Ordering in stretch-tunable polymeric opal fibers.
We demonstrate the production of high-quality polymer opal fibers in an industrially-scalable process. These fibers exhibit structural color, based on the self-assembly of sub-micron core-shell particles, with a spectrum which is stretch-tunable across the visible region. The internal substructure and ordering of fibers, as inferred from variations in spectral bandwidth, is studied using dark-field microscopy. We employ a granular model to examine flow and shear forces during the extrusion process, and the effects on particle ordering. In both theory and experiment, a concentric zone of the fiber near the exposed surface develops particularly strong structural color. Such elastically-tuned structurally colored fibers are of interest for many applications.


Withania somnifera L.: Insights into the phytochemical profile, therapeutic potential, clinical trials, and future prospective.
Withania somnifera L. is a multipurpose medicinal plant of family Solanaceae occurring abundantly in sub-tropical regions of the world. The folk healers used the plant to treat several diseases such as fever, cancer, asthma, diabetes, ulcer, hepatitis, eyesores, arthritis, heart problems, and hemorrhoids. The plant is famous for the anti-cancerous activity, low back pain treatment, and muscle strengthening, which may be attributed to the withanolide alkaloids. W. somnifera is also rich in numerous valued secondary metabolites such as steroids, alkaloids, flavonoids, phenolics, saponins, and glycosides. A wide range of preclinical trials such as cardioprotective, anticancer, antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective, anti-depressant, and hypoglycemic have been attributed to various parts of the plant. Different parts of the plant have also been evaluated for the clinical trials such as male infertility, obsessive-compulsive disorder, antianxiety, bone and muscle strengthening potential, hypolipidemic, and antidiabetic. This review focuses on folk medicinal uses, phytochemistry, pharmacological, and nutrapharmaceutical potential of the versatile plant.


Role of angiotensin I and glucagon in canine endotoxin shock: effect of converting enzyme inhibitor and prior immunization.
he intermediate and latter stages of canine endotoxin shock are characterized by a progressive decrease in cardiac output, increase in total peripheral resistance, and hypoglycemia. We have hypothesized that the renin-angiotensin system and glucagon may mediate the loss of cardiovascular and glucose homeostasis. E. Coli endotoxin shock (1 mg/kg; 055:B5) was induced in three groups of dogs and systemic hemodynamics, angiotensin I activity, and glucagon were monitored for 5 hr; endotoxin shock (n = 13); endotoxin shock + prior immunization with J5 mutant of E coli 0111 (n = 5); Endotoxin + captopril (20 micrograms/kg/hr; n = 9); and sham-operated time-matched controls (n = 8). Thirty minutes postshock, angiotensin I and glucagon began to increase. Angiotensin I activity reached a peak at 60 min postendotoxin (90 +/- 25 vs 5 +/- ng/ml/hr; p less than 0.001) and plateaued. Increased glucagon levels plateaued at 3.5 hr postshock (1500 +/- 200 vs 155 +/- 77 pg/ml; p less than 0.001). Cardiac output began to progressively decrease, total peripheral resistance began to increase, and persistent hypoglycemia developed at 3 hr postshock. Captopril inhibited the increase in total peripheral resistance and had no effect on the decrease in cardiac output or the hypoglycemia. The initial glucagon response was attenuated but there was no difference at 5 hr (950 +/- 150 vs 1200 +/- 200 pg/ml). Prior immunization significantly preserved cardiac output, total peripheral resistance, plasma glucose levels, glucagon levels, and angiotensin I activity. It is concluded that 1) the renin-angiotensin system is a physiologic and not a pathophysiologic compensatory mechanism during the course of endotoxin shock and that inhibition of this system is deleterious; 2) glucagon may serve as an important mediator of both the myocardial dysfunction and glucose dyshomeostasis of endotoxin shock; and 3) immunological inhibition of the initial phase of endotoxin shock significantly preserves cardiovascular and glucose homeostasis and adds support to the concept that the initial vascular phase of endotoxin shock plays a primary role in determining the severity of the endotoxin/septic shock syndrome.


NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors.
Interaction of the activating ligand H60 with NKG2D receptor constitutes a major stimulatory pathway for natural killer (NK) cells. The influence of inhibitory Ly49 receptors on NKG2D-mediated activation is not clearly understood. Here we show that the magnitude of NKG2D-mediated cytotoxicity is directly proportional to both the levels of H60 and the nature of major histocompatibility complex (MHC) class I molecules expressed on the target cells. The expression levels of H60 on the target cells determined the extent to which the inhibition by Ly49C/I receptors can be overridden. In contrast, even a higher expression of H60 molecule on the target cells failed to overcome the inhibition mediated by Ly49A/G receptors. Also, the level of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generated by NK cells through anti-NKG2D monoclonal antibody (mAb)-mediated activation is significantly reduced by the presence of immobilized anti-Ly49A/G mAbs. Thus, NKG2D-mediated cytotoxicity and cytokine secretion results from the fine balance between activating and inhibitory receptors, thereby defining the NK cell-mediated immune responses.


Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice.
Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.


Public Intention to Prepare for Earthquakes: Psychometric Properties of Persian Version.
People are still not prepared for earthquakes in vulnerable areas although preparedness considered an effective way of reducing the disastrous consequences. A proper tool was needed to assess the predicting factors of mitigation behaviors in a large vulnerable community who speak Persian. This study aimed to introduce the valid and reliable Persian version of public intention to prepare against earthquakes. Translation, validation and reliability checking articulated according to the standard methodology for Forward-Backward translation and psychometric evaluation. Totally, 369 Tehran households were selected through stratified random sampling from Oct 2016 to Jun 2017. Exploratory Factor Analysis used to check the construct validity of all scales. Face, content and construct validity of all scales confirmed (S-CVR: .65) and (S-CVI/Universal: .98). The finalized Persian version (69 items in 8 scales) showed good reliability over time in test-retest (ICC: .92) and high internal consistency both in the pilot (α: .94) and main studies (α: .94). No significant floor and ceiling effects were found in any of scales. Persian version of Earthquake Public Intention to Prepare is applicable as a valid and reliable instrument for research regarding disaster preparedness in Persian speaking communities.


A Filipino woman with autoimmune polyglandular syndrome.
A 47-year-old Filipino woman presented with goitre of 3 months' duration. She had no symptoms of thyrotoxicosis or hypothyroidism. Her thyroid was diffusely enlarged. Thyrotropin was elevated and free thyroxine was low. Ultrasound revealed slightly enlarged thyroid with diffuse parenchymal disease. Antithyroid peroxidase antibody was elevated. She was started on levothyroxine at 1.6 mcg/kg body weight/day and dose was adjusted to maintain the thyrotropin level within normal limits. Four years after the diagnosis of Hashimoto's thyroiditis was made, the patient started to experience malaise, generalised weakness and fatigue. Functional screening for other autoimmune endocrinopathy was done. Fasting 8 a.m serum cortisol was noted to be markedly decreased. She was diagnosed with autoimmune polyglandular syndrome type 2 (Schmidt syndrome). Physiologic dose of prednisone was started which afforded significant improvement in the patient's symptoms. The patient is on regular follow-up and clinically well.


Breadth of Genetic Testing Selected by Patients at Risk of Hereditary Breast and Ovarian Cancer.
The aim of this study was to evaluate the ability of patients at risk of hereditary breast and ovarian cancer (HBOC) syndrome to select the extent of genetic testing personally preferred and the impact of demographic factors on the breadth of testing pursued. A single-institution cohort was enumerated consisting of patients referred for clinical genetic counseling secondary to risk of HBOC syndrome. This was a retrospective study of consecutive patients seen for genetic counseling; all patients completed an epidemiologic questionnaire and provided personal and family medical histories. Patients meeting guidelines for testing were offered testing at 3 levels: single gene/condition (Single), small panels with highly penetrant genes (Plus), and large panels with high and moderately penetrant genes (Next). Associations between personal or family-related factors and breadth of testing selected were investigated. Continuous and categorical variables were compared using Student t and χ tests, as appropriate. Joint classification tables were used to test for effect modification, and a log-binomial model was used to compute rate ratios (RR) with a threshold of P < 0.05 considered significant. We identified 253 patients who underwent genetic counseling for HBOC syndrome. Most patients were personally affected by cancer (63.6%), reported at least some college (79.2%), met the National Comprehensive Cancer Network guidelines for BRCA testing (94.5%), and opted to undergo genetic testing (94.1%). Most (84.9%) patients opted for panel testing. An increased likelihood of choosing Next-level testing was found to be associated with patients having any college experience (RR, 1.53; 95% confidence interval, 1.02-2.30), as well as being unaffected by cancer (RR, 1.30; 95% confidence interval, 1.03-1.64). Clinical genetic counseling is a highly specialized service, which should be provided to patients at risk of hereditary cancer syndromes. Although some epidemiologic factors can predict a patient's preference for testing breadth, patients were sufficiently able to self-identify the level of testing they were comfortable with after receiving genetic counseling. Most practitioners do not have the time or expertise to provide the degree of counseling needed to enable and empower patients to choose the level of testing they are comfortable with. When available, referral to genetic counselors remains an important component of comprehensive care for women with a personal or family history of cancer suggestive of hereditary risk.


Personalized Radiotherapy Planning Based on a Computational Tumor Growth Model.
In this article, we propose a proof of concept for the automatic planning of personalized radiotherapy for brain tumors. A computational model of glioblastoma growth is combined with an exponential cell survival model to describe the effect of radiotherapy. The model is personalized to the magnetic resonance images (MRIs) of a given patient. It takes into account the uncertainty in the model parameters, together with the uncertainty in the MRI segmentations. The computed probability distribution over tumor cell densities, together with the cell survival model, is used to define the prescription dose distribution, which is the basis for subsequent Intensity Modulated Radiation Therapy (IMRT) planning. Depending on the clinical data available, we compare three different scenarios to personalize the model. First, we consider a single MRI acquisition before therapy, as it would usually be the case in clinical routine. Second, we use two MRI acquisitions at two distinct time points in order to personalize the model and plan radiotherapy. Third, we include the uncertainty in the segmentation process. We present the application of our approach on two patients diagnosed with high grade glioma. We introduce two methods to derive the radiotherapy prescription dose distribution, which are based on minimizing integral tumor cell survival using the maximum a posteriori or the expected tumor cell density. We show how our method allows the user to compute a patient specific radiotherapy planning conformal to the tumor infiltration. We further present extensions of the method in order to spare adjacent organs at risk by re-distributing the dose. The presented approach and its proof of concept may help in the future to better target the tumor and spare organs at risk.


Visualization of choroidal vasculature in pigmented mouse eyes from experimental models of AMD.
A variety of techniques exist to investigate retinal and choroidal vascular changes in experimental mouse models of human ocular diseases. While all have specific advantages, a method for evaluating the choroidal vasculature in pigmented mouse eyes has been more challenging especially for whole mount visualization and morphometric analysis. Here we report a simple, reliable technique involving bleaching pigment prior to immunostaining the vasculature in whole mounts of pigmented mouse choroids. Eyes from healthy adult pigmented C57BL/6J mice were used to establish the methodology. The retina and anterior segment were separated from the choroid. The choroid with retinal pigment epithelial cells (RPE) and sclera was soaked in 1% ethylenediaminetetraacetic acid (EDTA) to remove the RPE. Tissues were fixed in 2% paraformaldehyde (PFA) in phosphate-buffered saline (PBS). Choroids were subjected to melanin bleaching with 10% hydrogen peroxide (H2O2) at 55 °C for 90 min, washed in PBS and then immunostained with anti-podocalyxin antibody to label vascular endothelium followed by Cy3-AffiniPure donkey anti-goat IgG at 4 °C overnight. Images of immunostained bleached choroids were captured using a Zeiss 710 confocal microscope. In addition to control eyes, this method was used to analyze the choroids from subretinal sodium iodate (NaIO3) RPE atrophy and laser-induced choroidal neovascularization (CNV) mouse models. The H2O2 pretreatment effectively bleached the melanin, resulting in a transparent choroid. Immunolabeling with podocalyxin antibody following bleaching provided excellent visualization of choroidal vasculature in the flat perspective. In control choroids, the choriocapillaris (CC) displayed different anatomical patterns in peripapillary (PP), mid peripheral (MP) and far peripheral (FP) choroid. Morphometric analysis of the vascular area (VA) revealed that the CC was most dense in the PP region (87.4 ± 4.3% VA) and least dense in FP (79.9 ± 6.7% VA). CC diameters also varied depending on location from 11.4 ± 1.97 mm in PP to 15.1 ± 3.15 mm in FP. In the NaIO3-injected eyes, CC density was significantly reduced in the RPE atrophic regions (50.7 ± 5.8% VA in PP and 45.8 ± 6.17% VA in MP) compared to the far peripheral non-atrophic regions (82.8 ± 3.8% VA). CC diameters were significantly reduced in atrophic regions (6.35 ± 1.02 mm in PP and 6.5 ± 1.2 mm in MP) compared to non-atrophic regions (14.16 ± 2.12 mm). In the laser-induced CNV model, CNV area was 0.26 ± 0.09 mm2 and luminal diameters of CNV vessels were 4.7 ± 0.9 mm. Immunostaining on bleached choroids with anti-podocalyxin antibody provides a simple and reliable tool for visualizing normal and pathologic choroidal vasculature in pigmented mouse eyes for quantitative morphometric analysis. This method will be beneficial for examining and evaluating the effects of various treatment modalities on the choroidal vasculature in mouse models of ocular diseases such as age-related macular degeneration, and degenerative genetic diseases.


Complications and outcomes of cats with coxofemoral luxation treated with hip toggle stabilization using ultrahigh-molecular-weight-polyethylene or nylon (2009-2018): 48 cats.
To report overall rate and type of complications and outcomes of cats with coxofemoral luxation managed with hip toggle stabilization (HTS), to compare rate of postoperative complications and outcomes of cats treated with ultrahigh-molecular-weight-polyethylene (UHMWPE) or nylon, and to identify risk factors for reluxation and non-excellent outcomes. Multi-institutional retrospective cohort study. Forty-eight client-owned cats. Medical records of cats that underwent HTS from 2008-2018 using UHMWPE or nylon were reviewed. Univariable and multivariable logistic regression was performed to assess for factors associated with reluxation and non-excellent outcome. Final outcome was obtained from owner questionnaire. Intraoperative and postoperative complications were recorded in two (4.2%) and 11 (24.4%) cats, respectively. The most common postoperative complication was reluxation (n = 5 [11.1%]). Outcome was classified as excellent in 81.1% and good in 16.2% of cats after a median of 445.5 days (range, 53-3720). No difference in rate of complications or outcomes was identified between UHMWPE and nylon. Performance of additional orthopedic procedures, occurrence of intraoperative complications, and non-performance of capsulorrhaphy were associated with reluxation. Performance of additional non-hip procedures (orthopedic/nonorthopedic) was associated with non-excellent outcome. Hip toggle stabilization was associated with a low rate of intraoperative complications and reluxation and excellent long-term outcomes in most cats. No difference in rate of postoperative complications or outcomes of cats treated using UHMWPE or nylon was identified. Cats that underwent additional orthopedic procedures had greater risk of reluxation. Hip toggle stabilization is an effective technique for management of coxofemoral luxation in cats. Comparable results are expected using UHMWPE or nylon.


Impact of morphology, side-chains, and crystallinity on charge-transport properties of π-extended double helicenes.
We report a computational study on the effect of side-chain substitution, heteroaromatic substitution and unique crystal packing on the charge transport and mobility of three double helicene molecules. These double helicene (DH) molecules, having curved π-conjugation, are structural hybrids of non-planar [6]helicene and planar tribenzo[b,n,pqr]perylene (TBP). We find that side-chain substitution has only a effect on intrinsic electronic properties in DHs but dramatically impacts the packing arrangement, morphologies and transport network, exhibited in calculated charge transport parameters. Interestingly, the dimensionality of the transport evolves from one dimensional to three dimensional with side-chain substitution (DH2) and heteroaromatic substitution (DH3). Using two different well-known transport models, we have established a direct link between the morphology, transport connectivity, and hole mobilities. While both unsubstituted and substituted DHs exhibit high hole mobilities in the ordered phase, the results show that with inclusion of positional disorder, the mobilities of disordered DH1 and DH3 are lower while the mobility of DH2 remain nearly unchanged. We relate this effect to the dimensionality of their unique transport networks. These DH molecules are promising organic semiconductors with high mobilities in ordered and disordered phases, with predicted values that lie in the range of ∼1 to 10 cm2 V-1 s-1.


Point of care testing: testing the system?
Point of care testing is changing for the better the way we practice medicine. Whether it is an anesthesiologist doing a blood gas in the operating room, a nurse measuring serum glucose in the home or on the unit, or an intensive care nurse testing by the bedside before calling an intensivist, newer instrumentation provides for a limited number of quality tests to instantly add value to the critical decision-making process of modern staff. This movement is a true paradigm shift that will reduce unnecessary testing, provide timely measurement of critical values and avoid unnecessary and catastrophic mistakes.


First-row transition metal carbide nanosheets as high-performance cathode materials for lithium-sulfur batteries.
Despite the prodigious potential of lithium-sulfur (Li-S) batteries as future rechargeable electrochemical systems, their commercial implementation is hindered by several vital issues, including the shuttle effect and sluggish migration of lithium-polysulfides leading to rapid capacity fading. Here, we systematically investigate the potential of first-row two-dimensional transition metal carbides (TMCs) as sulfur cathodes for Li-S batteries. The adsorption strength of lithium-polysulfides on TMCs is induced by the amount of charge transfer from the former to the latter and the proposed periodic relationship between sulfur in Li2S and 3d-transition metals. Our findings show that the VC nanosheet possesses immense anchoring potential and exhibits a comparatively low migration energy barrier for lithium-ion and Li2S molecules. Additionally, we report ab initio molecular dynamics simulations for lithiated polysulfide species anchored on a TMC-based model with a liquid-electrolyte medium. The microscopic reaction mechanism, revealed by the evolution of the reaction voltage during lithiation, demonstrates that the dissolution of high-order lithium-polysulfides in the electrolytes can be prevented due to their robust interaction with TMC-based cathode materials. These appealing features suggest that TMCs present colossal performance improvements for anchoring lithium-polysulfides, stimulating the active design of sulfur cathodes for practical Li-S batteries.


Hard and soft anatomy in two genera of Dondersiidae (Mollusca, Aplacophora, Solenogastres).
Phylogenetic relationships and identifications in the aplacophoran taxon Solenogastres (Neomeniomorpha) are in flux largely because descriptions of hard parts--sclerites, radulae, copulatory spicules--and body shape have often not been adequately illustrated or utilized. With easily recognizable and accessible hard parts, descriptions of Solenogastres are of greater use, not just to solenogaster taxonomists, but also to ecologists, paleontologists, and evolutionary biologists. Phylogenetic studies of Aplacophora, Mollusca, and the Lophotrochozoa as a whole, whether morphological or molecular, would be enhanced. As an example, morphologic characters, both isolated hard parts and internal anatomy, are provided for two genera in the Dondersiidae. Five species are described or redescribed and earlier descriptions corrected and enhanced. Three belong to Dondersia: D. festiva Hubrecht, D. incali (Scheltema), and D. namibiensis n. sp., the latter differentiated unambiguously from D. incali only by sclerites and copulatory spicules. Two species belong to Lyratoherpia: L. carinata Salvini-Plawen and L. californica (Heath). Notes are given for other species in Dondersiidae: L. bracteata Salvini-Plawen, Ichthyomenia ichthyodes (Pruvot), and Heathia porosa (Heath). D. indica Stork is synonymized with D. annulata. A cladistic morphological analysis was conducted to examine the utility of hard parts for reconstructing solenogaster phylogeny. Results indicate monophyly of Dondersia and Lyratoherpia as described here.


Theoretical Study of the Photoisomerization Mechanism of All-Trans-Retinyl Acetate.
The compound 9-cis-retinyl acetate (9-cis-RAc) is a precursor to 9-cis-retinal, which has potential application in the treatment of some hereditary diseases of the retina. An attractive synthetic route to 9-cis-RAc is based on the photoisomerization reaction of the readily available all-trans-RAc. In the present study, we examine the mechanism of the photoisomerization reaction with the use of state-of-the-art electronic structure calculations for two polyenic model compounds: tEtEt-octatetraene and tEtEtEc-2,6-dimethyl-1,3,5,7,9-decapentaene. The occurrence of photoisomerization is attributed to a chain-kinking mechanism, whereby a series of S1/S0 conical intersections associated with kinking deformations at different positions along the polyenic chain mediate internal conversion to the S0 state, and subsequent isomerization around one of the double bonds. Two other possible photoisomerization mechanisms are taken into account, but they are rejected as incompatible with simulation results and/or the available spectroscopic data.


Virtual reality exposure therapy: 150-degree screen to desktop PC.
Virtual reality exposure therapy (VRET) developed using immersive or semi-immersive virtual environments present a usability problem for practitioners. To meet practitioner requirements for lower cost and portability VRET programs must often be ported onto desktop environments such as the personal computer (PC). However, success of VRET has been shown to be linked to presence, and the environment's ability to evoke the same reactions and emotions as a real experience. It is generally accepted that high-end virtual environments (VEs) are more immersive than desktop PCs, but level of immersion does not always predict level of presence. This paper reports on the impact on presence of porting a therapeutic VR application for schizophrenia from the initial research environment of a semi-immersive curved screen to PC. Presence in these two environments is measured both introspectively and across a number of causal factors thought to underlie the experience of presence. Results show that the VR exposure program successfully made users feel they were "present" in both platforms. While the desktop PC achieved higher scores on presence across causal factors participants reported they felt more present in the curved screen environment. While comparison of the two groups was statistically significant for the PQ but not for the IPQ, subjective reports of experiences in the environments should be considered in future research as the success of VRET relies heavily on the emotional response of patients to the therapeutic program.


A search for functional histamine H4 receptors in the human, guinea pig and mouse brain.
Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPγS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPγS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S-GTPγS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPγS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPγS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex.


Leber hereditary optic neuropathy in 2 of 4 siblings with 11778 mtDNA mutation: clinical variability or effect of toxic environmental exposure?
Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber's hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.


Variability in Opioid Prescribing Among Plastic Surgery Residents After Bilateral Breast Reduction.
Prescription opioid misuse in the United States accounts for significant avoidable morbidity and mortality. Over one third of all prescriptions written by surgeons are for opioids. Although opioids continue to provide needed analgesia for surgical patients, there are few guidelines in the plastic surgery literature for their safe and appropriate use after surgery. The consequence is wide variability and excessive opioid prescriptions. Understanding patterns of prescribing among plastic surgery residents is a crucial step toward developing safer practice models for managing postoperative pain. The authors performed a retrospective analysis of discharge opioid prescriptions after bilateral breast reduction at a single academic medical center from 2018 to 2021. Single factor 1-way analysis of variance was used to evaluate prescribing patterns by resident, postgraduate year, attending of record, and patient characteristics for 126 patients. A multivariate analysis was performed to determine the degree to which these factors predicted opioid prescriptions. This analysis revealed significant variability among residents prescribing opioids after bilateral breast reductions ( P < 0.001) irrespective of patient comorbidities and demographics. Residents were found to be the main predictor of opioid prescriptions after surgery ( P < 0.001) with a greater number of morphine milligram equivalents prescribed by the more junior residents ( P < 0.001). Excessive and variable opioid prescriptions among plastic surgery residents highlight the need for opioid prescribing education early in surgical training and improved oversight and communication with attending surgeons. Furthermore, implementation of evidence-based opioid-conscious analgesic protocols after common surgical procedures may improve patient safety by standardizing postoperative analgesic prescriptions.


Experience in the diagnosis of glomerulonephritis using combined light microscopical, ultrastructural and immunofluorescence techniques--an analysis of 134 cases.
The contribution of electron and immunofluorescence microscopy to renal biopsy diagnosis is illustrated by the results obtained in a personal series of patients with various types of glomerulonephritis. Introductory notes on the ultrastructure of the glomerular capillary and on immunological processes are also included. Immunofluorescent staining has particular value in demonstrating IgG-containing deposits in early membranous glomerulonephritis at a stage when ordinary microscopy is inconclusive. It is capable of throwing light on the mechanism of glomerular damage in severe extracapillary proliferation and in some cases of recurrent haematuria, but is less successful in separating minimal change disease from proliferative processes. Electron microscopy reveals the precise site of immune deposits and fibrin together with basement membrane changes, the microtubular structures common in SLE, and other details. It is concluded that for the accurate diagnosis of kidney disease it is essential to supplement light microscopy by one, or preferably both these methods.


Psychotherapists' approaches to gay and lesbian patients/clients: a qualitative study.
We used qualitative research methods to examine the core issues relating to the approaches of psychodynamic and psychoanalytic psychotherapists to gay and lesbian patients and clients. The paper begins with a review of the psychoanalytic approaches to gay and lesbian sexuality and continues with material of a clinical nature, providing information about the experience of lesbians and gay men in psychotherapy. It also explores the attitudes of therapists towards gay and lesbian sexuality by discussing a range of psychoanalytic theories and their application to clinical work with patients and clients.


Influence of human muscle length on fatigue.
The effect of muscle length on susceptibility to fatigue has been examined in human ankle dorsiflexor muscles. The fatiguing procedure consisted of either indirect tetanic stimulation at 20 Hz or maximal voluntary contraction; each procedure lasted 90 s. The amplitude of the evoked muscle compound action potential (M-wave) increased during the first 30 s or so of the tetanic fatiguing procedure and then decreased. The torque developed by the dorsiflexor muscles declined throughout the period of tetanization. A significantly greater reduction in twitch and tetanic torque was found after the fatiguing procedure had been conducted at the optimum muscle length rather than with the muscle in a shortened position. Relaxation after tetanic stimulation was slower after fatigue had been induced at the optimum muscle length. It is concluded that muscle fatigue is related to the number of actin-myosin cross-bridge interactions and is unlikely to be accounted for solely on the basis of changes in the ionic composition of the transverse tubular fluid.


Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism.
Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.


Plant Bio-Wars: Maize Protein Networks Reveal Tissue-Specific Defense Strategies in Response to a Root Herbivore.
In this study we examined global changes in protein expression in both roots and leaves of maize plants attacked by the root herbivore, Western corn rootworm (WCR, Diabrotica virgifera virgifera). The changes in protein expression Are indicative of metabolic changes during WCR feeding that enable the plant to defend itself. This is one of the first studies to look above- and below-ground at global protein expression patterns of maize plants grown in soil and infested with a root herbivore. We used advanced proteomic and network analyses to identify metabolic pathways that contribute to global defenses deployed by the insect resistant maize genotype, Mp708, infested with WCR. Using proteomic analysis, 4878 proteins in roots and leaves were detected and of these 863 showed significant changes of abundance during WCR infestation. Protein abundance patterns were analyzed using hierarchical clustering, protein correlation and protein-protein interaction networks. All three data analysis pipelines showed that proteins such as jasmonic acid biosynthetic enzymes, serine proteases, protease inhibitors, proteins involved in biosynthesis and signaling of ethylene, and enzymes producing reactive oxygen species and isopentenyl pyrophosphate, a precursor for volatile production, were upregulated in roots during WCR infestation. In leaves, highly abundant proteins were involved in signal perception suggesting activation of systemic signaling. We conclude that these protein networks contribute to the overall herbivore defense mechanisms in Mp708. Because the plants were grown in potting mix and not sterilized sand, we found that both microbial and insect defense-related proteins were present in the roots. The presence of the high constitutive levels of reduced ascorbate in roots and benzothiazole in the root volatile profiles suggest a tight tri-trophic interaction among the plant, soil microbiomes and WCR-infested roots suggesting that defenses against insects coexist with defenses against bacteria and fungi due to the interaction between roots and soil microbiota. In this study, which is one of the most complete descriptions of plant responses to root-feeding herbivore, we established an analysis pipeline for proteomics data that includes network biology that can be used with different types of "omics" data from a variety of organisms.


A Rare Presentation of Severe Organophosphate Poisoning: A Case Report and Review of Literature.
Organophosphates are chemicals commonly used as pesticides and work to inhibit acetylcholinesterase, leading to acetylcholine build up at muscarinic and nicotinic receptors throughout the body. Poisonings are often seen as small volume, chronic cases due to agricultural exposures, but can present as suicide attempts via organophosphate ingestion. Organophosphate poisonings, particularly when large volumes are ingested, require rapid and robust initiation of treatment. We present a case highlighting the appropriate management of profound organophosphate toxicity. We present a case of a 40-year-old female brought in by ambulance after purposefully ingesting two bottles of 100mL dichlorvos (DDVP), one of the largest volume organophosphate ingestions documented in the literature. She presented with severe salivation, diaphoresis and encephalopathy and was then intubated, requiring mechanical ventilation. She received multiple days of intensive care as she was treated with atropine, pralidoxime, intravenous fluids and vasopressors.


Prevalence of pathogenic Escherichia coli in the broiler house environment.
Matched sampling of Escherichia coli from broiler house litter and bird lesions of either cellulitis or colibacillosis was conducted to investigate the relationship of pathogenic E. coli to those found in the environment. Isolates were collected from six broiler flocks representing six geographically disparate ranches. Isolates were compared by flock for similarity in serotype and genotyped by pulsed-field gel electrophoresis. Serotyping revealed a considerable dissociation between the two groups of isolates. The prevalence of pathogenic E. coli that matched the environmental isolates from the same house was 0 to 3%. Statistical analysis of the serotype data showed a strong dependence of serotype on isolate source, indicating a high probability that a particular serotype would be found among lesions or litter but not in both groups. Genotyping of isolates on two farms supported the results of serotyping and provided differentiation of isolates that could not by typed by serology. These results suggested that the prevalence of pathogenic E. coli in the broiler house was independent of the prevalence of other commensal or environmental E. coli. Understanding the composition of E. coli populations in commercial poultry production may have bearing on the epidemiology and control of E. coli related diseases.


Evaluation of high resolution magic-angle coil spinning NMR spectroscopy for metabolic profiling of nanoliter tissue biopsies.
High-resolution magic-angle sample spinning (HR-MAS) (1)H NMR spectroscopy of tissue biopsies combined with chemometric techniques has emerged as a valuable methodology for disease diagnosis and environmental assessments. However, the tissue mass required for such experiments is of the order of 10 mg, and this can compromise the metabolic evaluation because of tissue heterogeneity. Tissue availability is often a limitation for clinical studies due to histopathological requirements, which are currently the gold standard for diagnosis, for example, in the case of tumors. Here, we introduce the use of a rotating micro-NMR detector that optimizes the coil filling factor such that mass-limited samples can be measured. We show the results for measuring nanoliter volume tissue biopsies using a commercial HR-MAS probe for the first time. The method has been tested with bovine muscle and human gastric mucosal tumor tissue samples. The gain in mass sensitivity is approximate up to 17-fold, and the adequate spectral resolution (3 Hz) allows the measurement of the metabolite profiles in nanoliter volume samples, thereby limiting the ambiguity resulting from heterogeneous tissues; thus, the approach presents diagnostic potential for studies by metabonomics of mass-limited biopsies.


Evaluation of methodologies for computing the deep brain stimulation volume of tissue activated.
Computational models are a popular tool for predicting the effects of deep brain stimulation (DBS) on neural tissue. One commonly used model, the volume of tissue activated (VTA), is computed using multiple methodologies. We quantified differences in the VTAs generated by five methodologies: the traditional axon model method, the electric field norm, and three activating function based approaches-the activating function at each grid point in the tangential direction (AF-Tan) or in the maximally activating direction (AF-3D), and the maximum activating function along the entire length of a tangential fiber (AF-Max). We computed the VTA using each method across multiple stimulation settings. The resulting volumes were compared for similarity, and the methodologies were analyzed for their differences in behavior. Activation threshold values for both the electric field norm and the activating function varied with regards to electrode configuration, pulse width, and frequency. All methods produced highly similar volumes for monopolar stimulation. For bipolar electrode configurations, only the maximum activating function along the tangential axon method, AF-Max, produced similar volumes to those produced by the axon model method. Further analysis revealed that both of these methods are biased by their exclusive use of tangential fiber orientations. In contrast, the activating function in the maximally activating direction method, AF-3D, produces a VTA that is free of axon orientation and projection bias. Simulating tangentially oriented axons, the standard approach of computing the VTA, is too computationally expensive for widespread implementation and yields results biased by the assumption of tangential fiber orientation. In this work, we show that a computationally efficient method based on the activating function, AF-Max, reliably reproduces the VTAs generated by direct axon modeling. Further, we propose another method, AF-3D as a potentially superior model for representing generic neural tissue activation.


Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells.
A malfunction of retinoid X receptor-alpha (RXRalpha) due to phosphorylation is associated with the development of hepatocellular carcinoma (HCC) and acyclic retinoid (ACR), which targets RXRalpha, can prevent the development of second primary HCC. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induces apoptosis and cell cycle arrest in cancer cells. VPA can also enhance the sensitivity of cancer cells to retinoids. The present study examined the possible combined effects of ACR plus VPA in HepG2 human HCC cell line. The combination of 5muM ACR and 1mM VPA, about the IC(25) value for both compounds, synergistically inhibited the growth of HepG2 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VPA also acted synergistically to induce apoptosis and G(0)-G(1) cell cycle arrest in HepG2 cells. This combination further exerted a synergistic inhibition of the phosphorylation of RXRalpha, ERK, Akt and GSK-3beta proteins and caused an accumulation of acetylated histones H3 and H4 proteins. VPA enhanced the ability of ACR to raise the cellular levels of RARbeta and p21(CIP1). The combination of these agents markedly increased both the RARE and RXRE promoter activities in HepG2 cells. These results suggest that ACR and VPA cooperatively increase the expression of RARbeta and p21(CIP1), while inhibiting the phosphorylation of RXRalpha, and these effects were associated with induction of apoptosis and the inhibition of cell growth in HepG2 cells. This combination might therefore be an effective regimen for the chemoprevention and chemotherapy of HCC.


Feline pemphigus foliaceus: original case series and a comprehensive literature review.
Since the first description of feline pemphigus foliaceus (PF) more than 30 years ago, numerous case reports have been published, while larger case series have remained rare. This large body of information, if extrapolated, could address clinical discrepancies and expand our knowledge about the treatment of feline PF. This manuscript reviews cases of feline PF published between 1950 and 2016 and adds additional 35 original cases to provide further insight into the clinical aspect and treatment outcome of this disease. Feline PF, while being a primary acantholytic pustular dermatosis, presents most often with crusts and erosions that predominantly affect the face and feet. More than half of cats with active disease exhibits non-dermatological signs such as lethargy, fever and/or anorexia. The prognosis of feline PF is good as the majority of cats rapidly achieve disease control even with the most basic treatment such as glucocorticoid monotherapy. Most PF-affected cats, however, require long-term treatment and, like other autoimmune diseases, feline PF has a tendency to relapse spontaneously or with treatment changes. Therefore, despite the overall good prognosis cats with PF can be given, owners should be informed and prepared for these circumstances, which may reduce the risk of euthanasia in the case of disease relapse, and improve treatment compliance.


Time-to-Surgery and Survival Outcomes in Resectable Colorectal Liver Metastases: A Multi-Institutional Evaluation.
Resection of colorectal liver metastases (CRLM) is associated with improved survival; however, the impact of time to resection on survival is unknown. The current multi-institutional study sought to evaluate the influence of time from diagnosis (Dx) to resection (Rx) on survival outcomes among patients with resectable, metachronous CRLM and to compare practice patterns across hospitals. Medical records of patients with ≤4 metachronous CRLM treated with surgery were reviewed and analyzed retrospectively. Time from Dx to Rx was analyzed as a continuous variable and also dichotomized into 2 groups (group 1: Dx to Rx <3 months and group 2: Dx to Rx ≥3 months) for additional analysis. Survival time distributions after resection were estimated using the Kaplan-Meier method. Between-group univariate comparisons were based on the log-rank test and multivariable analysis was done using Cox proportional hazards model. From 2000 to 2010, six hundred and twenty-six patients were identified. Type of initial referral (p < 0.0001) and use of neoadjuvant (p = 0.04) and/or adjuvant (p < 0.0001) chemotherapy were significantly different among hospitals. Patients treated with neoadjuvant chemotherapy (n = 108) and those with unresectable disease at laparotomy (n = 5) were excluded from final evaluation. Median overall survival and recurrence-free survival were 74 months (range 63.8 to 84.2 months) and 29 months (range 23.9 to 34.1 months), respectively. For the entire cohort, longer time from Dx to Rx was independently associated with shorter overall survival (hazard ratio = 1.12; 95% CI, 1.06-1.18; p < 0.0001), but not recurrence-free survival. Median overall survival for group 1 was 76 months (range 62.0 to 89.2 months) vs 58 months (range 34.3 to 81.7 months) in group 2 (p = 0.10). Among patients with available data pertaining to adjuvant chemotherapy (N = 457; 318 treated and 139 untreated), overall survival (87 months [range 71.2 to 102.8 months] vs 48 months [range 25.3 to 70.7 months]; p <0.0001), and recurrence-free survival (33 months [range 25.3 to 40.7 months] vs 22 months [range 14.5 to 29.5 months]; p = 0.05) were improved significantly. In select patients undergoing initial resection for CRLM, longer time from Dx to Rx is independently associated with worse overall survival. In addition, despite uniform disease characteristics, practice patterns related to definitely resectable CRLM vary significantly across hospitals.


Breast MRI surveillance in women with prior curative-intent therapy for breast cancer.
We sought to determine factors that predict the use of breast magnetic resonance imaging (MRI) surveillance in women previously treated for breast cancer and the incidence of in-breast recurrences and/or new cancers identified by MRI. We reviewed 141 patients who were treated between 2005 and 2008 who also underwent surveillance breast MRI following their treatment. Patient, tumor, treatment characteristics, and MRI findings were collected. Gail scores were calculated based on the patient's personal and family history prior to the breast cancer diagnosis. Data were compared using chi(2) and Fisher's exact test. The average age of the study population was 51 (range 24-73). One hundred forty-one women underwent 202 surveillance breast MRIs during the study period. Sixteen of 141 (11%) required second look imaging, and six of 141 (4%) required biopsy of suspicious lesions. Two of the six were invasive breast cancers, while four were benign. Overall, the rate of new cancer detection on surveillance MRI during the study period was 0.9% (two of 202 imaging studies). Of the 71 women with evaluable Gail scores, the average lifetime risk score was 16.7%. Eight patients had BRCA mutations and three previously underwent irradiation for Hodgkin's lymphoma. Patient age, Gail score, tumor stage, grade, histology, receptor status, and surgical treatment were not predictive of MRI surveillance use. Prospective studies are needed to determine which patients may potentially benefit from breast MRI surveillance following curative-intent treatment. The lack of standardized guidelines may result in excessive or inappropriate use, unnecessary follow-up procedures, and a concomitant low yield.


Cyclic nucleotide responses in control and cystic fibrosis labial glands.
Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) levels were measured in labial gland slices from controls and patients with cystic fibrosis (CF). Incubation in vitro with 10 microM epinephrine, 50 microM isoproterenol, or 10 microM carbachol increased cAMP levels by 2.3-fold, 3.1-fold, and 1.8-fold, respectively, in control glands and by similar amounts in CF glands. The only statistically significant CF-related difference was a decreased response to isoproterenol. Addition of MIX (3-isobutyl-1-methylxanthine) increased cAMP levels in control and CF glands by an order of magnitude under all conditions but did not eliminate the CF-related decrease in cAMP level obtained with isoproterenol. cGMP levels were measured only in the presence of MIX. Incubation with carbachol nearly doubled cGMP levels in control and CF glands but only the control gland response approached statistical significance (P = 0.06). cGMP levels in CF glands were nearly threefold greater than those in control glands, and disease-related differences obtained in the presence of carbachol and isoproterenol were statistically significant.


Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing.
Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance or prophylactic surgery. Besides clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. The influence of such variants on cancer risk is often unknown, making their presence a major clinical problem. When genetic methods are insufficient to classify these variants, functional assays with various cellular models are performed. We developed and applied a new syngeneic model of human cancer cells to test all variants of unknown significance in exon 18 identified by genetic testing of high-risk cancer patients in the Czech Republic, via introduction of constructs containing each of these variants into the wild-type allele of BRCA2-heterozygous DLD1 cells (BRCA2wt/Δex11). We found unaffected DNA repair function of BRCA2 in cell lines BRCA27997G>C/Δex11, BRCA28111C>T/Δex11, BRCA28149G>T/Δex11, BRCA28182G>A/Δex11, and BRCA28182G>T/Δex11, whereas the cell line BRCA28168A>G/Δex11 and the nonsense mutation carrying line BRCA28305G>T/Δex11 did affect protein function. Targeting the BRCA2 wild-type allele with a construct carrying the variant c.7988A> G resulted in incorporation exclusively into the already defective allele in all viable clones, strongly suggesting a detrimental phenotype. Our model thus offers a valuable tool for the functional evaluation of unclassified variants in the BRCA2 gene and provides a stable and distributable cellular resource for further research.


Ribosomal pausing and scanning arrest as mechanisms of translational regulation from cap-distal iron-responsive elements.
Iron regulatory protein 1 (IRP-1) binding to an iron-responsive element (IRE) located close to the cap structure of mRNAs represses translation by precluding the recruitment of the small ribosomal subunit to these mRNAs. This mechanism is position dependent; reporter mRNAs bearing IREs located further downstream exhibit diminished translational control in transfected mammalian cells. To investigate the underlying mechanism, we have recapitulated this position effect in a rabbit reticulocyte cell-free translation system. We show that the recruitment of the 43S preinitiation complex to the mRNA is unaffected when IRP-1 is bound to a cap-distal IRE. Following 43S complex recruitment, the translation initiation apparatus appears to stall, before linearly progressing to the initiation codon. The slow passive dissociation rate of IRP-1 from the cap-distal IRE suggests that the mammalian translation apparatus plays an active role in overcoming the cap-distal IRE-IRP-1 complex. In contrast, cap-distal IRE-IRP-1 complexes efficiently repress translation in wheat germ and yeast translation extracts. Since inhibition occurs subsequent to 43S complex recruitment, an efficient arrest of productive scanning may represent a second mechanism by which RNA-protein interactions within the 5' untranslated region of an mRNA can regulate translation. In contrast to initiating ribosomes, elongating ribosomes from mammal, plant, and yeast cells are unaffected by IRE-IRP-1 complexes positioned within the open reading frame. These data shed light on a characteristic aspect of the IRE-IRP regulatory system and uncover properties of the initiation and elongation translation apparatus of eukaryotic cells.


Design of a gaze-sensitive virtual social interactive system for children with autism.
Impairments in social communication skills are thought to be core deficits in children with autism spectrum disorder (ASD). In recent years, several assistive technologies, particularly Virtual Reality (VR), have been investigated to promote social interactions in this population. It is well known that children with ASD demonstrate atypical viewing patterns during social interactions and thus monitoring eye-gaze can be valuable to design intervention strategies. While several studies have used eye-tracking technology to monitor eye-gaze for offline analysis, there exists no real-time system that can monitor eye-gaze dynamically and provide individualized feedback. Given the promise of VR-based social interaction and the usefulness of monitoring eye-gaze in real-time, a novel VR-based dynamic eye-tracking system is developed in this work. This system, called Virtual Interactive system with Gaze-sensitive Adaptive Response Technology (VIGART), is capable of delivering individualized feedback based on a child's dynamic gaze patterns during VR-based interaction. Results from a usability study with six adolescents with ASD are presented that examines the acceptability and usefulness of VIGART. The results in terms of improvement in behavioral viewing and changes in relevant eye physiological indexes of participants while interacting with VIGART indicate the potential of this novel technology.


Postpartum Galactocele in Augmented Breast after Using Breast Pump Mimicking Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report.
Post-partum galactocele is a common benign disease among breastfeeding women, whereas retromammary and peri-implant galactocele are relatively rare conditions. Herein, a 34-year-old, 1 month-postpartum female, who had augmentation mammoplasty and a 1-month history of breast pump use, presented with left breast enlargement for 2 weeks. An initial left breast US revealed hyperechoic peri-implant fluid collection. Additional US-guided fine needle aspiration was done using a 21G-needle, draining the milk component in the process, and cytologic results revealed numerous crystals, suggestive of galactocele. Various diseases, especially breast implant-associated anaplastic large cell lymphoma, can cause peri-implant fluid collection in an augmented breast. Thus, correlating imaging features with clinical information and cytologic analysis plays an important role in appropriate management.


Magnesium intake in relation to systemic inflammation, insulin resistance, and the incidence of diabetes.
To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation, and insulin resistance among young American adults. A total of 4,497 Americans, aged 18-30 years, who had no diabetes at baseline, were prospectively examined for incident diabetes based on quintiles of magnesium intake. We also investigated the associations between magnesium intake and inflammatory markers, i.e., high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). During the 20-year follow-up, 330 incident cases of diabetes were identified. Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders. The multivariable-adjusted hazard ratio of diabetes for participants in the highest quintile of magnesium intake was 0.53 (95% CI, 0.32-0.86; P(trend) < 0.01) compared with those in the lowest quintile. Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR, and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR. Magnesium intake was inversely longitudinally associated with incidence of diabetes in young American adults. This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.


A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.
FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.


Central Sensitization and Pain: Pathophysiologic and Clinical Insights.
Central sensitization is an increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. To explain how the notion of central sensitization has changed our understanding of pain conditions, discuss how this knowledge can be used to improve the management of pain, and highlight knowledge gaps that future research needs to address. Overview of definitions, assessment methods, and clinical implications. Human pain models, and functional and molecular imaging have provided converging evidence that central sensitization occurs and is clinically relevant. Measures to assess central sensitization in patients are available; however, their ability to discriminate sensitization of central from peripheral neurons is unclear. Treatments that attenuate central sensitization are available, but the limited understanding of molecular and functional mechanisms hampers the development of target-specific treatments. The origin of central sensitization in human pain conditions that are not associated with tissue damage remains unclear. The knowledge of central sensitization has revolutionized our neurobiological understanding of pain. Despite the limitations of clinical assessment in identifying central sensitization, it is appropriate to use the available tools to guide clinical decisions towards treatments that attenuate central sensitization. Future research that elucidates the causes, molecular and functional mechanisms of central sensitization would provide crucial progress towards the development of treatments that target specific mechanisms of central sensitization.


Nonmaternal Care's Association With Mother's Parenting Sensitivity: A Case of Self-Selection Bias?
Although attachment theory posits that the use of nonmaternal care undermines quality of mothers' parenting, empirical evidence for this link is inconclusive. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 1,233), the authors examined the associations between nonmaternal care characteristics and maternal sensitivity during the first 3 years of children's lives, with special attention to selection effects and moderation by resource levels. Findings from fixed-effects regression models suggested that, on average, there is little relationship between nonmaternal care characteristics and maternal sensitivity, once selection factors are held constant. Some evidence of moderation effects was found, however. Excellent-quality care is related to more sensitivity for mothers with lower family income. Poor-quality care is related to lower sensitivity for single mothers, but not partnered mothers. In sum, nonmaternal care characteristics do not seem to have as much influence on mothers' parenting as attachment theory claims.


Examining item content and structure in health status and health outcomes instruments: toward the development of a grammar for better understanding of the concepts being measured.
Health outcomes instruments assess diverse health concepts. Although item-level concepts are considered fundamental elements, the field lacks structures for evaluating and organizing them for decision making. This article proposes a grammar using item stems, response options, and recall periods to systematically identify item-level concepts. The grammar uses "core concept," "evaluative component," and "recall period" as intuitive terms for communicating with stakeholders. Better characterization of concepts is necessary for classifying instrument content and linking it to treatment benefit. Items in 2 generic and 21 disease-specific instruments were evaluated to develop and illustrate the use of the grammar. Concepts were assigned International Classification of Functioning, Disability and Health codes for exploring the value that the grammar and a classification system add to the understanding of content across instruments. The 23 instruments include many core concepts; emotional function is the only concept assessed in all instruments. Concepts in disease-specific instruments show obvious patterns; for example, arthritis instruments focus on physical function. The majority of instruments used the same response options across all items, with five-point scales being the most common. Most instruments used one recall period for all items. Shorter recall periods were used for conditions associated with "flares," such as chronic obstructive pulmonary disease and "skin disease." Every diagnosis, however, showed variation across instruments in the recall period used. This analysis indicates the proposed grammar's potential for discerning the conceptual content within and between health outcomes instruments and illustrates its value for improving communication between stakeholders and for making decisions related to treatment benefit.


Diagnosis and treatment of concomitant aortic and coronary disease: a retrospective study and brief review.
Coronary arteriosclerosis seriously complicates the surgical treatment of aortic diseases. The aim of our retrospective study was to determine the incidence of coronary artery disease among our surgical patients in treatment for aortic dissection or aneurysm, and to determine whether coronary intervention before aortic surgery appears to affect outcomes. Between 1 January 1993 and 1 March 1998, our center treated 253 patients for aortic dissection or aneurysm. We examined these cases retrospectively for information on diagnostic and treatment methods, both for the aortic lesions and for concomitant coronary arteriosclerosis. Aortic dissection had been detected in 86 (33.9%) patients and aortic aneurysm in 167 (66.1%). Coronary angiography was performed to search for concomitant coronary artery disease in 29 (33.8%) patients with dissection and in 112 (67.1%) patients with aneurysm; of these, 11 (12. 7%) and 54 (32.3%), respectively, were found to have coronary disease. Among 43 patients with abdominal aortic aneurysm in whom coronary angiography was performed, concomitant coronary disease was detected in 36 (83.7%). Coronary artery bypass surgery was performed in 10 patients who had dissection and in 30 patients who had aneurysm; percutaneous transluminal coronary angioplasty was performed in 7 patients who had aneurysm. Perioperative mortality rates in the dissection and aneurysm groups, overall, were 23.2% and 13.8%, respectively Unfortunately, the prospective, random clinical study that would be necessary to prove the case for or against preoperative coronary angiography among subsets of patients in need of aortic repair would raise ethical questions, given the strength of the information already in our possession, gathered by less formal methods. Our study reinforces existing evidence that preoperative angiography can reduce mortality and morbidity in the elective repair of aortic aneurysm, especially thoracic or abdominal aneurysm. However, angiography should not be performed routinely in cases of aortic dissection and should be withheld in cases of type A dissection.


Investigation of the stabilizing effects of antioxidants and benzophenone-3 on desonide photostability.
Desonide is a topical corticoid used in the treatment of skin diseases and is marketed in different pharmaceutical dosage forms. Recently, the poor photostability of a commercially available hair solution after direct exposure to UVA light was verified. In this study, we investigated the ability of the antioxidants ascorbic acid, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), α-tocopherol, and the UV filter benzophenone-3 (BP-3) to prevent the photodegradation of desonide in hair solution (desonide 0.1%) and the stability of the proposed formulation under environmental conditions. The tested antioxidants were not able to prevent the photolysis of desonide, whereas the addition of 0.3% BP-3 enhanced the photostability of the drug. After 15 h of direct exposure to UVA radiation, the desonide remaining content in the hair solution with BP-3 was approximately 98%. Higher photostability was also verified under UVC radiation. Additionally, the results indicated that the formulation was stable under accelerated and room temperature conditions for 70 days, corresponding to the total period of the study.


Radiotherapy and Mortality in Pituitary Adenomas.
Pituitary adenomas (PA), comprising 10-20% of intracranial tumors, are classified as functioning and non-functioning and are further divided by size. Non-functioning tumors cause mechanical symptoms while functioning ones result in hormonal hypersecretion syndromes. Initial treatment involves surgery, with medical treatment for prolactinomas. Radiotherapy (RT) is employed as an adjuvant treatment, with various modalities including conventional, stereotactic radiosurgery (SRS), and fractionated stereotactic RT (FSRT). Although effective, RT is associated with complications and toxicities such as hypopituitarism, optic neuritis, secondary CNS tumors, and neurocognitive deficits. Describe the information on mortality from radiotherapy as treatment of functioning PA. A PubMed search spanning 2000-2017 was conducted for articles on pituitary RT. Conventional RT entails high-energy radiation over multiple sessions, while SRS delivers precise high doses in a single session. FSRT offers enhanced precision using a linear accelerator, delivering multiple doses. Optic structure proximity and tumor volume dictate RT modality. Studies have shown SRS and FSRT's efficacy in tumor and endocrine control, with variable risks and complications. Mortality rates in pituitary adenomas treated with RT have been evaluated, revealing complexities. Acromegaly, associated with increased mortality due to cerebrovascular disease, may result from RT. Irradiation of non-functioning pituitary macroadenomas also elevates cerebrovascular risk, while radiotherapy-induced hypopituitarism is associated with increased cardiovascular mortality. RT-induced damage is attributed to microvascular lesions and arteriolar changes. Modern techniques mitigate complications, and although safer, long-term studies are needed. Multidisciplinary evaluation guides the treatment decision, optimizing efficacy and minimizing risk, ultimately improving the patient's quality of life.


The relationship of plasma antioxidant levels to semen parameters: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial.
The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon's rank-sum test and linear regression models. At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility.


Comparative characterization of the reassortant Orthobunyavirus Ngari with putative parental viruses, Bunyamwera and Batai: in vitro characterization and ex vivo stability.
Bunyamwera (BUNV), Batai (BATV) and Ngari (NRIV) are mosquito-borne viruses that are members of the genus Orthobunyavirus in the order Bunyavirales. These three viruses are enveloped with single-stranded, negative-sense RNA genomes consiting of three segments, denoted as Small (S), Medium (M) and Large (L). Ngari is thought to be the natural reassortant progeny of Bunyamwera and Batai viruses. The relationship between these 'parental' viruses and the 'progeny' poses an interesting question, especially given that there is overlap in their respective transmission ecologies, but differences in their infection host ranges and pathogenesis. We compared the in vivo kinetics of these three viruses in a common laboratory system and found no significant difference in growth kinetics. There was, however, a tendency of BATV to have smaller plaques than either BUNV or NRIV. Furthermore, we determined that all three viruses are stable in extracellular conditions and retain infectivity for a week in non-cellular media, which has public health and biosafety implications. The study of this understudied group of viruses addresses a need for basic characterization of viruses that have not yet reached epidemic transmission intensity, but that have the potential due to their infectivity to both human and animal hosts. These results lay the groundwork for future studies of these neglected viruses of potential public and One Health importance.


Anionic subsites of the catalytic center of acetylcholinesterase from Torpedo and from cobra venom.
A peptide of acetylcholinesterase (AcChoEase; acetylcholine acetylhydrolase, EC 188.8.131.52) from the venom of the cobra Naja naja oxiana labeled by the affinity reagent N,N-dimethyl-2-phenylaziridinium (DPA) has been identified. The sequence is Gly-Ala-Glu-Met-Trp-Asn-Pro-Asn. In AcChoEase from Torpedo californica, a homologous peptide was labeled and isolated. Its sequence is Ser-Gly-Ser-Glu-Met-Trp-Asn-Pro-Asn, representing positions 79 through 87. In both cases labeling can be prevented by 0.1 mM edrophonium, indicating that the respective peptides form part of the anionic subsite of the catalytic center. The modified residue was tryptophan (Trp-84 in Torpedo AcChoEase) in both enzymes. In contrast to AcChoEase from Torpedo, the enzyme from cobra venom does not contain a peripheral anionic binding site.


Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes.
This review summarizes biomarkers in systemic juvenile idiopathic arthritis (sJIA). Broadly, the markers are classified under protein, cellular, gene expression and genetic markers. We also compare the biomarkers in sJIA to biomarkers in cryopyrin-associated periodic syndrome (CAPS). Recent publications showing the similarity of clinical response of sJIA and CAPS to anti-interleukin 1 therapies prompted a comparison at the biomarker level. sJIA traditionally is classified under the umbrella of juvenile idiopathic arthritis. At the clinical phenotypic level, sJIA has several features that are more similar to those seen in CAPS. In this review, we summarize biomarkers in sJIA and CAPS and draw upon the various similarities and differences between the two families of diseases. The main differences between sJIA and CAPS biomarkers are genetic markers, with CAPS being a family of monogenic diseases with mutations in NLRP3. There have been a small number of publications describing cellular biomarkers in sJIA with no such studies described for CAPS. Many of the protein marker's characteristics of sJIA are also seen to characterize CAPS. The gene expression data in both sJIA and CAPS show a strong upregulation of innate immunity pathways. In addition, we describe a strong similarity between sJIA and CAPS at the gene expression level in which several genes that form a part of the erythropoiesis signature are upregulated in both sJIA and CAPS.


Intra-articular loose body removal during hip arthroscopy.
Loose bodies are common findings in hip arthroscopy. Loose body removal can be challenging because of the inner position of the acetabulum in which the loose bodies tend to accumulate. Moreover, the standard removal procedure of a considerable number of loose bodies may need a long time under limb traction, thereby increasing the risk of complications. This article describes a new easy method for intra-articular loose body removal. A flexible endotracheal catheter, connected with suction system, is inserted via the anterior or midanterior portal. The catheter can easily be directed toward the inner parts of the joint in proximity of loose bodies. The suction system allows the loose body to be captured in contact with the tip of the catheter, which is then retrieved carrying the loose body outside the cannula. We performed this technique on 4 consecutive patients with synovial chondromatosis. Patients were evaluated preoperatively and 1 month postoperatively by completing self-administered questionnaires. The technique effectiveness was evaluated in terms of overall surgery time, traction time, radiographic appearance of loose bodies left in situ, and postoperative complications. Mean overall surgery time and central time was 175 and 78 minutes, respectively. All patients showed improvement in the operated hip. All radiographs showed hip joint space free of osteochondral loose bodies. No patients reported paraesthesia, nerve palsy, or other postoperative complications. This technique allows for retrieval of a greater amount of loose bodies in a short time, reducing the possibility of undesirable complications.


Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion.
There are several clinical situations in which large epicardial coronary arteries are deprived of blood flow, such as occurs when an obstructing thrombus or embolus lodges within a vessel or during coronary dissection. There is little information concerning the effect of flow deprivation on large epicardial coronary arteries. We studied a model in which a segment of a large epicardial coronary artery was deprived of blood flow using both proximal and distal clamps for 3 hours followed by reperfusion. On examination by light microscopy of cross sections of the arteries, 19 +/- 6 neutrophils were present in the intima of ischemic/reperfused vessels, whereas only a mean of 4 +/- 3 (SEM) were present in the intima of nonischemic vessels (p less than 0.02). On average, there were 17 +/- 9 neutrophils just under the elastic lamina in ischemic/reperfused vessels versus none in the nonischemic vessels (p less than 0.05); there were 16 +/- 10 neutrophils present within the media of ischemic/reperfused vessels, and none (p less than 0.05) in the nonischemic vessels. Electron microscopic analysis revealed that neutrophils in the ischemic/reperfused vessels were often "sandwiched" between the endothelial cells and the elastic lamina. Ultrastructural abnormalities within the myocardium also revealed damage to the microvasculature, including the presence of neutrophils within the vessels and erythrocyte stasis. To rule out the possibility that findings in the large epicardial arteries were due to toxic substances from static blood within the isolated arterial segment, a protocol was performed in which blood was removed from the isolated segment. Again, neutrophil infiltration into the vessel was observed. Resting mean epicardial coronary artery blood flow before coronary occlusion was 19 +/- 3 ml/min; mean coronary blood flow 2.5 hours after reperfusion was identical at 19 +/- 3 ml/min. Response to both endothelial-dependent vasodilation (acetylcholine) and endothelial-independent vasodilation (nitroglycerin) challenges was normal early after reperfusion but was depressed late after reperfusion, suggesting progressive vascular dysfunction and hence a form of vascular reperfusion injury in this model. When large epicardial coronary arteries are deprived of blood flow, followed by reperfusion in this model, neutrophils migrate into the vessel wall as well as into the microvasculature. These abnormalities are associated with reduced endothelial-dependent and endothelial-independent coronary vasodilator reserve.


Electrophilic cyanation of allylic boranes: synthesis of β,γ-unsaturated nitriles containing allylic quaternary carbon centers.
The electrophilic cyanation of allylic boranes, a process that is applicable to the construction of allylic quaternary carbon centers, is reported. The reaction has a broad substrate scope with a high functional group tolerance. The results represent an unprecedented and powerful tool for preparing synthetically useful β,γ-unsaturated nitriles, including derivatives that have been difficult to access using existing methods. The synthetic utility of the method was further demonstrated by functional group interconversions of the cyano group of the products.


Effect of dichloromethylene diphosphonate on liver regeneration following thioacetamide-induced necrosis in rats.
To study the effect of dichloromethylene diphosphonate (DMDP), a selective Kupffer cell toxicant in reference to liver damage and postnecrotic liver regeneration in rats induced by sublethal dose thioacetamide (TA). Rats, intravenously (iv) pre-treated with a single dose of DMDP (10 mg/kg), were intraperitoneally (ip) injected with TA 6.6 mmol/kg (per 500 mg/kg body weight). Hepatocytes were isolated from rats at 0, 24, 48 and 72 h following TA intoxication and blood and liver samples were obtained. To evaluate the mechanisms involved in the postnecrotic regenerative state, DNA distribution and ploidy time course were assayed in isolated hepatocytes. Circulating cytokine tumor necrosis factor-alpha (TNF-α) was assayed in serum and determined by reverse transcriptase-polymerase chain reaction in liver extract. The effect of DMDP induced noticeable changes in postnecrotic regeneration, causing an increased percentage of hepatocytes in the cell cycle S phase. The increase at 24 h in S1 population in rats pretreated with DMDP + TA was significantly (P < 0.05) different compared with that of the TA group (18.07% vs 8.57%). Hepatocytes increased their proliferation as a result of these changes. Also, TNF-α expression and serum level were increased in rats pre-treated with DMDP. Thus, DMDP pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. These results demonstrate that Kupffer cells are involved in TA-induced liver, as well as in postnecrotic proliferative liver states.


Use of non-absorbable markers in studies of human nutrient absorption.
Neutron activation analysis signifies a new era in the methodology of studies on nutrient utilization in humans. Yet the classical metabolic balance technique incorporating inert, non-absorbable markers will continue to be an invaluable tool for such studies. This review describes the use and abuse of a number of 'classical' inert markers, and describes the potential use of radioactive and naturally-occurring isotopes, and of heavy metals. The paucity of data critically appraising markers in infant balance trials is apparent. The comparative merits of conventional markers--carmine, polyethylene glycol 4000, chromium oxide--should be assessed. Indeed, it might be argued that the advancing knowledge on the use of naturally occurring isotopes in adults should make similar studies on infants a priority.


Xrp1 is a transcription factor required for cell competition-driven elimination of loser cells.
The elimination of unfit cells from a tissue is a process known in Drosophila and mammals as cell competition. In a well-studied paradigm "loser" cells that are heterozygous mutant for a haploinsufficient ribosomal protein gene are eliminated from developing tissues via apoptosis when surrounded by fitter wild-type cells, referred to as "winner" cells. However, the mechanisms underlying the induction of this phenomenon are not fully understood. Here we report that a CCAAT-Enhancer-Binding Protein (C/EBP), Xrp1, which is known to help maintaining genomic stability after genotoxic stress, is necessary for the elimination of loser clones in cell competition. In loser cells, Xrp1 is transcriptionally upregulated by an autoregulatory loop and is able to trigger apoptosis - driving cell elimination. We further show that Xrp1 acts in the nucleus to regulate the transcription of several genes that have been previously involved in cell competition. We therefore speculate that Xrp1 might play a fundamental role as a molecular caretaker of the genomic integrity of tissues.


Biology of somatostatin in breast cancer.
The biological effects of the neuropeptide somatostatin (SST) are mediated via a family of five somatostatin receptors (SSTRs) belonging to a family of G-protein-coupled receptors (GPCRs). SSTR regulate the secretion of hormones, growth factors, neurotransmission and cell growth in receptor-specific manner. In addition, SST plays an inhibitory role in several mammary cancer models. These effects are mediated both indirectly through inhibition of hormones and growth factors which promote tumor growth as well as directly via SSTRs present on tumor cells to inhibit mitogenic signaling of growth factor receptor kinases leading to growth arrest and induction of apoptosis. Here, we present an overview on the role of SST and its analogs in breast cancer.


Cellular basis of ECD brain retention.
Clinical observations have shown discrepancies between ECD and HMPAO regional cerebral perfusion, particularly in brain tumors and during stroke recovery. We investigated the nature of the process(es) involved in ECD accumulation in vitro at the cellular level. Time course incorporation of ECD was studied in a fast-growing human premonocytic line, U937, in a human astrocytic-derived cell line, U373, and a human hybridized endothelial cell line, EaHy926. Cells were further used in experiments aiming to correlate esterase activity and ECD retention. Significant differences in ECD retention between these cell lines were observed: %UECD (cpm cells/cpm standard of injected) plateaued within 2 hr in all cases but %UECD was significantly higher in U937 cells (25.1 +/- 3.9% at 120 min) than in the other cell lines (6.1 +/- 0.7% and 8.2 +/- 2.0% at 120 min for U373 and EaHy926, respectively). Contrary to what we expected, total cellular esterase activity (EATOT) was inversely correlated to %UECD.EATOT was 5-fold lower in U937 cells than in U373 and 20-fold lower than in EaHy926. Thus, we compared the membranar to the cytosolic esterase activity of U937 and analyzed the influence of temperature and diisopropylfluorophosphate (DFP, an inhibitor of cytosolic esterase activity) on both ECD retention and enzymatic activities. When cells were exposed to DFP, %UECD was reduced by 80%; while when cells were maintained at 4 degrees C, %UECD continuously increased, corresponding to a passive diffusion since both cytosolic and membranar esterase activities were inhibited. For optimal uptake of ECD, the membranar fraction of the esterase activity has to be low, while, in contrast, the cytosolic fraction of the esterase activity plays an important role in ECD cell retention. ECD-SPECT is likely able to reflect regional cerebral blood flow in normal and pathological states accurately, but in the event of unusual observations, the membranar esterase activity should be considered to explain reduced ECD retention.


Geriatric Conditions Among Middle-aged and Older Adults on Methadone Maintenance Treatment: A Pilot Study.
The number of older adults on methadone maintenance treatment (MMT) for opioid use disorder is increasing, but little is known about the characteristics and healthcare needs of this aging treatment population. This population may experience accelerated aging due to comorbidities and health behaviors. The aim of this study was to compare the prevalence of geriatric conditions among adults age ≥50 on MMT to a nationally representative sample of community-dwelling older adults. We performed a geriatric assessment on 47 adults age ≥50 currently on MMT enrolled in 2 opioid treatment programs, in New York City and in East Providence, Rhode Island. We collected data on self-reported geriatric conditions, healthcare utilization, chronic medical conditions, physical function, and substance use. The results were compared to 470 age, sex, and race/ethnicity-matched adults in the national Health and Retirement Study. The mean age of the study sample was 58.8 years and 23.4% were female. The most common chronic diseases were hypertension (59.6%) and arthritis (55.3%) with 66% reporting ≥2 diseases. For geriatric conditions, adults on MMT had a significantly higher prevalence of mobility, hearing, and visual impairments as well as falls, urinary incontinence, chronic pain, and insomnia than the Health and Retirement Study sample. Older adults on MMT in 2 large opioid treatment programs have a high prevalence of geriatric conditions. An interdisciplinary, geriatric-based approach to care that focuses on function and addresses geriatric conditions is needed to improve the health of this growing population.


Disease and injury statistics of Japanese Antarctic research expeditions during the wintering period: evaluation of 6837 cases in the 1st-56th parties - Antarctic health report in 1956-2016.
This study aimed to evaluate disease and injury trends among wintering members of the Japanese Antarctic Research Expedition. Obtained information is indispensable to the advancement of medical system and research. Summation was performed based on medical records of reports prepared by each expedition over the period 1956-2016. The clinical department's classification methods of the names of injuries and diseases varied among expeditions, but the names were integrated following the same classification. Of 1734 members (29 women), 6837 disease or injury cases (4 cases/person) were recorded. The rates of cases were as follows: surgical-orthopaedic (45.3%), internal medical (21.7%), dental (11.6%), dermatological (8.4%), ophthalmological (5.8%), otorhinolaryngological (5.3%), psychiatric (1.6%), and urological (0.1%) cases. There was no major change in rates by type of medical case in each expedition. This analysis made it possible to prepare medical facilities, content of physical examinations to select members, training of physicians before departure, preventive hygiene at sites, and medical research themes.


[Reduction of chromium (VI) by reference bacterial strains].
Collection bacterial strains were found to be capable of chromium (VI) reduction although they had not been in contact with chromium compounds before. Strains capable of nitrate respiration could use bichromate ions as a terminal electron acceptor in the absence of competing acceptors. Cr(VI) was reduced to Cr(III) when bichromate was added to the cultural broth whose redox potential reached -140 mV.


RNAcentral: a hub of information for non-coding RNA sequences.
RNAcentral is a comprehensive database of non-coding RNA (ncRNA) sequences, collating information on ncRNA sequences of all types from a broad range of organisms. We have recently added a new genome mapping pipeline that identifies genomic locations for ncRNA sequences in 296 species. We have also added several new types of functional annotations, such as tRNA secondary structures, Gene Ontology annotations, and miRNA-target interactions. A new quality control mechanism based on Rfam family assignments identifies potential contamination, incomplete sequences, and more. The RNAcentral database has become a vital component of many workflows in the RNA community, serving as both the primary source of sequence data for academic and commercial groups, as well as a source of stable accessions for the annotation of genomic and functional features. These examples are facilitated by an improved RNAcentral web interface, which features an updated genome browser, a new sequence feature viewer, and improved text search functionality. RNAcentral is freely available at https://rnacentral.org.


[Local noncircumscribed peritonitis in acute appendicitis].
An analysis of 280 clinical observations of acute appendicitis complicated by local noncircumscribed peritonitis was performed. It was shown that the pathology was characterized by more acute clinical course, later time of operative interventions, greater amount of postoperative complications and longer staying at the hospital. In the treatment of appendicitis complicated by local peritonitis main attention must be given to sanitation of the abdominal cavity and complex postoperative management after appendectomy.


Development of a lyophilised RH1 formulation: a novel DT diaphorase activated alkylating agent.
RH1 is a novel aziridinylbenzoquinone alkylating agent, which is activated in tumour cells by DT diaphorase. In common with previous aziridinylbenzoquinones, RH1 exhibits limited aqueous stability and solubility. The aim of this study was to examine the pharmaceutical properties of RH1 with a view to preparing a suitable formulation for clinical trial. Stability in a neutral phosphate-buffered solution was poor with a degradation half-life of 50 h at 55 degrees C, indicating that lyophilisation was preferable. The reaction kinetics indicated a similarity with previous studies for base-catalysed degradation of aziridinylbenzoquinones. Intrinsic aqueous solubility at 0.5 mg mL(-1) may be increased in solvent systems or by the use of polymers such as polyvinylpyrrolidone (PVP) or complexing agents like hydroxypropyl-beta-cyclodextrin (HPBCD). In the latter case this increased solubility by an order of magnitude to around 5 mg mL(-1). Four potential formulations based on lyophilisation of RH1 (1 mg mL(-1)) from buffered solution (pH 7, 0.01 M NaH2PO4) containing either 50 mg mL(-1) mannitol, 40 mg mL(-1) dextran, 20 mg mL(-1) PVP or 50 mg mL(-1) HPBCD were prepared and examined for stability characteristics. All formulations exhibited a temperature-dependent degradation. The mannitol and dextran formulations had limited stability and degraded rapidly at all temperatures. The PVP and HPBCD formulations degraded at elevated temperatures but remained stable for up to twelve months at 4 degrees C. Examination of the degradation kinetics in the latter systems demonstrated similarity to the solution degradation mechanism, while in the former alternative degradation pathways appeared to be occurring. The chemical stability of RH1 in lyophilised formulations is dependent upon the excipient employed and storage temperature. Either the PVP or HPBCD formulation would be suitable clinical trial formulations of RH1. The results indicate that the choice of lyophilisation excipient for aziridinylbenzoquinones cannot be based on previous literature studies of related agents.