Integration of Entrustable Professional Activities with the Milestones for Emergency Medicine Residents.
Medical education is moving toward a competency-based framework with a focus on assessment using the Accreditation Council for Graduate Medical Education Milestones. Assessment of individual competencies through milestones can be challenging. While competencies describe characteristics of the person, the entrustable professional activities (EPAs) concept refers to work-related activities. EPAs would not replace the milestones but would be linked to them, integrating these frameworks. Many core specialties have already defined EPAs for resident trainees, but EPAs have not yet been created for emergency medicine (EM). This paper describes the development of milestone-linked EPAs for EM. Ten EM educators from across North America formed a consensus working group to draft EM EPAs, using a modified Glaser state-of-the-art approach. A reactor panel with EPA experts from the United States, Canada and the Netherlands was created, and an iterative process with multiple revisions was performed based on reactor panel input. Following this, the EPAs were sent to the Council of Residency Directors for EM (CORD-EM) listserv for additional feedback. The product was 11 core EPAs that every trainee from every EM program should be able to perform independently by the time of graduation. Each EPA has associated knowledge, skills, attitudes and behaviors (KSAB), which are either milestones themselves or KSABs linked to individual milestones. We recognize that individual programs may have additional focus areas or work-based activities they want their trainees to achieve by graduation; therefore, programs are also encouraged to create additional program-specific EPAs. This set of 11 core, EM-resident EPAs can be used as an assessment tool by EM residency programs, allowing supervising physicians to document the multiple entrustment decisions they are already making during clinical shifts with trainees. The KSAB list within each EPA could assist supervisors in giving specific, actionable feedback to trainees and allow trainees to use this list as an assessment-for-learning tool. Linking each KSAB to individual EM milestones allows EPAs to directly inform milestone assessment for clinical competency committees. These EPAs serve as another option for workplace-based assessment, and are linked to the milestones to create an integrated framework.


Hepatitis C virus infects and perturbs liver stem cells.
Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk remains unclear. Here, we identify bipotent liver stem cells as novel targets for HCV infection, and their erroneous differentiation as the potential cause of impaired liver regeneration and cancer development. We show 3D organoids generated from liver stem cells from actively HCV-infected individuals carry replicating virus and maintain low-grade infection over months. Organoids can be infected with a primary HCV isolate. Virus-inclusive single-cell RNA sequencing uncovered transcriptional reprogramming in HCV+ cells supporting hepatocytic differentiation, cancer stem cell development, and viral replication while stem cell proliferation and interferon signaling are disrupted. Our data add a new pathogenesis mechanism-infection of liver stem cells-to the biology of HCV infection that may explain progressive liver damage and enhanced cancer risk through an altered stem cell state.ImportanceThe hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.


Adverse effects of spinal manipulative therapy in children younger than 3 years: a retrospective study in a chiropractic teaching clinic.
The purpose of this study is to identify any adverse effects to chiropractic care occurring in the pediatric patient and to evaluate the risk of complications arising in the pediatric patient resulting from chiropractic care. A 3-year retrospective study of pediatric case files from the Anglo-European College of Chiropractic (AECC) (Bournemouth, England) teaching clinic practice in Bournemouth, England. All files (n = 781) of pediatric patients younger than 3 years of age were selected manually in sequential order from current files stored in the AECC clinic presenting to the AECC clinic during a specific period. Most (73.5%) patients presenting were 12 weeks of age or younger (n = 574). Six hundred ninety-seven children received a total of 5242 chiropractic treatments, with 85% of parents reporting an improvement. Seven parents reported an adverse effect. There was a reaction rate of approximately 1 child in 100, or one reaction reported for every 749 treatments. There were no serious complications resulting from chiropractic treatment (reactions lasting >24 hours or severe enough to require hospital care). This study shows that for the population studied, chiropractic manipulation produced very few adverse effects and was a safe form of therapy in the treatment of patients in this age group.


Effective potentials for representing polymers in melts as chains of interacting soft particles.
This paper outlines the derivation of an analytical pair potential in a coarse grained description of polymer melts where each chain is represented as a collection of soft spheres. Each particle is located at the center of mass of a polymer subchain, while the polymer is divided into an arbitrary number of identical chain subsections, each comprised of a large number of monomers. It is demonstrated that the soft effective pair potentials acting between these center-of-mass sites is described by a soft repulsive region at separation distances less than the average size of each coarse grained unit and a long repulsive tail, with a small attractive component. The attractive component is located at a length scale beyond the size of the coarse grained unit and its form varies with the level of interpenetration between the coarse-grained units. Consistent with numerically derived potentials, it is found that the short range features of the potential dominate the liquid structure, while the long-tail features dominate the virial-route thermodynamics of the system. It follows that the accurate determination of the effective potential in both short and large separation distances is relevant for ensuring structural and thermodynamic consistency in the coarse-grained description of the macromolecular liquid. It is further shown that due to the sensitivity of thermodynamic properties to the large-scale features of the potential, which are irrelevant to the reproducibility of structural correlations, the determination of thermodynamically accurate potentials by numerical optimization of structure alone is not a reliable strategy in the high-density regime for high levels of coarse-graining.


From Sidney to OLGA: an overview of atrophic gastritis.
Chronic gastritis is a long-lasting disease that can lead to a loss of appropriate gastric glands. Gastritis, as term, apply to an inflammation of the stomach, histologically proven, sometimes with structural mucosal changes. Worldwide Helicobacter pylori's infection play a pivotal role as the main etiological effector of chronic active gastritis. H. p. is a bacterium with a selective tropism for the gastric mucosa, able to survive in a hostile environment for colonization of organisms other than itself, able to develop strategies for survival and for avoidance of the defence mechanisms, causing inflammatory changes, that vary from asymptomatic mild gastritis to more severe injury such as peptic ulcer as well as premalignant lesions and malignant tumours. The pattern and distribution of gastritis strongly correlate with these sequelae and chronic atrophic gastritis with intestinal metaplasia is now assessed as a precancerous lesion with definite risk of evolution towards intraepithelial lesions of both low and high grade, as expected in the model of the Correa's cascade. In fact, the leading complication of chronic gastritis remains its close correlation with gastric cancer being biologically linked to H. pylori infection, nowadays known as a class I carcinogen. Gastric carcinogenesis is due to environmental factors, as well as to bacterial strain, host responses and gastric mucosal microbiome dysbiosis. Since, individual patients show different gastric cancer risk, it is mandatory to identify patients at risk of developing gastric cancer to offer a targeted search for lesions with a more rapid development of neoplasm liable, in an early phase, to a less destructive treatment. OLGA staging system is the most reliable and powerful system that allow the recognition of patient with a higher risk of developing gastric cancer.


Bempedoic acid: new evidence and recommendations on use.
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients. Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin- ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and are unable to reach targeted LDL-C values. Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in the lipid-lowering management.


Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction.
Coordinated activity-induced transcriptional changes across multiple neuron subtypes of the prefrontal cortex (PFC) play a pivotal role in encoding and regulating major cognitive behaviors. Yet, the specific transcriptional programs in each neuron subtype remain unknown. Using single-cell RNA sequencing (scRNA-seq), here we comprehensively classify all unique cell subtypes in the PFC. We analyze transcriptional dynamics of each cell subtype under a naturally adaptive and an induced condition. Adaptive changes during adolescence (between P21 and P60), a highly dynamic phase of postnatal neuroplasticity, profoundly impacted transcription in each neuron subtype, including cell type-specific regulation of genes implicated in major neuropsychiatric disorders. On the other hand, an induced plasticity evoked by chronic cocaine addiction resulted in progressive transcriptional changes in multiple neuron subtypes and became most pronounced upon prolonged drug withdrawal. Our findings lay a foundation for understanding cell type-specific postnatal transcriptional dynamics under normal PFC function and in neuropsychiatric disease states.


A data-driven, hyper-realistic method for visualizing individual mental representations of faces.
Research in person and face perception has broadly focused on group-level consensus that individuals hold when making judgments of others (e.g., "X type of face looks trustworthy"). However, a growing body of research demonstrates that individual variation is larger than shared, stimulus-level variation for many social trait judgments. Despite this insight, little research to date has focused on building and explaining individual models of face perception. Studies and methodologies that have examined individual models are limited in what visualizations they can reliably produce to either noisy and blurry or computer avatar representations. Methods that produce low-fidelity visual representations inhibit generalizability by being clearly computer manipulated and produced. In the present work, we introduce a novel paradigm to visualize individual models of face judgments by leveraging state-of-the-art computer vision methods. Our proposed method can produce a set of photorealistic face images that correspond to an individual's mental representation of a specific attribute across a variety of attribute intensities. We provide a proof-of-concept study which examines perceived trustworthiness/untrustworthiness and masculinity/femininity. We close with a discussion of future work to substantiate our proposed method.


Linkage disequilibrium under skewed offspring distribution among individuals in a population.
Correlations in coalescence times between two loci are derived under selectively neutral population models in which the offspring of an individual can number on the order of the population size. The correlations depend on the rates of recombination and random drift and are shown to be functions of the parameters controlling the size and frequency of these large reproduction events. Since a prediction of linkage disequilibrium can be written in terms of correlations in coalescence times, it follows that the prediction of linkage disequilibrium is a function not only of the rate of recombination but also of the reproduction parameters. Low linkage disequilibrium is predicted if the offspring of a single individual frequently replace almost the entire population. However, high linkage disequilibrium can be predicted if the offspring of a single individual replace an intermediate fraction of the population. In some cases the model reproduces the standard Wright-Fisher predictions. Contrary to common intuition, high linkage disequilibrium can be predicted despite frequent recombination, and low linkage disequilibrium under infrequent recombination. Simulations support the analytical results but show that the variance of linkage disequilibrium is very large.


Effects of the hierarchical macro/mesoporous structure on the osteoblast-like cell response.
To improve the success of medical devices, implants with strong surface bioactivity are urgently required. Coatings with a macroporous structure produced by micro-arc oxidation possess advantages, such as strong adhesion to substrate and excellent resistance to wear and corrosion. Mesoporous structures contain pores with sizes of 2-50 nm, which can endow the biomaterials with the ability to enhance osteogenesis and to be loaded with diverse drugs. Thus, in this study, we aimed to evaluate the effects of both macroporous and mesoporous structures using a hierarchical macro/mesoporous structure to modify the titanium implant surface. The behaviors of SaOS-2 human osteosarcoma cells on the macro/mesoporous structure, including initial adhesion, proliferation, alkaline phosphatase (ALP) activity, and collagen secretion, were investigated. Cells that attached on the macro/mesoporous surface showed the highest cell numbers and greatest spreading area after incubation for 1, 2, and 4 h compared with the polished smooth substrate and macroporous surface in the presence of fetal bovine serum (FBS). However, in the absence of FBS, cell adhesion on the polished substrate, macroporous structure, and macro/mesoporous structure did not differ significantly. Cell proliferation on the macroporous and macro/mesoporous surfaces increased compared with that on the smooth substrate surface. Furthermore, ALP activity and collagen secretion were enhanced on the macro/mesoporous structure. Our findings provided important insights into the cellular responses to macro/mesoporous structures in the field of implant surface modification. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1896-1902, 2018.


Current status and progress of focal therapy in Asia.
With the increasing incidence of low-to-intermediate risk of prostate cancer (PCa) by the introduction of prostate-specific antigen (PSA) screening, focal therapy has become one of the promising treatment options in the world. In Asia, same movement are occurring using several technologies including cryoablation, high-intensity focused ultrasound, brachytherapy and irreversible electroporation. However, these are still not common strategies to treat organ-confined PCa. The purpose of this review is to summarize the most updated experience and future direction of focal therapy in Asian countries. The prevalence and diagnosis of PCa are increasing in Asian countries. This increase is related to various factors including the widespread implementation of PSA testing and lifestyle changes to more Westernized diets. With the increasing detection rate of early stage PCa, overdetection and overtreatment are recognized even in Asia. In this setting, accumulating data on multiparametric MRI and MRI-targeted biopsy as well as MRI-transrectal ultrasound (TRUS) fusion biopsy suggest the potential in improving the detection of clinically significant PCa in Asia. Furthermore, targeted focal therapy has emerged as a promising treatment strategy aiming for both providing oncological outcome and maintaining functional preservation in many Asian countries. At present, focal therapy is not a current standard choice for the treatment of localized PCa in Asian countries. However, with the increase of localized PCa and patient's preference for less invasive treatment with preservation of organ-function, focal therapy should become a definite treatment option for localized PCa in Asia.


The impact of hypotension due to the trigeminocardiac reflex on auditory function in vestibular schwannoma surgery.
Surgical manipulation of the fifth cranial nerve during its intra- or extracranial course may lead to bradycardia or even asystole as well as arterial hypotension, a phenomenon described as the trigeminocardiac reflex (TCR). The authors studied the impact of this reflex on postoperative auditory function in patients undergoing vestibular schwannoma (VS) surgery. One hundred patients scheduled for VS surgery were studied prospectively for parameters influencing the postoperative auditory function. The evaluation included sex, age, pre- and postoperative auditory function, preoperative mean arterial blood pressure, preoperative medical diseases or medication (for example, antiarrhythmia drugs), tumor size and localization, and the intraoperative occurrence of the TCR. The TCR, which occurred in 11% of the patients, influenced the postoperative hearing function in the patients with Hannover Class T3 and T4 VSs. With an overall hearing preservation of 47%, 11.1% of the patients in the TCR group and 51.4% of those in the non-TCR group experienced preserved hearing function postoperatively. In cases involving larger tumors (Hannover Class T3 and T4), an intraoperative TCR was associated with a significantly worse postoperative hearing function during VS surgery (p = 0.005). The hypotension following TCR is a negative prognostic factor for hearing preservation in patients undergoing VS surgery. Patients' knowledge of this can be increased pre- and postoperatively. Further study of this phenomenon will advance the understanding of the underlying mechanisms and may help to improve hearing preservation by controlling the occurrence of the TCR.


Retention cuff pressure study of 3 indwelling stool management systems: randomized study of 10 healthy subjects.
The purpose of this study was to compare retention cuff pressures of 3 indwelling stool management systems while subjects assumed different body positions and while cuffs were inflated to different volumes. Retention cuff pressure study of 3 indwelling stool management systems was a randomized, crossover, open-label pilot study of 10 healthy adult volunteers in 3 body positions (supine, right side, and left side), 3 head-of-bed elevations (20°, 30°, and 40°), and 3 cuff overfill volumes (5, 10, and 15 mL). The devices were DigniCare Stool Management System (device A; Bard Medical Division, C. R. Bard, Inc, Covington, Georgia), Flexi-Seal Fecal Management System (device B; ConvaTec, a division of E. R. Squibb & Sons, LLC, Princeton, New Jersey), and ActiFlo Indwelling Bowel Catheter System (device C; Hollister, Inc, Libertyville, Illinois). We assessed cuff pressure by manometry and rectal mucosa by digital examination and small-diameter, flexible endoscopy. Cuffs were appropriately seated in the rectal vault for all 3 devices in all body positions and overfill volumes. Rectal mucosal abnormalities were observed in 4 of 10 subjects (40%) after removal of device A, 1 of 5 (20%) after removal of device B, and 3 of 5 (60%) after removal of device C. Retention cuff pressure was at least 2-fold lower for device A than for device B or C in all body positions, head-of-bed elevations, and device overfill volumes. For example, mean pressure while subjects were on their left sides was 25.0 mm Hg for device A, 79.2 mm Hg for device B, and 67.2 mm Hg for device C. Corresponding pressures at 15 mL of overfill were 52.5, 102.0, and 94.0 mm Hg. Subject comfort scores were comparable for all 3 devices. All devices appeared to seat well within the rectal vault, but device A was associated with cuff pressure measurements that were consistently lower than those of devices B and C. More studies are needed to elucidate the clinical relevance of these findings and whether they translate to differences in patient safety or comfort.


RAF protein-serine/threonine kinases: structure and regulation.
A-RAF, B-RAF, and C-RAF are a family of three protein-serine/threonine kinases that participate in the RAS-RAF-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, differentiation, proliferation, and transformation to the cancerous state. RAS mutations occur in 15-30% of all human cancers, and B-RAF mutations occur in 30-60% of melanomas, 30-50% of thyroid cancers, and 5-20% of colorectal cancers. Activation of the RAF kinases requires their interaction with RAS-GTP along with dephosphorylation and also phosphorylation by SRC family protein-tyrosine kinases and other protein-serine/threonine kinases. The formation of unique side-to-side RAF dimers is required for full kinase activity. RAF kinase inhibitors are effective in blocking MEK1/2 and ERK1/2 activation in cells containing the oncogenic B-RAF Val600Glu activating mutation. RAF kinase inhibitors lead to the paradoxical increase in RAF kinase activity in cells containing wild-type B-RAF and wild-type or activated mutant RAS. C-RAF plays a key role in this paradoxical increase in downstream MEK-ERK activation.


Analysis of anaphase figures in routine histologic sections distinguishes chromosomally unstable from chromosomally stable malignancies.
A classification of neoplasms as chromosomally stable vs. unstable is of importance in assessing inherited risks but is primarily defined in cell lines where rates of instability can be directly measured. The confirmation of such a mechanistic theory in primary tissues is desirable. We examined anaphase figures in histologic slides to evaluate such criteria. The process of chromosomal instability (CIN) involves mis-segregation of chromosomes at anaphase in some or most instances, whereas chromosomally stable tumors should lack these particular abnormalities. Anaphase bridges are associated with chromosome mis-segregation and have occasionally been observed in colorectal neoplasia and in sarcomas, but have not been considered for use as a diagnostic tool. We assembled series of sarcomas, colorectal and pancreatic carcinomas belonging to two groups: those associated with or lacking chromosomal instability. Among the chromosomally stable tumors, all lacked anaphase bridges, while anaphase bridges were found in most sarcomas and carcinomas having complex genomic alterations. These results confirm a mechanistic explanation involving chromosome mis-segregation for primary human cancers having aneuploidy/CIN. A basic mechanistic distinction between neoplasms with CIN and those with minimal chromosomal changes is supported. Most importantly, our data suggest a diagnostic utility for the examination of anaphase bridges in the routine practice of pathology with a high potential to impact clinical decision-making processes regarding colorectal cancer treatment.


Marinomonas mediterranea is a lysogenic bacterium that synthesizes R-bodies.
The melanogenic marine bacterium Marinomonas mediterranea synthesizes R-bodies as revealed by transmission electron microscopy. These structures were previously described in some obligate symbionts of paramecia and some free-living bacteria, none of which was isolated from sea water. In other micro-organisms, the synthesis of R-bodies has been related to extrachromosomal elements. Accordingly, M. mediterranea induction by mitomycin C or UV radiation resulted in the production of defective phages resembling bacteriocins, indicating that it is a lysogenic bacterium. Two mitomycin-C-resistant strains defective in prophage replication have been isolated. These mutants, and the previously obtained strains ngC1, T102 and T103, the latter mutated in the ppoS gene encoding a sensor histidine kinase, are affected not only in phage replication but also in polyphenol oxidase activities and melanin synthesis, suggesting a relationship between the control of all these processes.


An in vitro model for the induction of angiotensin-converting enzyme in sarcoidosis. Evidence for a soluble ACE-inducing factor.
Normal peripheral blood T-lymphocytes (T) enhance monocyte (Mo) angiotensin converting enzyme (ACE) production in vitro. To evaluate the possible role of a soluble mediator in enzyme induction, the ability of conditioned medium (CM) from Mo-T cocultures to stimulate ACE in fresh Mo was examined. These studies demonstrated that CM promoted a dose-dependent increase in ACE. Generation of the active factor required both Mo and T during culture since neither cell alone yielded active CM. Time course studies revealed that the ACE-inducing activity appeared in CM after 3 to 4 days of culture and increased steadily thereafter. The CM effectively induced ACE in Mo from several donors in contrast to T-dependent induction, which required autologous conditions. The time courses for T-dependent and CM-dependent ACE induction were similar, and the results suggested that the Mo must go through some period of maturation before they respond to CM. We conclude that a soluble mediator derived from Mo-T cocultures enhances Mo ACE production. This in vitro system may be a useful experimental model of the in vivo induction of ACE in the Mo-derived sarcoid epithelioid cell.


Ischemic chiasma syndrome.
Thirty patients with chiasma syndrome attributed to ischemic processes of various origins are described. The initial diagnosis was made after an investigation based on polytome pneumoencephalography and angiography. This diagnosis was confirmed later with the use of high-resolution computed tomography (CT) and refined angiographic techniques. The ischemic chiasma syndrome may be classified into five pathogenetic categories: (1) mechanical compression of the chiasm secondary to ectatic tortuous arteries; (2) vascular occlusion secondary to atheromatous plaque formation; (3) arachnoiditis with fibrosis; (4) arteritis of various origins; and (5) postpartum necrosis. Sophisticated neurologic procedures including magnification angiography and high-resolution CT are essential in ruling out a mass lesion and correlating the clinical and radiologic findings of this syndrome.


Pharmacological Characterization of the αvβ6 Integrin Binding and Internalization Kinetics of the Foot-and-Mouth Disease Virus Derived Peptide A20FMDV2.
A20FMDV2 is a peptide derived from the foot-and-mouth disease virus with a high affinity and selectivity for the alpha-v beta-6 (αvβ6) arginyl-glycinyl-aspartic acid (RGD)-binding integrin. It has been shown to be an informative tool ligand in pre-clinical imaging studies for selective labelling of the αvβ6 integrin in a number of disease models. In a radioligand binding assay using a radiolabelled form of the peptide ([3H]A20FMDV2), its high affinity (K(D): 0.22 nmol/l) and selectivity (at least 85-fold) for αvβ6 over the other members of the RGD integrin family was confirmed. [3H]A20FMDV2 αvβ6 binding could be fully reversed only in the presence of EDTA, whereas a partial reversal was observed in the presence of excess concentrations of an RGD-mimetic small molecule (SC-68448) or unlabelled A20FMDV2. Using flow cytometry on bronchial epithelial cells, the ligand-induced internalization of αvβ6 by A20FMDV2 and latency-associated peptide-1 was shown to be fast (t(1/2): 1.5 and 3.1 min, respectively), concentration-dependent (EC50: values 1.1 and 3.6 nmol/l, respectively) and was followed by a moderately slow return of integrin to the surface. The results of the radioligand binding studies suggest that the binding of A20FMDV2 to the RGD-binding site on αvβ6 is required to maintain its engagement with the hypothesised A20FMDV2 synergy site on the integrin. In addition, there is evidence from flow cytometric studies that the RGD-ligand engagement of αvβ6 post-internalization plays a role in delaying recycling of the integrin to the cell surface. This mechanism may act as a homeostatic control of membrane αvβ6 following RGD ligand engagement.


[Behavioral functions of serotonin and octopamine: some paradoxes of comparative physiology].
Evaluation of recent data on monoaminergic control of invertebrate behavior suggests that behavioral functions of serotonin in molluscs and octopamine in insects are remarkably similar. Specifically, in the respective taxa, these monoamines are responsible for activation of food searching and intense locomotion, increase in food consumption and general activity, enhancement of cardial and respiratory rhythms, facilitation of learning, sensitization of sensory circuits. At the same time, in insects, behavioral effects of serotonin are opposite to those of octopamine. It seems thus that two monoamines have exchanged their behavioral roles in the two major invertebrate taxa. Possible reasons of this paradoxical inversion touches inevitably upon basic questions of signal molecular evolution.


Evidence for Rho-dependent control of a virulence switch in Acinetobacter baumannii.
Acinetobacter baumannii is a significant cause of infections in the healthcare setting. More recently, A. baumannii has been a leading cause of secondary bacterial pneumonia in patients infected with SARS-CoV-2 and the overall frequency of A. baumannii infection increased 78% during the COVID-19 pandemic. A. baumannii can exist in virulent or avirulent subpopulations and this interconversion is mediated by the expression of a family of TetR-type transcriptional regulators. In this study, we demonstrate that Rho is a key regulatory component in the expression of these TetR regulators. Overall, this study is the first to address a role for Rho in A. baumannii and provides additional evidence for the role of Rho in regulating diversity in bacterial subpopulations.


Treatment of benign prostatic hyperplasia using transurethral split of the prostate with a columnar balloon catheter.
Transurethral dilation of the prostate (TUDP) with a spherical balloon catheter is a traditional treatment for patients with benign prostatic hyperplasia (BPH). TUDP, however, has been abandoned in clinical application because of its unsatisfying treatment benefit and severe complications. In this study, we redesigned an improved TUDP surgical procedure-transurethral split of the prostate (TUSP)-by replacing the spherical balloon with a columnar balloon. To evaluate the clinical therapeutic effect, we compared the lower urinary tract symptoms (LUTS) of patients with BPH after TUSP treatment and analyzed the urethra through CT films. Animal experiments were performed on aged dogs to investigate the urine function and electromyography (EMG) changes. Histopathology was used to evaluate the inflammation and injury. In addition, collagen content was detected by Trichrome Masson. TUSP attenuated LUTS and reconstructed the urethra in patients with BPH. The attenuation of LUTS was reflected in terms of LUTS parameters such as peak urine flow rate, postvoid residual urine volume, quality of life score, and International Prostate Symptom Score. TUSP expanded the urethra in experimental dogs by splitting the prostate tissues and decreasing the collagen content, with maintenance of normal urinary function and EMG characteristics. The successful clinical application of TUSP with significant therapeutic effect and limited complications made TUSP an ideal choice for the patients with BPH.


High degree of population subdivision in a widespread amphibian.
In general, amphibians are known to exhibit a higher degree of population subdivision than any other major animal taxa, but large-scale population genetic surveys of widely distributed species are still scarce, especially in the Eurasian continent. Using microsatellite markers and mitochondrial DNA sequences, we investigated the large-scale population genetic structure of the common frog (Rana temporaria)--one of the most widespread amphibians of the Palearctic region. Analyses of cytochrome b sequences revealed evidence for two distinct lineages inhabiting western and eastern parts of Europe. The separation of these lineages c. 700,000 years ago may have been induced by the onset of the Middle Pleistocene continental glaciations. Analyses of the variability of microsatellite loci within each of the clades revealed evidence for evolution of a high degree of population subdivision (FST approximately 0.23) even in northern Fennoscandia, colonized less than 10,000 years ago. The high level of substructuring is puzzling in the face of an apparently high dispersal capacity, as evidenced by the rather rapid recolonization of northern Europe. This suggests that processes other than restricted dispersal capacity need to be explored as explanations for the high degree of population subdivision in amphibians. The colonization of northern Europe has been accompanied by loss of genetic variability as evidenced by decreasing levels of intrapopulational genetic variability in microsatellite loci from south to north across Europe.


Clinical Neurology in Practice: The Tongue (part 2).
The tongue is an essential organ for the development of certain crucial functions such as swallowing and speech. The examination of the tongue can be very useful in neurology, as the various types of lingual alterations can lead to certain specific diagnoses, the tongue being a kind of 'mirror' of some neurological function. To discuss the elements of clinical examination of the tongue in relation to neurological disorders. After reviewing the different superficial lesions of the tongue, we deal with various movement disorders of the tongue (fasciculations/myokimia, orolingual tremor, choreic movements of the tongue, dystonia of the tongue, lingual myoclonus, and psychogenic movements), disorders of taste and lingual sensitivity and lingual pain. Examination of the tongue should not be limited to studying its motility and trophicity. It is equally important to check the sensory function and understand how to interpret abnormal movements involving the tongue. This study also aimed to demonstrate the importance of nonmotor tongue function in neurological practice.


Decreased serotonin transporter immunoreactivity in the human hypothalamic infundibular nucleus of overweight subjects.
That serotonin plays a role in the regulation of feeding behavior and energy metabolism has been known for a long time. Serotonin transporters (SERT) play a crucial role in serotonin signaling by regulating its availability in the synaptic cleft. The neuroanatomy underlying serotonergic signaling in humans is largely unknown, and until now, SERT immunoreactivity in relation to body weight has not been investigated. To clarify the distribution of SERT immunoreactivity throughout the human hypothalamus and to compare SERT immunoreactivity in the infundibular nucleus (IFN), the human equivalent of the arcuate nucleus, in lean and overweight subjects. First, we investigated the distribution of serotonin transporters (SERT) over the rostro-caudal axis of six post-mortem hypothalami by means of immunohistochemistry. Second, we estimated SERT immunoreactivity in the IFN of lean and overweight subjects. Lastly, double-labeling of SERT with Neuropeptide Y (NPY) and melanocortin cell populations was performed to further identify cells showing basket-like SERT staining. SERT-immunoreactivity was ubiquitously expressed in fibers throughout the hypothalamus and was the strongest in the IFN. Immunoreactivity in the IFN was lower in overweight subjects (p = 0.036). Basket-like staining in the IFN was highly suggestive of synaptic innervation. A very small minority of cells showed SERT double labeling with NPY, agouti-related protein and α-melanocyte stimulating hormone. SERT is ubiquitously expressed in the human hypothalamus. Strong SERT immunoreactivity, was observed in the IFN a region important for appetite regulation, in combination with lower SERT immunoreactivity in the IFN of overweight and obese subjects, may point toward a role for hypothalamic SERT in human obesity.


Differential visual processing for equivalent retinal information from near versus far space.
Converging evidence from animal neurophysiology and human clinical studies has suggested that visual information arising from near versus far space may be mediated predominantly by different visual subsystems in the human brain. In five experiments, healthy observers either detected or identified brief peripheral targets presented in near (peripersonal) versus far (extrapersonal) space. Apparent size (subtended visual angle) and luminance were equated to provide equivalent retinal information across near and far viewing conditions. Peripheral detection accuracy declined more rapidly with increasing target eccentricity in far viewing versus near viewing conditions. Peripheral identification accuracy under similar conditions showed no such dissociation of near versus far processing with eccentricity. These data suggest that retinal information from near versus far space may be preferentially processed by substantially different neural substrates, with active modulation of the relative contributions of involved magnocellular-dorsal and parvocellular-ventral visual pathways, depending on various potential ecological uses of the retinal information.


Variation in the measurement of cranial volume and surface area using 3D laser scanning technology.
Three-dimensional (3D) laser scanner models of human crania can be used for forensic facial reconstruction, and for obtaining craniometric data useful for estimating age, sex, and population affinity of unidentified human remains. However, the use of computer-generated measurements in a casework setting requires the measurement precision to be known. Here, we assess the repeatability and precision of cranial volume and surface area measurements using 3D laser scanner models created by different operators using different protocols for collecting and processing data. We report intraobserver measurement errors of 0.2% and interobserver errors of 2% of the total area and volume values, suggesting that observer-related errors do not pose major obstacles for sharing, combining, or comparing such measurements. Nevertheless, as no standardized procedure exists for area or volume measurements from 3D models, it is imperative to report the scanning and postscanning protocols employed when such measurements are conducted in a forensic setting.


Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention.
Sleep-disordered breathing (SDB) has been associated with insulin resistance and glucose intolerance, and is frequently found in people with type 2 diabetes. SDB not only causes poor sleep quality and daytime sleepiness, but has clinical consequences, including hypertension and increased risk of cardiovascular disease. In addition to supporting the need for further research into the links between SDB and diabetes, the International Diabetes Federation Taskforce on Epidemiology and Prevention strongly recommends that health professionals working in both type 2 diabetes and SDB adopt clinical practices to ensure that a patient presenting with one condition is considered for the other.


Maternal Periodontal Disease: A Possible Risk Factor for Adverse Pregnancy Outcomes in the Qassim Region of Saudi Arabia.
In periodontal disease, pathogenic inflammatory factors hold a vital part in adverse pregnancy outcomes. In recent years, there has been a large amount of literature concerning the association between periodontal disease and adverse pregnancy outcomes such as preterm birth (PTB) and low-birth-weight baby (LBWB). In the Middle-east region, reports indicate a higher rate of adverse pregnancy outcomes, and periodontitis is believed to be one of several risk factors for adverse pregnancy outcomes. This cross-sectional, epidemiological study aimed to investigate the prevalence of periodontal diseases among pregnant women in the Qassim region and its association as a possible risk factor for adverse pregnancy outcomes. This was a cross-sectional, epidemiological study of 380 pregnant women from the 8th week postconception to parturition who were attending to Maternal and Children's Hospital in Buraidah, Qassim, KSA. The data were collected through questionnaire and oral examination. Plaque scores (Silness and Loe) and gingival disease scores (Ramfjord Periodontal Disease Index [PDI]) were used to assess oral hygiene status. The questionnaire data collected included gestational age, plaque control habits, previous incidences of premature birth, and awareness of expectant mothers about periodontal disease. Data were collected for 380 participants. Our results based on the plaque index and PDI showed that all (100%) of these 380 pregnant women suffered periodontal diseases (gingivitis 78.9% and periodontitis 21.1%). The distribution of gingivitis was the highest among 3rd trimester patients and lowest among 1st trimester patients. Mild-to-moderate types of periodontitis (4 mm-5 mm) were more prevalent among the participants compared with severe (more than 6 mm) forms of periodontitis with a higher prevalence in the 3rd trimester (7-9 months) of gestational age. A very strong significant association of pregnancy and periodontal disease in the Saudi population (Qassim Region) and periodontal disease is risk factor for PTB and LBWB for these patients.


In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources.
Preclinical noninvasive imaging can be an indispensable tool for studying animal models of disease. In vivo imaging to assess anatomical, functional, and molecular features requires verification by a comparison to the macroscopic and microscopic morphological features, since all noninvasive in vivo imaging methods have much lower resolution than standard histopathology. Comprehensive pathological evaluation of the animal model is underutilized; yet, many institutions have veterinary or human pathologists with necessary comparative pathology expertise. By performing a rigorous comparison to gross or histopathology for image interpretation, these trained individuals can assist scientists with the development of the animal model, experimental design, and evaluation of the in vivo imaging data. These imaging and pathology corroboration studies undoubtedly increase scientific rigor and reproducibility in descriptive and hypothesis-driven research. A review of case examples including ultrasound, nuclear, optical, and MRI is provided to illustrate how a wide range of imaging modalities data can be confirmed by gross or microscopic pathology. This image confirmation and authentication will improve characterization of the model and may contribute to decreasing costs and number of animals used and to more rapid translation from preclinical animal model to the clinic.


Matrix metalloproteinases 2 and 9, and extracellular matrix in Kaposi's sarcoma.
Matrix metalloproteinases (MMPs) are associated with Kaposi's sarcoma (KS) tumorigenesis and may contribute to the mechanism of KS invasive growth. To date, only a few MMPs have been studied in KS lesions, and exactly which MMPs are involved in KS development and progression remains unanswered. However, MMPs 2 and 9 have been associated with different phases of angiogenesis, but their role in the proteolytic modification of the extracellular matrix has not been investigated. The results of this study confirm that MMPs, specifically MMP-2 and MMP-9, can contribute to angiogenesis by disrupting the vessel basement membrane and other extracellular matrix barriers, and enabling endothelial cells migration through the surrounding tissues.


CrossCheck: an open-source web tool for high-throughput screen data analysis.
Modern high-throughput screening methods allow researchers to generate large datasets that potentially contain important biological information. However, oftentimes, picking relevant hits from such screens and generating testable hypotheses requires training in bioinformatics and the skills to efficiently perform database mining. There are currently no tools available to general public that allow users to cross-reference their screen datasets with published screen datasets. To this end, we developed CrossCheck, an online platform for high-throughput screen data analysis. CrossCheck is a centralized database that allows effortless comparison of the user-entered list of gene symbols with 16,231 published datasets. These datasets include published data from genome-wide RNAi and CRISPR screens, interactome proteomics and phosphoproteomics screens, cancer mutation databases, low-throughput studies of major cell signaling mediators, such as kinases, E3 ubiquitin ligases and phosphatases, and gene ontological information. Moreover, CrossCheck includes a novel database of predicted protein kinase substrates, which was developed using proteome-wide consensus motif searches. CrossCheck dramatically simplifies high-throughput screen data analysis and enables researchers to dig deep into the published literature and streamline data-driven hypothesis generation. CrossCheck is freely accessible as a web-based application at http://proteinguru.com/crosscheck.


Effectiveness of Platelet-Rich Plasma in the Prevention of Chlamydia-Induced Hydrosalpinx in a Murine Model.
Chlamydia trachomatis (C. trachomatis) is a major pathogen implicated in the formation of hydrosalpinx in the female reproductive tract. In mice, a related strain of Chlamydia, Chlamydia trachomatis (C. trachomatis) can induce almost 100% bilateral hydrosalpinx. This model was used as a hydrosalpinx induction model to test whether oviduct delivery of platelet-rich plasma (PRP) can attenuate chlamydia induction of hydrosalpinx in a mouse model. Mice were infected intravaginally with Chlamydia muridarum organisms, and 21 days after the infection, PRP was instilled into the lumen of one oviduct, and a sham instillation with phosphate buffer solution was performed on the contralateral oviduct. Mice were then sacrificed at designated time points after infection for oviduct pathologic evaluation including incidence, severity, and histopathologic grade of chronic inflammation. Oviduct instillation of PRP was associated with a 36% reduction in the incidence of hydrosalpinx and a 33% reduction in severity compared with sham. The median grade of chronic inflammation on histopathology was significantly lower with PRP instillation compared with sham and control. No differences were observed in vaginal or rectal shedding of C. muridarum between the test group and the control group. In short, the results suggest that oviduct instillation of PRP can significantly reduce the incidence and severity of C. muridarum-induced hydrosalpinx without affecting chlamydial infection courses in CBA/J mice.


Nebulizing conditions of pneumatic electrospray ionization significantly influence electrolyte effects on compound measurement.
Composition of mobile phase can greatly influence the success of electrospray ionization (ESI)-interfaced liquid chromatography-mass spectrometry analysis. To investigate the relationship between formic-acid-based modification of mobile phase and ESI nebulizing conditions, an API 4000 ESI source and a TSQ Quantum one were compared under the same chromatographic conditions. Ginkgo terpene lactones and flavonols were measured in plasma, which involved using ascorbic acid to circumvent cross-interference between the analytes. ESI responses to using formic acid included changes in signal intensity, matrix effect, and upper limit of quantification. Significant disparities in the responses were observed between the two ESI sources, suggesting that the use of electrolyte modifier in liquid chromatography mobile phase and the pneumatic nebulization for ESI should be properly balanced to accomplish optimal ESI-based analysis. The distribution of unpaired ions toward the surface of the initial droplet was assumed to be an important step in the pneumatic ESI process. When using the electrolyte in mobile phase, a too fast droplet reduction by rapid-heating-assisted pneumatic nebulization could negatively decrease the time available for the unpaired ions to migrate from droplet interior to its surface. Ascorbic acid was identified as a major interfering substance for the bioanalytical assay; the interference mechanism might be associated with hindering the unpaired analyte ions from distributing toward the droplet surface rather than outcompeting the analyte ions for the limited excess charge on droplets surface. The current work extends the knowledge base of pneumatic ESI, which has implication for optimal use of the ESI-interfaced liquid chromatography-mass spectrometry technique.


N-methyl-D-aspartate receptors, nitric oxide, and ethanol tolerance.
Several experimental models have been used to study tolerance to ethanol. The development of tolerance to the motor incoordinating effect of a single administration of ethanol occurs within 8-24 h after the effect of the first dose has disappeared. This form of tolerance is designated rapid tolerance and seems to involve functional rather than pharmacokinetic mechanisms. Like chronic tolerance, rapid tolerance has been shown to be influenced by processes related to learning and memory. It is known that N-methyl-D-aspartate (NMDA) receptor systems are involved in the expression and maintenance of one form of long-term potentiation (LTP), a synaptic adaptive process which has been suggested to be the cellular basis of memory or associative memory. Considering the similarities between learning and tolerance, the effects of NMDA agonists and antagonists on tolerance to ethanol were investigated. Our studies demonstrated that NMDA antagonists that impair learning, such as dizocilpine or ketamine, inhibit tolerance, while NMDA agonists that improve learning, such as D-cycloserine, increase tolerance. Moreover, the nitric oxide synthase inhibitor L-nitroarginine blocks tolerance to the effects of ethanol. Taken together, these data confirm the involvement of the NMDA system in ethanol tolerance and emphasize the participation of learning in this phenomenon.


Rhemulatologists' performance in dailiy practice.
To assess rheumatologists' performance for 8 rheumatologic conditions and to explore possible explanatory factors. After written informed consent was obtained, 27 rheumatologists (21% of all Dutch rheumatologists) practicing in 16 outpatient departments were each visited by 8 incognito "standardized patients" (SPs). The diagnoses of these 8 cases account for about 23% of all new referred patients in the Netherlands. Results for ordered lab tests as well as real radiographs with corresponding results from a radiologist were simulated. Information from the visits was obtained from the SPs, who completed predefined case-specific checklists, and by collecting data on resource utilization. Feedback was provided. Altogether 254 encounters took place, of which 201 were first visits and 53 were followup visits. SPs were unmasked twice during a visit. There was considerable variation in resource utilization (lab tests and imaging) between cases and between rheumatologists. Mean costs per rheumatologist ranged from US $ 4.67 to $ 65.36 per visit for lab tests and from US $ 33.15 to $ 226.84 per visit for imaging tests. No significant correlations were seen between resource utilization costs and number of years of clinical experience or performance on checklist scores. Rheumatologists with longer experience had lower total item checklist scores (r = -0.47; P < 0.05). A considerable variation in resource utilization was found among 27 Dutch rheumatologists. The information obtained is an excellent source for discussion on the appropriateness of care.


Co-infection of Acipenserid herpesvirus 2 (AciHV-2) and Streptococcus iniae in cultured white sturgeon Acipenser transmontanus.
A mortality event in cultured white sturgeon Acipenser transmontanus (Richardson, 1836) sub-adults was investigated. After transfer between farms, high mortality was observed in fish, associated with back arching, abnormal swimming, and ulcerative skin lesions. Necropsy of moribund individuals revealed hemorrhagic ascites and petechial hemorrhages in the coelomic peritoneum and serosa of internal organs. Acipenserid herpesvirus 2 (AciHV-2) was isolated from external tissue samples, then identified and genotyped by sequencing of the terminase and polymerase genes. In addition, Streptococcus iniae was recovered from internal organs of affected fish. Histologic changes were limited to interstitial hematopoietic areas of the kidney and consisted of small foci of necrosis accompanied by fibrin deposition, minimal inflammatory response, and small numbers of bacterial cocci compatible with streptococci. Identity was confirmed by partial sequencing of the 16S rRNA, rpoB, and gyrB genes. Genetic fingerprinting demonstrated a genetic profile distinct from S. iniae isolates recovered from previous outbreaks in wild and cultured fish in North America, South America, and the Caribbean. Although the isolates were resistant to white sturgeon complement in serum killing assays, in vivo challenges failed to fulfill Koch's postulates. However, the clinical presentation, coupled with consistent recovery of S. iniae and AciHV-2 from moribund fish, suggests viral and bacterial co-infection were the proximate cause of death. To our knowledge, this represents the first report of AciHV-2 and S. iniae co-infection in cultured white sturgeon.


Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters.
In order to investigate whether the stimulation of liver DNA synthesis might be used to detect one class of hepatic tumor promoters, the incorporation of orally administered radiolabelled thymidine into liver DNA was determined in rats and mice 24 h after a single oral gavage of test compounds at various dose levels. Three DNA-binding hepatocarcinogens, aflatoxin B1, benzidine and carbon tetrachloride, did not stimulate but rather inhibited DNA synthesis (not for CCl4). Four hepatic tumor promoters, clofibrate, DDT, phenobarbital and thioacetamide, gave rise to a stimulation in a dose-dependent manner. Single oral doses between 0.02 and 0.3 mmol/kg were required to double the level of thymidine incorporation into liver DNA (= doubling dose, DD). Differences between species or sex as observed in long-term carcinogenicity studies were reflected by a different stimulation of liver DNA synthesis. In agreement with the bioassay data, aldrin was positive only in male mice (DD = 0.007 mmol/kg) but not in male rats of female mice. 2,3,7,8-TCDD was positive in male mice (DD = 10(-6) mmol/kg) and in female rats (DD = 2 X 10(-6) mmol/kg) but not in male rats. The assay was also able to distinguish between structural isomers with different carcinogenicities. [alpha]Hexachlorocyclohexane stimulated liver DNA synthesis with a doubling dose of about 0.2 mmol/kg in male rats whereas the [gamma]-isomer was ineffective even at 1 mmol/kg. So far, only one result was inconsistent with carcinogenicity bioassay data. The different carcinogenicity of di(2-ethylhexyl)adipate (negative in rats) and di(2-ethylhexyl)phthalate (positive) was not detectable. Both plasticizers were positive in this short-term system with DD's of 0.7 mmol/kg for DEHA and 0.5 mmol/kg for DEHP. The proposed assay is discussed as an attempt to devise short-term assays for carcinogens not detected by the routine genotoxicity test systems.


Cryptic chytridiomycosis linked to climate and genetic variation in amphibian populations of the southeastern United States.
North American amphibians have recently been impacted by two major emerging pathogens, the fungus Batrachochytrium dendrobatidis (Bd) and iridoviruses in the genus Ranavirus (Rv). Environmental factors and host genetics may play important roles in disease dynamics, but few studies incorporate both of these components into their analyses. Here, we investigated the role of environmental and genetic factors in driving Bd and Rv infection prevalence and severity in a biodiversity hot spot, the southeastern United States. We used quantitative PCR to characterize Bd and Rv dynamics in natural populations of three amphibian species: Notophthalmus perstriatus, Hyla squirella and Pseudacris ornata. We combined pathogen data, genetic diversity metrics generated from neutral markers, and environmental variables into general linear models to evaluate how these factors impact infectious disease dynamics. Occurrence, prevalence and intensity of Bd and Rv varied across species and populations, but only one species, Pseudacris ornata, harbored high Bd intensities in the majority of sampled populations. Genetic diversity and climate variables both predicted Bd prevalence, whereas climatic variables alone predicted infection intensity. We conclude that Bd is more abundant in the southeastern United States than previously thought and that genetic and environmental factors are both important for predicting amphibian pathogen dynamics. Incorporating both genetic and environmental information into conservation plans for amphibians is necessary for the development of more effective management strategies to mitigate the impact of emerging infectious diseases.


Unravelling functional neurology: does spinal manipulation have an effect on the brain? - a systematic literature review.
A recent hypothesis purports that spinal manipulation may cause changes at a brain level. Functional Neurology, a mainly chiropractic approach, promotes the use of spinal manipulation to improve 'brain function' as if it were a proven construct. No systematic review has been performed to investigate how well founded this hypothesis is. To investigate whether spinal manipulation has an effect on 'brain function' that is associated with any clinical benefits. In this systematic review, the literature was searched in PubMed, Embase, and PEDro (final search February 2018). We included randomized or non-randomized controlled studies, in which spinal manipulation was performed to any region of the spine, applied on either symptomatic or asymptomatic humans, and compared to a sham or to another type of control. The outcome measures had to be stated as direct or proxy markers of 'brain function'. Articles were reviewed blindly by at least two reviewers, using a quality checklist designed for the specific needs of the review. Studies were classified as of 'acceptable', 'medium', or 'low' methodological quality. Results were reported in relation to (i) control intervention (sham, 'inactive control', or 'another physical stimulus') and (ii) study subjects (healthy, symptomatic, or with spinal pain" subjects/spinal pain"), taking into account the quality. Only results obtained from between-group or between-intervention comparisons were considered in the final analysis. Eighteen of 1514 articles were included. Studies were generally of 'low' or 'medium' methodological quality, most comparing spinal manipulation to a control other than a sham. Thirteen out of the 18 studies could be included in the final analysis. Transitory effects of different types of 'brain function' were reported in the three studies comparing spinal manipulation to sham (but of uncertain credibility), in "subclinical neck/spinal pain" subjects or in symptomatic subjects. None of these three studies, of 'medium' or 'acceptable' quality, investigated whether the neurophysiological effects reported were associated with clinical benefits. The remaining 10 studies, generally of 'low' or 'medium' quality, compared spinal manipulation to 'inactive control' or 'another physical stimulus' and similarly reported significant between-group differences but inconsistently. The available evidence suggests that changes occur in 'brain function' in response to spinal manipulation but are inconsistent across and - sometimes - within studies. The clinical relevance of these changes is unknown. It is therefore premature to promote the use of spinal manipulation as a treatment to improve 'brain function'.


1,5-Di-meth-oxy-naphthalene.
The title compound, C12H12O2, lies across an inversion centre. The mol-ecular structure suggests that the meth-oxy groups in the 1- and 5-positions of the naphthalene moiety do not significantly distort the planar conformation of the ring system, which has a maximum deviation of 0.0025 (9) Å. In the crystal, mol-ecules pack in a herringbone arrangement in layers parallel to (100) and with chains propagating along [101] formed by very weak C-H⋯O inter-actions.


Assessment of causality between climate variables and production for whole crop maize using structural equation modeling.
This study aimed to assess the causality of different climate variables on the production of whole crop maize (Zea mays L.; WCM) in the central inland region of the Korea. Furthermore, the effect of these climate variables was also determined by looking at direct and indirect pathways during the stages before and after silking. The WCM metadata (n = 640) were collected from the Rural Development Administration's reports of new variety adaptability from 1985-2011 (27 years). The climate data was collected based on year and location from the Korean Meteorology Administration's weather information system. Causality, in this study, was defined by various cause-and-effect relationships between climatic factors, such as temperature, rainfall amount, sunshine duration, wind speed and relative humidity in the seeding to silking stage and the silking to harvesting stage. All climate variables except wind speed were different before and after the silking stage, which indicates the silking occurred during the period when the Korean season changed from spring to summer. Therefore, the structure of causality was constructed by taking account of the climate variables that were divided by the silking stage. In particular, the indirect effect of rainfall through the appropriate temperature range was different before and after the silking stage. The damage caused by heat-humidity was having effect before the silking stage while the damage caused by night-heat was not affecting WCM production. There was a large variation in soil surface temperature and rainfall before and after the silking stage. Over 350 mm of rainfall affected dry matter yield (DMY) when soil surface temperatures were less than 22°C before the silking stage. Over 900 mm of rainfall also affected DMY when soil surface temperatures were over 27°C after the silking stage. For the longitudinal effects of soil surface temperature and rainfall amount, less than 22°C soil surface temperature and over 300 mm of rainfall before the silking stage affected yield through over 26°C soil surface temperature and less than 900 mm rainfall after the silking stage, respectively.


Savant-like numerosity skills revealed in normal people by magnetic pulses.
Oliver Sacks observed autistic twins who instantly guessed the exact number of matchsticks that had just fallen on the floor, saying in unison "111". To test the suggestion that normal individuals have the capacity for savant numerosity, we temporarily simulated the savant condition in normal people by inhibiting the left anterior temporal lobe of twelve participants with repetitive transcranial magnetic stimulation (rTMS). This site has been implicated in the savant condition. Ten participants improved their ability to accurately guess the number of discrete items immediately following rTMS and, of these, eight became worse at guessing as the effects of the pulses receded. The probability of as many as eight out of twelve people doing best just after rTMS and not after sham stimulation by chance alone is less than one in one thousand.


Identification of 2-oxohistidine Interacting Proteins Using E. coli Proteome Chips.
Cellular proteins are constantly damaged by reactive oxygen species generated by cellular respiration. Because of its metal-chelating property, the histidine residue is easily oxidized in the presence of Cu/Fe ions and H2O2 via metal-catalyzed oxidation, usually converted to 2-oxohistidine. We hypothesized that cells may have evolved antioxidant defenses against the generation of 2-oxohistidine residues on proteins, and therefore there would be cellular proteins which specifically interact with this oxidized side chain. Using two chemically synthesized peptide probes containing 2-oxohistidine, high-throughput interactome screening was conducted using the E. coli K12 proteome microarray containing >4200 proteins. Ten interacting proteins were identified, and successfully validated using a third peptide probe, fluorescence polarization assays, as well as binding constant measurements. We discovered that 9 out of 10 identified proteins seemed to be involved in redox-related cellular functions. We also built the functional interaction network to reveal their interacting proteins. The network showed that our interacting proteins were enriched in oxido-reduction processes, ion binding, and carbon metabolism. A consensus motif was identified among these 10 bacterial interacting proteins based on bioinformatic analysis, which also appeared to be present on human S100A1 protein. Besides, we found that the consensus binding motif among our identified proteins, including bacteria and human, were located within α-helices and faced the outside of proteins. The combination of chemically engineered peptide probes with proteome microarrays proves to be an efficient discovery platform for protein interactomes of unusual post-translational modifications, and sensitive enough to detect even the insertion of a single oxygen atom in this case.


A new method for analyzing auditory brain-stem response waveforms using a moving-minimum subtraction procedure of digitized analog recordings.
The auditory brain-stem response (ABR) waveform comprises a set of waves (labeled I-VII) recorded with scalp electrodes over 10 ms after an auditory stimulation with a brief click sound. Quite often, the waves are fused (confluent) and baseline-irregular and sloped, making wave latencies and wave amplitudes difficult to establish. In the present paper, we describe a method, labeled moving-minimum subtraction, based on digitization of the analog ABR waveform (154 data points/ms) in order to achieve alignment of the ABR response to a straight baseline, often with clear baseline separation of waves and resolution of fused waves. Application of the new method to groups of patients showed marked differences in ABR waveforms between patients with schizophrenia versus patients with adult attention deficit/hyperactivity disorder versus healthy controls. The findings show promise regarding the possibility to identify ABR markers to be used as biomarkers as support for clinical diagnoses of these and other neuropsychiatric disorders.


Hydrothermal vents trigger massive phytoplankton blooms in the Southern Ocean.
Hydrothermal activity is significant in regulating the dynamics of trace elements in the ocean. Biogeochemical models suggest that hydrothermal iron might play an important role in the iron-depleted Southern Ocean by enhancing the biological pump. However, the ability of this mechanism to affect large-scale biogeochemistry and the pathways by which hydrothermal iron reach the surface layer have not been observationally constrained. Here we present the first observational evidence of upwelled hydrothermally influenced deep waters stimulating massive phytoplankton blooms in the Southern Ocean. Captured by profiling floats, two blooms were observed in the vicinity of the Antarctic Circumpolar Current, downstream of active hydrothermal vents along the Southwest Indian Ridge. These hotspots of biological activity are supported by mixing of hydrothermally sourced iron stimulated by flow-topography interactions. Such findings reveal the important role of hydrothermal vents on surface biogeochemistry, potentially fueling local hotspot sinks for atmospheric CO2 by enhancing the biological pump.


Na(+)/H(+) exchange inhibition-induced cardioprotection in dogs: effects on neutrophils versus cardiomyocytes.
Numerous studies have examined the effect of Na(+)/H(+) exchanger (NHE) inhibition on the myocardium; however, the effect of NHE-1 inhibition on neutrophil function has not been adequately examined. An in vivo canine model of myocardial ischemia-reperfusion injury in which 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion was used to examine the effect of NHE-1 inhibition on infarct size (IS) and neutrophil function. BIIB-513, a selective inhibitor of NHE-1, was infused before ischemia. IS was expressed as a percentage of area at risk (IS/AAR). NHE-1 inhibition significantly reduced IS/AAR and reduced neutrophil accumulation in the ischemic myocardium. NHE-1 inhibition attenuated both phorbol 12-myristate 13-acetate- and platelet-activating factor-induced neutrophil respiratory burst but not CD18 upregulation. Furthermore, NHE-1 inhibition directly protected cardiomyocytes against metabolic inhibition-induced lactate dehydrogenase release and hypercontracture. This study provides evidence that the cardioprotection induced by NHE-1 inhibition is likely due to specific protection of cardiomyocytes and attenuation of neutrophil activity.


Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling.
Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract disease. Retinoic acid-inducible gene-I (RIG-I) serves as an innate immune sensor and triggers antiviral responses upon recognizing viral infections including RSV. Since tripartite motif-containing protein 25 (TRIM25)-mediated K63-polyubiquitination is crucial for RIG-I activation, several viruses target initial RIG-I activation through ubiquitination. RSV NS1 and NS2 have been shown to interfere with RIG-I-mediated antiviral signaling. In this study, we explored the possibility that NS1 suppresses RIG-I-mediated antiviral signaling by targeting TRIM25. Ubiquitination of ectopically expressed RIG-I-2Cards domain was decreased by RSV infection, indicating that RSV possesses ability to inhibit TRIM25-mediated RIG-I ubiquitination. Similarly, ectopic expression of NS1 sufficiently suppressed TRIM25-mediated RIG-I ubiquitination. Furthermore, interaction between NS1 and TRIM25 was detected by a co-immunoprecipitation assay. Further biochemical assays showed that the SPRY domain of TRIM25, which is responsible for interaction with RIG-I, interacted sufficiently with NS1. Suppression of RIG-I ubiquitination by NS1 resulted in decreased interaction between RIG-I and its downstream molecule, MAVS. The suppressive effect of NS1 on RIG-I signaling could be abrogated by overexpression of TRIM25. Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling.


Electrical synapse formation disrupts calcium-dependent exocytosis, but not vesicle mobilization.
Electrical coupling exists prior to the onset of chemical connectivity at many developing and regenerating synapses. At cholinergic synapses in vitro, trophic factors facilitated the formation of electrical synapses and interfered with functional neurotransmitter release in response to photolytic elevations of intracellular calcium. In contrast, neurons lacking trophic factor induction and electrical coupling possessed flash-evoked transmitter release. Changes in cytosolic calcium and postsynaptic responsiveness to acetylcholine were not affected by electrical coupling. These data indicate that transient electrical synapse formation delayed chemical synaptic transmission by imposing a functional block between the accumulation of presynaptic calcium and synchronized, vesicular release. Despite the inability to release neurotransmitter, neurons that had possessed strong electrical coupling recruited secretory vesicles to sites of synaptic contact. These results suggest that the mechanism by which neurotransmission is disrupted during electrical synapse formation is downstream of both calcium influx and synaptic vesicle mobilization. Therefore, electrical synaptogenesis may inhibit synaptic vesicles from acquiring a readily releasable state. We hypothesize that gap junctions might negatively interact with exocytotic processes, thereby diminishing chemical neurotransmission.


Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form.
Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy-MM). Herein, we analyzed some predictors of development of sy-MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA). From January 1980 to July 2010, 397 patients with SMM observed in 12 centers of the Multiple Myeloma GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Latium Working Group have been analyzed. At progression to sy-MM, the severity of clinical presentation was graded according to the need of intensive supportive care. After a median follow-up of 135 months, the cumulative incidence of progression rates to sy-MM were 45%, 55%, and 75% at 10, 15, and 20 years, respectively. Hemoglobin ≤12.5 g/dL, monoclonal component ≥2.5 g/dL, and BMPC ≥60% were the only parameters negatively affecting the cumulative incidence of progression. In particular, 10 of 397 (2.5%) patients with BMPC ≥60% had a 5.6-fold increased risk of fast progression (within 2 years), which occurred with severe clinical manifestations in 62% of cases. BMB was more sensitive for the detection of BMPC involvement, even though BMA was a more reliable indicator of a rapid progression to sy-MM. The highest risk of rapid evolution to sy-MM and the severity of clinical manifestation at the progression suggest that SMM patients with a BMPC ≥60% should be treated soon after diagnosis. Moreover, BMPC is a more reliable index for progression to sy-MM if assessed by BMA.


[Effect of thyroidectomy and hyperthyroidism on Ca2+/2H+-antiporter activity in rat liver mitochondria].
The manifestation of Ca2+/2H+ antiporter activity in rat liver mitochondria was shown to be inhibited in thyroidectomy and stimulated in hyperthyroidosis. Experiments with measuring the kinetics of the swelling of deenergized mitochondria in isoosmotic solutions Ca (NO3)2, pH 8.1 demonstrated inhibition of the swelling of liver mitochondria during thyroidectomy and stimulation because of administering thyroid hormones in vivo. During thyroidectomy, the phosphate-induced swelling of rat liver mitochondria was powerfully inhibited. Meanwhile administration of thyroxine to rats stimulated the swelling of mitochondria.


CD20-directed serotherapy in patients with multiple myeloma: biologic considerations and therapeutic applications.
Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase II clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m2 rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months; range, 3-27+ months). All six patients who had a PR or SD had CD20+ BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-y) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-y. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-gamma (1-100 U/mL). In conclusion, these studies suggest that MM patients with CD20+ BMPCs may benefit from rituximab therapy. Furthermore, IFN-gamma induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.


Abscisic acid and gibberellin differentially regulate expression of genes of the SNF1-related kinase complex in tomato seeds.
The SNF1/AMP-activated protein kinase subfamily plays central roles in metabolic and transcriptional responses to nutritional or environmental stresses. In yeast (Saccharomyces cerevisiae) and mammals, activating and anchoring subunits associate with and regulate the activity, substrate specificity, and cellular localization of the kinase subunit in response to changing nutrient sources or energy demands, and homologous SNF1-related kinase (SnRK1) proteins are present in plants. We isolated cDNAs corresponding to the kinase (LeSNF1), regulatory (LeSNF4), and localization (LeSIP1 and LeGAL83) subunits of the SnRK1 complex from tomato (Lycopersicon esculentum Mill.). LeSNF1 and LeSNF4 complemented yeast snf1 and snf4 mutants and physically interacted with each other and with LeSIP1 in a glucose-dependent manner in yeast two-hybrid assays. LeSNF4 mRNA became abundant at maximum dry weight accumulation during seed development and remained high when radicle protrusion was blocked by abscisic acid (ABA), water stress, far-red light, or dormancy, but was low or undetected in seeds that had completed germination or in gibberellin (GA)-deficient seeds stimulated to germinate by GA. In leaves, LeSNF4 was induced in response to ABA or dehydration. In contrast, LeSNF1 and LeGAL83 genes were essentially constitutively expressed in both seeds and leaves regardless of the developmental, hormonal, or environmental conditions. Regulation of LeSNF4 expression by ABA and GA provides a potential link between hormonal and sugar-sensing pathways controlling seed development, dormancy, and germination.


Comparison of swept source optical coherence tomography and spectral domain optical coherence tomography in polypoidal choroidal vasculopathy.
Swept source optical coherence tomography (SS-OCT, Topcon Medical System, Japan) is known to have longer wavelength than spectral domain OCT (SD-OCT, Spectralis, Heidelberg Engineering, Germany), allowing a deeper penetration into retina and choroidal layers. This objective of this study was to compare the visibility of retinal and choroidal features in polypoidal choroidal vasculopathy (PCV) using SS-OCT and SD-OCT. This study employs prospective comparative observational case series in Singapore National Eye Center. There were 20 eyes (20 patients) with PCV confirmed with indocyanine green angiogram. Six pre-specified OCT parameters (presence of polyps, sharp pigment epithelial detachment [PED] peak, notched PED and visibility of full maximum height of PED, inner segment/outer segment [IS/OS] line and choroid-scleral interface [CSI]) were graded using SS-OCT and SD-OCT. The Kappa statistics between the two imaging modalities were calculated. Both SS-OCT and SD-OCT were able to detect polypoidal lesions in the majority of eyes (90% and 85%, respectively). However, SS-OCT had better detection for CSI and IS/OS lines (CSI: 80% vs 45%, P = 0.05; IS/OS line: 65% vs 45%, P = 0.34). For sharp PED peak, notched PED, ability to visualize the full PED height and retinal pigment epithelial line, both OCT machines were able to detect in ≥80% of the eyes. In conclusion, SS-OCT and SD-OCT appeared to be similarly effective at detecting most features associated with PCV. However, SS-OCT is more superior in detecting the CSI.


Structure and biochemical functions of SIRT6.
SIRT6 is a member of the evolutionarily conserved sirtuin family of NAD(+)-dependent protein deacetylases and functions in genomic stability and transcriptional control of glucose metabolism. Early reports suggested that SIRT6 performs ADP-ribosylation, whereas more recent studies have suggested that SIRT6 functions mainly as a histone deacetylase. Thus, the molecular functions of SIRT6 remain uncertain. Here, we perform biochemical, kinetic, and structural studies to provide new mechanistic insight into the functions of SIRT6. Utilizing three different assays, we provide biochemical and kinetic evidence that SIRT6-dependent histone deacetylation produces O-acetyl-ADP-ribose but at a rate ∼1,000 times slower than other highly active sirtuins. To understand the molecular basis for such low deacetylase activity, we solved the first crystal structures of this class IV sirtuin in complex with ADP-ribose and the non-hydrolyzable analog of O-acetyl-ADP-ribose, 2'-N-acetyl-ADP-ribose. The structures revealed unique features of human SIRT6, including a splayed zinc-binding domain and the absence of a helix bundle that in other sirtuin structures connects the zinc-binding motif and Rossmann fold domain. SIRT6 also lacks the conserved, highly flexible, NAD(+)-binding loop and instead contains a stable single helix. These differences led us to hypothesize that SIRT6, unlike all other studied sirtuins, would be able to bind NAD(+) in the absence of an acetylated substrate. Indeed, we found that SIRT6 binds NAD(+) with relatively high affinity (K(d) = 27 ± 1 μM) in the absence of an acetylated substrate. Isothermal titration calorimetry and tryptophan fluorescence binding assays suggested that ADP-ribose and NAD(+) induce different structural perturbations and that NADH does not bind to SIRT6. Collectively, these new insights imply a unique activating mechanism and/or the possibility that SIRT6 could act as an NAD(+) metabolite sensor.


Viral exanthems.
Determining the viral cause of a rash presents significant diagnostic challenges. We review contemporary literature on viral exanthems and suggest a structured approach to aid diagnosis. Strains responsible for, and the clinical presentation of, enteroviral infections have diverged from classic descriptions. The causative relationship between antibiotic administration and rash in Epstein-Barr virus infection has been recently questioned. Major measles virus outbreaks have recently occurred in Europe and the USA. The largest Ebola virus outbreak in West Africa has resulted in importation of the virus to other countries and secondary local transmission. Autochthonous transmission of Chikungunya virus has occurred in nonendemic areas, including Europe, the Caribbean and Americas. Zika virus has re-emerged in the Pacific with local transmission from imported cases. Climate change, global warming and spillover of zoonotic viruses are contributing to the emergence and spread of viral diseases. Important clues to the diagnosis of viral exanthems include their distribution and morphology, geographic location and potential exposure to vector-borne or blood-borne viruses. Diagnosis is commonly made via serology, nucleic acid tests or, rarely, viral culture. Skin biopsy is not usually required. In general, viral exanthems are self-limiting and treatment is supportive.


Bronchoscopic instillation of DNase to manage refractory lobar atelectasis in a lung cancer patient.
Lobar atelectasis is a common complication in lung cancer. It can be caused by direct endobronchial tumorous seeding or indirectly by mucus plugs due to bacterial lung infections. Treatment is usually conservative, with or without therapeutic bronchoscopy. Dornase alfa is a recombinant human deoxyribonuclease I (rhDNase), an enzyme that selectively cleaves DNA, thus reducing mucous viscosity. rhDNase has been used as a mucolytic agent in cystic fibrosis (CF) patients. Though bronchoscopically instilled rhDNase has been reported as a treatment for persistent lobar atelectasis in newborn and pediatric populations, its use in adults has not been well established.


Ontogenetic changes in jaw-muscle architecture facilitate durophagy in the turtle Sternotherus minor.
Differential scaling of musculoskeletal traits leads to differences in performance across ontogeny and ultimately determines patterns of resource use during development. Because musculoskeletal growth of the feeding system facilitates high bite-force generation necessary to overcome the physical constraints of consuming more durable prey, durophagous taxa are well suited for investigations of the scaling relationships between musculoskeletal growth, bite-force generation and dietary ontogeny. To elucidate which biomechanical factors are responsible for allometric changes in bite force and durophagy, we developed and experimentally tested a static model of bite-force generation throughout development in the durophagous turtle Sternotherus minor. Moreover, we quantified the fracture properties of snails found in the diet to evaluate the relationship between bite force and the forces required to process durable prey. We found that (1) the static bite-force model accurately predicts the ontogenetic scaling of bite forces, (2) bite-force positive allometry is accomplished by augmenting muscle size and muscle pennation, and (3) the rupture forces of snails found in the diet show a similar scaling pattern to bite force across ontogeny. These results indicate the importance of muscle pennation for generating high bite forces while maintaining muscle size and provide empirical evidence that the allometric patterns of musculoskeletal growth in S. minor are strongly linked to the structural properties of their primary prey.


Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.
Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation.


Intraoperative fine-needle aspiration and rapid diagnosis of thoracic lesions.
Rapid cytologic diagnosis of thoracic lesions by intraoperative fine-needle aspiration is a valuable aid to the surgeon at the time of thoracotomy or mediastinoscopy, especially for lesions which are difficult or hazardous to biopsy by standard methods. The technique is simple, quick, and accurate and aids in determining the immediate surgical management of suspicious lesions. One hundred fifty-four IOFNAs of thoracic masses performed over an 8-year period were evaluated. Diagnostic accuracy was 97.7% for the diagnosis of benign lesions, 95.4% for the diagnosis of malignancy, and 100% for the differentiation of small cell carcinoma from non-small cell carcinoma of the lung.


Optimal sampling and estimation in PASL perfusion imaging.
Pulsed arterial spin labeling (PASL) techniques potentially allow the absolute, noninvasive quantification of brain perfusion using MRI. This can be achieved by fitting a kinetic model to the data acquired at a number of sampling times. However, the intrinsically low signal-to-noise ratio of PASL measurements usually requires substantial signal averaging, which may result in undesirably long scanning times. A judicious choice of the sampling points is, therefore, crucial in order to minimize scanning time, while optimizing estimation accuracy. On the other hand, a priori information regarding the model parameters may improve estimation performance. Here, we propose a Bayesian framework to determine an optimal sampling strategy and estimation method for the measurement of brain perfusion and arterial transit time (ATT). A Bayesian Fisher information criterion is used to determine the optimal sampling points and a MAP criterion is employed for the estimation of the model parameters, both taking into account the uncertainty in the model parameters as well as the amount of noise in the data. By Monte Carlo simulations, we show that using optimal compared to uniform sampling strategies, as well as the Bayesian estimator relative to a standard least squares approach, improves the accuracy of perfusion and ATT measurements. Moreover, we also demonstrate the applicability of the proposed approach to real data, with the advantage of reduced intersubject variability relative to conventional sampling and estimation approaches.


A new method specifically designed to expose cells isolated in vitro to radon and its decay products.
A system was set up to provide direct exposure of cells cultured in vitro to radon and its decay products. Radon gas emanating from a uranium source was introduced at a measured concentration in a closed 10-m(3) exposure chamber. Cells were cultured on the microporous membrane of an insert that was floating over the culture medium in a six-well cluster plate. Plates with cells were placed in an open thermoregulated bath within the chamber. Under these conditions, cells were irradiated by direct deposition of radon and radon decay products. During exposure, all parameters, including radon gas concentrations, decay product activities, and potential alpha-particle energy concentrations, were determined by periodic air-grab samplings inside the chamber. The energy spectrum of deposited decay products was characterized. An estimation of alpha-particle flux density on the area containing cells was performed using CR-39 detector films that were exposed in cell-free wells during the cell exposure. The number of alpha-particle traversals per cell was deduced both from the mean number of CR-39 tracks per surface unit and from measurements of entire cells or nuclear surfaces. This paper describes the design of experiment, the dosimetry of radon and radon decay product, and the procedures for aerosol measurements. Our preliminary data show the usefulness of the in vitro cell culture approach to the study of the early cellular effects of radon and its decay products.


TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma.
Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors.


[Alport syndrome in the light of current molecular genetics].
Alport syndrome is a hereditary nephropathy, inconstantly associated with sensorineural deafness and ocular abnormalities. These manifestations result from a structural defect in type IV collagen. Recent genetic advances have provided a molecular basis for the two main subsets of the disease, namely the X-linked and the autosomal recessive forms. It has just been shown that the autosomal dominant entity known as benign familial haematuria is actually due to a heterozygote mutation of the gene accounting for the autosomal recessive form of Alport syndrome. The genetic breakthrough has already clinical and pathophysiological implications.


Comparison of Collection Methods for Fecal Samples for Discovery Metabolomics in Epidemiologic Studies.
The gut metabolome may be associated with the incidence and progression of numerous diseases. The composition of the gut metabolome can be captured by measuring metabolite levels in the feces. However, there are little data describing the effect of fecal sample collection methods on metabolomic measures. We collected fecal samples from 18 volunteers using four methods: no solution, 95% ethanol, fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT). One set of samples was frozen after collection (day 0), and for 95% ethanol, FOBT, and FIT, a second set was frozen after 96 hours at room temperature. We evaluated (i) technical reproducibility within sample replicates, (ii) stability after 96 hours at room temperature for 95% ethanol, FOBT, and FIT, and (iii) concordance of metabolite measures with the putative "gold standard," day 0 samples without solution. Intraclass correlation coefficients (ICC) estimating technical reproducibility were high for replicate samples for each collection method. ICCs estimating stability at room temperature were high for 95% ethanol and FOBT (median ICC > 0.87) but not FIT (median ICC = 0.52). Similarly, Spearman correlation coefficients (rs) estimating metabolite concordance with the "gold standard" were higher for 95% ethanol (median rs = 0.82) and FOBT (median rs = 0.70) than for FIT (median rs = 0.40). Metabolomic measurements appear reproducible and stable in fecal samples collected with 95% ethanol or FOBT. Concordance with the "gold standard" is highest with 95% ethanol and acceptable with FOBT. Future epidemiologic studies should collect feces using 95% ethanol or FOBT if interested in studying fecal metabolomics. Cancer Epidemiol Biomarkers Prev; 25(11); 1483-90. ©2016 AACR.