[Cooperative Surgery with Gastroenterological Surgeons in Gynecologic Malignant Tumors].
Secondary debulking surgery(SDF)for gynecologic malignancies may improve prognosis. However, recurrent lesions may be invasions of the intestinal tract and observed peritoneal dissemination. SDF can be safely carried out by performing cooperative surgery with a gastroenterological surgeon and gynecologists. Precise cooperation is indispensable for the operation, especially when it comes to aspects such as the contact method and perioperative management at that time. In our hospital, if the gynecologist suspects other organs invasion during a preoperative examination, they contact the gastroenterological surgeon in an elective manner. If other organs invasion is not clear during a preoperative examination or bowel injury occurs during surgery, the gastroenterological surgeon would be contacted urgently. To ensure smooth cooperation, it is necessary to run regular joint conferences. By sharing in planned and combining the expertise of all the department of interest, it is possible to perform highly curative and safe surgery.


Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons.
Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C ε (PKCε) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCε, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells.


Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus.
Activating transcription factor 5 (ATF5) is a basic-leucine-zipper transcription factor of the ATF/CREB family. The Atf5 gene generates two transcripts, Atf5α and Atf5β, of which Atf5α is known to be selectively translated upon endoplasmic reticulum stress response in non-neuronal cells. ATF5 is highly expressed in the developing brain where it modulates proliferation of neural progenitor cells. These cells show a high level of ATF5 that has to decrease to allow them to differentiate into mature neurons or glial cells. This has led to the extended notion that differentiated neural cells do not express ATF5 unless they undergo tumourigenic transformation. However, no systematic analysis of the distribution of ATF5 in adult brain or of its potential role in neuronal endoplasmic reticulum stress response has been reported. By immunostaining here we confirm highest ATF5 levels in neuroprogenitor cells of the embryonic and adult subventricular zone but also found ATF5 in a large variety of neurons in adult mouse brain. By combining Atf5 in situ hybridization and immunohistochemistry for the neuronal marker NeuN we further confirmed Atf5 messenger RNA in adult mouse neurons. Quantitative reverse transcriptase polymerase chain reaction demonstrated that Atf5α is the most abundant transcript in adult mouse encephalon and injection of the endoplasmic reticulum stress inducer tunicamycin into adult mouse brain increased neuronal ATF5 levels. Accordingly, ATF5 levels increased in hippocampal neurons of a mouse model of status epilepticus triggered by intra-amygdala injection of kainic acid, which leads to abnormal hippocampal neuronal activity and endoplasmic reticulum stress. Interestingly, ATF5 upregulation occurred mainly in hippocampal neuronal fields that do not undergo apoptosis in this status epilepticus model such as CA1 and dentate gyrus, thus suggesting a neuroprotective role. This was confirmed in a primary neuronal culture model in which ATF5 overexpression resulted in decreased endoplasmic reticulum stress-induced apoptosis and the opposite result was achieved by Atf5 RNA interference. Furthermore, in vivo administration of the eIF2α phosphatase inhibitor salubrinal resulted in increased ATF5 hippocampal levels and attenuated status epilepticus-induced neuronal death in the vulnerable CA3 subfield. In good agreement with the neuroprotective effect of increased ATF5, we found that apoptosis-resistant epileptogenic foci from patients with temporal lobe epilepsy also showed increased levels of ATF5. Thus, our results demonstrate that adult neurons express ATF5 and that they increase its levels upon endoplasmic reticulum stress as a pro-survival mechanism, thus opening a new field for neuroprotective strategies focused on ATF5 modulation.


Expanding Developmental and Behavioral Health Capacity in Pediatric Primary Care.
The Development and Behavior Access Clinic (DBAC) deploys a general pediatrician with brief/intensive training and proctoring by developmental-behavioral pediatricians (DBP) to provide developmental-behavioral (DB) care to children referred with mild/moderate complexity needs as determined by a team of clinical psychologists. This pilot study utilizes visit data, chart review, and surveys to assess wait times, need for subspecialty care, and referring clinician satisfaction. In its first 18 months, DBAC decreased the need for subspecialty DB care, providing initial services for 44% of patients referred for DB pediatric care from the study site; 89% did not require subsequent subspecialty evaluation. Among DBAC participants, average wait times for DB care decreased from a baseline of 218 to 41 calendar days. This pilot study provides a model for building DB clinical skills among interested general pediatricians, decreasing wait times, and building the capacity of primary care settings to address mild-to-moderate complexity DB concerns.


Asymmetric photon transport in organic semiconductor nanowires through electrically controlled exciton diffusion.
The ability to steer the flow of light toward desired propagation directions is critically important for the realization of key functionalities in optical communication and information processing. Although various schemes have been proposed for this purpose, the lack of capability to incorporate an external electric field to effectively tune the light propagation has severely limited the on-chip integration of photonics and electronics. Because of the noninteractive nature of photons, it is only possible to electrically control the flow of light by modifying the refractive index of materials through the electro-optic effect. However, the weak optical effects need to be strongly amplified for practical applications in high-density photonic integrations. We show a new strategy that takes advantage of the strong exciton-photon coupling in active waveguides to effectively manipulate photon transport by controlling the interaction between excitons and the external electric field. Single-crystal organic semiconductor nanowires were used to generate highly stable Frenkel exciton polaritons with strong binding and diffusion abilities. By making use of directional exciton diffusion in an external electric field, we have realized an electrically driven asymmetric photon transport and thus directional light propagation in a single nanowire. With this new concept, we constructed a dual-output single wire-based device to build an electrically controlled single-pole double-throw optical switch with fast temporal response and high switching frequency. Our findings may lead to the innovation of concepts and device architectures for optical information processing.


[Effect of pepsin on low density serum lipoproteins].
Native lipoproteins of low density from human blood serum were intensively hydrolyzed by pepsin in 0.1 M solution of beta-alanine-HCl at pH 1.9. About 50% and 90% of all the protein part of the substances were split off within 60 min and 22 hrs, respectively. Analytical ultracentrifugation showed that the proteolysis occurred in several steps with formation of discrete intermediates (sedimentation coefficients 2.9 S and 2.3 S at solution density 1,012 g/ml).


[Does scientific-technological progress endanger human dignity?].
1) The goal of modern science, to which also today's medicine is obliged, is the unlimited advance of knowledge and ability. It objectifies, neutralises and levels all of its objects to parameters which can be analysed, calculated, manipulated and performed; it abstracts from all personal mentality, experience and achievements in our surroundings and from all goals and personal daily appraisals of ourselves and the world around us. 2) The goal of scientific knowledge, its progress and its translation into technology is in today s understanding the abolition of distress, disease and suffering as well as the increase of ways and means to make human existence more endurable, comfortable, richer in experience and longer. As such a functionally defined good, science is bound to the laws and dynamics of the (national and global) market. 3) The term 'human dignity' as it is used in article 1 of the German constitution is based on the idea of self-purpose, respectively self-worth, which a human has a right to for his own sake, irrespective of other goods or purposes. This term finds its binding interpretation in the system of basic rights (R. Zippelius). Here, an elemental legal right of the individual is addressed, which cannot be put to disposition for any benefit or damage to the state or the society, one last taboo which protects every individual 'without consideration of the person' from interference and complete instrumentation by others. 4) Man as an object of modern, scientific research is 'objectified' like any other object. The drive to knowledge is limitless. The general and scientific relations between the progress of knowledge and ability and the goods and market values mentioned above offer no protection of man as a person from complete objectification and instrumentation. In the context of a society-dominated naturalistic concept of man, in which man is considered no more than a complex system of needs and interests, human dignity does in fact seem to be endangered. Some see a prime example of the conflict on the limits of man s self-instrumentation in the current discussion on the ethical limitations of stem cell research.


Lifestyle correlates of self-reported sleep duration among Saudi adolescents: a multicentre school-based cross-sectional study.
Lifestyle factors are important determinants of adequate sleep among adolescents. However, findings on sleep duration relative to lifestyle factors are conflicting. Therefore, this study examined the association of self-reported sleep duration with physical activity, sedentary behaviours and dietary habits among Saudi adolescents. A multicentre school-based cross-sectional study was conducted in three major cities in Saudi Arabia. The sample included 2868 secondary-school students (51.9% girls) aged 15-19 years, randomly selected using a multistage stratified cluster sampling technique. In addition to anthropometric measurements, sleep duration, physical activity, sedentary behaviours and dietary habits were assessed using self-reported questionnaire. Several lifestyle factors were associated with sleep duration in adolescents. While controlling for some potential confounders, the findings showed that high screen time [>5 h/day; adjusted odds ratio (aOR) = 1.505, 95% confidence interval (CI) = 1.180-1.920, P = 0.001] and low (aOR = 1.290, 95% CI = 1.064-1.566, P = 0.010) to medium (aOR = 1.316, 95% CI = 1.075-1.611, P = 0.008) physical activity levels were significantly related to daily sleep of 8 h or longer. Furthermore, having low intake of breakfast (<3 day/week compared with 5 days or more per week) decreased the odd of having adequate sleep duration by a factor of 0.795 (95% CI = 0.667-0.947, P < 0.010). Short sleep duration (<8 h/day) among Saudi adolescents 15-19 year olds was significantly associated with several lifestyle factors. Intervention programs aiming for improving sleeping habits among adolescents need to consider such potential association of lifestyle variables with sleep duration.


Proportional hazards modeling of saccadic response times during reading.
In this article we use proportional hazards models to examine how low-level processes affect the probability of making a saccade over time, through the period of fixation, during reading. We apply the Cox proportional hazards model to investigate how launch distance (relative to word beginning), fixation location (relative to word center), and word frequency affect the hazard of a saccadic response. This model requires that covariates have a constant impact on the hazard over time, the assumption of proportional hazards. We show that this assumption is not supported. The impact of the covariates changes with the time passed since fixation onset. To account for the non-proportional hazards we fit step functions of time, resulting in a model with time-varying effects on the hazard. We evaluate the ability to predict the timing of saccades on held-out fixation data. The model with time-varying effects performs better in predicting the timing of saccades for fixations as short as 100 ms and as long as 500 ms, when compared both to a baseline model without covariates and a model which assumes constant covariate effects. This result suggests that the time-varying effects model better recovers the time course of low-level processes that influence the decision to move the eyes.


Structural differences between the ectodomains of murine and human CD98hc.
The CD98 heavy chain (CD98hc) constitutes both a promising cell surface target for the treatment of cancers and a transcytosis receptor potentially useful for the brain delivery of therapeutics. However, pharmacokinetic studies and safety assessment of cognate antibodies or nonimmunoglobulin binding proteins in rodents is hampered by cross-species variability of both amino acid sequence and glycosylation pattern. Here, we report the crystal structure of the murine CD98hc extracellular domain and a comprehensive comparison with its human ortholog, revealing only one conserved surface patch that is neither shielded by glycosylation nor by the cell membrane with an accessible surface area typical for an antibody epitope. Our results imply the necessity of a surrogate approach for CD98hc-specific binding proteins with predictive power for clinical investigations.


How to manage falls in hospitalized patients: A single center experience in allogeneic stem cell transplantation setting.
In allogeneic hematopoietic stem cell transplantation (AHSCT), falls can lead to immediate and late consequences and in some cases to death. We analyzed risks and causes of falls with root cause analysis (RCA) based on which improvement interventions were implemented.A retrospective observational study was conducted to analyze with RCA data of incidence reports and medical records of patients admitted; an expert panel identified actions to prevent falls, which were collected in a checklist.Between December 2017 and November 2019, 214 patients were admitted to ordinary hospital stays for AHSCT or AHSCTrelated complications. In this period, 15 falls, involving 11 patients, occurred resulting in a 2.32 d/patient incidence. In 66.67% of cases minor head trauma occurred. Diuretic drugs (93.33%), induced hyper-diuresis in nonbladder catheter patients (93.33%) and antihypertensive drugs (93.33%) were reported as most common cause in our incident reports. The most frequent fall time slot was between 10 PM and 7 AM (60%). We determined with RCA diuretics and consequent induced hyper-diuresis (80%), self-insufficiency (40%), antihypertensive (33.3%) and noncompliance (33.3%) as the most common cause of falls. Finally, 16 actions, collected in a "safe comfort" checklist, were identified to prevent falls.Diuretic drugs inducing hyper-diuresis, self-insufficiency, poor patient compliance, orthostatic hypotension, fever, night-time and obstacles within inpatient units are the most common contributing factors. Therefore, administration of diuretic and antihypertensive drugs should be rescheduled and a multidimensional risk assessment scale integrated with a preventive action plan, such as the safe comfort checklist, should be implemented to reduce falls.


[Acute occlusion of the renal artery treated by means of rheolytic thrombectomy].
A 64-year-old woman presented with recurrent infarction of the right kidney. Because of suspected dysfunction of the contralateral kidney, revascularisation of the occluded right renal artery was attempted. Local thrombolysis with urokinase was unrewarding. So-called rheolytic thrombectomy by means of a Hydrolyser was successful in opening the right main renal artery. Although recovery of right renal function was not complete, renal scintigraphy confirmed salvage of most of the right kidney parenchyma.


Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts.
Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case-control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60-1.48), 0.96 (95% CI, 0.61-1.52), and 1.21 (95% CI, 0.75-1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54-1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.


A novel bioluminescence mouse model for monitoring oropharyngeal candidiasis in mice.
Oropharyngeal Candida albicans (C. albicans) infection usually occurs in patients with altered cell-mediated immune response. Many animal models have been developed for studying the pathogenesis of disease. Here we describe a new model for real-time monitoring of oral candidiasis. Mice were rendered susceptible to oral candidiasis by injection with cortisone acetate. Oral infection was performed by placing a swab saturated with genetically engineered bioluminescent strain of C. albicans sublingually. An in vivo imaging technique, exploiting stably trasformed C. albicans that costitutively express luciferase, was adopted. This novel longitudinal study represents a powerful tool to: (1) test real-time progression of infection, (2) identify the target site of C. albicans in specific organs, (3) evaluate the efficacy of antifungal therapies and (4) explore the spread of C. albicans from the local to systemic compartment in a new way.


The histological analysis, colorimetric evaluation, and chemical quantification of melanin content in 'suntanned' fish.
Human melanocytes respond to UV irradiation by increasing the synthesis of melanin. While much is now understood of the pathways governing this process and the nature of the melanin synthesized, little is known of melanins produced by lower vertebrates and their capacity to respond to UV. Here we report that a fish, red seabream, can undergo 'suntanning'. Histological, colorimetric and chemical assays were performed for suntanned red seabream fish bred in net cages to analyse the melanins and compared with shaded or wild red seabream fish. For color evaluation, the L* values of suntanned fish were dramatically lower than those in the other two groups. Pyrrole-2,3,5-tricarboxylic acid (PTCA), an indicator of eumelanin, was detected in suntanned fish at five times higher levels than in shaded or wild fish while 4-amino-3-hydroxyphenyl-alanine (4-AHP), a marker for pheomelanin, could not be detected in any of the samples. Histological analysis showed that melanocytes in the suntanned skin enlarged and increased in number to form a monolayer at the surface of the skin. Analysis of L* values and PTCA levels showed quite a high correlation coefficient (r = -0.843). When comparing shaded and wild red seabream fish, the scores were closer but some significant differences were still found in some body areas. These results indicate that eumelanin accumulates in suntanned fish during the increase in skin color, which is induced by sunlight, presumably by ultraviolet radiation.


Aire and Foxp3 expression in a particular microenvironment for T cell differentiation.
The thymus is the primary lymphoid organ responsible for T cell development and the establishment of central self-tolerance. Among thymic epithelial cells, thymic nurse cells (TNC) interact closely with immature thymocytes and constitute a special microenvironment for T cell differentiation and selection. In addition, TNC express neuroendocrine self-antigens such as oxytocin and insulin-like growth factor-2, whose intrathymic transcription is regulated by the autoimmune regulator gene/protein (Aire). Both effector and natural regulatory T cell (nTreg) lineages develop in the thymus, but the mechanisms leading to nTreg selection in the thymus are still unclear. Foxp3 is the most specific nTreg marker that is required for nTreg functional activity, but not for engagement into the Treg lineage. Aire has been suggested to be a potential factor implicated in this role. The objective of this study was to characterize Aire and Foxp3 expression in TNC/thymocyte complexes. Aire and Foxp3 expression was investigated by RT-qPCR in TNC/thymocyte complexes isolated by enzymatic digestion and sedimentation. Aire and Foxp3 proteins were located by confocal microscopy and specific immunocytochemistry. Both Aire and Foxp3 transcripts were detected in TNC/thymocyte complexes. Foxp3 was detected in the nucleus of thymocytes internalized into TNC. Aire was located mainly in TNC cytoplasm and, although to a lower degree, in the nucleus of some TNC-associated thymocytes. Aire and Foxp3 are present in the particular TNC microenvironment which has previously been shown to support thymic selection. The differential localization of these two markers suggests a role for TNC in nTreg development.


Sonography of the temporomandibular joint from 60 examinations and comparison with MRI and axiography.
Establishing a diagnosis of temporomandibular joint disorder is mainly based on clinical assessment, functional examination, nuclear magnetic resonance imaging (MRI) and axiography. Sonographic examination was compared with MRI and axiography in assessing temporomandibular joint (TMJ) function in 55 patients. Fifty-five patients with different TMJ problems were examined clinically, by means of axiography, sonography and some also by MRI. The range of motion was measured by sonography and axiography and the results compared using Student's t-test. Anatomical details diagnostic for disc-displacement were tested by sonography and MRI. The average time required for sonography was 2 min and for axiography 20 min. The mean measurement differences for condylar movement in maximal mouth opening was 1.7 mm, for protrusion 1.6 mm and for mediotrusion 2.5 mm. The range of condylar movement as measured by sonography and axiography coincided for opening and for protrusion (statistically significant). No significance was found for lateral excursions. The concordance in diagnosis of disc dislocation, hypermobility and impaired range of motion when comparing ultrasound with MRI was 83%. All sonographic examinations were performed by one person only. Sixty repeat examinations in patients produced no complaints and showed an absolute range of difference of 0.6 mm, with a relative range of 7%. Student's t-test was significant (p<0.05) (two repetitive measurements). Sonography proved to be a fast and reliable method for evaluating the range of movement of the TMJ. The lateral joint capsule, lateral disc, and upper condyle could be demonstrated. Pathological processes such as anterior or lateral disc displacement, disc perforation, seroma following contusion, capsular fibrosis, crystalline structures in the synovia and fracture dislocation of the condyle could be diagnosed with considerable reliability when compared with MRI. However, the medial aspect of the joint, medial disc dislocation and the angulation of the condylar slope could not be seen.


[The correlation of the size of the pinna and the auditory bulla in specialized desert rodents].
Relation between size of pinna and auditory bulla in specialized desert rodents (families Allactagidae, Dipodidae, Gerbillidae, Heteromyidae, and genus Selevinia) is statistically significant and described by hyperbola. The empirical distribution of respective sizes can be interpreted as a total of two main trends. One is enlargement of the pinna, the bulla remains small (most of Allactagidae), another is enlargement of the bulla, the pinna remains small (Gerbillidae, Heteromyidae, Selevinia, most Dipodidae). A few species display moderate enlargement of both pinna and bulla, while in Euchoreutes they both are hypertrophied. Biomechanical preconditions are supposed to be following. Enlargement of the pinna is responsible for increasing of both sensitivity and locatory abilities of the hearing organ, while enlargement of the bulla is responsible for the first function only. So, the two main trends are results of selection of development of the hearing organ at the level of either pinna or bulla. It is shown by dispersion and correlation analyses that size of the parts of the hearing organ under investigation are correlated mostly with mobility and escaping mode. It is concluded therefore that the rodents characterized by active and speedy escaping from predation display the first of the above trends, while the rodents characterized by passive escaping from predation display the second trend.


Organoid-Transplant Model Systems to Study the Effects of Obesity on the Pancreatic Carcinogenesis in vivo.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoid models of pancreatic cancer have provided insight into the fundamental pathways driving tumor progression from a normal cell to non-invasive precursor lesion and finally to widely metastatic disease, offering new opportunities for identifying the key driver of cancer evolution. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poorer prognosis and treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose a feasible and manageable organoid-based preclinical tool to study the effects of obesity on pancreatic carcinogenesis. Therefore, we tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of the syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived-organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our results suggest that organoid-derived transplant in obese mice represents a suitable system to study early steps of pancreatic carcinogenesis and supports the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.


Chloroform Extract of Rasagenthi Mezhugu, a Siddha Formulation, as an Evidence-Based Complementary and Alternative Medicine for HPV-Positive Cervical Cancers.
Rasagenthi Mezhugu (RGM) is a herbomineral formulation in the Siddha system of traditional medicine and is prescribed in the southern parts of India as a remedy for all kinds of cancers. However, scientific evidence for its therapeutic efficacy in cervical cancer is lacking, and it contains heavy metals. To overcome these limitations, RGM was extracted, and the fractions were tested on HPV-positive cervical cancer cells, ME-180 and SiHa. The extracts, free from the toxic heavy metals, affected the viability of both the cells. The chloroform fraction (cRGM) induced DNA damage and apoptosis. Mitochondria-mediated apoptosis was indicated. Though both the cells responded to the treatment, ME-180 was more responsive. Thus, this study brings up scientific evidence for the efficacy of RGM against the HPV-mediated cervical cancer cells and, if the toxic heavy metals are the limitation in its use, cRGM would be a suitable candidate as evidence-based complementary and alternative medicine for HPV-positive cervical cancers.


Role of antiplatelet therapy in the durability of hemodialysis access.
Antiplatelet therapy (APT) is often used on anecdotal grounds to improve vascular access patency. The aim of this study was to assess the role of APT in hemodialysis (HD) patients undergoing arteriovenous fistula (AVF) or graft (AVG) placement. All patients in a large HD vascular qualitative initiative database (2011-2017) were included and divided into no antiplatelet therapy (no-APT) vs. any APT [aspirin (ASA) or P2Y12 inhibitors (PI)]. Multivariate [logistic (MLR) and Cox (MCR) regression] analyses were used as appropriate. A total of 24,847 patients undergoing HD access creation were identified (78% AVF). APT was noted among 49 and 46% of AVG and AVF patients, respectively. In MLR analysis, patients on no-APT vs. APT had a 12-fold increased risk of in-hospital mortality (odds ratio (OR) 11.79, [95% confidence interval 5.30-26.26]) and the risk of developing steal syndrome was higher among patients discharged on APT (OR 1.81, [1.19-2.76]). In patients undergoing AVF, primary patency (PP) was similar between APT and no-APT. However, in patients undergoing AVG, PP rates at 12 months were significantly higher for APT: ASA (47 vs. 41%) and PI (51 vs. 41%) than for no-APT (p = 0.008). At MCR analysis, the loss of PP at 12 months was 13% lower in ASA users (hazard ratio (HR) 0.87, [0.77-0.97], p = 0.02) and 24% lower in PI users (HR 0.76, [0.57-0.99], p = 0.046) compared to no-APT. In a large national database, we showed that antiplatelet therapy was associated with lower in-hospital mortality. Aspirin and P2Y12-inhibitor use among AVG patients demonstrated improved PP rates compared to no antiplatelet therapy. We recommend the use of antiplatelet therapy especially in patients on AVG.


Iron-mediated deuterium addition cascade cyano insertion/cyclization of N-arylacrylamides to access deuterium-labelled phenanthridines.
Deuterated molecules feature important biological activities and pharmacokinetic properties for the design of pharmaceuticals. Radical cyclization cascades involving the deuteration of alkenes to form heterocyclic compounds have rarely been reported. Herein, a deuterium addition cascade cyano insertion/cyclization of N-arylacrylamides to synthesize deuterated phenanthridines is described. Cheap Fe(NO3)3·9H2O enables the generation of a deuterium radical from NaBD4in situ. These reactions proceed under mild conditions in a short time and a variety of functional groups are well tolerated.


[Spinal cord dural arteriovenous fistulae: analysis of a series with surgical curative treatment].
Spinal dural arteriovenous fistulae (SDAVF) are elusive to an early diagnosis. Otherwise, there is no agreement regarding the best treatment. To review our series of spinal arteriovenous malformations to illustrate the treatment and outcome of FAVDE. Descriptive series of cases diagnosed and treated at our hospital within the last ten years. Ten suspicious MRI, followed by angiograms, got the next diagnosis: 3 intraspinal malformations, 2 cavernoms and 5 FAVDE, reported here. Four out of 5 FAVDE were men. Mean age was 61year (53-77), and mean interval to diagnosis 10.8 months (1-24). The clinical course consisted of progressive paraparesis, wich was acute in one case, with wheelchair confinement. Sensory involvement and sphinter dysfunction were also always present; severe pain affected 2 cases. MRI revealed the FAVDE at low thoracic or lumbar levels, with tortuous flow voids over the surface of the affected area. Angiograms disclosed the single feeding vessel between D8-L3. Laminectomy and interruption of the draining vein was the chosen treatment. Postoperative complications were not found. Improvement followed until full recovery, that occurred in 4 cases. One patient, previously embolized, was the only one with just modest recovery, although the angiogram proved that deferred surgery ran well. Mean follow-up was 3.8 years (1.5-6); neither clinical deterioration nor suspicious MR finding were found. Postoperative angiogram, performed in two cases, confirmed the fistulae as occluded. FAVDE mainly involves old males with progressive paraparesis. Suitable MR findings and characteristic angiograms allow the diagnosis. Novel patients are subsidiary to selective and simple surgery, that is usually curative without recurrencies.


Regulatory Effect of PD1/PD-Ligand 1 (PD-L1) on Treg Cells in Patients with Idiopathic Pulmonary Fibrosis.
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a serious irreversible lung disease. The mechanism of immune checkpoint in idiopathic pulmonary fibrosis is still unknown. MATERIAL AND METHODS First, the expression levels of PD-1/PD-L1 on the surface of CD4+ T cells and the proportion of Treg cells in IPF or controls were detected by flow cytometry. Then, expression of TGF-ß in blood samples was detected with ELISA. Moreover, a co-culture system was composed of fibroblasts stimulated by TGF-ß and CD4+ T cells from healthy people. The proportions of Treg cells and PD-1 in the co-culture system were detected. In addition, we detected the proportion of Treg cells and the level of collagen-1 after adding PD-1 or PD-L1 protein antibody blocker to the co-culture system. RESULTS Flow cytometry revealed the upregulated expression of PD-1/PD-L1 in CD4+ T cells of IPF patients. PD-1 appears to inhibit the differentiation of CD4+ T cells into Treg cells. Co-culture of myofibroblasts and CD4+ T cells induced the generation of collagen-1 and reduced the proliferation of CD4+ T cells. When PD-1 was blocked, the inhibition of Treg cell differentiation was reversed, accompanied by decreased collagen-1 production. CONCLUSIONS This work identified the molecular mechanism of PD-1 in patients with IPF. It may provide a new perspective on the therapeutic effect of PD-1.


Ocular dominance peaks at pinwheel center singularities of the orientation map in cat visual cortex.
In the primary visual cortex of monkey and cat, ocular dominance and orientation are represented continuously and simultaneously, so that most neighboring neurons respond optimally to visual stimulation of the same eye and orientation. Maps of stimulus orientation are punctuated by singularities referred to as "pinwheel centers," around which all orientations are represented. Given that the orientation map is mostly continuous, orientation singularities are a mathematical necessity unless the map consists of perfectly parallel rows, and there is no evidence that the singularities play a role in normal function or development. We report here that in cats there is a strong tendency for peaks of ocular dominance to lie on the pinwheel center singularities of the orientation map. This relationship predicts but is not predicted by the tendencies, previously reported, for pinwheels to lie near the center lines of ocular dominance bands and for iso-orientation bands to cross ocular dominance boundaries at right angles. The coincidence of ocular dominance peaks with orientation singularities is likely to reflect a strong underlying functional link between the two visual cortical maps.


Differential sensitivities of the human ATP-binding cassette transporters ABCG2 and P-glycoprotein to cyclosporin A.
Several ATP-binding cassette (ABC) transporters can confer multidrug resistance to cancer cells by functioning as energy-dependent efflux pumps. The half-transporter ABCG2 and the widely studied P-glycoprotein (P-gp) are two ABC transporters that, when overexpressed, are capable of extruding a variety of structurally unrelated chemotherapy agents from cells. In this study, we demonstrate that human ABCG2 and P-glycoprotein, despite overlapping substrate specificities, differ in sensitivity to the immunomodulator cyclosporin A. In this study, we used human ABCG2 and human P-gp, each expressed separately in drug-selected MCF-7 sublines and transiently transfected HeLa cells. By flow cytometric analysis using the fluorescent substrates rhodamine 123 and mitoxantrone, we showed that cyclosporin A inhibits P-gp function at low micromolar concentrations, whereas ABCG2 function was unaffected. Furthermore, P-gp, but not ABCG2, was able to transport [3H]cyclosporin A directly in intact cells. We also demonstrated, for the first time, that [125I]iodoarylazidoprazosin, a photoaffinity analog of the substrate prazosin, labels multiple variants of ABCG2 specifically and that this labeling, although competed by some ABCG2 substrates, is unaffected by cyclosporin A. These labeling data also suggest the presence of multiple drug binding sites in ABCG2. In addition, cyclosporin A had no effect on the basal or prazosin-stimulated ATPase activity of ABCG2, whereas both the basal and verapamil-stimulated ATPase activities of P-gp were inhibited markedly. Together, our results suggest that cyclosporin A is neither a substrate nor an inhibitor of the human ABCG2 transporter, under the conditions and concentrations examined.


Abnormal trace mineral metabolism in adult X-linked hypophosphatemic mice: a possible role of increased food intake.
X-linked hypophosphatemia is a human and mouse disease characterized by reduced renal tubular reabsorption of phosphate, hypophosphatemia, and dwarfism. The gene is X-linked and dominant. There have been conflicting reports in the literature regarding possible malabsorption of minerals by the intestine as well. In this study we examined the mineral status in adult X-linked hypophosphatemic (Hyp) mice by measuring trace minerals in blood, bone, muscle, liver and hair and by performing a balance study for Ca, P, Mg, Na and K. The results indicate that Hyp mice have higher than normal levels of plasma iron, bone manganese and zinc, liver iron, and muscle zinc. The trace minerals in hair were not significantly affected. The balance study showed that the content of Ca, P, Mg, Na and K of the urine and feces of normal and Hyp mice were nonsignificantly different. Hyp mice did consume more diet per gram body weight. We conclude that there is no deficiency in intestinal mineral absorption in adult Hyp mice. No tissues studied were found to have reduced trace mineral levels. In fact, where differences occurred, Hyp mice had elevated trace mineral levels in various tissues and blood. This was probably the result of the increased dietary intake per gram body weight in the Hyp mice.


Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase.
Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells.


Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice.
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.


Patterns of seizure occurrence in catamenial epilepsy.
The pattern of seizure occurrence was analysed over 44 menstrual cycles in 12 epileptic women who considered they had menstrually related seizures. Two peaks in the daily seizure rate were apparent. A significant increase in seizures occurred during the days of menstrual flow and the two days preceding it, with a second peak in the four days at midcycle. The lowest seizure rate was in the late phase of the menstrual cycle. Daily salivary progesterone levels were assayed in 11 women, and 12 ovulatory and eight anovulatory cycles were identified on this basis. No increase in seizures occurred at midcycle if ovulation did not occur, but the perimenstrual increase took place irrespective of ovulatory status.


Taxonomic response of bacterial and fungal populations to biofertilizers applied to soil or substrate in greenhouse-grown cucumber.
Reductions in the quality and yield of crops continuously produced in the same location for many years due to annual increases in soil-borne pathogens. Environmentally-friendly methods are needed to produce vegetables sustainably and cost effectively under protective cover. We investigated the impact of biofertilizers on cucumber growth and yield, and changes to populations of soil microorganisms in response to biofertilizer treatments applied to substrate or soil. We observed that some biofertilizers significantly increased cucumber growth and decreased soil-borne pathogens in soil and substrate. Rhizosphere microbial communities in soil and substrate responded differently to different biofertilizers, which also led to significant differences in microbial diversity and taxonomic structure at different times in the growing season. Biofertilizers increase the prospects of re-using substrate for continuously producing high-quality crops cost-effectively from the same soil each year while at the same time controlling soil-borne disease.


Heat shock protein 90 as a drug target: some like it hot.
Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH(2)-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.


Role of lncRNA NEAT1 mediated by YY1 in the development of diabetic cataract via targeting the microRNA-205-3p/MMP16 axis.
We aimed at investigating the possible role and mechanism of NEAT1 in the pathogenesis of diabetic cataract. YY1 and NEAT1 expressions in anterior lens capsule collected from diabetic cataract (DC) patients and normal controls were examined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and their correlation was analyzed. The binding site between YY1 and NEAT1 sequences was predicted by JASPAR and detected by Dual-Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. The proliferation and apoptosis of high-glucose-induced cells with NEAT1 knockdown were detected. Potential downstream targets of NEAT1 were predicted by bioinformatics and detected by Dual-Luciferase reporter assay. YY1 and NEAT1 expressions in the anterior capsule tissue of DC lens were remarkably reduced and positively correlated. Dual-Luciferase reporter assay and ChIP confirmed that YY1 could bind to locus 2 of NEAT1. Knockdown of NEAT1 inhibited proliferation while promoted apoptosis under high glucose conditions. Further mechanism studies revealed that knockdown of NEAT1 could upregulate microRNA-205-3p, and MMP16 was a potential target of miR-205. The low expression of YY1 induces NEAT1 downregulation, which regulates microRNA-205-3p/MMP16 axis and thus participates in the development of DC.


Biochemical changes in the leaves of wheat plants infected by Pyricularia oryzae.
Blast, caused by the fungus Pyricularia oryzae, is a major disease of the wheat crop in the Brazilian Cerrado and represents a potential threat to world wheat production. However, information about the wheat-P. oryzae interaction is still limited. In this work, the activities of the enzymes superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), glutathione-S-transferase (GST), ascorbate peroxidase (APX), glutathione reductase (GR), and glutathione peroxidase (GPX) and the concentrations of superoxide (O₂(-)), hydrogen peroxide (H₂O₂), and malondialdehyde (MDA) as well as the electrolyte leakage (EL) were studied in wheat plants 'BR 18' and 'BRS 229', which are susceptible and partially resistant, respectively, to leaf blast at the vegetative growth stage, during the infection process of P. oryzae. The blast severity in BRS 229 was 50% lower than in BR 18 at 96 h after inoculation (hai). The activities of SOD, POX, APX, and GST increased for both cultivars in the inoculated plants compared with noninoculated plants and the increases were more pronounced for BRS 229 than for BR 18 at 96 hai. The GR and CAT activities only increased in inoculated plants from BRS 229 at 96 hai. For BR 18, the GR activity was not influenced by plant inoculation, and the CAT activity was lower in inoculated plants. The GPX activity only increased in inoculated plants from BR 18 at 48 and 72 hai. The P. oryzae infection increased the O₂(-), H₂O₂, and MDA concentrations and EL. However, the greater increases of the SOD, POX, APX, GST, GR, and CAT activities for BRS 229 compared with BR 18 contributed to the lower O₂(-), H₂O₂, and MDA concentrations and EL verified in the former. These results show that a more efficient antioxidative system in the removal of excess of reactive oxygen species generated during the infection process of P. oryzae limits the cellular damage caused by the fungus, thus contributing to greater wheat resistance to blast.


Ecological approaches in veterinary epidemiology: mapping the risk of bat-borne rabies using vegetation indices and night-time light satellite imagery.
Rabies remains a disease of significant public health concern. In the Americas, bats are an important source of rabies for pets, livestock, and humans. For effective rabies control and prevention, identifying potential areas for disease occurrence is critical to guide future research, inform public health policies, and design interventions. To anticipate zoonotic infectious diseases distribution at coarse scale, veterinary epidemiology needs to advance via exploring current geographic ecology tools and data using a biological approach. We analyzed bat-borne rabies reports in Chile from 2002 to 2012 to establish associations between rabies occurrence and environmental factors to generate an ecological niche model (ENM). The main rabies reservoir in Chile is the bat species Tadarida brasiliensis; we mapped 726 occurrences of rabies virus variant AgV4 in this bat species and integrated them with contemporary Normalized Difference Vegetation Index (NDVI) data from the Moderate Resolution Imaging Spectroradiometer (MODIS). The correct prediction of areas with rabies in bats and the reliable anticipation of human rabies in our study illustrate the usefulness of ENM for mapping rabies and other zoonotic pathogens. Additionally, we highlight critical issues with selection of environmental variables, methods for model validation, and consideration of sampling bias. Indeed, models with weak or incorrect validation approaches should be interpreted with caution. In conclusion, ecological niche modeling applications for mapping disease risk at coarse geographic scales have a promising future, especially with refinement and enrichment of models with additional information, such as night-time light data, which increased substantially the model's ability to anticipate human rabies.


Heterologous constitutive production of short-chain-length polyhydroxyalkanoates in Pseudomonas putida KT2440: the involvement of IbpA inclusion body protein.
Designing cell factories for the production of novel polyhydroxyalkanoates (PHAs) via smart metabolic engineering is key to obtain à la carte materials with tailored physicochemical properties. To this end, we used the model medium-chain-length-PHA producing bacterium, P. putida KT2440 as a chassis, which is characterized by its metabolic versatility and stress tolerance. Different PHA biosynthetic modules were assembled in expression plasmids using the Golden gate/MoClo modular assembly technique to implement an orthogonal short-chain-lengh-PHA (scl-PHA) switch in a "deaf" PHA mutant. This was specifically constructed to override endogenous multilevel regulation of PHA synthesis in the native strain. We generated a panel of engineered approaches carrying the genes from Rhodospirillum rubrum, Cupriavidus necator and Pseudomonas pseudoalcaligenes, demonstrating that diverse scl-PHAs can be constitutively produced in the chassis strain to varying yields from 23% to 84% PHA/CDW. Co-feeding assays of the most promising engineered strain harboring the PHA machinery from C. necator resulted to a panel of PHBV from 0.6% to 19% C5 monomeric incorporation. Chromosomally integrated PHA machineries with high PhaCCn synthase dosage successfully resulted in 68% PHA/CDW production. Interestingly, an inverse relationship between PhaC synthase dosage and granule size distribution was demonstrated in the heterologous host. In this vein, it is proposed the key involvement of inclusion body protein IbpA to the heterologous production of tailored PHA in P. putida KT2440.


Lightning Strike.
This scenario was developed to educate emergency medicine residents on the various presentations and management of a patient struck by lightning. Annually, there are approximately 1.4 billon lightning strikes around the world; of these, an estimated 24,000 strikes cause significant injury or death.1 In the United States, there are approximately 400 lightning-related injuries every year resulting in 40 average annual deaths.1 Although only one in approximately 14,000 people will ever be struck by lightning, this still represents a significant injury mechanism for which emergency department providers must be prepared.2 Lightning is formed by static electricity built up due to ice crystals in clouds which creates a differential charge between the cloud and another object, such as the ground. Approximately one in every five lightning strikes is a cloud-to-ground strike which can result in injury or death. Lightning current flows may be as high as 100,000 amperes; this is survived 90% of the time only because the strong current of the bolt is applied in a very small timeframe, limiting the amount of energy transferred.3 Even so, with such large amperages, substantial injuries or death are possible. Not limited to a single mechanism, lightning can harm people in a variety of ways, including a direct strike, side-splash, ground current or upward streamers from the ground, or cause blast-type injury.2 The large electric currents involved can generate non-perfusing cardiac rhythms resulting in death if the patient is not immediately resuscitated through cardiopulmonary resuscitation (CPR) techniques with respiratory support.2. At the conclusion of the simulation session, learners will be able to: 1) Describe how to evaluate for scene safety in an outdoor space during a thunderstorm, 2) Obtain a relevant focused physical examination of the lightning strike patient, 3) Describe the various manifestations of thermo-electric injury, 4) Discuss the management of the lightning strike patient, including treatment and disposition, 5) Outline the principles of reverse triage for lightning strike patients, and 6) Describe long-term complications of lightning strike injuries. This session was conducted using a simulation scenario with a mix of high-fidelity manikins and standardized patients followed by a debriefing session on the presentation, differential diagnosis, and management of lightning strike patients. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board examination case. The residents are provided a survey at the completion of the debriefing session to rate different aspects of the simulation, as well as to provide qualitative feedback on the scenario. This survey is specific to the local institution's simulation center. Feedback from the residents was overwhelmingly positive, although several learners struggled with identifying Lichtenberg figures and keraunoparalysis either due to the low-light setting, unfamiliarity of the pathology, or that the depictions were not as expected. The subsequent debriefings allowed for multiple areas of discussion. Debriefing topics included the comparing and contrasting low voltage/high voltage/lightning strike injuries, possible clinical presentations of the lightning strike patient, reverse triage principles, categorizing blast injuries, discussion of disposition, and the determination of prehospital scene safety.The local institution's simulation center feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form4 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Thirty-one learners completed a feedback form. This session received all 6 and 7 scores (consistently effective/very good and extremely effective/outstanding, respectively) other than one isolated 5 score. The statement, "Before the simulation, the instructor set the stage for an engaging learning experience," received the lowest average score with 6.81, while "The instructor structured the debriefing in an organized way" received an average score of 6.94.The form also includes an area for general feedback about the case at the end. Illustrative examples of feedback include: "Absolutely loved this sim. Tested multiple aspects of massCal care. Communication, critical care, scene safety, etc., nailed it," and "Very engaging and fun with a lot (of) good debriefing." This is an easily reproducible method for reviewing management of the lightning strike patient. Faculty may choose to use a combination of high- or low-fidelity manikins, task trainers, standardized patients, or confederate actors/volunteers as patients. There are multiple potential presentations and complications of the lightning strike patient to further customize the experience for learners' needs. For those who are looking to scale down the scenario, victims may be limited to one or two individuals, using whatever preferred mixture of manikins or standardized patients is needed or desired. Medical simulation, lightning strike patient, thermo-electrical burn, wilderness first-aid, blast injuries, wilderness medicine, emergency medicine, austere medicine.


No GIST-type c-kit gain of function mutations in neuroblastic tumours.
Neuroblastic tumours (NTs) have been shown to respond to imatinib treatment in vivo and in vitro, possibly via inactivating the c-kit receptor. The purpose of this study was to identify gastrointestinal stromal tumour (GIST)-type c-kit gene associated mutations in exons 9, 11, 13, and 17 in NTs to recognise a subset of tumours that would probably respond to imatinib treatment. Expression of the c-kit protein was detected immunohistochemically in a total of 37 archival paraffin wax embedded NTs using polyclonal rabbit antihuman c-kit antibody. After immunohistochemistry, c-kit gene associated chromosomal mutations in all cases of NT were detected with denaturing high performance liquid chromatography (HPLC). Denaturing HLPC analysis did not reveal GIST-type mutations in four immunohistochemically detected c-kit positive or in 33 c-kit negative NTs. c-kit receptor expression and GIST-type c-kit gene mutations are rare events in NTs. Oncogenic activation of c-kit in NTs presumably differs from that of GISTs, which may influence their responsiveness to imatinib treatment. Whether c-kit has an essential role in the pathogenesis of NTs remains to be investigated.


Mild and Chemoselective Phosphorylation of Alcohols Using a Ψ-Reagent.
An operationally simple, scalable, and chemoselective method for the direct phosphorylation of alcohols using a P(V)-approach based on the Ψ-reagent platform is disclosed. The method features a broad substrate scope of utility in both simple and complex settings and provides access to valuable phosphorylated alcohols that would be otherwise difficult to obtain.


Comparing Efficacy and Safety of Empirical vs. Guided Therapy for Non-cardiac Chest Pain: A Pragmatic Randomized Trial.
Background: Non-cardiac chest pain is common with two-thirds due to gastroesophageal reflux disease (GERD). Objective: To evaluate the effectiveness and safety of guided vs. empirical therapy in non-cardiac chest pain. Methods: Adults with normal angiogram or stress test were randomized into either a guided or empirical group. In the guided group, after the ambulatory pH-impedance test, if GERD then dexlansoprazole 30 mg/day for 8 weeks, but if functional or hypersensitive chest pain, then theophylline SR 250 mg/day for 4 weeks. In the empirical group, dexlansoprazole 60 mg/day was given for 2 weeks. The primary outcome was global chest pain visual analog score (VAS) and secondary outcomes were Quality of Life in Reflux and Dyspepsia (QOLRAD), GERD questionnaire (GERDQ), and pH parameters, all determined at baseline, 2nd and 8th weeks. Results: Of 200 screened patients, 132 were excluded, and of 68 randomized per-protocol, 33 were in the guided group and 35 in the empirical group. For between-group analysis, mean global pain scores were better with guided vs. empirical group at 8th week (P = 0.005) but not GERDQ or QOLRAD or any of pH measures (all P > 0.05). For within-group analysis, mean QOLRAD improved earliest at 8th week vs. baseline (P = 0.006) in the guided group and 2nd week vs. baseline (P = 0.011) in the empirical group but no differences were seen in other secondary outcomes (P > 0.05). No serious adverse events were reported. Conclusions: Guided approach may be preferred over short-term empirical therapy in symptom response, however QOLRAD, acid-related symptoms, or pH measures are not significantly different (trial registration ID no. NCT03319121).


Structure-function correlations in the reaction of bis(thiosemicarbazonato) copper(II) complexes with Ehrlich ascites tumor cells.
Examination of a series of substituted bis(thiosemicarbazonato) copper(II) complexes shows that their reaction with Ehrlich ascites tumor cells can be understood in terms of the relative reactivity of the complexes with sulfhydryl groups. In general, the order of reactivity of the complexes correlates directly with their respective degrees of cytotoxicity and ability to inhibit DNA synthesis and cellular respiration. The parent complex, 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) copper(II), leads to widespread cellular effects with the suppression of DNA synthesis particularly sensitive to the complex. The apparent reversible inhibition of DNA synthesis and thymidine uptake hy 3-ethoxy-2-oxobutyraldehyde bis(N4-dimethylthiosemicarbazonato) copper(II) and its lack of cytotoxicity are explained in terms of the chemical properties of this complex.


Upper extremity compartment syndrome after minor trauma: an imperative for increased vigilance for a rare, but limb-threatening complication.
Compartment syndrome of any extremity is a limb-threatening emergency requiring an emergent surgical management. Thus, ruling out compartment syndrome is often high on the list of priorities when treating high-energy injuries and fractures. However, even in the most seemingly benign injuries, this dangerous diagnosis must always remain on the differential and suspicion must remain high. 23-year-old factory worker presents after a low energy entrapment injury to his left forearm. Initial work-up and evaluation noted an isolated radial head dislocation with a normal physical motor and sensory exam. However, maintaining high suspicion for compartment syndrome despite serial normal physical exams, led objective compartment pressure measurement leading to definitive diagnosis. Emergent surgical intervention via compartment fasciotomies was performed, along with closed reduction and ligament repair. At 1 year follow-up, the patient was well-healed, back to work with full range of motion and not activity limitations. Despite a seemingly benign injury pattern, and a relatively low energy mechanism, vigilant concern for compartment syndrome following any kind of entrapment injury should initiate serial examinations and compartment pressure measurements especially in circumstances with continued swelling and inability to perform an accurate clinical assessment due to an obtunded or medicated patient.


Dr. Betty Clements: Breaking Gender Barriers in the Air Force and Neurology.
Women currently make up 45.9% of neurology residents and fellows, although little is known about the individual women who broke gender barriers to train as neurologists. Grace Elizabeth Betty Clements (1918-1965) was the first woman trainee at the Mayo Clinic to practice neurology and later became a founder of the Barrow Neurological Institute. Before paving the way for future women trainees in neurology, she served as a Women Airforce Service Pilot including flying atomic bomb planning missions during World War II. Following the war, her path to medicine included volunteering in the American Red Cross in the Philippines where she treated patients with Hansen disease (leprosy). Clements returned to her home state to complete medical school at the University of Nebraska before seeking neurologic training at the Mayo Clinic in 1954. Following additional training at Queen Square, she became a founder of the Barrow Neurological Institute in Phoenix, Arizona. Many early women in neurology have remarkable backgrounds that have equipped them for their career in medicine which Clements exemplifies.


Late cardiovascular toxicity following chemotherapy for germ cell tumors.
The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity.


Popularity of Video Games and Collective Memory.
Describing the permanence of cultural objects is an important step in understanding societal trends. A relatively novel cultural object is the video game, which is an interactive media, that is, the player is an active contributor to the overall experience. This article aims to investigate video game permanence in collective memory using their popularity as a proxy, employing data based on the Steam platform from July 2012 to December 2020. The objectives include characterizing the database; studying the growth of players, games, and game categories; providing a model for the relative popularity distribution; and applying this model in three strata, global, major categories, and among categories. We detected linear growth trends in the number of players and the number of categories, and an exponential trend in the number of games released. Furthermore, we verified that lognormal distributions, emerging from multiplicative processes, provide a first approximation for the popularity in all strata. In addition, we proposed an improvement via Box-Cox transformations with similar parameters (from -0.12 (95% CI: -0.18, -0.07) to -0.04 (95% CI: -0.08, 0)). We were able to justify this improved model by interpreting the magnitude of each Box-Cox parameter as a measure of memory effects.


Microbial associations of shallow-water Mediterranean marine cave Solenogastres (Mollusca).
The first cave-dwelling Solenogastres-marine shell-less worm-like mollusks-were sampled from Mediterranean marine caves floor silt in the Marseille area. The mollusks were 1.5 mm in length, had a transparent body with shiny spicules and appear to represent a new Tegulaherpia species. Electron microscopy revealed a high number of microbial cells, located on the surface of the spicules as well as in the cuticle of Tegulaherpia sp. The observed microbial cells varied in morphology and were unequally distributed through the cuticle, reaching a highest density on the dorsal and lateral sides and being practically absent on the ventral side. Next Generation Sequencing (NGS) of V4 region of 16S rRNA gene amplicons, obtained from the DNA samples of whole bodies of Tegulaherpia sp. revealed three dominating microorganisms, two of which were bacteria of Bacteroidetes and Nitrospirae phyla, while the third one represented archaea of Thaumarchaeota phylum. The Operational Taxonomic Unit (OTU), affiliated with Bacteroidetes was an uncultured bacteria of the family Saprospiraceae (93-95% of Bacteroidetes and 25-44% of the total community, depending on sample), OTU, affiliated with Nitrospirae belonged to the genus Nitrospira (8-30% of the community), while the thaumarchaeal OTU was classified as Candidatus Nitrosopumilus (11-15% of the community). Members of these three microbial taxa are known to form associations with various marine animals such as sponges or snails where they contribute to nitrogen metabolism or the decomposition of biopolymers. A similar role is assumed to be played by the microorganisms associated with Tegulaherpia sp.


3D time-varying simulations of Ca2+ dynamics in arterial coupled cells: A massively parallel implementation.
Preferential locations of atherosclerotic plaque are strongly associated with the areas of low wall shear stress and disturbed haemodynamic characteristics such as flow detachment, flow recirculation and oscillatory flow. The areas of low wall shear stress are also associated with the reduced production of adenosine triphosphate in the endothelial layer, as well as the resulting reduced production of inositol trisphosphate (IP3 ). The subsequent variation in Ca2+ signalling and nitric oxide synthesis could lead to the impairment of the atheroprotective function played by nitric oxide. In previous studies, it has been suggested that the reduced IP3 and Ca2+ signalling can explain the correlation of atherosclerosis with induced low WSS and disturbed flow characteristics. The massively parallel implementation described in this article provides insight into the dynamics of coupled smooth muscle cells and endothelial cells mapped onto the surface of an idealised arterial bifurcation. We show that variations in coupling parameters, which model normal and pathological conditions, provide vastly different smooth muscle cell Ca2+ dynamics and wave propagation profiles. The extensibility of the coupled cells model and scalability of the implementation provide a solid framework for in silico investigations of the interaction between complex cellular chemistry and the macro-scale processes determined by fluid dynamics. © 2016 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.


[We control our bodies: the biological and social dialectic].
This article aims at reviewing the discussion of biological and social factors in the analysis of women's social condition. With the appearance of a feminist perspective, the dominance of earlier biologically-based explanations was substituted by an emphasis on the social construction of female identity. Even when women's identification with the body and with nature, and their secondary status, were considered universal, biological determinism was rejected. In this process of re-definition of the object of study, the ideological role of science was pointed out, since male dominance in science and society accompanied the historical tendency which relegated "the woman question" to the sphere of natural fact. Although growing awareness of the socially-constructed nature of scientific activity itself is producing a tendency to abandon the biological/social dichotomy at the conceptual level, differences between men and women in the reproductive sphere continue to exist. It is argued that analysis of reproduction requires characterization of the sexes as biosocial entities in relationship, situated in specific historical contexts, and that in modern society women are subject to a double reproductive contradiction.


Hand-eye calibration using a target registration error model.
Surgical cameras are prevalent in modern operating theatres and are often used as a surrogate for direct vision. Visualisation techniques (e.g. image fusion) made possible by tracking the camera require accurate hand-eye calibration between the camera and the tracking system. The authors introduce the concept of 'guided hand-eye calibration', where calibration measurements are facilitated by a target registration error (TRE) model. They formulate hand-eye calibration as a registration problem between homologous point-line pairs. For each measurement, the position of a monochromatic ball-tip stylus (a point) and its projection onto the image (a line) is recorded, and the TRE of the resulting calibration is predicted using a TRE model. The TRE model is then used to guide the placement of the calibration tool, so that the subsequent measurement minimises the predicted TRE. Assessing TRE after each measurement produces accurate calibration using a minimal number of measurements. As a proof of principle, they evaluated guided calibration using a webcam and an endoscopic camera. Their endoscopic camera results suggest that millimetre TRE is achievable when at least 15 measurements are acquired with the tracker sensor ∼80 cm away on the laparoscope handle for a target ∼20 cm away from the camera.


Reducing the Breast Cancer Risk and Radiation Dose of Radiography for Scoliosis in Children: A Phantom Study.
Full-spinal radiographs (FRs) are often the first choice of imaging modality in the investigation of scoliosis. However, FRs are strongly related to breast cancer occurrence due to multiple large-field radiographic examinations taken during childhood and adolescence, which may increase the risk for breast cancer in adulthood among women with scoliosis. The purpose of this study was to consider various technical parameters to reduce the patient radiation dose of FRs for scoliosis. To evaluate breast surface doses (BSDs) in FRs, radio photoluminescence dosimeters were placed in contact with a child phantom. Using the PC-based Monte Carlo (PMC) program for calculating patient doses in medical X-ray examinations, the breast organ dose (BOD) and the effective dose were calculated by performing Monte Carlo simulations using mathematical phantom models. The BSDs in the posteroanterior (PA) view were 0.15-0.34-fold those in the anteroposterior (AP) view. The effective dose in the PA view was 0.4-0.61-fold that in the AP view. BSD measurements were almost equivalent to the BODs obtained using PMC at all exposure settings. During FRs, the PA view without an anti-scatter grid significantly reduced the breast dose compared to the AP view with an anti-scatter grid.


[Irritable Bowel Syndrome, Emotion Regulation, and Gut Microbiota].
Irritable bowel syndrome (IBS) is defined as a representative functional gastrointestinal disorder which is characterized by chronic or recurrent abdominal pain and/or abdominal discomfort associated with abnormal bowel movement. Gut microbiota are related to the pathophysiology of IBS. In the field of IBS, post-infectious etiology, stress-induced alteration of microbiota, increased mucosal permeability, bacterial overgrowth, disease-specific microbiota, microbial products, and brain-gut interactions are being investigated. In some individuals, IBS develops after recovery from acute gastroenteritis known as post-infectious IBS. Gut microbiota in IBS patients differ from those in healthy individuals, and the profiles of gut microbiota in IBS patients also vary among IBS patients with constipation, diarrhea, and mixed subtypes. In Japan, gut microbiota in IBS patients also differ from those observed in healthy individuals, and organic acid by-products observed in the patients correlated with symptoms, quality of life, and alexithymia. Further research on gut microbiota in IBS patients is warranted.


Susceptibility testing of anaerobes--fact, fancy, and wishful thinking.
Some of the problems encountered in anaerobic bacteriology and anaerobic susceptibility testing are reviewed. These include the lack of identification of Bacteroides fragilis group species, standardization of test media, methodology, and clinically relevant minimum inhibitory concentration breakpoints. Methodologic variations may lead to marked differences in the degree of activity reported, especially for newer antimicrobial agents. Studies on the correlation of clinical efficacy and in vitro susceptibility data performed by the various techniques are needed.


Primary care and care for older persons: position paper of the European Forum for Primary Care.
This article explores how to address the needs of the growing number of older patients in primary care practice. Primary care is not a fixed organisational structure but a combination of functional characteristics which has developed variably in European countries with differing responses to the emerging needs of older persons. Multimorbidity, frailty, disability and dependence play out differently in older persons; a key challenge for primary care is to provide a response that is adapted to the needs of individuals - as they see them and not as the professional defines them. Indeed, growing experience shows how to involve older persons in taking decisions. Contrary to popular opinion, older persons often rate their quality of life as high. Indeed, comprehensive primary care offers health promotion and prevention: also older people may benefit from measures that support their health and independence and some case descriptions show this potential. Although most people prefer to be in their own environment (home, community) during the last stage of life, providing end-of-life care in the community is a challenge for primary care because it requires continuity and coordination with specialist care. Successful models of care however do exist. Delivering seamless integrated care to older persons is a central theme in primary care. Rather than disease management, in primary care, case management is the preferred approach. Proactive geriatric assessment of individual medical, functional and social needs, including loneliness and isolation, has been shown to be useful and its place in primary care is the subject of further research. Clinical practice guidelines for multimorbidity are badly needed. Non-adherence to medication, linked to multiple and uncoordinated prescriptions, is a widespread and costly problem. Successful approaches in primary care are being developed, including the use of electronic patient files. With the general practitioner (GP) as the central care provider, primary care is increasingly teamwork, and the role of nurses and other (new) professions in primary care is developing constantly. The composition and coordination of teams are two components of one of the major complexities to address: how to provide individualised care with standardisation at organisation the level. (Lack of) Coordination with specialist care remains a widespread problem and needs attention from policy makers and practitioners alike. Alignment with home care and social services remains a challenge in all countries, not least because of the different funding arrangements between the services. Further priorities for research and development are summarised.


Interwoven traditions in Bell Beaker metallurgy: Approaching the social value of copper at Bauma del Serrat del Pont (Northeast Iberia).
Debates on early metallurgy in Western Europe have frequently focused on the social value of copper (between utilitarian and symbolic) and its purported role in the emergence and consolidation of hierarchies. Recent research shows that generalisations are increasingly untenable and highlights the need for comparative regional studies. Given its location in an intermediate area, the early metallurgy of Northeast Iberia provides an interesting case in point to explore the interaction between the well-characterised traditions of southern Iberia and southern France during the 3rd and 2nd millennia BCE. Here the analytical study of seven Bell Beaker (decorated and undecorated) vessels reused as crucibles at Bauma del Serrrat del Pont (Tortellà, Girona) are presented. We employed pXRF, metallography, SEM-EDS and lead isotope analyses. The results show evidence for copper smelting employing a remarkable variety of ore sources, including Solana del Bepo, Turquesa and Les Ferreres mines, and an extra unknown area. The smelting vessels were manufactured using the same clay, which contained both mineral and organic inclusions. Our results are discussed with reference to all the evidence available for metals and metallurgy in the Northeast, and more broadly in comparison to southern Iberia and southern France, with special emphasis on issues of production organisation and social complexity. Taken together, our results support the notion that copper metallurgy played a predominantly utilitarian role in Bell Beaker societies and highlight idiosyncratic aspects of the metallurgical trajectory in the Northeast. Differences between territories challenge unilinear explanations of technological and social development after the introduction of metallurgy. Separate trajectories can only be explained in relation to area-specific socio-cultural and environmental factors.


Challenges in the Management of Pregnancy and Lactation Associated Osteoporosis: Literature Review and Retrospective Study.
Pregnancy and lactation-associated osteoporosis (PLO) is a rare and special form of osteoporosis, which is poorly known with regard to its etiology, pathophysiology and therapy. However, PLO can cause vertebral compression fractures (VCFs) and height loss, which could cause further kyphosis of the spine. Therefore, PLO should be taken into account in the differential diagnosis when a woman presents with severe back pain during or after pregnancy. In our current study, we reviewed the novel literatures that demonstrate the current understanding of and treatment for PLO. In addition, we retrospectively studied four patients who suffered from back pain and VCFs during or after pregnancy. We also examine their clinical medicine treatment methods and outcomes in order to provide evidence for a better understanding of PLO and its relevant medical treatment.


Clinical appraisal of vinpocetine for the removal of intractable tumoral calcinosis in haemodialysis patients with renal failure.
Previous studies have shown that vinpocetine [14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine] scavenges minerals and/or metals in the soft tissues of rabbits with artificially induced arteriosclerosis. The present study was carried out to determine whether or not vinpocetine would bring about the removal of intractable tumoral calcinosis in haemodialysis patients with renal failure. After administration of 15 mg/day vinpocetine for 3-12 months in haemodialysis patients with X-ray evidence of tumoral calcinosis, calcinosis was completely eliminated in all eight cases. Serum alkaline phosphatase and bone osteocalcin concentrations tended to decrease after treatment with vinpocetine compared with before treatment. Vinpocetine thus appears to be an effective scavenger of tumoral calcinosis in haemodialysis patients with renal failure without any side-effects during treatment.


Kinetics of the effect of amiloride on the permeability of the apical membrane of rabbit descending colon to sodium.
The effects of the addition of graded concentrations of amiloride, (A)m, to the mucosal bathing solution on the permeability of the apical membrane of rabbit descending colon to Na (PmNa) were determined when the Na activity in the mucosal bathing solution, (Na)m, was 18, 32 or 100 mM. PmNa was obtained from current-voltage relations determined on tissues bathed with a high-K serosal solution before and after the addition of a maximally inhibitory concentration of amiloride to the mucosal solution as described by Turnheim et al. (Turnheim, K., Thompson, S.M., Schultz, S.G. 1983. J. Membrane Biol. 76:299-309). The results indicate that: (1) As demonstrated previously (Turnheim et al., 1983), PmNa decreases with increasing (Na)m. (2) PmNa also decreases hyperbolically with increasing (A)m. Kinetic analyses of the effect of amiloride on PmNa are consistent with the conclusions that: (i) the stoichiometry between the interaction of amiloride with apical membrane receptors that results in a decrease in PmNa is one-for-one; (ii) there is no evidence for cooperativity between amiloride and these binding sites; (iii) the value of (A)m needed to halve PmNa at a fixed (Na)m is 0.6-1.0 microM; and, (iv) this value is independent of (Na)m over the fivefold range studied. These findings are consistent with the notion that the sites with which amiloride interacts to bring about closure of the channels through which Na crosses the apical membrane are kinetically distinct from the sites with which (Na)m interacts to bring about closure (i.e., "self-inhibition"). In short, the effects of (Na)m and (A)m on PmNa in this tissue appear to be independent and additive.


The Health Benefits of Egg Protein.
Once the general public accepts that dietary cholesterol is not a concern for cardiovascular disease risk, foods that have been labeled as high-cholesterol sources, including eggs, may be appreciated for their various other dietary components. One of the nutrients in eggs that deserves further discussion is egg protein. Egg protein has been recognized to be highly digestible and an excellent source of essential amino acids, with the highest attainable protein digestibility-corrected amino acid score. Egg protein has been shown to decrease malnutrition in underdeveloped countries, possibly increase height in children, and protect against kwashiorkor. Egg protein has been demonstrated to be important to skeletal muscle health and protective against sarcopenia. Egg protein also can decrease appetite, resulting in a reduction in the caloric intake from the next meal and weight reduction. Other protective effects of egg protein addressed in this review include protection against infection as well as hypotensive and anti-cancer effects.


Dissection of the functions of antigen-presenting cells in the induction of T cell activation.
The functions of antigen-presenting cells (APC) in the initiation of T cell activation was examined by culturing antigen-bearing guinea pig macrophages (M phi) with T cells obtained from antigen-primed animals. Although such antigen-bearing M phi stimulated primed syngeneic T cell DNA synthesis, as assessed by tritiated thymidine incorporation, paraformaldehyde fixation (0.15% for 1 min at 37 degrees C) abolished this capacity. Analysis with acridine orange staining indicated that fixed antigen-bearing M phi could not trigger primed syngeneic T cells to progress from the G0 to the G1 phase of the cell cycle. The addition of control non-antigen-bearing syngeneic or allogeneic M phi but not interleukin 1 or 2 to cultures of T cells and fixed APC permitted a proliferative response. Although the interaction between fixed antigen-bearing M phi and responding T cells was genetically restricted, there was no similar restriction for the supplemental control M phi. In fact, completely Ia-negative endothelial cells (EC) and fibroblasts (FB) could restore antigen responsiveness to cultures of fixed antigen-bearing M phi and syngeneic responding T cells, although they could not directly present antigen. Moreover, metabolically intact accessory cells, including Ia-negative EC and FB, could take up and process antigen to an immunogenic moiety, which fixed Ia-positive M phi could present to primed T cells. These data indicate that recognition of the antigen-Ia complex on an APC is necessary but not sufficient to trigger proliferation of freshly obtained primed T cells. The results additionally support the conclusion that APC carry out at least two separate functions necessary for the initiation of antigen-induced T cell activation. Not only must the APC display the antigen-Ia complex, but it must also convey another required effect. This influence, which apparently involved the establishment of cell to cell contact, was neither Ia nor antigen dependent and could only be provided by a metabolically intact cell. By contrast, genetically restricted antigen presentation could be accomplished by a fixed Ia-positive cell. Only when both the antigen-Ia complex and the influence of an intact accessory cell were provided by the same or different accessory cell were T cells triggered to enter the cell cycle.


Neural regulation of pupariation in tsetse larvae.
A neural mechanism coordinates pupariation behavior and tanning in the tsetse larva. At parturition, the mature larva has already received sufficient ecdysteroid to commit the epidermal cells to metamorphosis but, before sclerotization and tanning of the cuticle can begin, the larva must first select a pupariation site and then proceed through a stereotypic sequence of pupariation behavior that culminates in the formation of a smooth, ovoid puparium. Both pupariation behavior and tanning are inhibited by the central nervous system (CNS) during the wandering phase. This central inhibition is maintained by sensory input originating in the extreme posterior region of the body. At the transition from wandering to pupariation, the posterior signal that induces inhibition of pupariation behavior is removed and the larva begins the contractions associated with pupariation, but the CNS inhibition of tanning persists. At this point, separation of the body into two halves by ligation or nerve transection prevents tanning of the anterior half (containing the CNS), whereas the denervated integument of the posterior half tans completely. Transection of nerves to the midline of the body produces larvae with a tanning pattern that ends abruptly along a sagittal plane, implying that the central control of this process is uncoupled between the left and right regions of the CNS. A few minutes later, when the final shape of the puparium is completed, the CNS inhibition is lifted and the tanning process begins. At this time, separation of the body into two halves by ligation or nerve transection has no inhibitory effects on either part. Exogenous ecdysteroids fail to release the CNS inhibition, and hemolymph containing the pupariation factors from Sarcophaga bullata have no accelerating effects on tsetse pupariation. These results imply that regulation of metamorphosis in the insect integument is not the exclusive domain of blood-borne hormones.


Single visit root canal treatment: a prospective study.
The aim was to determine the success rate of single visit root canal treatment (RCT) and thus encourage clinicians to offer this treatment option appropriately. This was a longitudinal clinical study involving all teeth of the secondary dentition except third molars in the upper and lower jaws. Teeth having irreversible pulpitis, pulp necrosis or periapical periodontitis were included in the study. RCT and obturation was done at a single visit. The patients were monitored over 6 months. Forty-five teeth were treated in 21 females and 24 males, aged 18-56 years (34.4+/-12.7). Preoperatively, pain was present in 84.4%, tenderness to percussion in 53.3%, and periapical radiolucency in 24.4% teeth. Forty percent had irreversible pulpitis and 60% had apical periodontitis. Post-operatively, pain reduced to 51.1% on day 1, 15.5% at 1 week, and 0% for the rest of the period. Tenderness to percussion reduced to 15.6% at 1 week and 0% by 1 month. Periapical radiolucency reduced to 9.5% at 6 months. Favorable outcome of 33.3% was recorded on day 1 and increased to 90.5% at 6 months. Six months success rate for teeth which had irreversible pulpitis was 100% and 83.3% for apical periodontitis. The mean time needed to complete a single visit RCT ranged from 77 min for a tooth having one canal to 132 min for one having four canals. Single visit RCT is a viable treatment option for teeth having irreversible pulpitis or apical periodontitis irrespective of tooth type or number of canals. A lot of patients are lost to follow-up visits for teeth requiring RCT once the pulp is extirpated at the first visit due to cessation of pain, subsequently leading to treatment failure. Single visit endodontics eliminates the need for follow-up visits and improves treatment prognosis.


Characterizing Swisher Little Cigar-Related Posts on Twitter in 2018: Text Analysis.
Little cigars are growing in popularity in the United States, and Swisher is the market leader. The contexts and experiences associated with the use of Swisher-related products is understudied, but such information is available via publicly available posts on Twitter. This study aimed to analyze Twitter posts to characterize Twitter users' recent experiences with Swisher-related products. Twitter posts containing the term "swisher" were analyzed from January 1, 2018, to December 31, 2018. Text classifiers were used to identify topics in posts (n=81,333). The most prevalent topic was Person Tagging (mentioning a Twitter account in a post; 32.77%), followed by Flavors (eg, Grape and Strawberry; 20.96%) and Swisher use (eg, smoke swisher; 17.44%). Additional topics included Cannabis use (eg, blunt, roll, and gut swisher; 6.26%), Appeal (eg, like Swisher; 5.92%), Dislike (eg, posts that showed dissatisfaction with Swisher products; 3.53%), Purchases (eg, buy swisher; 1.90%), and Cigar comparison (eg, mentions of other cigar products including White-owl and Backwoods; 1.64%). This paper describes common contexts and experiences associated with the use of Swisher little cigars from the population posting on Twitter in 2018. These online messages may have offline consequences for tobacco-related behaviors, indicating the need for countering from public health officials. Findings should inform us about targets for surveillance, policy, and interventions addressing Swisher little cigars as well as communication planning and tobacco product counter messaging on Twitter.


Experimental rugged fitness landscape in protein sequence space.
The fitness landscape in sequence space determines the process of biomolecular evolution. To plot the fitness landscape of protein function, we carried out in vitro molecular evolution beginning with a defective fd phage carrying a random polypeptide of 139 amino acids in place of the g3p minor coat protein D2 domain, which is essential for phage infection. After 20 cycles of random substitution at sites 12-130 of the initial random polypeptide and selection for infectivity, the selected phage showed a 1.7x10(4)-fold increase in infectivity, defined as the number of infected cells per ml of phage suspension. Fitness was defined as the logarithm of infectivity, and we analyzed (1) the dependence of stationary fitness on library size, which increased gradually, and (2) the time course of changes in fitness in transitional phases, based on an original theory regarding the evolutionary dynamics in Kauffman's n-k fitness landscape model. In the landscape model, single mutations at single sites among n sites affect the contribution of k other sites to fitness. Based on the results of these analyses, k was estimated to be 18-24. According to the estimated parameters, the landscape was plotted as a smooth surface up to a relative fitness of 0.4 of the global peak, whereas the landscape had a highly rugged surface with many local peaks above this relative fitness value. Based on the landscapes of these two different surfaces, it appears possible for adaptive walks with only random substitutions to climb with relative ease up to the middle region of the fitness landscape from any primordial or random sequence, whereas an enormous range of sequence diversity is required to climb further up the rugged surface above the middle region.