Abstract
Mastitis is an inflammation of the mammary gland that occurs when pathogenic microorganisms enter the udder. Even though tremendous advancements in veterinary diagnosis and therapeutics, mastitis is still the most frequent and costly disease of dairy herds overall the world. The purpose of this research was to isolate and identify the lytic phages as a potential method for biological control of bovine mastitis. In this study Klebsiella oxytoca was isolated from contaminated milk samples of Isfahan dairy herds, Isfahan, Iran and characterized as K. oxytoca ABG-IAUF-1 and its 16s-rDNA sequence was deposited in GenBank under the accession numbers of MF175803.1. Then, the four novel specific lytic bacteriophages of K. oxytoca ABG-IAUF-1 from Isfahan public wastewater were isolated and identified. The results of transmission electron microscopy indicated that theses isolated phages were related to Myoviridae and Podoviridae families of bacteriophages. Also the analysis of the growth curve of K. oxytoca ABG-IAUF-1 before and after treatment with lytic phage showed the 97% success rate of the phages in preventing of bacterial growth. This is the first report indicating the use of bacteriophages as the potential agents for eliminating the pathogenic bacteria responsible for bovine mastitis in Iran. The applications of these lytic phages could be an asset for biocontrolling of pathogenic agents in medical and veterinary biotechnology.Τετάρτη 12 Σεπτεμβρίου 2018
Non-conventional Yeast cell factories for sustainable bioprocesses
Abstract
The non-conventional yeasts Kluyveromyces lactis, Yarrowia lipolytica, Ogataea polymorpha and Pichia pastoris have been developed as eukaryotic expression hosts because of their desirable growth characteristics, including inhibitor and thermo-tolerance, utilization of diverse carbon substrates, and high amount of extracellular protein secretion. These yeasts already have established in the heterologous production of vaccines, therapeutic proteins, food additives, and bio-renewable chemicals, but recent advances in genetic tool box have the potential to greatly expand and diversify their impact on biotechnology. The diversity of these yeasts includes many strains possessing highly useful, and in some cases even uncommon, metabolic capabilities potentially helpful for bioprocess industry. This review outlines the recent updates of non-conventional yeast in sustainable bioprocesses.Cancer in Sexual and Gender Minority Patients: Are We Addressing Their Needs?
Abstract
Purpose of Review
To describe the current literature regarding the cancer care of sexual and gender minority patients and to identify significant knowledge gaps that hinder our understanding of the unique needs of sexual and gender minority patients with cancer.
Recent Findings
Sexual and gender minorities suffer from cancer-related disparities, including lower rates of cancer screening, higher incidence of certain cancers, and higher cancer mortality rates. Sexual side effects, depression, and social isolation are especially common among sexual minority individuals with cancer. While the aforementioned disparities are concerning, the cancer-specific needs of sexual and gender minorities remain understudied. Population-based, prospective studies evaluating cancer-specific risks, mortality, and survivorship issues facing gender and sexual minorities are lacking.
Summary
There is a paucity of literature guiding the cancer care of sexual and gender minority patients. Areas that require further study include epidemiologic evaluations, cancer screening recommendations, and cancer treatment and survivorship.
Polymorphic Erythematous Macules and Plaques With Dysesthesia
A woman in her 50s presented with a 2-year history of disseminated dermatosis involving the trunk and limbs; the dermatosis was characterized by polymorphic erythematous macules and plaques with elevated and indurated borders without evanescence to pressure. What is your diagnosis?
RCM and En Face Histopathologic Correlation of the Dermoscopic “Circle Within a Circle” in LM
This case report describes a process by which the dermoscopic "circle within a circle" feature can be correlated with findings of reflectance confocal microscopic (RCM) and en face histopathologic findings from a lentigo maligna lesion.
Prescription to OTC Switch of Metronidazole and Azelaic Acid for Rosacea
This Viewpoint considers the advantages and disadvantages of topical treatments for rosacea, specifically metronidazole and azelaic acid, undergoing review to switch from prescription to over-the-counter availability.
Association of Low SES With Hidradenitis Suppurativa
This cohort analysis evaluates the association of low socioeconomic status with hidradenitis suppurativa among patients in the United States.
Scabies—An Ancient Disease With Unanswered Questions in Modern Times
This Viewpoint discusses the global disease burden of scabies, as well as its diagnosis and treatment.
Sunscreen Use and Melanoma Risk Among Young Australian Adults
This population-based, case-control family study of data collected for the Australian Melanoma Family Study assesses the association of sunscreen use in childhood and early adulthood with the risk of cutaneous melanoma before age 40 years.
Necrotizing Anogenital Ulcer in a Healthy 8-Month-Old Male
A healthy 8-month-old male infant was admitted for management of a rapidly progressive, painful anogenital ulcer; the lesion had developed acutely over 48 hours and had an associated symptom, but no fevers, chills, or other systemic symptoms. What is your diagnosis?
Evaluation of a Brief Dermatologist-Delivered Intervention vs Usual Care on Sun Protection Behavior
This longitudinal controlled cohort study examines the association of a brief dermatologist-delivered intervention with patient satisfaction and sun protection behavior among adults receiving dermatology care.
A Comparison of Tanning Habits Among Gym Tanners and Other Tanners
This survey study evaluates the incidence of tanning in adults who use indoor gyms.
Association Between Mediterranean Anti-inflammatory Dietary Profile and Severity of Psoriasis
This cohort study uses a self-completed questionnaire by respondents in the French NutriNet-Santé study to evaluate the association between a Mediterranean anti-inflammatory dietary profile and the severity of psoriasis.
Topical Crisaborole—A Potential Treatment for Recalcitrant Palmoplantar Psoriasis
This case report describes the use of topical crisaborole to treat previously treatment-refractory palmoplantar psoriasis
Economic Analysis of a Noninvasive Molecular Pathologic Assay for Pigmented Skin Lesions
This economic analysis assesses the costs of use of the pigmented lesion assay vs visual and histopathologic assessment in model inputs of patients with primary pigmented lesions suggestive of melanoma.
Characteristics and Skin Cancer Risk Behaviors of US Adult Sunless Tanners
This secondary analysis of a cross-sectional study using data from the 2015 National Health Interview Survey assesses the demographic characteristics and skin cancer risk behaviors of US adults who are sunless tanners.
Incidence of Endemic Human Cutaneous Leishmaniasis in the United States
This observational study reviews cases of endemic human leishmaniasis occurring in the United States, mostly in Texas, over a 10-year period.
Linear Keratotic Lesions in a Young Woman
A woman in her 20s presented with linear hyperkeratotic papules on her right arm in a Blaschkoid pattern. What is your diagnosis?
Dermatology Procedures Billed by Advanced Practice Professionals, 2012-2015
This longitudinal study uses Medicare data from 2012 through 2015 to review the trends in scope and volume of dermatology procedures performed by advanced practice professionals such as nurse practitioners and physician assistants.
Facial-Aging App Availability in Waiting Rooms as a Potential Opportunity for Skin Cancer Prevention
This survey study explores whether a single exposure of adult patients in a waiting room to an app that approximates facial UV damage may lead to altered UV protection behavior.
Effect of Stress Ball Use or Hand-holding on Anxiety During Skin Cancer Excision
This randomized clinical trial examines the effects of hand-holding vs stress ball use compared with usual care on anxiety in patients undergoing excisional removal of nonmelanoma skin cancer of the head or neck with local anesthesia.
Association of Lichen Planopilaris With Dyslipidemia
This cohort study evaluates the association between lichen planopilaris, hyperlipidemia, and metabolic syndrome.
Immunoglobulin A anti‐phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual
Clinical &Experimental Immunology, EarlyView.
Formation characteristics of carbonaceous and nitrogenous disinfection by-products depending on residual organic compounds by CGS and DAF
Abstract
Allogenic organic matter (AOM) composed of extracellular and intracellular organic matter (EOM and IOM) is a major precursor of halogenated carbonaceous and nitrogenous disinfection by-products (C-DBPs and N-DBPs) upon chlorination. The EOM and IOM extracted from Microcystis aeruginosa were analyzed based on bulk parameters and organic fractions with different molecular weight by liquid chromatography with organic carbon detection (LC-OCD). It investigated the efficiency of a conventional gravity system (CGS) and dissolved air flotation (DAF) in the removal of organic precursors, together with measurement of the formation of four major trihalomethanes (THMs) and haloacetonitriles (HANs) in treated water upon chlorination. The results showed that EOM accounted for 59% of building blocks and humic substances, whereas for IOM, 54% were low molecular weight (LMW) neutrals. Both CGS and DAF showed 57–59% removal of dissolved organic carbon (DOC) from EOM and IOM. Regarding DON removal, DAF was found to be more effective, i.e., 8% higher than CGS for EOM. Moreover, the removal of LMW acids and neutrals (not easy to remove and are major precursors of DBPs) from EOM and IOM by DAF was higher than from CGS. The amounts of DBPs measured in all the samples treated for interchlorination were much lower than in the samples for prechlorination. Although the precursors of EOM had a higher concentration than in IOM, THMs and HANs were detected for IOM at a higher concentration, which might be attributed to higher amounts of aromatic, aliphatic moisture and protein compounds in the IOM. Comparatively, DAF showed lower THM and HAN values than CGS water, particularly for IOM. Also, DAF showed a sharp decrease in THMs and an insignificant increase in HANs according to time.
Human health risks of Hg, As, Mn, and Cr through consumption of fish, Ticto barb ( Puntius ticto ) from a tropical river, Bangladesh
Abstract
Metals tend to accumulate in higher organisms, e.g., fish and human through biomagnification effects in food chain. So, their presence in any component of the environment has become a global ecosystem and health concern. Here, we measured four health concerned metals like As, Cr, Mn, and Hg via inductively coupled plasma-mass spectrometry (ICP-MS) and analyzed applying some chemometrics for the assessment of human health risk through consumption of Puntius ticto, a very commonly consumed small fish in Bangladesh. The average concentration (wet weight) of metals was in the following descending order: Hg (0.006 mg/kg) > Cr (0.004 mg/kg) > Mn (0.003 mg/kg) > As (0.002 mg/kg). Hg level exceeded the provisional tolerable weekly intake (PTWI), and all other metals were within the permissible limit. The estimated daily intake (EDI) index of heavy metals showed that all the concentration levels were under the recommended daily intake (RDA) except Hg. Increased level of Hg is of particular concern to human health due to its biomagnification nature and can cause several neurological and physiological disorders including kidney failure. The total target hazard quotients (TTHQs) and carcinogenic risk (CR) matrices revealed that the intakes of Hg and As through fish consumption were higher than the recommended values, indicating consumers' remain non-carcinogenic and carcinogenic (THQ > 1; CR > 10−5) health risks for lifetime consumption. Multivariate analyses (cluster and principal component) explained the sources of heavy metals in the study area originating from both anthropogenic and geological origin.
Baccharis dracunculifolia (Asteraceae) essential oil toxicity to Culex quinquefasciatus (Culicidae)
Abstract
The control of mosquitoes by means of chemical insecticides has been a problem, mainly due to the possibility of resistance developed by insects to xenobiotics. For this reason, demand for botanical insecticides has increased. In this sense, the present work aims to verify the susceptibility and morphological and biochemical alterations of Culex quinquefasciatus larvae after exposure to essential oil (EO) of leaves of Baccharis dracunculifolia. To observe the larvicidal action, larvae were exposed to EO at concentrations of 25, 50, 100, and 200 mg/L, until their emergence to adults. The control group was exposed to deionized water and dimethyl sulfoxide. Morphological analyses were also carried out using hematoxylin and eosin, mercury bromophenol blue, Nile blue, and periodic acid Schiff. Biochemical analyses of total glucose, triacylglyceride (TAG), protein, and acetylcholinesterase levels were performed. The phytochemical analysis of the EO showed (E)-nerolidol as the major compound (30.62%). Larvae susceptibility results showed a LC50 of 34.45 mg/L for EO. Morphological analysis showed that there were histological changes in midgut. For biochemical analyses, the glucose level in the larvae exposed to EO for 24 h decreased significantly, unlike the TAG levels, which increased. The total protein level of the larvae also increased after exposure for 24 h, and acetylcholinesterase levels decreased significantly. Taking all our data into account, we can conclude that EO causes destabilization in larva, leading to histological changes, metabolic deregulation and, consequently, their death.
Stress response of NAD + -dependent formate dehydrogenase in Gossypium hirsutum L. grown under copper toxicity
Abstract
Cotton (Gossypium hirsutum L.), which is not directly involved in the food chain, appears to be a suitable candidate to remove heavy metals from the food chain and to be a commercial plant which could be planted in contaminated soils. The key point of this approach is selection of the right genotype, which has heavy metal resistance or hyperaccumulation properties. Therefore, in the present study, two G. hirsutum genotypes, Erşan-92 and N-84S, were grown under copper stress and investigated to obtain further insights about the heavy metal tolerance mechanisms of plants by focusing on the expression of NAD+-dependent formate dehydrogenase (FDH). In accordance with the results, which were obtained from RT-PCR analysis and activity measurements, in the Erşan-92 root tissue, FDH activity increased significantly with increasing metal concentrations and a 6.35-fold higher FDH activity was observed in the presence of 100-μM Cu. As opposed to Erşan-92, the maximum FDH activity in the roots of N-84S, which were untreated with copper as the control plants, was measured as 0.0141-U mg−1 g−1 FW, and the activity decreased significantly with the increasing metal concentrations. The metallothionein (GhMT3a) transcript level of the plants grown in a medium containing different Cu concentrations showed nearly the same pattern as that of the FDH gene transcription. It was observed that while the tolerance of N-84S in the lower Cu concentration reduces remarkably, Erşan-92 continues to struggle up to 100-μM Cu. The results of the SOD analysis also confirm this activity of Erşan-92 against the Cu stress.
Facile synthesis of Fe 3 O 4 @MOF-100(Fe) magnetic microspheres for the adsorption of diclofenac sodium in aqueous solution
Abstract
In this research, the adsorptive removal of diclofenac sodium, one of the representative pharmaceuticals and personal care products, from aqueous solution using Fe3O4@MOF-100(Fe) magnetic microspheres was studied for the first time. The Fe3O4@MOF-100(Fe) microspheres exhibit strong magnetism and stability, which were observed as a core-shell structure. The maximum adsorption capacity of Fe3O4@MOF-100(Fe) for diclofenac sodium can reach 377.36 mg L−1, which was higher than most of the adsorbents reported. The adsorption kinetics follows the pseudo-second-order kinetic equation. And the adsorption equilibrium of DCF can be described with Langmuir isotherm. In the cycle experiment, Fe3O4@MOF-100(Fe) material performed high adsorption efficiency for low-concentration diclofenac sodium solution, and the removal rate can still reach 80% after 5 cycles of adsorption without desorption. The mechanisms including electrostatic interaction, H-bond interaction, and π-π interaction that coexisted in the adsorption processes would be of benefit to enhance the adsorption capacity. The Fe3O4@MOF-100(Fe) magnetic microspheres offer exciting opportunities for further application.
Lifestyle chemical carcinogens associated with mutations in cell cycle regulatory genes increases the susceptibility to gastric cancer risk
Abstract
In the present study, we correlated the various lifestyle habits and their associated mutations in cell cycle (P21 and MDM2) and DNA damage repair (MLH1) genes to investigate their role in gastric cancer (GC). Multifactor dimensionality reduction (MDR) analysis revealed the two-factor model of oral snuff and smoked meat as the significant model for GC risk. The interaction analysis between identified mutations and the significant demographic factors predicted that oral snuff is significantly associated with P21 3′UTR mutations. A total of five mutations in P21 gene, including three novel mutations in intron 2 (36651738G > A, 36651804A > T, 36651825G > T), were identified. In MLH1 gene, two variants were identified viz. one in exon 8 (37053568A > G; 219I > V) and a novel 37088831C > G in intron 16. Flow cytometric analysis predicted DNA aneuploidy in 07 (17.5%) and diploidy in 33 (82.5%) tumor samples. The G2/M phase was significantly arrested in aneuploid gastric tumor samples whereas high S-phase fraction was observed in all the gastric tumor samples. This study demonstrated that environmental chemical carcinogens along with alteration in cell cycle regulatory (P21) and mismatch repair (MLH1) genes may be stimulating the susceptibility of GC by altering the DNA content level abnormally in tumors in the Mizo ethic population.
Drosophila Exo70 Is Essential for Neurite Extension and Survival under Thermal Stress
The octomeric exocyst complex governs the final step of exocytosis in both plants and animals. Its roles, however, extend beyond exocytosis and include organelle biogenesis, ciliogenesis, cell migration, and cell growth. Exo70 is a conserved component of the exocyst whose function in Drosophila is unclear. In this study, we characterized two mutant alleles of Drosophila exo70. exo70 mutants exhibit reduced synaptic growth, locomotor activity, glutamate receptor density, and mEPSP amplitude. We found that presynaptic Exo70 is necessary for normal synaptic growth at the neuromuscular junction (NMJ). At the neuromuscular junction, exo70 genetically interacts with the small GTPase ralA to regulate synaptic growth. Loss of Exo70 leads to the blockage of JNK signaling-, activity-, and temperature-induced synaptic outgrowths. We showed that this phenotype is associated with an impairment of integral membrane protein transport to the cell surface at synaptic terminals. In octopaminergic motor neurons, Exo70 is detected in synaptic varicosities, as well as the regions of membrane extensions in response to activity stimulation. Strikingly, mild thermal stress causes severe neurite outgrowth defects and pharate adult lethality in exo70 mutants. exo70 mutants also display defective locomotor activity in response to starvation stress. These results demonstrated that Exo70 is an important regulator of induced synaptic growth and is crucial for an organism's adaptation to environmental changes.
SIGNIFICANCE STATEMENT The exocyst complex is a conserved protein complex directing secretory vesicles to the site of membrane fusion during exocytosis, which is essential for transporting proteins and membranes to the cell surface. Exo70 is a subunit of the exocyst complex whose roles in neurons remain elusive, and its function in Drosophila is unclear. In Drosophila, Exo70 is expressed in both glutamatergic and octopaminergic neurons, and presynaptic Exo70 regulates synaptic outgrowth. Moreover, exo70 mutants have impaired integral membrane transport to the cell surface at synaptic terminals and block several kinds of induced synaptic growth. Remarkably, elevated temperature causes severe arborization defects and lethality in exo70 mutants, thus underpinning the importance of Exo70 functions in development and adaptation to the environment.
Adult Ube3a Gene Reinstatement Restores the Electrophysiological Deficits of Prefrontal Cortex Layer 5 Neurons in a Mouse Model of Angelman Syndrome
E3 ubiquitin ligase (UBE3A) levels in the brain need to be tightly regulated, as loss of functional UBE3A protein is responsible for the severe neurodevelopmental disorder Angelman syndrome (AS), whereas increased activity of UBE3A is associated with nonsyndromic autism. Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS. Whole-cell recordings from layer 5 mPFC pyramidal neurons obtained in brain slices from adult mice of both sexes revealed that loss of UBE3A results in a strong decrease of spontaneous inhibitory transmission and increase of spontaneous excitatory transmission potentially leading to a marked excitation/inhibition imbalance. Additionally, we found that loss of UBE3A led to decreased excitability and increased threshold for action potential of layer 5 fast spiking interneurons without significantly affecting the excitability of pyramidal neurons. Because we previously showed that AS mouse behavioral phenotypes are reversible upon Ube3a gene reactivation during a restricted period of early postnatal development, we investigated whether Ube3a gene reactivation in a fully mature brain could reverse any of the identified physiological deficits. In contrast to our previously reported behavioral findings, restoring UBE3A levels in adult animals fully rescued all the identified physiological deficits of mPFC neurons. Moreover, the kinetics of reversing these synaptic deficits closely followed the reinstatement of UBE3A protein level. Together, these findings show a striking dissociation between the rescue of behavioral and physiological deficits.
SIGNIFICANCE STATEMENT Here we describe significant physiological deficits in the mPFC of an Angelman syndrome mouse model. We found a marked change in excitatory/inhibitory balance, as well as decreased excitability of fast spiking interneurons. A promising treatment strategy for Angelman syndrome is aimed at restoring UBE3A expression by activating the paternal UBE3A gene. Here we find that the physiological changes in the mPFC are fully reversible upon gene reactivation, even when the brain is fully mature. This indicates that there is no critical developmental window for reversing the identified physiological deficits in mPFC.
SCN VIP Neurons Are Essential for Normal Light-Mediated Resetting of the Circadian System
The suprachiasmatic nucleus (SCN) synchronizes circadian rhythms in behavior and physiology to the external light cycle, but the mechanisms by which this occurs are unclear. As the neuropeptide vasoactive intestinal peptide (VIP) is important for circadian light responses, we tested the hypothesis that rhythmic VIP-producing SCN neurons mediate circadian light responses in male and female mice. Using in vivo fiber photometry over multiple days, we found daily rhythms in spontaneous calcium events of SCN VIP neurons that peaked during the subjective day and were disrupted by constant light. The light-evoked calcium responses peaked around subjective dusk and were greater during the subjective night. Using novel VIP sensor cells, we found that the activity patterns in SCN VIP neurons correlated tightly with spontaneous and NMDA-evoked VIP release. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons exhibit circadian rhythms in spontaneous and light-responsive activity and are essential for the normal resetting of daily rhythms by environmental light.
SIGNIFICANCE STATEMENT Daily rhythms in behavior and physiology, including sleep/wake and hormone release, are synchronized to local time by the master circadian pacemaker, the suprachiasmatic nucleus (SCN). The advent of artificial lighting and, consequently, light exposure at night, is associated with an increased risk of disease due to disrupted circadian rhythms. However, the mechanisms by which the SCN encodes normal and pathological light information are unclear. Here, we find that vasoactive intestinal peptide (VIP)-producing SCN neurons exhibit daily rhythms in neuronal activity and VIP release, and that blocking the activity of these neurons attenuates light-induced phase shifts. We conclude that rhythmic VIP neurons are an essential component of the circadian light transduction pathway.
Mast Cells in the Developing Brain Determine Adult Sexual Behavior
Many sex differences in brain and behavior are programmed during development by gonadal hormones, but the cellular mechanisms are incompletely understood. We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. Newborn male rats had greater numbers and more activated mast cells in the preoptic area (POA), a brain region essential for male copulatory behavior, than female littermates during the critical period for sexual differentiation. Inhibiting mast cells with a stabilizing agent blunted the masculinization of both POA neuronal and microglial morphology and adult sex behavior, whereas activating mast cells in females, even though fewer in number, induced masculinization. Treatment of newborn females with a masculinizing dose of estradiol increased mast cell number and induced mast cells to release histamine, which then stimulated microglia to release prostaglandins and thereby induced male-typical synaptic patterning. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors.
SIGNIFICANCE STATEMENT We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors.
Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus
Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer–commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERβ or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERβ. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories.
SIGNIFICANCE STATEMENT There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.
Influence of vmPFC on dmPFC Predicts Valence-Guided Belief Formation
When updating beliefs about their future prospects, people tend to disregard bad news. By combining fMRI with computational and dynamic causal modeling, we identified neurocircuitry mechanisms underlying this optimism bias to test for valence-guided belief formation. In each trial of the fMRI task, participants (n = 24, 10 male) estimated the base rate (eBR) and their risks of experiencing negative future events, were confronted with the actual BR, and finally had the opportunity to update their initial self-related risk estimate. We demonstrated an optimism bias by revealing greater belief updates in response to good over bad news (i.e., learning that the actual BR is lower or higher than expected) while controlling for confounds (estimation error and personal relevance of the new information). Updating was favorable when the final belief about risks improved (or at least did not worsen) relative to the initial risk estimate. This valence of updating was encoded by the ventromedial prefrontal cortex (vmPFC) associated with the valuation of rewards. Within the updating circuit, the vmPFC filtered the incoming signal in a valence-dependent manner and influenced the dorsomedial prefrontal cortex (dmPFC). Both the valence-encoding activity in the vmPFC and its influence on the dmPFC predicted individual magnitudes of the optimism bias. Our results indicate that updating was biased by the motivation to maximize desirable beliefs, mediated by the influence of the valuation system on further cognitive processing. Therefore, although it provides the very basis for human reasoning, belief formation is essentially distorted to promote desired conclusions.
SIGNIFICANCE STATEMENT The question of whether human reasoning is biased by desires and goals is crucial for everyday social, professional, and economic decisions. How much our belief formation is influenced by what we want to believe is, however, still debated. Our study confirms that belief updates are indeed optimistically biased. Critically, the bias depends on the recruitment of the brain valuation system and the influence of this system on neural regions involved in reasoning. These neurocircuit interactions support the notion that the motivation to maximize pleasant beliefs reinforces those cognitive processes that are most likely to yield the desired conclusion.
Accounting for Taste: A Multi-Attribute Neurocomputational Model Explains the Neural Dynamics of Choices for Self and Others
How do we make choices for others with different preferences from our own? Although neuroimaging studies implicate similar circuits in representing preferences for oneself and others, some models propose that additional corrective mechanisms come online when choices for others diverge from one's own preferences. Here we used event-related potentials (ERPs) in humans, in combination with computational modeling, to examine how social information is integrated in the time leading up to choices for oneself and others. Hungry male and female participants with unrestricted diets selected foods for themselves, a similar unrestricted eater, and a dissimilar, self-identified healthy eater. Across choices for both oneself and others, ERP value signals emerged within the same time window but differentially reflected taste and health attributes based on the recipient's preferences. Choices for the dissimilar recipient were associated with earlier activity localized to brain regions implicated in social cognition, including temporoparietal junction. Finally, response-locked analysis revealed a late ERP component specific to choices for the similar recipient, localized to the parietal lobe, that appeared to reflect differences in the response threshold based on uncertainty. A multi-attribute computational model supported the link between specific ERP components and distinct model parameters, and was not significantly improved by adding time-dependent dual processes. Model simulations suggested that longer response times previously associated with effortful correction may alternatively arise from higher choice uncertainty. Together, these results provide a parsimonious neurocomputational mechanism for social decision-making, additionally explaining divergent patterns of choice and response time data in decisions for oneself and others.
SIGNIFICANCE STATEMENT How do we choose for others, particularly when they have different preferences? Whereas some studies suggest that similar neural circuits underlie decision-making for oneself and others, others argue for additional, slower perspective-taking mechanisms. Combining event-related potentials with computational modeling, we found that integration of others' preferences occurs over the same timescale as for oneself while differentially tracking recipient-relevant attributes. Although choosing for others took longer and produced differences in late-emerging neural responses, computational modeling attributed these patterns to greater response caution rather than egocentric bias correction. Computational simulations also correctly predicted when and why choosing differently for others takes longer, suggesting that a model incorporating value integration and evidence accumulation can parsimoniously account for complex patterns in social decision-making.
Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion
Activation of opioid receptors (KORs) produces analgesia and aversion via distinct intracellular signaling pathways, but whether G protein-biased KOR agonists can be designed to have clinical utility will depend on a better understanding of the signaling mechanisms involved. We found that KOR activation produced conditioned place aversion and potentiated CPP for cocaine in male and female C57BL/6N mice. Consistent with this, males and females both showed arrestin-mediated increases in phospho-p38 MAPK following KOR activation. Unlike in males, however, KOR activation had inconsistent analgesic effects in females and KOR increased Gβ-mediated ERK phosphorylation in males, but not females. KOR desensitization was not responsible for the lack of response in females because neither Grk3 nor Pdyn gene knock-out enhanced analgesia. Instead, responsiveness was estrous cycle dependent because KOR analgesia was evident during low estrogen phases of the cycle and in ovariectomized (OVX) females. Estradiol treatment of OVX females suppressed KOR-mediated analgesia, demonstrating that estradiol was sufficient to blunt Gβ-mediated KOR signals. G protein-coupled receptor kinase 2 (GRK2) is known to regulate ERK activation, and we found that the inhibitory, phosphorylated form of GRK2 was significantly higher in intact females. GRK2/3 inhibition by CMPD101 increased KOR stimulation of phospho-ERK in females, decreased sex differences in KOR-mediated inhibition of dopamine release, and enhanced mu opioid receptor and KOR-mediated analgesia in females. In OVX females, estradiol increased the association between GRK2 and Gβ. These studies suggest that estradiol, through increased phosphorylation of GRK2 and possible sequestration of Gβ by GRK2, blunts G protein-mediated signals.
SIGNIFICANCE STATEMENT Chronic pain disorders are more prevalent in females than males, but opioid receptor agonists show inconsistent analgesic efficacy in females. opioid receptor (KOR) agonists have been tested in clinical trials for treating pain disorders based on their analgesic properties and low addictive potential. However, the molecular mechanisms underlying sex differences in KOR actions were previously unknown. Our studies identify an intracellular mechanism involving estradiol regulation of G protein-coupled receptor kinase 2 that is responsible for sexually dimorphic analgesic responses following opioid receptor activation. Understanding this mechanism will be critical for developing effective nonaddictive opioid analgesics for use in women and characterizing sexually dimorphic effects in other inhibitory G protein-coupled receptor signaling responses.
Behavioral Effect of Chemogenetic Inhibition Is Directly Related to Receptor Transduction Levels in Rhesus Monkeys
We used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male rhesus monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hSyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD-transduced cells using stereological analysis of mCherry-immunolabeled neurons. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared with monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.
SIGNIFICANCE STATEMENT Cognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (designer receptor exclusively activated by designer drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N-oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.
Loss of Synaptic Tagging in the Anterior Cingulate Cortex after Tail Amputation in Adult Mice
Anterior cingulate cortex (ACC) is known to play important roles in key brain functions such as pain perception, cognition, and emotion. Different forms of homosynaptic plasticity such as long-term potentiation (LTP) and long-term depression have been studied in ACC synapses. However, heterosynaptic plasticity such as synaptic tagging has not been reported. Here, we demonstrate synaptic tagging in the ACC of adult male mice by using a 64-channel multielectrode array recording system. Weak theta burst stimulation (TBS), normally inducing early-phase LTP or No-LTP in most of the activated channels, produced late phase-LTP (L-LTP) in a majority of channels when a strong TBS was applied earlier to a separate input within a certain time window. Similar to hippocampus, synaptic tagging in the ACC depends on the synthesis of new proteins. Tail amputation-induced peripheral injury caused a loss of this heterosynaptic L-LTP and occluded strong TBS-evoked L-LTP as well. Together, we provide the first report of the synaptic tagging-like phenomenon in the ACC of adult mice, and the loss of synaptic tagging to amputation may contribute to injury-related cognitive changes and phantom limb sensation and pain.
SIGNIFICANCE STATEMENT ACC is an important cortical region involved in many brain functions. Previous studies have dissected the molecular mechanism of multiple types of homosynaptic plasticity of ACC synapses. Here, we report a novel form of heterosynaptic plasticity occurring in the ACC. This newly identified, protein synthesis-dependent neocortical synaptic tagging is sensitive to peripheral tail amputation injury and may provide basic mechanisms for synaptic pathophysiology of phantom pain and related cognitive changes.
Robustness of Spike Deconvolution for Neuronal Calcium Imaging
Calcium imaging is a powerful method to record the activity of neural populations in many species, but inferring spike times from calcium signals is a challenging problem. We compared multiple approaches using multiple datasets with ground truth electrophysiology and found that simple non-negative deconvolution (NND) outperformed all other algorithms on out-of-sample test data. We introduce a novel benchmark applicable to recordings without electrophysiological ground truth, based on the correlation of responses to two stimulus repeats, and used this to show that unconstrained NND also outperformed the other algorithms when run on "zoomed out" datasets of ~10,000 cell recordings from the visual cortex of mice of either sex. Finally, we show that NND-based methods match the performance of a supervised method based on convolutional neural networks while avoiding some of the biases of such methods, and at much faster running times. We therefore recommend that spikes be inferred from calcium traces using simple NND because of its simplicity, efficiency, and accuracy.
SIGNIFICANCE STATEMENT The experimental method that currently allows for recordings of the largest numbers of cells simultaneously is two-photon calcium imaging. However, use of this powerful method requires that neuronal firing times be inferred correctly from the large resulting datasets. Previous studies have claimed that complex supervised learning algorithms outperform simple deconvolution methods at this task. Unfortunately, these studies suffered from several problems and biases. When we repeated the analysis, using the same data and correcting these problems, we found that simpler spike inference methods perform better. Even more importantly, we found that supervised learning methods can introduce artifactual structure into spike trains, which can in turn lead to erroneous scientific conclusions. Of the algorithms we evaluated, we found that an extremely simple method performed best in all circumstances tested, was much faster to run, and was insensitive to parameter choices, making incorrect scientific conclusions much less likely.
Autophosphorylated CaMKII Facilitates Spike Propagation in Rat Optic Nerve
Repeated spike firing can transmit information at synapses and modulate spike timing, shape, and conduction velocity. These latter effects have been found to result from voltage-induced changes in ion currents and could alter the signals carried by axons. Here, we test whether Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates spike propagation in adult rat optic nerve. We find that small-, medium-, and large-diameter axons bind anti-Thr286-phosphorylated CaMKII (pT286) antibodies and that, in isolated optic nerves, electrical stimulation reduces pT286 levels, spike propagation is hastened by CaMKII autophosphorylation and slowed by CaMKII dephosphorylation, single and multiple spikes slow propagation of subsequently activated spikes, and more frequent stimulation produces greater slowing. Likewise, exposing freely moving animals to flickering illumination reduces pT286 levels in optic nerves and electrically eliciting spikes in vivo in either the optic nerve or optic chiasm slows subsequent spike propagation in the optic nerve. By increasing the time that elapses between successive spikes as they propagate, pT286 dephosphorylation and activity-induced spike slowing reduce the frequency of propagated spikes below the frequency at which they were elicited and would thus limit the frequency at which axons synaptically drive target neurons. Consistent with this, the ability of retinal ganglion cells to drive at least some lateral geniculate neurons has been found to increase when presented with light flashes at low and moderate temporal frequencies but less so at high frequencies. Activity-induced decreases in spike frequency may also reduce the energy required to maintain normal intracellular Na+ and Ca2+ levels.
SIGNIFICANCE STATEMENT By propagating along axons at constant velocities, spikes could drive synapses as frequently as they are initiated. However, the onset of spiking has been found to alter the conduction velocity of subsequent ("follower") spikes in various preparations. Here, we find that spikes reduce spike frequency in rat optic nerve by slowing follower spike propagation and that electrically stimulated spiking ex vivo and spike-generating flickering illumination in vivo produce net decreases in axonal Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation. Consistent with these effects, propagation speed increases and decreases, respectively, with CaMKII autophosphorylation and dephosphorylation. Lowering spike frequency by CaMKII dephosphorylation is a novel consequence of axonal spiking and light adaptation that could decrease synaptic gain as stimulus frequency increases and may also reduce energy use.
Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort
This longitudinal cohort study describes nevus acquisition from the ages of 3 to 16 years among white youths and evaluates variation by sex, Hispanic ethnicity, and body sites that are chronically vs intermittently exposed to the sun.
Management of Flat Pigmented Spitz and Reed Nevi in Children
This database study evaluated the efficacy of monitoring flat symmetric pigmented spitzoid-looking lesions in prepubertal children.
Glycolic Acid Plus Lovastatin-Cholesterol Combination Cream to Treat Congenital Ichthyoses
This case series evaluates the use of topical glycolic acid plus a lovastatin-cholesterol combination cream to treat autosomal recessive congenital ichthyoses.
Picosecond Laser Treatment for Acquired Bilateral Nevus of Ota–like Macules
This report of cases describes the use of picosecond laser to treat acquired bilateral nevus of Ota–like macules.
Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis
Abstract
Objectives
To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs).
Methods
A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression.
Results
Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54–7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29–5.40, p = 0.01).
Conclusion
Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.
Panpsychism, intuitions, and the great chain of being
Abstract
Some philosophical theories of consciousness imply consciousness in things we would never intuitively think are conscious—most notably, panpsychism implies that consciousness is pervasive, even outside complex brains. Is this a reductio ab absurdum for such theories, or does it show that we should reject our original intuitions? To understand the stakes of this question as clearly as possible, we analyse the structured pattern of intuitions that panpsychism conflicts with (what we call the 'Great Chain of Being' intuition). We consider a variety of ways that the tension between this intuition and panpsychism (or other counter-intuitive theories) could be resolved, ranging from complete rejection of the theory to complete dismissal of the intuition, but argue in favour of more nuanced approaches which try to reconcile the two.
Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
Abstract
Background
A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in the United States, Canada, and European Union as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. Patients and methods
Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. Results
Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grade 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. Conclusions
The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. Clinical trial numbers
NCT01721772, NCT01668784, NCT01673867, NCT01642004Alectinib versus crizotinib in treatment-naïve anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study
Abstract
Background
The phase III ALEX study in patients with treatment-naïve advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC), met its primary endpoint of improved progression-free survival (PFS) with alectinib versus crizotinib. Here we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods
Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. Endpoints (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included: PFS, CNS objective response rate (ORR), and time to CNS progression. Results
In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58); 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy, and 78.6% versus 40.0%, respectively, in those who had not. Conclusion
Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration
ClinicalTrials.gov NCT02075840Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma: A Systematic Literature Review and Network Meta-Analysis
Publication date: Available online 11 September 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Thomas B. Casale, Maud Pacou, Laura Mesana, Gaelle Farge, Shawn X. Sun, Mario Castro
Background
The interaction of interleukin (IL)-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials.
Objective
To indirectly compare reslizumab with benralizumab in similar patient populations using a network meta-analysis.
Methods
A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte Carlo simulation method and a Bayesian statistical framework.
Results
Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels ≥300 cells/μL (n = 1537) and a reslizumab subgroup in GINA step 4/5 with ≥2 prior exacerbations and ≥400 eosinophils/μL (n = 318). Safety was analyzed in the full population (N = 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab Q4W and there were reasonably high posterior probabilities that reslizumab is superior to benralizumab Q4W and Q8W for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations.
Conclusions
This indirect comparison suggests reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in GINA step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/μL; reslizumab, ≥400/μL) and ≥2 exacerbations in the previous year.
Anaphylaxis to trometamol excipient in gadolinium based contrast agents for clinical imaging.
Publication date: Available online 11 September 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Joanna Lukawska, Deepal Mandaliya, A.W. Edith Chan, Amy Foggitt, Therese Bidder, Jennifer Harvey, Lisa Stycharczuk, Sotirios Bisdas
Uncharted Waters: Challenges in the Era of Biologic Therapies for Nasal Polyposis
Publication date: Available online 11 September 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Jayant M. Pinto, Fuad M. Baroody, Robert M. Naclerio
Several new, promising, targeted therapies for nasal polyposis are being tested in large-scale clinical trials. These agents target pathways thought to be involved in the disease, including IgE, IL-5, IL-4/IL-13, and others. Designing these trials poses significant challenges: who and when to enroll is not completely clear, optimal dosing is not known, outcome measures are insufficiently robust, there are no validated biomarkers, trial regimens may not comport with how clinicians might use these drugs once approved, and cost-benefit ratios have not been assessed. Thus, there is a need to consider such questions, as trials of these novel treatments continue and these biologics become available. Despite these uncertainties about trial design, there remains a great deal of excitement in the field as we approach the dawn of a new era of therapeutic options for nasal polyposis. In this rostrum, we enumerate these issues and call for a conference that will allow stakeholders in the field to confront them as we enter this new era of opportunity to advance the treatment of nasal polyposis.
Reference method for digital surface measurement of target lesions in vitiligo: a comparative analysis
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
Diagnostic Accuracy of Content Based Dermatoscopic Image Retrieval with Deep Classification Features
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
Synthesis of mycosporine-like amino acids by a size-fractionated marine phytoplankton community of the arctic beaufort sea
Publication date: Available online 12 September 2018
Source: Journal of Photochemistry and Photobiology B: Biology
Author(s): Sun-Yong Ha, Jun-Oh Min, HyoungMin Joo, Min-Seob Kim, Sung-Ho Kang, Kyung-Hoon Shin
Abstract
During the RV-ARAON cruise, a comparative study on the biosynthesis of mycosporine-like amino acids (MAAs) was conducted for the size-fractionated phytoplankton of the Beaufort Sea (Arctic). The MAAs contents in the micro-phytoplankton community (>20 μm size) is considerably higher than that observed in the nano- (20–2 μm size) and pico-phytoplankton (<2 μm size) communities. The micro-phytoplankton of the Mackenzie Shelf had a relatively higher Chlorophyll a (Chl a) concentration. Considering the total phytoplankton community, the MAAs concentration as well as net production of individual MAAs (such as shinorine and palythine) were higher at the Mackenzie Shelf rather than at the sites located beyond the Beaufort Sea; precisely, the highest net production rates of shinorine and palythine were 0.211 (±0.02) ng C L−1 d−1 and 0.136 (±0.001) ng C L−1 d−1 respectively (No other MAAs were detected). The micro-phytoplankton used around 0.5% of the total carbon uptake for the synthesis of MAAs. Compared to the smaller phytoplankton community, the micro-phytoplankton utilized more of their energy for the biosynthesis of MAAs; on the other hand, nano- and pico-phytoplankton focused on cellular activity and had poor biosynthesis of MAAs. This clearly indicates the phytoplankton size-dependent variation in the biosynthesis of MAA in the natural phytoplankton community. This study revealed the environmental adaptation of the various sizes of phytoplankton community as well as their physiological response in the Arctic Beaufort Sea.
Influence of wideband visible light with an padding red component on the functional state of mice embryos and embryonic stem cells
Publication date: Available online 12 September 2018
Source: Journal of Photochemistry and Photobiology B: Biology
Author(s): A.S. Chernov, D.A. Reshetnikov, A. Kovalitskaya Yu, A.A. Manokhin, S.V. Gudkov
Abstract
It is known that visible light, including sunlight and laboratory lighting, adversely affect the development of embryos in vitro. In with article we present a technology for the synthesis of composite screens, capable to photoconvert UV and a part of the blue spectrum into red light with the maximum ~630 nm. It is established that the application of such transformed light with an evident red component raises the chances of embryos to survive and protects embryonic stem cells. To create photoconversion screens, the CdZn/Se quantum dots were obtained, the average size being about 7 nm. When the quantum dots are excited by electromagnetic waves of the UV and blue spectral range, photoluminescence is observed. The average photon energy for photoluminescence is of the order of 2 eV. On the basis of CdZn/Se quantum dots and methylphenylsiloxane polymer, light-transforming composite screens were made. In case of the light-transforming composite screen, the UV component disappeared from the energy spectrum, and the intensity of the blue region of the spectrum was reduced. On the contrary, in the red region (λmax = 630 nm) one can see a little more than two-fold increase of intensity. It is shown that when exposed to 2-cell embryos by transformed light, the proportion of normally developing embryos increases by 20%, the number of dead embryos decreases twice, and number of dead and apoptotic cells was lower in blastocysts, what's decreased by 70%, as compared to the control group. When blastocysts are transferred to the feeder substrate, colonies of embryonic stem cells are formed. Cells obtained from blastocysts irradiated with transformed visible light are in a normal state in 90% of cases and did not change expression levels, biochemistry and morphology for at least 20 passages. It is assumed that the data obtained can be used for the design of systems of efficient cultivation of embryonic cells for tissue engineering and cell therapy.
Graphical abstract
Photodynamic inactivation of Enterococcus faecalis by non-peripherally substituted magnesium phthalocyanines entrapped in lipid vesicles
Publication date: Available online 12 September 2018
Source: Journal of Photochemistry and Photobiology B: Biology
Author(s): Lukasz Sobotta, Jolanta Dlugaszewska, Mateusz Gierszewski, Adam Tillo, Marek Sikorski, Ewa Tykarska, Jadwiga Mielcarek, Tomasz Goslinski
Abstract
Photophysical properties and photodynamic antibacterial potential of magnesium phthalocyanines bearing 2-propoxy, benzyloxy, 3,5-bis(benzyloxy)benzyloxy substituents at non-peripheral positions were studied. The UV–Vis absorption spectra of researched phthalocyanine derivatives were found typical. Extension of peripheral substituent size from 2-propoxy to benzyloxy and finally 3,5-bis(benzyloxy)benzyloxy was accompanied by the rise of quantum yield of fluorescence up to 0.17 and 0.04 in DMF and DMSO, respectively. Similarly, the expansion of the phthalocyanine periphery from the 2-propoxy to benzyloxy and 3,5-bis(benzyloxy)benzyloxy groups resulted in a detectable increase of the singlet oxygen quantum yield values to 0.04, 0.12, 0.14 respectively, which was assessed following direct method of singlet oxygen phosphorescence measurement at 1270 nm. Studied phthalocyanines undergo photobleaching process with the quantum yields at the level of 10−6 in DMSO and 10−5 in DMF. The size of phthalocyanine impacted the process of liposomal formulation. Small liposome vesicles containing non-peripherally substituted phthalocyanines with 2-propoxy and benzyloxy substituents were obtained following extrusion method. The unification process of the liposomes loaded with 3,5-bis(benzyloxy)benzyloxy non-peripherally substituted phthalocyanines was not possible. In in vitro antimicrobial photodynamic inactivation study, log reduction values of bacterial (Enterococcus faecalis) growth at 3.61 and 2.99 were achieved for liposomal formulations containing phthalocyanines with 2-propoxy and benzyloxy substituents respectively, whereas phthalocyanine with 3,5-bis(benzyloxy)benzyloxy substituents was inactive. Phthalocyanine with 2-propoxy substituents exhibited relatively low toxicity in Vibrio fischeri bioluminescence test, whereas phthalocyanine with benzyloxy substituents revealed intense bioluminescence, which could be associated with hormesis phenomenon.
Graphical Abstract
Photophysical properties and photodynamic potential of magnesium phthalocyanines bearing 2-propoxy, benzyloxy, 3,5-bis(benzyloxy)benzyloxy at non-peripheral positions was studied. In in vitro antimicrobial photodynamic inactivation study, log reductions of bacterial (Enterococcus faecalis) growth at 3.61, 2.99 were obtained for liposomal formulations containing non-peripherally substituted 2-propoxy and benzyloxy phthalocyanines, respectively.
Granulomes cutanés à corps étrangers après embolisation artérielle de la sphère cervico-faciale : trois cas
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): M. Gillard, E. Archier, O. Monnet, A. Souteyrand, F. Turner, R. Gras, N. Quiles-Tsimaratos
Résumé
Introduction
La survenue de granulomes à corps étrangers au niveau facial est classiquement rapportée dans la littérature dans les suites d'injections sous-cutanées à visée esthétique. Nous décrivons pour la première fois trois cas de réactions faciales granulomateuses par migration sous-cutanée de microbilles injectées pour embolisation dans le réseau artériel cervico-facial.
Observations
Une procédure d'embolisation des artères faciales par microbilles Embogold® était réalisée chez trois patients dans le cadre d'épistaxis ou d'hémostase tumorale. Dix à 45 jours plus tard apparaissaient des nodules douloureux de l'hémiface homolatérale. Les prélèvements histologiques montraient une réaction inflammatoire avec cellules géantes et la présence de microbilles dans le tissu cutané. L'évolution était favorable spontanément dans un cas et sous colchicine dans un autre ; le troisième cas était perdu de vue.
Discussion
Nous avons observé une destruction inflammatoire des parois des vaisseaux embolisés, puis une migration des microbilles dans le tissu sous-cutané facial, entraînant une réaction granulomateuse. La survenue simultanée des trois cas, avec plusieurs opérateurs et lots de produits, est étonnante pour un produit employé depuis 10 ans sans incident antérieur. Il n'existait pas de comorbidité commune aux trois cas, et l'étude des lots de produits s'est avérée sans particularité. La coloration à l'or colloïdal de ces microparticules semble jouer un rôle pro-inflammatoire important.
Conclusion
Ces trois cas rares illustrent l'intérêt d'évoquer une réaction granulomateuse à corps étrangers devant l'apparition de lésions nodulaires de la face dans les suites d'une embolisation artérielle cervico-faciale. La colchicine paraît être une alternative thérapeutique intéressante.
Summary
Background
Foreign body granuloma is an inflammatory tissue reaction to exogenous material. Classically it appears on the face after aesthetic procedures. Herein we report for the first time three cases of facial granulomatous reactions to microbeads after arterial cervico-facial embolization.
Patients and methods
Three patients underwent embolization of the facial arteries using Embogold® microbeads in a setting of epistaxis or tumoral hemostasis. Within 10 to 45 days painful, inflammatory, subcutaneous nodules appeared on the homolateral side of the face. Histological samples showed an inflammatory response with giant cells as well as the presence of microbeads in the skin. A favorable outcome was achieved with colchicine in one patient and with surgery in another; the third patient was lost to follow-up.
Discussion
The embolizing microspheres produced a local inflammatory reaction, with destruction of the vascular wall and bead migration to facial tissue leading to a granulomatous reaction. The occurrence of three cases within a period of few weeks, with several different operators and batches of products, is surprising considering the long-standing use of the product. There was no common comorbidity in the patients and no suggestion of trauma. Retrospective analysis of the product batches was normal. Gold staining could play a role in severe inflammatory response to Embogold® particles.
Conclusion
These three cases illustrate the value of discussing potential foreign body granulomatous reaction in cases of facial nodules following cervico-facial embolization. Colchicine may offer a valuable therapeutic alternative.
Cytopénies sous imiquimod topique chez deux patients traités par hydroxyurée
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): C. Joachim, V. Gras-Champel, J.-P. Marolleau, G. Chaby, M. Dairi, E. Carmi
Résumé
Introduction
L'imiquimod topique (Aldara®) est un traitement immunomodulateur local. Les risques de passage systémique sont minimes, des effets indésirables généraux sont rarement décrits.
Observations
Cas 1. De l'imiquimod était prescrit à raison de cinq sachets par semaine pour une maladie de Bowen de l'avant-bras chez un patient suivi pour une thrombocytémie essentielle traitée par hydroxyurée (Hydrea®). L'hémogramme était normal (230 000 plaquettes/mm3, 6000 leucocytes/mm3, dont 2200 neutrophiles). Quinze sachets par semaine étaient délivrés par la pharmacie. Deux semaines plus tard apparaissait une bicytopénie (3000 leucocytes/mm3 dont 1400 neutrophiles/, 119 000 plaquettes/mm3). L'hydroxyurée et l'imiquimod étaient suspendus, permettant une normalisation de l'hémogramme. L'hydroxyurée était repris ensuite, sans récidive de cytopénie. Il existait un antécédent d'épisode identique sous imiquimod. Cas 2. De l'imiquimod était prescrit à raison de cinq sachets par semaine pour des kératoses actiniques du vertex chez un patient suivi pour une maladie de Vaquez sous hydroxyurée. L'hémogramme était normal en dehors d'une anémie (Hb 11,5 g/dL, 160 000 plaquettes/mm3, 1100 lymphocytes/mm3). Douze sachets d'imiquimod par semaine étaient délivrés par la pharmacie. Dix jours plus tard, on observait une aggravation de l'anémie (Hb 10 g/dL), une lymphopénie (800/mm3) et une thrombopénie (115 000/mm3). L'imiquimod était suspendu, permettant un retour aux valeurs antérieures.
Discussion
La littérature rapporte des cas de lymphopénie dose-dépendante sous imiquimod per os, mais aucun pour l'Aldara®. La Base nationale de pharmacovigilance recense dix cas d'affections hématologiques où l'imiquimod serait suspect. L'hydroxyurée est pourvoyeur de cytopénies, son imputabilité seule n'est pas retenue ici, mais son rôle favorisant est vraisemblable chez ces patients atteints d'hémopathies. Nos observations mettent en évidence, au cours d'un mésusage, un possible risque hématologique de l'imiquimod, chez des patients traités par hydroxyurée, une association médicamenteuse fréquente.
Summary
Background
Aldara® is a topical immunomodulatory treatment. The risks of systemic passage are minimal. There have been rare reports of systemic adverse effects.
Patients and methods
Case 1. Five sachets weekly of imiquimod were prescribed for Bowen's disease on the forearm in a patient known to have essential thrombocytosis under Hydrea®. His CBC was normal (6000 leukocytes/mm3, 2200 PMN/mm, 230,000 platelets/mm3). Imiquimod was given in 15 sachets weekly. Fifteen day later, the patient presented bicytopenia (3000 leukocytes/mm3, 1400 PMN/mm3, 119,000 platelets/mm3). Hydroxyurea and imiquimod were suspended until normalization of CBC. Hydroxyurea was resumed without recurrence of the bicytopenia. The patient's history included an identical episode following application of imiquimod. Case 2. Five sachets weekly of imiquimod were prescribed for actinic keratosis on the scalp in a patient known to have primary polycythemia under hydroxyurea. Her CBC was normal except for anemia (Hb 11.5 g/L, 160,000 platelets/mm3, 1100 lymphocytes/mm3). Imiquimod was given in 12 sachets weekly. Ten days later, anemia increased (Hb 10 g/dL) with lymphopenia (800/mm3) and thrombocytopenia (115,000/mm3). Suspension of imiquimod resulted in normalization of the previous CBC values.
Discussion
. The literature review identified reports of dose-dependent lymphopenia under oral imiquimod but not under Aldara®. The National Pharmacovigilance Database listed 10 cases of hematological disorders most likely caused by Aldara®. Hydroxyurea may induce cytopenia, and while it was not considered the sole causative agent in this case, it is likely to have had a triggering role in these patients with blood dyscrasias. Our findings show that misuse of imiquimod carries a potential risk of hematologic abnormality in patients receiving concomitant hydroxyurea, a commonly combined drug.
Macules hypochromiques ou achromiques multiples de l’enfant et risque de sclérose tubéreuse de Bourneville
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): M. Battini, E. Casassa, A. Maza, I. Dreyfus, J. Mazereeuw-Hautier
Résumé
But
Décrire dans une large cohorte pédiatrique les caractéristiques des macules hypopigmentées ou complètement dépigmentées (hypo- ou achromiques) qui n'ont pas de diagnostic évident, mais pourraient faire suspecter une sclérose tubéreuse de Bourneville (STB).
Méthodes
Il s'agit d'une étude rétrospective monocentrique réalisée entre 2010 et 2017 dans un centre de référence des maladies rares de la peau, incluant tout enfant consultant pour des macules hypo- ou achromiques multiples. Une analyse descriptive des caractéristiques des macules sans diagnostic évident était conduite, permettant de les répartir secondairement en trois groupes : STB certaine, STB infirmée, STB incertaine.
Résultats
Parmi les 3300 enfants vus pendant ces 7 années, 265 consultaient pour des macules hypo- ou achromiques, dont 18 ne présentaient pas de diagnostic évident : 7 filles et 11 garçons, d'âge médian 7,21 ans (de 4 mois à 16 ans et 7 mois). Les lésions étaient congénitales chez 7 d'entre eux. Leur nombre était variable, jusqu'à plus de 20. La forme majoritaire était celle « en feuille de sorbier », suivie de la forme ovalaire. Deux enfants étaient diagnostiqués dès l'examen clinique, 16 avaient des examens complémentaires, permettant de retenir le diagnostic de STB certaine chez 6 d'entre eux. Aucune caractéristique particulière des macules ne semblait orienter à l'examen clinique vers une STB ou des lésions isolées. Les taches café-au-lait étaient plus fréquentes dans le groupe avec STB infirmée que dans les deux autres groupes : 67 % versus 33 % et 33 %. L'atteinte neurologique était plus fréquente chez les enfants avec STB certaine ou incertaine que chez ceux avec STB infirmée (83 % et 67 % versus 11 %).
Conclusion
Aucune caractéristique des taches n'a été identifiée comme permettant à l'examen clinique d'affirmer ou infirmer une sclérose tubéreuse. La recherche d'autre signes cutanés de STB est primordiale. Les examens complémentaires augmentent l'acuité diagnostique.
Summary
Aim
To describe in a large paediatric cohort the characteristics of hypopigmented and depigmented (hypochromatic and achromic) macules with no clear diagnosis but potentially evocative of tuberous sclerosis (TS).
Patients and methods
This was a retrospective multicentre study performed between 2010 and 2017 at a reference centre for rare skin diseases; it included all children consulting for hypochromic and achromic macules. A descriptive analysis was made of the characteristics of macules with no clear diagnosis, enabling them to be classified in three secondary groups: TS certain, TS ruled out, TS uncertain.
Results
Of the 3300 children seen during this 7-year period 7,265 were consulting for hypochromic or achromic macules, with no clear diagnosis in 18 cases: 7 girls and 11 boys of median age at 7.21 years (range: 4 months to 16 years and 7 months). The lesions were congenital in 7 cases. The number of macules varied, with over 20 in some cases. The majority were in the form of ash-leaf spots, followed by the oval form. Two children were diagnosed at clinical examination, and 16 underwent it is not examinations, resulting in a diagnosis of certain ST in 6 of these cases. No particular characteristics of the macules appeared to guide the clinical examination towards ST or isolated lesions. Café-au-lait spots were more frequent in the group in which ST was ruled out than in the other two groups: 67% vs. 33% and 33%. Neurologic involvement was more common in children with certain or uncertain ST than in children in whom ST was ruled out (83% and 67% vs. 11%).
Conclusion
No identified characteristics of stains enabled the clinical examination to confirm or rule out tuberous sclerosis. Screening for acute any signs of ST is essential. Diagnostic efficacy is enhanced by additional exams.
Lupus-engelures familial : quatre cas sur trois générations
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): A.-S. Beltoise, C. Audouin-Pajot, P. Lucas, E. Tournier, G.-I. Rice, Y.-J. Crow, J. Mazereeuw-Hautier
Résumé
Introduction
Le lupus-engelures familial (LEF) est une forme héréditaire de lupus érythémateux cutané du jeune enfant, de transmission autosomique dominante, dû à des mutations du gène TREX-1 ou plus rarement des gènes SAMHD1 ou TMEM173 (STING). Il fait partie des interféronopathies de type I, pathologies inflammatoires associées à une production excessive d'interféron et caractérisées par une « signature interféron » positive. Il s'agit d'une entité rare, avec moins de 10 familles décrites à ce jour. Nous rapportons une nouvelle famille suivie pendant plusieurs années.
Observations
Il s'agissait de quatre sujets d'une même famille répartis sur trois générations (un frère et une sœur de 17 et 15 ans, leur mère de 39 ans et leur grand-père de 60 ans). Les premières lésions cutanées étaient apparues dans l'enfance et étaient restées stables au cours de la vie, s'améliorant durant l'été. Il s'agissait de papules érythémato-violacées infiltrées et hyperkératosiques, prurigineuses ou douloureuses, siégeant sur les extrémités. Il existait des anomalies immunologiques, notamment la présence d'anticorps antinucléaires. La signature interféron était positive chez tous les patients. L'analyse moléculaire des gènes TREX-1, SAMHD1 et STING réalisée chez les deux enfants ne mettait en évidence aucune mutation.
Discussion
L'atteinte cutanée était classique en dehors de l'absence d'évolution cicatricielle et mutilante, de photosensibilité et de vasculopathie telles que rapportées dans les autres familles. Il n'existait pas de variabilité intrafamiliale en dehors des anomalies immunologiques, qui étaient inconstantes. Sur le plan moléculaire, aucune mutation dans les gènes connus n'était mise en évidence. Une analyse moléculaire complémentaire est en cours.
Conclusion
Nous rapportons une nouvelle famille de LEF qui permet d'améliorer les connaissances sur cette forme très rare de lupus érythémateux.
Summary
Background
Familial chilblain lupus is a hereditary form of cutaneous lupus erythematosus seen in young children. It shows autosomal dominant inheritance due to mutations in the TREX-1 gene, or, more rarely, SAMHD1 or TMEM173 (STING). It belongs to the type I interferonopathies, i.e. inflammatory diseases associated with excessive interferon production and characterized by a positive "interferon signature". This is a rare entity with fewer than 10 families described to date. We report a new family followed over several years.
Patients and methods
The patients were four subjects from the same family and spanning three generations (a brother and sister aged 17 and 15 years, their 39-year-old mother, and their 60-year-old grandfather). The initial cutaneous lesions on the extremities were described as papular, erythematous, purplish, infiltrated, hyperkeratotic, pruritic and/or painful. They occurred in childhood, improved during summer and stabilized over time. Immunological abnormalities such as positive antinuclear antibodies were noted. The interferon signature was positive in all patients. Molecular analysis of TREX-1, SAMHD1 and STING genes in both children showed no evidence of mutation.
Discussion
The cutaneous involvement was classic except for absence of the scarring and mutilating progression, photosensitivity and vasculopathy reported in other families. There was no intrafamily variability other than unconstant immunological abnormalities. At the molecular level, no mutations in the known genes were identified. A complementary molecular analysis is in progress.
Conclusion
We report a new case of familial LEF, thus adding to knowledge about this very rare form of lupus erythematosus.
Dermite livédoïde de Nicolau sus-pubienne après injections sous-cutanées d’acétate de glatiramère
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): A. Blind, C. Lenormand, C. Schissler, B. Cribier, D. Lipsker
Résumé
Introduction
L'acétate de glatiramère, commercialisé sous le nom de Copaxone®, administré par voie sous-cutanée, est un traitement des formes récurrentes-rémittentes de sclérose en plaques. Ses effets indésirables sont principalement des réactions cutanées aux sites d'injection. La dermite livédoïde de Nicolau est un accident iatrogène rare mais grave. Nous en rapportons un cas survenu dans un contexte de modification de posologie et de rythme d'administration de la Copaxone®.
Observation
Une femme de 64 ans, traitée depuis 2010 par Copaxone® à raison d'une injection sous-cutanée quotidienne de 20 mg/mL, constatait l'apparition d'une zone douloureuse érythémateuse et indurée de la région sus-pubienne après être passée à 3 injections hebdomadaires de 40 mg/mL. Les injections étaient poursuivies dans la région sus-pubienne et des macules grisâtres hypoesthésiques de forme géographique à bordure purpurique apparaissaient. Une tomodensitométrie des parties molles écartait le diagnostic de gangrène de Fournier. Le diagnostic de dermite livédoïde de Nicolau était retenu.
Discussion
Nous rapportons ce cas afin de rendre le lecteur attentif au caractère non exceptionnel de cette complication avec l'acétate de glatiramère, en particulier à la posologie de 40 mg/mL, 3 fois par semaine. Sa survenue semble être favorisée dans notre cas par la poursuite des injections dans des zones déjà inflammatoires ; la réinjection du médicament dans ces sites doit être proscrite.
Summary
Background
Subcutaneous glatiramer acetate, commercialized under the name of Copaxone®, is licensed for the treatment of relapsing multiple sclerosis. Its major adverse effects are skin reactions at the injection site. Nicolau syndrome is a rare but serious iatrogenic accident. Herein we report a case seen in a setting of change of dosage and administration rate of Copaxone®.
Patients and methods
A 64-year-old woman, treated since 2010 with daily sub-cutaneous injections of Copaxone® 20 mg/L, reported the appearance of a painful, indurated and erythematous plaque in the suprapubic area following changeover to 40 mg/mL injections three times weekly. The suprapubic injections were continued and ugly greyish spots with stellate purpuric borders appeared. Fournier gangrene was ruled out by means of a soft tissue scan.
Discussion
We report this latest case of Nicolau syndrome to alert readers to the non-exceptional nature of this complication associated with use of glatiramer acetate, particularly at a dosage of 40 mg/L injections three times weekly. In our case, onset of Nicolau syndrome appears to have been favored by continued injection in areas already showing inflammation. Re-injection of the drug in these areas should thus be proscribed.
Leishmaniose cutanée végétante : une forme clinique rare
Publication date: Available online 11 September 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): S. Diadie, M. Ndiaye, B.-A. Diatta, B. Faye, M. Diallo, S.-O. Niang, A. Kane, M.-T. Dieng
Association between itch and cancer in 16,925 pruritus patients: Experience at a tertiary care center
Publication date: Available online 11 September 2018
Source: Journal of the American Academy of Dermatology
Author(s): Valerie A. Larson, Olive Tang, Sonja Stander, Sewon Kang, Shawn G. Kwatra
Abstract
Background
Pruritus has been associated with cancer. However, limited data is available on the types of underlying malignancy associated with pruritus.
Objective
We sought to characterize the association between pruritus and different cancer types, as well as variations by racial group.
Methods
Cross-sectional study of patients ≥ 18 years old seen at the Johns Hopkins Health System from 2013-2017. Patients with pruritus were compared to patients without pruritus. Analyses were stratified by race.
Results
Patients with pruritus are more likely to have concomitant malignancy than those without pruritus (OR 5.76; 95% CI 5.53-6.00). Most strongly associated are cancers of the liver, gallbladder and biliary tract, hematopoietic system, and skin. Compared to whites, black patients more frequently have soft tissue, dermatological, and hematological malignancies, and less frequently have liver, respiratory, GI, and gynecological malignancies.
Limitations
Cross-sectional design precludes analysis of the temporal association between pruritus and malignancy. The study is limited to a single tertiary care center.
Conclusion
Pruritus is most strongly associated with cancers of the liver, skin, and hematopoietic system. Black patients with pruritus have a higher likelihood of skin, soft tissue, and hematological malignancies than whites, while whites have higher likelihood of liver, respiratory, GI, and gynecological malignancies.
Issue Information
Photochemistry and Photobiology, Volume 94, Issue 5, Page 825-826, September/October 2018.
Editorial: Symposium‐in‐Print on the Occasion of XIII ELAFOT (XIII Encuentro Latinoamericano de Fotoquímica y Fotobiología)
Photochemistry and Photobiology, Volume 94, Issue 5, Page 827-828, September/October 2018.
Erratum zu: Neue Ergebnisse zur Immuntherapie hämatologischer Neoplasien
Erratum zu:
Der Onkologe 2018
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Im Untertitel der Originalpublikation stand versehentlich das Jahr 2017. Korrekt ist 23. Kongress der European Hematology Association (EHA), 14.–17.06.2018 in Stockholm, …
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