissue level. Turing showed, using mathematical modeling, how spatial patterns could arise from the reactions of a diffusive activator-inhibitor pair in an initially homogenous two-dimensional field. Most activators and inhibitors studied in biological systems are proteins, and the roles of cell-cell interaction, ions, bioelectricity, etc. are only now being identified. Gap junctions (GJs) mediate direct exchanges of ions or small molecules between cells, enabling rapid long-distance communications in a cell collective. They are therefore good candidates for propagating non-protein-based patterning signals that may act according to the Turing principles. Here, we explore the possible roles of GJs in Turing-type patterning using feather pattern formation as a model. We found seven of the twelve investigated GJ isoforms are highly dynamically expressed in the developing chicken skin. In ovo functional perturbations of the GJ isoform, connexin 30, by siRNA and the dominant-negative mutant applied before placode development led to disrupted primary feather bud formation, including patches of smooth skin and buds of irregular sizes. Later, after the primary feather arrays were laid out, inhibition of gap junctional intercellular communication in the ex vivo skin explant culture allowed the emergence of new feather buds in temporal waves at specific spatial locations relative to the existing primary buds. The results suggest that gap junctional communication may facilitate the propagation of long-distance inhibitory signals. Thus, the removal of GJ activity would enable the emergence of new feather buds if the local environment is competent and the threshold to form buds is reached. We propose Turing-based computational simulations that can predict the appearance of these ectopic bud waves. Our models demonstrate how a Turing activator-inhibitor system can continue to generate patterns in the competent morphogenetic field when the level of intercellular communication at the tissue scale is modulated.


Coordination of RNA Processing Regulation by Signal Transduction Pathways.
Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.


Combined Liver, Pancreas-Duodenum, and Kidney Transplantation for Patients with Hepatitis B Cirrhosis, Uremia, and Insulin-Dependent Diabetes.
BACKGROUND Abdominal organ cluster transplantation for the treatment of upper abdominal end-stage diseases is a serious conundrum for surgeons. CASE REPORT We performed clinical assessment of quadruple organ transplantation (liver, pancreas, duodenum, and kidney) for a patient with end-stage liver disease, post-chronic hepatitis B cirrhosis, uremia, and insulin-dependent diabetes mellitus, and explored the optimal surgical procedure. Simultaneous classic orthotopic liver, pancreas-duodenum, and heterotopic renal transplantation was performed on a 46-year-old man. The process was an improvement of surgery implemented with a single vascular anastomosis (Y graft of the superior mesenteric artery and the celiac artery open together in the common iliac artery). The pancreatic secretions and bile were drained through a modified uncut jejunal loop anastomosis, and the donor's kidneys were placed in the right iliac fossa. The patient was prescribed basiliximab, glucocorticoid, tacrolimus, and mycophenolate mofetil for immunosuppression. The hepatic function recovered satisfactorily on postoperative day (POD) 3, and pancreatic function recovered satisfactorily in postoperative month (POM) 1. Hydronephrosis occurred in the transplanted kidney, with elevated creatinine on POD 15. Consequently, renal pelvic puncture and drainage were performed. His creatinine dropped to a normal level on POD 42. No allograft rejections or other complications, like pancreatic leakage, thrombosis, or localized infections, occurred. The patient had normal liver, renal, and pancreas functions with insulin-independent after POD 365. CONCLUSIONS Simultaneous classic orthotopic liver, pancreas-duodenum, and heterotopic renal transplantation is a promising therapeutic option for patients with insulin-dependent diabetes combined with end-stage hepatic and renal disease, and our center's experience can provide a reference for clinical multiorgan transplantation.


[Tumor hyperacidulation through glucose infusion enhanced by nicotinamide adenine dinucleotide (author's transl)].
Tumor peracidity in Walker carcinosarcoma 256-bearing Wistar rats attained by glucose (Gk) infusion was significantly (t-Test; p = 3.49) increased by a following infusion of 200 mg NAD in 7 ml 40 per cent. Gk-solution. The mean pH values obtained on six animals amounted 6.88 (start), 5.21 (after Gk) and 5.79 (after Gk + NAD). Three animals were cured through the hyperacidification process.


Room for Improvement in Nutrition Knowledge and Dietary Intake of Male Football (Soccer) Players in Australia.
Athletes require sufficient nutrition knowledge and skills to enable appropriate selection and consumption of food and fluids to meet their health, body composition, and performance needs. This article reports the nutrition knowledge and dietary habits of male football (soccer) players in Australia. Players age 18 years and older were recruited from 1 A-League club (professional) and 4 National Premier League clubs (semiprofessional). No significant difference in general nutrition knowledge (GNK; 54.1% ± 13.4%; 56.8% ± 11.7%; M ± SD), t(71) = -0.91, p = .37, or sports nutrition knowledge (SNK; 56.9% ± 15.5%; 61.3% ± 15.9%), t(71) = -1.16, p = .25) were noted between professional (n = 29) and semiprofessional (n = 44) players. In general, players lacked knowledge in regard to food sources and types of fat. Although nutrition knowledge varied widely among players (24.6-82.8% correct responses), those who had recently studied nutrition answered significantly more items correctly than those who reported no recent formal nutrition education (62.6% ± 11.9%; 54.0% ± 11.4%), t(67) = 2.88, p = .005). Analysis of 3-day estimated food diaries revealed both professionals (n = 10) and semiprofessionals (n = 31) consumed on average less carbohydrate (3.5 ± 0.8 gC/kg; 3.9 ± 1.8 gC/kg) per day than football-specific recommendations (FIFA Medical and Assessment Research Centre [F-MARC]: 5-10 gC/kg). There was a moderate, positive correlation between SNK and carbohydrate intake (n = 41, ρ = 0.32, p = .04), indicating that players who exhibited greater SNK had higher carbohydrate intakes. On the basis of these findings, male football players in Australia would benefit from nutrition education targeting carbohydrate and fat in an attempt to improve nutrition knowledge and dietary practices.


Cost-effectiveness of MicroRNA for Pancreatic Cancer Screening in Patients With Diabetes.
The study aimed to assess the cost-effectiveness of microRNA compared with carbohydrate antigen 19-9, abdominal ultrasound, magnetic resonance imaging, endoscopic ultrasound, computed tomography, positron emission tomography, and no screening for pancreatic cancer (PC) screening in patients with diabetes. We developed a state-transition model from a health care payer perspective and a lifetime horizon. We targeted 3 hypothetical cohorts of patients with long-standing type 2 diabetes (LSD), new-onset diabetes (NOD), and LSD having intraductal papillary mucinous neoplasm (IPMN), aged 40, 50, 60, and 70 years. The main outcomes were costs, quality-adjusted life-years, life expectancy life-years, incremental cost-effectiveness ratios, and deaths from PC. In the base-case analysis, abdominal ultrasound in patients with LSD and microRNA in patients with NOD and LSD having IPMN were the most cost-effective for all age groups. Cost-effectiveness was sensitive to PC incidence and the cost of microRNA. Probabilistic sensitivity analysis showed that microRNA was 42% to 54% cost-effective for NOD and 76% to 78% cost-effective for LSD having IPMN at a willingness-to-pay level of US $100,000 per quality-adjusted life-year gained. MicroRNA prevented 30,641 PC deaths in diabetic patients compared with no screening. In patients with NOD and LSD having IPMN, microRNA-based PC screening is cost-effective and recommended for early PC detection.


Steroid treatment promotes an M2 anti-inflammatory macrophage phenotype in childhood lupus nephritis.
M1-type proinflammatory macrophages (MΦ) promote glomerular injury in lupus nephritis (LN). However, whether this phenotype is altered by steroid therapy is unclear. Therefore, we investigated the effect of steroid treatment on MΦ phenotype in LN. Patients with LN (7-18 years old) were divided into 2 groups: those with no treatment (N) before biopsy (n = 17) and those who underwent steroid (S) treatment (3-73 days) before biopsy (n = 15). MΦ number and phenotype were assessed by immunofluorescence. In vitro studies used monocyte-derived MΦ from healthy volunteers. Age at biopsy, urine findings, and kidney function (eGFR) were comparable between the two groups. Biopsies in N group had higher levels of active lesions such as endocapillary hypercellularity, necrosis, and cellular crescent formation (p < 0.05). The total CD68+ MΦ infiltrate was comparable between N and S groups. However, N group had more M1 MΦ (CD68+ CD86+ cells) (p < 0.05) and fewer M2 MΦ (CD68+ CD163+ cells) (p < 0.05), giving a 6-fold increase in the M2/M1 ratio in S vs. N groups. Dexamethasone treatment of cultured MΦ induced upregulation of CD163 expression, increased production of anti-inflammatory (IL-10, IL-19) and profibrotic factors (FGF-22, PDGF), and upregulated the scavenger receptor, stabilin-1. Upregulation of stabilin-1 in CD163+ M2 MΦ was confirmed in biopsies from S group. Initial steroid treatment induces MΦ phenotypic change from proinflammatory M1 to anti-inflammatory or profibrotic M2 in LN with acute/active lesions. Although steroid treatment is effective for resolution of M1-medated injury, promotion of fibrotic lesions via M2 MΦ is a potential downside of steroid single therapy in LN.


Incidence and Impact of Thrombocytopenia in Patients Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents.
Platelets are crucial in the pathophysiology of coronary artery disease and are a major target of antithrombotic agents in patients receiving percutaneous coronary intervention (PCI). We sought to evaluate the incidence and prognostic impact of thrombocytopenia on clinical outcomes in patients undergoing PCI with drug-eluting stents (DES). We evaluated consecutive patients who received PCI with DES in the IRIS-DES registry between April 2008 and December 2017. Patients were divided into 2 groups based on the presence of thrombocytopenia (platelet count <150 × 109/L) at baseline. The primary outcome was all-cause mortality, and secondary outcomes included the composite outcome of death, myocardial infarction (MI), and stroke, and major bleeding. Complete follow-up data were available for 1 to 5 years (median, 3.1). Among 26,553 eligible patients, 1,823 (6.9%) had thrombocytopenia at baseline. At 5 years, the incidences of all-cause mortality (15.6% vs 8.1%, p <0.001), composite outcome (23.2% vs 15.6%, p <0.001), and major bleeding (3.7% vs 2.2%, p <0.001) were significantly higher in patients with thrombocytopenia than in those without thrombocytopenia. In multivariable Cox proportional-hazards models, thrombocytopenia was significantly associated with increased risks of all-cause mortality (hazard ratio 1.26, 95% confidence interval 1.07 to 1.48, p = 0.01) and major bleeding (hazard ratio 1.41, 95% confidence interval 1.04 to 1.91, P=0.03). In conclusion, among who patients underwent PCI with DES, the incidence of thrombocytopenia was 6.9%. Baseline thrombocytopenia was significantly associated with increased risks of mortality and major bleeding.


Avian embryonic brain reaggregate culture system. I. Characterization for organophosphorus compound toxicity studies.
An avian reaggregate culture system was characterized biochemically and morphologically for use in acute and chronic organophosphorus compound (OP) toxicity studies. Ten-day-old chick embryo brains were dissociated, reaggregated, and maintained in a chemically defined, serum- and antibiotic-free media. Acetylcholinesterase (ACHE), neuropathy target esterase (NTE), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) were examined due to inhibition of these enzymes as a result of acute OP toxicity (ACHE) or delayed toxicity (NTE, CNP). The selected enzymes also indicate reaggregate neuronal (ACHE, possibly NTE), oligodendroglial (CNP), and astrocytic (glutamine synthetase (GS)) activities. Enzyme activities were compared to those in age-matched chick embryo and hatched chick brains. Reaggregate ACHE specific activity was similar to or higher than that of chick embryo or hatched chick. Reaggregate NTE specific activity was initially similar to that of 10-day-old chick embryo, and then increased but subsequently averaged 7.8 nmol/min/mg protein. In chick brain, NTE peaked at hatching and averaged 28 nmol/min/mg protein thereafter. Reaggregate CNP specific activity ranged from 103 to 426 nmol/min/mg protein, whereas activity gradually increased in chick embryo brain to an average of 140 nmol/min/mg protein posthatching. The mean GS activity ranged from 0.15 (Culture Day 4) to 1.09 nmol/min/mg protein (Culture Day 62). Mean protein values per flask ranged from 2.47 to 7.58 mg. Ultrastructurally, myelination was detected at Culture Day 7 and synapses at Day 6. The biochemical and ultrastructural features demonstrate that this reaggregate culture is a practical and sensitive in vitro system for studying both the acute and the long-term neurotoxicological effects of organophosphorus compounds.


[Terrorism, public health and health services].
Today the terrorism is a problem of global distribution and increasing interest for the international public health. The terrorism related violence affects the public health and the health care services in an important way and in different scopes, among them, increase mortality, morbidity and disability, generates a context of fear and anxiety that makes the psychopathological diseases very frequent, seriously alters the operation of the health care services and produces important social, political and economic damages. These effects are, in addition, especially intense when the phenomenon takes place on a chronic way in a community. The objective of this paper is to examine the relation between terrorism and public health, focusing on its effects on public health and the health care services, as well as to examine the possible frames to face the terrorism as a public health concern, with special reference to the situation in Spain. To face this problem, both the public health systems and the health care services, would have to especially adapt their approaches and operational methods in six high-priority areas related to: (1) the coordination between the different health and non health emergency response agencies; (2) the reinforcement of the epidemiological surveillance systems; (3) the improvement of the capacities of the public health laboratories and response emergency care systems to specific types of terrorism as the chemical or biological terrorism; (3) the mental health services; (4) the planning and coordination of the emergency response of the health services; (5) the relations with the population and mass media and, finally; (6) a greater transparency in the diffusion of the information and a greater degree of analysis of the carried out health actions in the scope of the emergency response.


Expression patterns of developmental regulatory genes show comparable divisions in the telencephalon of Xenopus and mouse: insights into the evolution of the forebrain.
In this study, we review data on the existence of comparable divisions and subdivisions in the telencephalon of different groups of tetrapods based on expression of some developmental regulatory genes, having a particular focus in the comparison of the anuran amphibian Xenopus and the mouse. The available data on Xenopus, mouse, chick and turtle indicate that apparently all tetrapod groups possess the same molecularly distinct divisions and subdivisions in the telencephalon. This basic organization was likely present in the telencephalon of stem tetrapods. Each division/subdivision is characterized by expression of a unique combination of developmental regulatory genes, and appears to represent a self-regulated and topologically constant histogenetic brain compartment that gives rise to specific groups of cells. This interpretation has an important consequence for searching homologies, since a basic condition for cell groups in different vertebrates to be considered homologous is that they originate in the same compartment. However, evolution may allow individual cell groups derived from comparable (field homologous) subdivisions to be either similar or dissimilar across the vertebrate groups, giving rise to several possible scenarios of evolution, which include both the evolutionary conservation of similar (homologous) cells or the production of novel cell groups. Finally, available data in the lamprey, a jawless fish, suggest that not all telencephalic subdivisions were present at the origin of vertebrates, raising important questions about their evolution.


Development and psychometric evaluation of the FACE-Q satisfaction with appearance scale: a new patient-reported outcome instrument for facial aesthetics patients.
Satisfaction with appearance and improved quality of life are key outcomes for patients undergoing facial aesthetic procedures. The FACE-Q is a new patient-reported outcome (PRO) instrument encompassing a suite of independently functioning scales designed to measure a range of important outcomes for facial aesthetics patients. FACE-Q scales were developed with strict adherence to international guidelines for PRO instrument development. This article describes the development and psychometric evaluation of the core FACE-Q scale, the Satisfaction with Facial Appearance scale. Both modern and traditional psychometric methods were used to confirm that this new 10-item scale is a reliable, valid, and responsive measure.


Methamphetamine-induced behavioral and physiological effects in adolescent and adult HIV-1 transgenic rats.
We recently reported that six consecutive days of treatment with a moderate dose of methamphetamine (METH) induced greater behavioral sensitization in adult HIV-1 transgenic (HIV-1 Tg) rats than in adult Fischer 344/NHsd (F344) non-transgenic, wild-type control animals. In the present study, we evaluated the effects of a moderate dose of METH on the brains of adolescent versus adult HIV-1 Tg male rats using both behavioral (METH-induced, stereotypic head movement) and physiological (rectal body temperature) parameters. We found that both the acute and behavior-sensitizing effects of METH were greater in HIV-1 Tg rats compared with controls and also in adolescent rats compared with adult animals, regardless of HIV-1 status. We determined that acute hyperthermic effects of METH as well as tolerance to METH-induced hyperthermia were greater in HIV-1 Tg rats than in controls. Taken together, these results suggest that both the neuroadaptations seen in HIV infection and the immaturity of the adolescent brain are associated with increased sensitivity to the psychoactive and behavior-sensitizing properties of METH. Thus, HIV-infected individuals and adolescents may be more vulnerable to the development of METH abuse and dependence than non-infected individuals and adults.


Learners favour high resolution oesophageal manometry with better diagnostic accuracy over conventional line tracings.
High resolution manometry (HRM) provides a colourful representation of oesophageal motility. Novice and intermediate learners were tested to compare HRM Clouse plots and conventional manometry for accuracy, ease of interpretation and knowledge retention. 36 learners evaluated 60 randomised motility sequences (30 HRM Clouse plots with corresponding line tracings) 4 months apart, following a tutorial. Learners rated prior knowledge of oesophageal pathophysiology and manometry and scored ease and speed of interpretation on 10 cm visual analogue scales (VAS). Understanding of oesophageal pathophysiology was low in all cohorts (2.9±0.4 on VAS) and knowledge of HRM and conventional motility studies was even lower (1.9±0.4 and 1.8±0.3, respectively, p=NS). After the tutorial, diagnostic accuracy was significantly higher with HRM Clouse plots than with line tracings (p<0.001). HRM gains in diagnostic accuracy were evident over line tracings (43.1%), particularly with aperistalsis (36.1%), oesophageal body hypomotility (25.8%) and relaxation of the lower oesophageal sphincter (21.0%) (p<0.001 for each comparison); these were maintained at the second evaluation. Gains were independent of academic level (F=0.56, p=0.5) and did not correlate with prior experience of learners (r=-0.18, p=0.29). Learners favoured HRM Clouse plots (80.6%) over line tracings and reported faster interpretation (94.4%). HRM Clouse plots provide ease of interpretation that translates into higher diagnostic accuracy and better knowledge retention in novice and intermediate learners of oesophageal manometry. These results implicate the value of pattern recognition in HRM interpretation, irrespective of academic level and prior understanding of oesophageal motor function.