Τετάρτη 24 Οκτωβρίου 2018
Apremilast as therapeutic option in a HIV positive patient with severe psoriasis
Dermatologic Therapy, EarlyView.
Polarity-specific modulation of pain processing by transcranial direct current stimulation – a blinded longitudinal fMRI study
To enrich the hitherto insufficient understanding regarding the mechanisms of action of transcranial direct current stimulation (tDCS) in pain disorders, we investigated its modulating effects on cerebral pain...
Thyroid cancer radiotheragnostics: the case for activity adjusted 131 I therapy
Abstract
Radiotheragnostics represents the systematic integration of diagnostic imaging and therapeutics using radionuclides targeting specific characteristics of tumor biology. Radioiodine (131I) is the classic radiotheragnostic agent used for the diagnosis and treatment of differentiated thyroid cancer based on sodium-iodine symporter expression in normal and neoplastic thyroid tissue. Application of radiotheragnostics principles in thyroid cancer involves using pre-ablation diagnostic scans (Dx Scans) for detection of iodine-avid regional and distant metastatic disease and patient-individualized targeted 131I therapy with goal of maximizing the benefits of the first therapeutic 131I administration. Clinically available nuclear medicine imaging technology has significantly evolved over the past 10 years with the introduction of hybrid SPECT/CT and PET/CT systems, as well as advances in iterative image reconstruction with modeling of image degrading physical factors. This progress makes possible the acquisition of accurate diagnostic radioiodine scintigraphy capable of identifying regional and distant metastatic disease, which can be used for 131I treatment planning and delivery of activity adjusted 131I therapy for achieving intended treatment goals (e.g., remnant ablation, adjuvant 131I treatment and targeted 131-I treatment). The overarching aim of thyroid cancer radiotheragnostics is to optimize the balance between 131I therapeutic efficacy and potential side-effects on non-target tissues.
Abdominal Contouring and Combining Procedures
The abdomen is the most common area of concern among patients with massive weight loss (MWL). Abdominal contouring techniques in the MWL population include panniculectomy, standard abdominoplasty, fleur-de-lis abdominoplasty, reverse abdominoplasty and various combinations of these techniques as part of circumferential procedures such as, circumferential abdominoplasty, and lower body lift. The authors believe that the optimal surgical approach to the abdomen is an integration of the patient aesthetic preferences and the surgeon assessment and experience. The authors recommend to limit total body reconstruction of MWL patients to 2 stages, and include the abdominal area in the first stage.
The different roles of 5-HT1A/2A receptors in fluoxetine ameliorated pigmentation of C57BL/6 mouse skin in response to stress
Stress, specifically chronic unpredictable stress and chronic restrained stress, induce depigmentation in C57BL/6 mice. Fluoxetine promoted melanin production and the migration of melanocytes via 5-HT1 A receptor and 5-HT2 A receptor, respectively.
There's Good News To Be Found — Just Look At A Grain Of Salt
Salt is to be admired for its atomic beauty and proof of order in the universe. Our astrophysicist friend Adam Frank says you can find some good news in something as simple as a single grain of salt.
David Rubinsztein
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Tuesday, October 23, 2018 - 09:15
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Sunday, October 24, 2021 - 09:15
Nature and Nurture: Brain Region-Specific Inheritance of Sleep Neurophysiology in Adolescence
Sleep-specific oscillations of spindles and slow waves are generated through thalamocortical and corticocortical loops, respectively, and provide a unique opportunity to measure the integrity of these neuronal systems. Understanding the relative contribution of genetic factors to sleep oscillations is important for determining whether they constitute useful endophenotypes that mark vulnerability to psychiatric illness. Using high-density sleep EEG recordings in human adolescent twin pairs (n = 60; 28 females), we find that over posterior regions 80–90% of the variance in slow oscillations, slow wave, and spindle activity is due to genes. Surprisingly, slow (10–12 Hz) and fast (12–16 Hz) anterior spindle amplitude and power are largely driven by environmental factors shared among the twins. To our knowledge this is the first example of a neural phenotype that exhibits a strong influence of nature in one brain region, and nurture in another. Overall, our findings highlight the utility of the sleep EEG as a reliable and easy to measure endophenotype during adolescence. This measure may be used to measure disease risk in development before the onset of a psychiatric disorder; the location within the brain of deficits in sleep neurophysiology may suggest whether the ultimate cause is genetic or environmental.
SIGNIFICANCE STATEMENT Two cardinal oscillations of sleep, slow waves and sleep spindles, play an important role in the core functions of sleep including memory consolidation, synaptic plasticity, and the recuperative function of sleep. In this study, we use a behavioral genetics approach to examine the heritability of sleep neurophysiology using high-density EEG in a sample of early adolescent twins. Our findings reveal a strong influence of both environmental and genetic factors in shaping these oscillations, dependent on brain region. Thus, during a developmental period when brain structure and function is in flux, we find that the sleep EEG is among the most heritable of human traits over circumscribed brain regions.
A Subpopulation of Foxj1-Expressing, Nonmyelinating Schwann Cells of the Peripheral Nervous System Contribute to Schwann Cell Remyelination in the Central Nervous System
New myelin sheaths can be restored to demyelinated axons in a spontaneous regenerative process called remyelination. In general, new myelin sheaths are made by oligodendrocytes newly generated from a widespread population of adult CNS progenitors called oligodendrocyte progenitor cells (OPCs). New myelin in CNS remyelination in both experimental models and clinical diseases can also be generated by Schwann cells (SCs), the myelin-forming cells of the PNS. Fate-mapping studies have shown that SCs contributing to remyelination in the CNS are often derived from OPCs and appear not to be derived from myelinating SCs from the PNS. In this study, we address whether CNS remyelinating SCs can also be generated from PNS-derived cells other than myelinating SCs. Using a genetic fate-mapping approach, we have found that a subpopulation of nonmyelinating SCs identified by the expression of the transcription factor Foxj1 also contribute to CNS SC remyelination, as well as to remyelination in the PNS. We also find that the ependymal cells lining the central canal of the spinal cord, which also express Foxj1, do not generate cells that contribute to CNS remyelination. These findings therefore identify a previously unrecognized population of PNS glia that can participate in the regeneration of new myelin sheaths following CNS demyelination.
SIGNIFICANCE STATEMENT Remyelination failure in chronic demyelinating diseases such as multiple sclerosis drives the current quest for developing means by which remyelination in CNS can be enhanced therapeutically. Critical to this endeavor is the need to understand the mechanisms of remyelination, including the nature and identity of the cells capable of generating new myelin sheath-forming cells. Here, we report a previously unrecognized subpopulation of nonmyelinating Schwann cells (SCs) in the PNS, identified by the expression of the transcription factor Foxj1, which can give rise to SCs that are capable of remyelinating both PNS and CNS axons. These cells therefore represent a new cellular target for myelin regenerative strategies for the treatment of CNS disorders characterized by persistent demyelination.
Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus
Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits.
SIGNIFICANCE STATEMENT Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.
Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans
A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson's disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2–10 ms), and long latency (10–100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10–20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.
SIGNIFICANCE STATEMENT This is the first physiological demonstration of the corticosubthalamic hyperdirect pathway and its topography at high spatial resolution in humans. We studied cortical potentials evoked by deep-brain stimulation in patients with Parkinson's disease undergoing awake lead implantation surgery. Subthalamic stimulation resulted in multiple short-latency responses consistent with activation of hyperdirect pathway, whereas no such response was present during pallidal stimulation. We contrast these findings with very short latency, direct corticospinal tract activations, and long-latency responses evoked through polysynaptic orthodromic projections. These findings underscore the importance of incorporating the hyperdirect pathway into models of human basal ganglia function.
The Divalent Metal Transporter 1 (DMT1) Is Required for Iron Uptake and Normal Development of Oligodendrocyte Progenitor Cells
The divalent metal transporter 1 (DMT1) is a multimetal transporter with a primary role in iron transport. Although DMT1 has been described previously in the CNS, nothing was known about the role of this metal transporter in oligodendrocyte maturation and myelination. To determine whether DMT1 is required for oligodendrocyte progenitor cell (OPC) maturation, we used siRNAs and the Cre-lox system to knock down/knock out DMT1 expression in vitro as well as in vivo. Blocking DMT1 synthesis in primary cultures of OPCs reduced oligodendrocyte iron uptake and significantly delayed OPC development. In vivo, a significant hypomyelination was found in DMT1 conditional knock-out mice in which DMT1 was postnatally deleted in NG2- or Sox10-positive OPCs. The brain of DMT1 knock-out animals presented a decrease in the expression levels of myelin proteins and a substantial reduction in the percentage of myelinated axons. This reduced postnatal myelination was accompanied by a decrease in the number of myelinating oligodendrocytes and a rise in proliferating OPCs. Furthermore, using the cuprizone model of demyelination, we established that DMT1 deletion in NG2-positive OPCs lead to less efficient remyelination of the adult brain. These results indicate that DMT1 is vital for OPC maturation and for the normal myelination of the mouse brain.
SIGNIFICANCE STATEMENT To determine whether divalent metal transporter 1 (DMT1), a multimetal transporter with a primary role in iron transport, is essential for oligodendrocyte development, we created two conditional knock-out mice in which DMT1 was postnatally deleted in NG2- or Sox10-positive oligodendrocyte progenitor cells (OPCs). We have established that DMT1 is necessary for normal OPC maturation and is required for an efficient remyelination of the adult brain. Since iron accumulation by OPCs is indispensable for myelination, understanding the iron incorporation mechanism as well as the molecules involved is critical to design new therapeutic approaches to intervene in diseases in which the myelin sheath is damaged or lost.
Stac Proteins Suppress Ca2+-Dependent Inactivation of Neuronal L-type Ca2+ Channels
Stac protein (named for its SH3- and cysteine-rich domains) was first identified in brain 20 years ago and is currently known to have three isoforms. Stac2, Stac1, and Stac3 transcripts are found at high, modest, and very low levels, respectively, in the cerebellum and forebrain, but their neuronal functions have been little investigated. Here, we tested the effects of Stac proteins on neuronal, high-voltage-activated Ca2+ channels. Overexpression of the three Stac isoforms eliminated Ca2+-dependent inactivation (CDI) of l-type current in rat neonatal hippocampal neurons (sex unknown), but not CDI of non-l-type current. Using heterologous expression in tsA201 cells (together with β and α2-1 auxiliary subunits), we found that CDI for CaV1.2 and CaV1.3 (the predominant, neuronal l-type Ca2+ channels) was suppressed by all three Stac isoforms, whereas CDI for the P/Q channel, CaV2.1, was not. For CaV1.2, the inhibition of CDI by the Stac proteins appeared to involve their direct interaction with the channel's C terminus. Within the Stac proteins, a weakly conserved segment containing ~100 residues and linking the structurally conserved PKC C1 and SH3_1 domains was sufficient to fully suppress CDI. The presence of CDI for l-type current in control neonatal neurons raised the possibility that endogenous Stac levels are low in these neurons and Western blotting indicated that the expression of Stac2 was substantially increased in adult forebrain and cerebellum compared with neonate. Together, our results indicate that one likely function of neuronal Stac proteins is to tune Ca2+ entry via neuronal l-type channels.
SIGNIFICANCE STATEMENT Stac protein, first identified 20 years ago in brain, has recently been found to be essential for proper trafficking and function of the skeletal muscle l-type Ca2+ channel and is the site of mutations causing a severe, inherited human myopathy. In neurons, however, functions for Stac protein have remained unexplored. Here, we report that one likely function of neuronal Stac proteins is tuning Ca2+ entry via l-type, but not that via non-l-type, Ca2+ channels. Moreover, there is a large postnatal increase in protein levels of the major neuronal isoform (Stac2) in forebrain and cerebellum, which could provide developmental regulation of l-type channel Ca2+ signaling in these brain regions.
Spinal RNF20-Mediated Histone H2B Monoubiquitylation Regulates mGluR5 Transcription for Neuropathic Allodynia
To date, histone H2B monoubiquitination (H2Bub), a mark associated with transcriptional elongation and ongoing transcription, has not been linked to the development or maintenance of neuropathic pain states. Here, using male Sprague Dawley rats, we demonstrated spinal nerve ligation (SNL) induced behavioral allodynia and provoked ring finger protein 20 (RNF20)-dependent H2Bub in dorsal horn. Moreover, SNL provoked RNF20-mediated H2Bub phosphorylated RNA polymerase II (RNAPII) in the promoter fragments of mGluR5, thereby enhancing mGluR5 transcription/expression in the dorsal horn. Conversely, focal knockdown of spinal RNF20 expression reversed not only SNL-induced allodynia but also RNF20/H2Bub/RNAPII phosphorylation-associated spinal mGluR5 transcription/expression. Notably, TNF-α injection into naive rats and specific neutralizing antibody injection into SNL-induced allodynia rats revealed that TNF-α-associated allodynia involves the RNF20/H2Bub/RNAPII transcriptional axis to upregulate mGluR5 expression in the dorsal horn. Collectively, our findings indicated TNF-α induces RNF20-drived H2B monoubiquitination, which facilitates phosphorylated RNAPII-dependent mGluR5 transcription in the dorsal horn for the development of neuropathic allodynia.
SIGNIFICANCE STATEMENT Histone H2B monoubiquitination (H2Bub), an epigenetic post-translational modification, positively correlated with gene expression. Here, TNF-α participated in neuropathic pain development by enhancing RNF20-mediated H2Bub, which facilitates phosphorylated RNAPII-dependent mGluR5 transcription in dorsal horn. Our finding potentially identified neuropathic allodynia pathophysiological processes underpinning abnormal nociception processing and opens a new avenue for the development of novel analgesics.
Neuronal Response Latencies Encode First Odor Identity Information across Subjects
Odorants are coded in the primary olfactory processing centers by spatially and temporally distributed patterns of glomerular activity. Whereas the spatial distribution of odorant-induced responses is known to be conserved across individuals, the universality of its temporal structure is still debated. Via fast two-photon calcium imaging, we analyzed the early phase of neuronal responses in the form of the activity onset latencies in the antennal lobe projection neurons of honeybee foragers. We show that each odorant evokes a stimulus-specific response latency pattern across the glomerular coding space. Moreover, we investigate these early response features for the first time across animals, revealing that the order of glomerular firing onsets is conserved across individuals and allows them to reliably predict odorant identity, but not concentration. These results suggest that the neuronal response latencies provide the first available code for fast odor identification.
SIGNIFICANCE STATEMENT Here, we studied early temporal coding in the primary olfactory processing centers of the honeybee brain by fast imaging of glomerular responses to different odorants across glomeruli and across individuals. Regarding the elusive role of rapid response dynamics in olfactory coding, we were able to clarify the following aspects: (1) the rank of glomerular activation is conserved across individuals, (2) its stimulus prediction accuracy is equal to that of the response amplitude code, and (3) it contains complementary information. Our findings suggest a substantial role of response latencies in odor identification, anticipating the static response amplitude code.
Dreaming in NREM Sleep: A High-Density EEG Study of Slow Waves and Spindles
Dreaming can occur in both rapid eye movement (REM) and non-REM (NREM) sleep. We recently showed that in both REM and NREM sleep, dreaming is associated with local decreases in slow wave activity (SWA) in posterior brain regions. To expand these findings, here we asked how specific features of slow waves and spindles, the hallmarks of NREM sleep, relate to dream experiences. Fourteen healthy human subjects (10 females) underwent nocturnal high-density EEG recordings combined with a serial awakening paradigm. Reports of dreaming, compared with reports of no experience, were preceded by fewer, smaller, and shallower slow waves, and faster spindles, especially in central and posterior cortical areas. We also identified a minority of very steep and large slow waves in frontal regions, which occurred on a background of reduced SWA and were associated with high-frequency power increases (local "microarousals") heralding the successful recall of dream content. These results suggest that the capacity of the brain to generate experiences during sleep is reduced in the presence of neuronal off-states in posterior and central brain regions, and that dream recall may be facilitated by the intermittent activation of arousal systems during NREM sleep.
SIGNIFICANCE STATEMENT By combining high-density EEG recordings with a serial awakening paradigm in healthy subjects, we show that dreaming in non-rapid eye movement sleep occurs when slow waves in central and posterior regions are sparse, small, and shallow. We also identified a small subset of very large and steep frontal slow waves that are associated with high-frequency activity increases (local "microarousals") heralding successful recall of dream content. These results provide noninvasive measures that could represent a useful tool to infer the state of consciousness during sleep.
Anterior Temporal Lobectomy Impairs Neural Classification of Body Emotions in Right Superior Temporal Sulcus and Reduces Emotional Enhancement in Distributed Brain Areas without Affecting Behavioral Classification
Humans with amygdalar lesions show proportional reductions of the emotional response to facial expressions in the fusiform face area as well as deficits in emotion recognition from facial expressions. While processing of bodily expressions shares many similarities with facial expressions, there is no substantial evidence that lesions of the amygdala result in similar behavioral and neural sequelae. We combined behavioral assessment with functional neuroimaging in a group of male and female humans with unilateral anterior temporal lobe (ATL) resections, including the amygdala (right: n = 10; left: n = 10) and 12 matched controls. The objective was to assess whether the amygdala is crucial for the recognition of body expressions and for modulatory effects on distant areas during perception of body expressions. The behavioral results revealed normal performance in both patient groups on emotion categorization of body expressions. The neuroimaging results showed that ATL patients displayed no enhanced activations in right fusiform body area and left extrastriate body area and that left ATL patients additionally displayed no enhanced activations in right posterior superior temporal sulcus and right extrastriate body area, respectively. Multivoxel pattern analysis revealed altered categorization capacity between emotional and neutral stimuli in right posterior superior temporal sulcus in right ATL patients. In addition, we also found emotional enhancement in frontal, parietal, occipital, and cingulate regions in controls. Together, our data show that the amygdala and ATLs are not necessary for recognition of dynamic body expressions, but suggest that amygdala lesions affect body emotion processing in distant brain areas.
SIGNIFICANCE STATEMENT For humans, information from emotional expressions of others is crucial to support social interactions. The majority of emotion studies has focused on facial expressions; however, in daily life, we also use information from body postures and body movement. Visual processing of body expressions relies on a brain network, including body-specific visual areas and visuomotor areas. Even though the importance of the amygdala and its modulatory effects on distant brain regions have been documented, it remains unclear whether the amygdala plays a crucial role in emotional body processing. By combining behavioral and neuroimaging data in patients with amygdalar lesions, we provide further evidence for its modulatory effect on distant areas during the perception of body expressions.
CACHD1 is an {alpha}2{delta}-Like Protein That Modulates CaV3 Voltage-Gated Calcium Channel Activity
The putative cache (Ca2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2 voltage-gated Ca2+ channel auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus, and cerebellum, with a broadly similar tissue distribution to CaV3 subunits, in particular CaV3.1. In expression studies, CACHD1 increased cell-surface localization of CaV3.1, and these proteins were in close proximity at the cell surface, consistent with the formation of CACHD1-CaV3.1 complexes. In functional electrophysiological studies, coexpression of human CACHD1 with CaV3.1, CaV3.2, and CaV3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, α2-1 had no effect on peak current density or maximal conductance in CaV3.1, CaV3.2, or CaV3.3. A comparison of CACHD1-mediated increases in CaV3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female embryonic day 19 rats, CACHD1 overexpression increased CaV3-mediated action potential firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an α2-like protein that functionally modulates CaV3 voltage-gated calcium channel activity.
SIGNIFICANCE STATEMENT This is the first study to characterize the Ca2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is widely expressed in the CNS, in particular in the thalamus, hippocampus, and cerebellum. CACHD1 distribution is similar to that of low voltage-activated (CaV3, T-type) calcium channels, in particular to CaV3.1, a protein that regulates neuronal excitability and is a potential therapeutic target in conditions such as epilepsy and pain. CACHD1 is structurally an α2-like protein that functionally increases CaV3 calcium current. CACHD1 increases the presence of CaV3.1 at the cell surface, forms complexes with CaV3.1 at the cell surface, and causes an increase in channel open probability. In hippocampal neurons, CACHD1 causes increases in neuronal firing. Thus, CACHD1 represents a novel protein that modulates CaV3 activity.
A Druggable Genome Screen Identifies Modifiers of {alpha}-Synuclein Levels via a Tiered Cross-Species Validation Approach
Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. α-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the α-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type α-Syn levels. These findings are further bolstered by animal studies which show that overexpression of α-Syn is sufficient to cause PD-like features. Thus, increased α-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of α-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate α-Syn levels and toxicity in cell lines, Drosophila, human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins.
SIGNIFICANCE STATEMENT We present a research strategy for the systematic identification and validation of genes modulating the levels of α-Synuclein, a protein involved in Parkinson's disease. A cell-based screen of the druggable genome (>7,500 genes that are potential therapeutic targets) yielded many modulators of α-Synuclein that were subsequently confirmed and validated in Drosophila, human neurons, and mouse brain. This approach has broad applicability to the multitude of neurological diseases that are caused by mutations in genes whose dosage is critical for brain function.
Amnesiac Is Required in the Adult Mushroom Body for Memory Formation
It was proposed that the Drosophila amnesiac gene (amn) is required for consolidation of aversive memory in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the fly center for olfactory learning and memory (Waddell et al., 2000). Yet, a conditional analysis showed that it was not possible to rescue the memory deficit of amnX8 null mutant flies when amn expression was restored only in the adult (DeZazzo et al., 1999), which led the authors to suggest that amn might be involved in the development of brain structures that normally promote adult olfactory memory. To further investigate temporal and spatial requirements of Amnesiac (AMN) peptide in memory, we used RNA interference in combination with conditional drivers. Experiments were conducted either in both sexes, or in either sexes. Our data show that acute modulation of amn expression in adult DPM neurons does not impact memory. We further show that amn expression is required for normal development of DPM neurons. Detailed enhancer trap analyses suggest that amn transcription unit contains two distinct enhancers, one specific of DPM neurons, and the other specific of α/β MB neurons. This prompted us to investigate extensively the role of AMN in the adult MB. Together, our results demonstrate that amn is acutely required in adult α/β MB neurons for middle-term and long-term memory. The data thus establish that amn plays two distinct roles. Its expression is required in DPM neurons for their development, and in adult MB for olfactory memory.
SIGNIFICANCE STATEMENT The Drosophila amnesiac gene encodes a neuropeptide whose expression was proposed to be required for consolidation of aversive memory in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the olfactory memory center. Here, we investigated amnesiac temporal and spatial requirement using conditional tools that allowed us to manipulate its expression in selected neurons. This work leads to a complete reassessment of the role of amnesiac in brain development and memory. We show that amnesiac is required for two distinct processes: for normal development of DPM neurons, and in adult MB for memory.
Association of Quality of Life With Surgical Excision of Head and Neck Melanoma
This study examines the preoperative and postoperative changes in quality of life as perceived and reported by patients who received surgical treatment for Tis or T1a melanoma of the head and neck.
Herpetic Whitlow—A Case of Inadvertent Inoculation With Melanoma Viral Therapy
This case report describes an occurrence of herpetic whitlow following inadvertent inoculation with melanoma viral therapy
Association of Psoriasis With Inflammatory Bowel Disease
This systematic review and meta-analysis of 9 studies comprising more than 7 million patients examines the association between psoriasis and inflammatory bowel disease.
APOA5 and APOC3 Polymorphisms and Hypertriglyceridemia in Bexarotene-Treated CTCL
This case series study examines the association between APOA5 and APOC3 polymorphisms and triglyceride levels in patients with cutaneous T-cell lymphoma before, during, and after treatment with bexarotene.
Restrictive Immigration Law and Birth Outcomes of Immigrant Women
Abstract
Unauthorized immigration is one of the most contentious policy issues in the United States. In an attempt to curb unauthorized migration, many states have considered restrictive laws intended to make life so difficult for unauthorized immigrants that they would choose to leave the country. Arizona's Senate Bill 1070, enacted in 2010, pioneered these efforts. Using population-level natality data and causal inference methods, we examine the effect of SB1070 on infants exposed before birth in Arizona. Prenatal exposure to the bill resulted in lower birthweight among Latina immigrant women, but not among US-born white, black, or Latina women. The decline in birthweight resulted from exposure to the bill being signed into law, rather than from its (limited) implementation. The findings indicate that the threat of a punitive law, even in the absence of implementation, can have a harmful effect on the birth outcomes of the next generation.Estimating the Severity Profile of Enterovirus A71 Infections in Children: A Bayesian Synthesis Framework
Abstract
Enterovirus A71 (EV-A71) is responsible for the majority of severe hand- foot-and-mouth disease, but little evidence is available on the severity profile of EV-A71 infections. We formulated a hierarchical Bayesian model which synthesized data on EV-A71 associated diseases/events and EV-A71 antibody responses to infection among unvaccinated children from large clinical trials of EV-A71 vaccination which were conducted in Jiangsu and Beijing during 2012 and 2013, to reconstruct the severity profile in a unified framework. On average 15.1% of the children aged 6 to 35 months were infected by EV-A71 during one-year follow-up in a mild epidemic season. We estimated that 9.7%, 2.2%, and 0.6% of EV-A71 infected children were diagnosed with EV-A71 associated diseases, were hospitalized and showed severe complications, respectively. We estimated on average 1.0 deaths per 10,000 EV-A71 infections for children aged 6 to 35 months. Around 70% of children had ≥4-fold rises in antibody titers after infection. Most EV-A71 infections in young children are mild, and overall 2.2% of the infected patients were hospitalized. There remain several uncertainties about the immune response after infection, and the duration of immunity against EV-A71 re-infection.Propensity Score-Based Estimators with Multiple Error-Prone Covariates
Abstract
Propensity score methods are an important tool to help reduce confounding in non-experimental studies. Most propensity score methods assume that covariates are measured without error. However, covariates are often measured with error, which leads to biased causal effect estimates if the true underlying covariates are the actual confounders. Although some studies have investigated the impact of a single mismeasured covariate on estimating a causal effect and proposed methods for handling the measurement error, even fewer papers have investigated the case where multiple covariates are mismeasured, and none discussed correlated measurement errors. In this paper, we examine the consequences of multiple error-prone covariates when estimating causal effects using propensity score-based estimators via extensive simulation studies and real data analyses. We find that causal effect estimates are less biased when the propensity score model includes mismeasured covariates whose true underlying values are strongly correlated with each other. However, when the measurement errors are correlated with each other, additional bias is introduced. In addition, it is beneficial to include correctly measured auxiliary variables that are correlated with confounders whose true underlying values are mismeasured in the propensity score model.A Prospective Cohort Study Examining the Association Between Maternal Arsenic Exposure, Fetal Loss, and Neonatal Mortality
Abstract
Arsenic crosses the placenta, possibly increasing the risk of adverse reproductive outcomes. We aimed to examine the association between maternal arsenic exposure and fetal/neonatal survival using a prospective cohort of 1,616 maternal-infant pairs recruited at ≤ 16 weeks gestational age in Bangladesh (2008-2011). Arsenic concentration was measured in maternal drinking water at enrollment. Extended Cox regression (both time-dependent coefficients and step functions) was used to estimate the time-varying association between maternal arsenic exposure and fetal/neonatal death (all mortality between enrollment and one month after birth). A sensitivity analysis assessed gestational arsenic exposure using maternal urine at enrollment. We observed 203 fetal losses and 20 neonatal deaths. Higher arsenic exposure was associated with a slightly increased mortality rate through the second trimester, and then switched directions around 32 weeks gestation. In the step function model, the hazard ratios (HR) of mortality for each unit increase in natural log drinking water arsenic (μg/L) ranged from HR=1.7 in weeks 25-28 (95% CI: 1.3, 2.1), to HR=0.9 in weeks 33-36 (95% CI: 0.6, 1.2). This non-linear association suggests that arsenic may exert survival pressure on developing fetuses, potentially contributing to survival bias, and may also indicate that arsenic toxicity differs by fetal developmental stage.Is the Black-White Mental Health Paradox Consistent across Gender and Psychiatric Disorders?
Abstract
This study assessed whether the Black-White mental health epidemiological paradox (i.e. Blacks' lower or similar rates of mental disorder relative to Whites) extends across 12 lifetime and past-year psychiatric disorders and varies by gender. We used data from the National Comorbidity Survey-Replication (NCS-R) and National Survey of American Life (NSAL), 2001-2003 (N=4,584 African Americans; 6,668 non-Hispanic Whites). Results showed overwhelming evidence of the paradox across lifetime and past-year disorders for women and men. In addition, Blacks' mental health advantage over Whites widened after adjusting for socioeconomic factors. There was one exception: Black women experienced higher risk of lifetime post-traumatic stress disorder (PTSD) compared to White women. These findings provide strong evidence for the "Black-White mental health paradox"; however, additional research is needed to understand Black women's heightened risk for post-traumatic stress disorder (PTSD).Association between phenotypic characteristics and melanoma in a large prospective cohort study
To delineate causal pathways for melanoma, it is essential to derive unbiased estimates of risk. Extant knowledge derives largely from case-control studies with potential for bias. In a population-based prospective study (QSkin, n=38,854), we assessed melanoma risks associated with pigmentation characteristics and other phenotypes, and explored additive interactions.We fitted Cox proportional hazards models adjusting for other factors to estimate independent effects of each characteristic on melanoma risk.
Antagonization of IL-17A attenuates skin inflammation and vascular dysfunction in mouse models of psoriasis
Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. Interleukin-17A (IL-17A) plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis.We analyzed three murine models with varying severity of psoriasis-like skin disease concerning their vascular function and inflammation: K14-IL-17Aind/+ mice with keratinocyte-specific IL-17A overexpression and an early onset severe psoriasis-like phenotype, homozygous CD11c-IL-17Aind/ind and heterozygous CD11c-IL-17Aind/+ mice overexpressing IL-17A in CD11c+ cells leading to a delayed onset of moderate psoriasis-like skin disease, and the acute model of imiquimod-induced psoriasis-like skin inflammation.
An atypical occurrence of Aspergillosis in leukemic patient: Brief description of a clinical case
Publication date: Available online 23 October 2018
Source: Journal de Mycologie Médicale
Author(s): L. Pastrone, M.-T. Corsetti, L. Depaoli, S. Sampò, M. Colonna, A. Rocchetti
Abstract
Herein we describe a 43 year-old Caucasian female patient with acute myeloid leukemia that developed an unconventional form of invasive Aspergillosis. For therapeutic reasons, a Groshong-type central venous catheter was positioned. Monitoring the patient's clinical conditions, positive values for C-reactive protein and galactomannan were correlated with a probably Aspergillosis. Surprisingly no pulmonary evidences were observed. Due to worsening conditions, she was re-hospitalized and a blood culture was performed, whom positivity resulted as the first clinical evidence of Aspergillus fumigatus. Further evidence about species identification was obtained by sequencing the fungal ITS region. We support the clinical value of blood culture as a decisive factor to improve the diagnosis of catheter-related Aspergillosis.
Droplet-based microfluidics as a future tool for strain improvement in lactic acid bacteria
Abstract
Strain development is frequently used to improve the performance and functionality of industrially important microbes. As traditional mutagenesis screen is especially utilized by the food industry to improve strains used in food fermentation, high-throughput and cost-effective screening tools are important in mutant selection. The emerging droplet-based microfluidics technology miniaturizes the volume for cell cultivation and phenotype interrogation down to the pico-liter scales, which facilitates screening of microbes for improved phenotypical properties tremendously. In this mini-review, we present recent application of the droplet-based microfluidics in microbial strain improvement with a focus on its potential use in the screening of lactic acid bacteria.Recommandations diagnostiques et thérapeutiques pour les maladies sexuellement transmissibles : herpès génital
Publication date: Available online 23 October 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): B. Milpied, M. Janier, J. Timsit, N. Spenatto, E. Caumes, O. Chosidow, L. Sentilhes, M.-V. Senat, Groupe infectiologie dermatologique et infections sexuellement transmissibles (GrIDIST) de la Société française de dermatologie et du Collège national des gynécologues obstétriciens français (CNGOF)
Résumé
Traitement de la primo-infection ou du premier épisode clinique d'herpès génital en cours de grossesse
Le traitement de la primo-infection ou du premier épisode clinique d'herpès génital est basé sur l'aciclovir oral, 200 mg × 5/j pendant 5 à 10 jours en fonction de l'état clinique. Concernant le valaciclovir, la posologie recommandée est de 1 g × 2 jours avec une durée de traitement identique à celle proposée pour l'aciclovir.
Traitement de la récurrence herpétique en cours de grossesse
Il n'y a pas d'étude permettant d'évaluer l'efficacité d'un traitement antiviral sur la symptomatologie en cas de récurrence d'herpès génital pendant la grossesse. Le traitement antiviral par aciclovir ou valaciclovir peut cependant être proposé devant une symptomatologie le justifiant (durée et intensité des symptômes). Le valaciclovir pourra être préféré (efficacité d'utilisation même si les données d'innocuité sont plus nombreuses pour l'aciclovir). Le valaciclovir peut être utilisé à la dose de 1cp à 500 mg per os deux fois par jour pendant 5 jours.
Traitement antiviral prophylactique en cas de grossesse
Chez les femmes ayant eu une infection initiale ou une récurrence pendant la grossesse, bien qu'il n'existe pas de bénéfice démontré du traitement prophylactique pour réduire le risque d'herpès néonatal, il est recommandé de proposer une prophylaxie antivirale à partir de 36 SA (semaines d'aménorrhée) afin de réduire le risque de césarienne pour lésion herpétique. Les antiviraux recommandés sont l'aciclovir à la posologie de 400 mg trois fois par jour per os ou le valaciclovir à la posologie de 500 mg deux fois par jour per os jusqu'à l'accouchement.
Summary
Treatment of the initial infection or first clinical episode of genital herpes
An initial infection or first clinical episode of genital herpes is treated with oral aciclovir 200 mg × 5/d for 5 to 10 days depending on clinical status. The recommended dosage for valaciclovir is 1 g × 2/d and treatment duration is identical to that for aciclovir.
Treatment of herpes recurring during pregnancy
There are no studies of the efficacy of antiviral therapy on the symptoms of genital recurring during pregnancy. However, initial anti-viral treatment using aciclovir or valaciclovir may be given where warranted by symptoms (i.e. duration and severity of symptoms). Valaciclovir may be used instead (equivalent efficacy but better safety data for aciclovir). Valaciclovir may be given at a dosage of 1 × 500 mg b.i.d. p.o. for 5 days.
Prophylactic anti-viral treatment during pregnancy
In female patients presenting an initial infection or infection recurring during pregnancy, although there is no demonstrated benefit for prophylactic treatment in reducing the risk of neonatal herpes, anti-viral prophylaxis is recommended after 36 WA (weeks' amenorrhoea) to limit the need for Caesarean section due to herpetic lesions. The recommended antivirals are aciclovir at a dosage of 400 mg t.i.d p.o. or valaciclovir at a dosage of 500 mg b.i.d. p.o. until delivery.
Ulcérations buccales aphtoïdes inaugurales d’une maladie inflammatoire chronique de l’intestin induite par le sécukinumab
Publication date: Available online 23 October 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): X. Grimaux, S. Leducq, P. Goupille, A. Aubourg, E. Miquelestorena-Standley, M. Samimi
Résumé
Introduction
Le sécukinumab, anticorps monoclonal humanisé ciblant l'interleukine 17A, a été associé à la survenue de maladies inflammatoires digestives. Nous rapportons le cas d'une patiente ayant développé des ulcérations buccales inaugurales d'une maladie inflammatoire chronique intestinale (MICI) induite par le sécukinumab. Cette patiente avait eu six ans auparavant des ulcérations buccales similaires au cours d'un traitement par tocilizumab (ciblant l'IL6R), suggérant un lien immunologique entre les deux épisodes.
Observation
Une femme de 36 ans avait une spondylarthrite ankylosante réfractaire. En 2010, elle avait présenté des ulcérations buccales au cours d'un traitement par tocilizumab. En 2011, le tocilizumab avait été arrêté et l'aphtose résolutive. En 2016, l'introduction du sécukinumab s'accompagnait d'une récidive d'ulcérations buccales aphtoïdes puis d'une iléo-pancolite. Une corticothérapie, puis un traitement par ustékinumab, permettaient une évolution partiellement favorable.
Discussion
Cette patiente a développé une maladie inflammatoire chronique intestinale au cours d'un traitement par sécukinumab, précédée par des ulcérations buccales aphtoïdes. Elle avait développé, six ans auparavant, des ulcérations buccales similaires au cours d'un traitement ciblant l'IL6R. L'IL6 est une cytokine pléiotrope qui peut activer la voie Th17. Ainsi, le tocilizumab a pu induire un effet « anti-IL17-like » expliquant la survenue de lésions buccales aphtoïdes possiblement en lien avec une maladie inflammatoire digestive a minima.
Conclusion
La survenue d'ulcérations buccales au cours d'un traitement par sécukinumab peut être inaugurale d'une maladie inflammatoire chronique intestinale. La notion d'aphtose préalable, notamment au cours de traitements biologiques antérieurs, devrait faire discuter le rapport bénéfices/risques de la prescription d'un anti-IL17.
Summary
Background
Secukinumab, a humanized monoclonal antibody targeting interleukin 17A, has been associated with the development of inflammatory bowel diseases. We report a case of a female patient developing recurrent oral ulcers prior to inflammatory bowel disease induced by secukinumab. The patient had developed similar oral ulcers 6 years earlier while on tocilizumab (targeting IL6R), suggesting an immunological link between the two episodes.
Patients and methods
A 36-year-old female patient had refractory spondylarthrosis. In 2010, she had presented oral aphthous ulcers during treatment with tocilizumab. In 2011, tocilizumab was stopped and the ulcers resolved. In 2016, secukinumab was introduced and led to recurrence of oral aphthous ulcers followed by ileitis-pancolitis. Corticosteroids and ustekinumab resulted in partial remission.
Discussion
The patient developed inflammatory bowel disease during treatment with secukinumab, preceded by recurrent oral aphthous ulcers. She had presented similar oral ulcers 6 years earlier while on a treatment targeting IL6R. IL6 is a pleiotropic cytokine that may activate the Th17 pathway. Thus, tocilizumab could have induced an "anti-IL17-like" effect, accounting for the occurrence of oral aphthous ulcers, possibly related to mild inflammatory bowel disease.
Conclusion
The occurrence of oral ulcers during treatment with secukinumab may herald inflammatory bowel disease. In patients with a previous history of recurrent aphthous stomatitis, especially where induced by previous biologics, consideration must be given to the risk-benefit ratio of prescribing an anti-IL17 antibody.
Knocking On Doors To Get Opioid Overdose Survivors Into Treatment
Within days of an OD from opioids or other drugs, users in Huntington, W.Va., are visited by a quick-response team at home, the hospital or in jail. Reversing an OD is just recovery's first step.
(Image credit: Sarah McCammon/NPR)
Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: Further results from the prospective PANTHER study with focus on obese patients
Abstract
Background
Adjuvant chemotherapy (ACT) for breast cancer improves relapse free (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial. Patients and methods
PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose dense epirubicin/cyclophosphamide (EC) and docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary endpoint was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after dose dense ACT. Results
Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (p = 0.495), while obese patients in this group (BMI ≥30) had improved BCRFS compared to non-obese ones (BMI <30) (HR = 0.51, 95% CI 0.30 – 0.89, p = 0.02). Moreover, tDD was associated with improved BCRFS compared to standard treatment only in obese patients (HR = 0.49, 95% CI 0.26 – 0.90, p = 0.022) but not in non-obese ones (HR = 0.79, 95% CI 0.60 – 1.04, p = 0.089). The differences were not formally statistically significant (p for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups. Conclusions
Dose tailoring is a feasible strategy which can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies. ClinicalTrials.gov identifier
NCT00798070An Adaptive Population Enrichment Phase 3 Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients with Advanced Angiosarcoma (TAPPAS Trial)
Abstract
Background
Major challenges in clinical trials of ultra orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the treatment effect and, therefore, determining optimal sample size. Angiosarcoma (AS), a particularly aggressive form of soft tissue sarcoma with an incidence of about 2,000 cases per year in the United States and Europe is poorly addressed by current systemic therapies. Pazopanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) is approved for the treatment of AS, with modest benefit. TRC105 (carotuximab) is a monoclonal antibody to endoglin, an essential angiogenic target highly expressed on proliferating endothelium and both tumor vessels and tumor cells in AS, that has the potential to complement VEGFR tyrosine kinase inhibitors (TKIs). In a phase 1/2 study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging PFS. In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous. Design
This paper describes the design of a recently initiated Phase 3 trial of TRC105 and Pazopanib versus Pazopanib alone in patients with Advanced AngioSarcoma (TAPPAS trial). Given the ultra-orphan status of the disease and the paucity of reliable prior data on progression free survival or overall survival (endpoints required for regulatory approval as a pivotal trial), an adaptive design incorporating population enrichment and sample size re-estimation was implemented. The design incorporated regulatory input from the FDA and EMA, and proceeded following special protocol assessment designation by the FDA. Conclusions
It is shown that the benefit of the adaptive design as compared to a conventional single-look design arises from the learning and subsequent improvements in power that occur after an unblinded analysis of interim data.Registered on Clinicaltrials.gov: NCT02979899Activity of the Hsp90 inhibitor Luminespib Among Non-Small Cell Lung Cancers Harboring EGFR Exon 20 Insertions
Abstract
Background
There are currently no approved targeted therapies for NSCLC patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations which are generally refractory to 1st/2nd generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and Methods
29 patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between 8/2013 and 10/2016. The primary endpoint was objective response rate (ORR), with a pre-determined target rate of effectiveness (defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥ 3 months) of 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype. Results
Among the 29 patients (18 female, median age 60 years,) the ORR was 17%, median progression-free survival (mPFS) was 2.9 mos (95% CI, 1.4-5.6,) and mOS was 13 mos (95% CI, 4.9-19.5.) The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or SD ≥ 3 months. The most common luminespib-related toxicities were diarrhea (83%,) visual changes (76%) and fatigue (45%). All study treatment was stopped on 2/28/17 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion
The study met its primary endpoint, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted.Study on the correlation between age and changes in mosquito bite response
The Journal of Dermatology, EarlyView.
Effects of topical 0.8% piroxicam and 50+ sunscreen filters on actinic keratosis in hypertensive patients treated with or without photosensitizing diuretic drugs: an observational cohort study.
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Effects of topical 0.8% piroxicam and 50+ sunscreen filters on actinic keratosis in hypertensive patients treated with or without photosensitizing diuretic drugs: an observational cohort study.
Clin Cosmet Investig Dermatol. 2018;11:485-490
Authors: Mazzilli S, Garofalo V, Ventura A, Diluvio L, Milani M, Bianchi L, Campione E
Abstract
Background: Photosensitizing diuretics use (especially thiazide compounds) is associated with a significantly higher risk of squamous cell carcinoma (SCC). Actinic keratosis (AK) is a precursor of SCC.
Study aim: To evaluate in a prospective cohort study the efficacy of topical piroxicam 0.8% and sunscreen 50+ (ACTX) in the treatment of AK in hypertensive subjects with or without TD treatment.
Subjects and methods: A total of 119 hypertensive subjects with multiple AK (39 under chronic TD treatment; and 80 treated with other non-TD, non-photosensitizing antihypertensive drugs) were enrolled after their informed consent in a 6-month observational cohort study. All the subjects were treated with ACTX twice daily. The primary endpoint was the evolution of AK lesions at baseline, after 3 and 6 months. The secondary endpoint was the clearance of AK target lesions and field of cancerization by dermoscopic evaluation using a score evaluating erythema, scaling, pigmentation, and follicular plugs (ESPFP score; ranging from 0 to 20). An investigator, unaware of the type of antihypertensive treatments (TD or non-TD), performed all the clinical and dermoscopy evaluations.
Results: At baseline, AK mean (SD) lesion number in TD group was 14.1(4) and 14.6(4) in the non-TD group. ESPFP mean (SD) score at baseline was 5.8(1.2) in both groups. A significant reduction of AK lesions in comparison with baseline was observed in both groups. A statistically significant greater reduction was observed in TD in comparison with the non-TD group (-54% vs -32%). ESPFP score was reduced in a higher proportion in the TD group in comparison with the non-TD group (-60% vs -37%, respectively). ACTX treatment was very well tolerated.
Conclusion: In hypertensive subjects with multiple AK, the topical use of ACTX is associated with a significant reduction of lesions count with an improvement in the field cancerization. The clinical efficacy is more pronounced in subjects under thiazide diuretics treatment.
PMID: 30349346 [PubMed]
Genetic polymorphism analysis of patients with primary hyperhidrosis.
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Genetic polymorphism analysis of patients with primary hyperhidrosis.
Clin Cosmet Investig Dermatol. 2018;11:477-483
Authors: Simes BC, Moore JP, Brown TC, Rushforth TJ, Bookout AL, Richardson CL
Abstract
Background: Hyperhidrosis affects 220 million people worldwide. The hallmark of this condition is excessive sweating, which negatively impacts the social, emotional, and occupational lives of these individuals. A familial predisposition has been established; however, the specific genes involved have yet to be identified.
Objective: The aim of this study was to determine possible genetic variations contributing to primary hyperhidrosis, specifically single-nucleotide polymorphisms (SNPs).
Patients and methods: Twenty-one case and 21 control DNA samples were extracted and genotyped for 20 SNPs associated with the Butyrylcholinesterase (BCHE) and Cholinergic Receptor Nicotinic Alpha-7 subunit (CHRNA7) genes.
Results: For rs1126680, the -116A variant allele (P-value=0.15) was found only in hyperhidrosis patients who also had the K-variant allele (P-value=0.65) in rs1803274. Further analysis testing the null hypothesis of independence between the combined genotypes and case/control status yielded a P-value of 0.30.
Conclusion: Our results are consistent with previous research that shows the K-variant requires the -116A variant to be present in order to observe a decrease in BChE activity levels. These results are not statistically significant (P-value >0.05), but the exclusive association between the -116A and K-variants on the BCHE gene in hyperhidrosis patients warrants further investigation using a larger sample size.
PMID: 30349345 [PubMed]
Evaluating the role of small particle hyaluronic acid fillers using micro-droplet technique in the face, neck and hands: a retrospective chart review.
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Evaluating the role of small particle hyaluronic acid fillers using micro-droplet technique in the face, neck and hands: a retrospective chart review.
Clin Cosmet Investig Dermatol. 2018;11:467-475
Authors: Nikolis A, Enright KM
Abstract
Background: Loss of the viscoelastic properties of the skin is a primary sign of aging and contributes to the appearance of wrinkles. Hyaluronic acid (HA) fillers are one of the most commonly used treatments for age-related soft-tissue reduction and volume loss. Evidence is also emerging that HA fillers rejuvenate the skin.
Methods: A retrospective chart review was completed on 20 subjects treated with small particle HA (SP-HA), to investigate its effects on skin properties. Subjects having received three treatments in the face, neck, and/or hands were considered in the analyses. Skin hydration, trans-epidermal water loss (TEWL), and pH were assessed at baseline (injection #1), Week 4 (injection #2), Week 8 (injection #3), and Week 12 (follow-up).
Results: Treatment with SP-HA significantly improved hydration levels in the face, neck, and hands. Significant results were seen in the face following the first three treatments, with subjects moving up to the next hydration level (ie, hydration went from dry to moisturized) and by the second treatment in the neck and hands. TEWL scores on the face and neck remained within healthy values throughout all visits. At baseline, TEWL scores on the hands were within critical condition and after three injections they recuperated to healthy values, while pH values remained within the normal range throughout treatment.
Conclusion: A treatment regimen consisting of three SP-HA injections was safe and well tolerated. SP-HA use demonstrated a hydrating effect while positively impacting the skin's ability to retain moisture.
PMID: 30349344 [PubMed]
Can emollients of similar composition be assumed to be therapeutically equivalent: a comparison of skin occlusivity and emulsion microstructure.
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Can emollients of similar composition be assumed to be therapeutically equivalent: a comparison of skin occlusivity and emulsion microstructure.
Clin Cosmet Investig Dermatol. 2018;11:461-465
Authors: Antonijević MD, Novac O, O'Hagan BM
Abstract
Introduction: Emollient therapy is the mainstay for treating skin conditions such as atopic dermatitis and psoriasis. New emollients have been introduced recently and are assumed to be therapeutically interchangeable with the innovator products because, superficially, they appear to have similar compositions. This study compares a) the ex vivo human skin occlusion performance and b) the visual and microscopic properties of Isomol gel (IMG) and Doublebase gel (DBG).
Materials and Methods: Occlusion was measured gravimetrically by reduction in cumulative 48-hour evaporative weight loss from ex vivo human skin samples following single applications of the two test emollients and Vaseline®. Skin samples from a single donor were mounted in Franz diffusion cells and then the emollients were spread over the skin surface with an applied dose of approximately 2 mg/cm2. The assemblies (four replicates per treatment) were then accurately weighed at baseline (T0) and again after 5-, 24-, and 48-hour postapplication. The quality of the two emollient gel formulations was compared by visual examination of their film-forming characteristics and by microstructural examination using environmental scanning electron microscopy (ESEM).
Results: Occlusivity of the DBG emollient gel formulation was comparable with Vaseline and substantially better than IMG, with the DBG-treated skin samples losing less than half as much weight as the IMG-treated skin samples over 48 hours and at a much slower rate during the first 5 hours. The film-forming characteristics and microstructure of the gels were also very different. Whereas DBG maintained a smooth, uniform film over 24 hours, the IMG formulation phase-separated. ESEM results showed that the DBG emulsion has a stable structural matrix with uniform oil droplets, whereas for IMG the emulsion system is inhomogeneous with the oil phase coalescing into larger irregular shaped rafts.
Conclusions: We have demonstrated substantial performance differences between two prescribed emollient gels.
PMID: 30349343 [PubMed]
Calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: case series and review of the literature.
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Calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: case series and review of the literature.
Clin Cosmet Investig Dermatol. 2018;11:451-459
Authors: Pinter A, Thormann H, Angeletti F, Jalili A
Abstract
An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources - randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) - underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.
PMID: 30349342 [PubMed]
Effects of oral supplementation with FOS and GOS prebiotics in women with adult acne: the "S.O. Sweet" study: a proof-of-concept pilot trial.
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Effects of oral supplementation with FOS and GOS prebiotics in women with adult acne: the "S.O. Sweet" study: a proof-of-concept pilot trial.
Clin Cosmet Investig Dermatol. 2018;11:445-449
Authors: Dall'Oglio F, Milani M, Micali G
Abstract
Background: We evaluated the effects of 3-month prebiotic oral supplementation with fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) on glucose and lipid metabolic parameters in women with adult acne (female adult acne).
Methods: Twelve women, mean age 35 years, with mild to moderate acne were enrolled. Exclusion criteria were severe acne, body mass index (BMI) >25, history of diabetes mellitus, polycystic ovary syndrome, regular intake of prebiotics or probiotics, and history of inflammatory intestinal diseases. At baseline visit (T0), at month 1 (T1), and at month 3 (T2) fasting glucose, blood insulin, glycated hemoglobin (HbA1c), C-peptide, triglycerides, total cholesterol levels, and BMI were measured. Subjects were treated with a food supplement containing FOS (100 mg) and GOS (500 mg), one sachet daily, for 3 months. Subjects were instructed to follow their regular diet, and no dietary restrictions were suggested.
Results: At baseline, the BMI, mean ± SD, was 23±0.7. No modification of BMI was observed during the study. At baseline, fasting blood glucose levels were 92±7 mg/dL. A significant (P=0.02) reduction was observed at month 1 (86±5 mg/dL) and at month 3 (85±7 mg/dL) (-10%). Total cholesterol levels were reduced significantly (P=0.018) from 184±19 to 161±10 mg/dL (-13%) at the end of the study. Triglycerides at baseline were 51 mg/dL and were reduced to 46 mg/dL (P=0.05). Insulin and C-peptide plasma levels showed a nonsignificant reduction trend from baseline to the end of the study. In subjects with baseline insulin level >6 µUI/mL (n=6) the FOS/GOS supplementation induced a significant (P=0.03) reduction from 7.8 to 4.3 µUI/mL at day 90 (-45%). C-peptide was reduced from 2.1 to 1.6 ng/mL (month 3). HbA1c at baseline was 35 mg/dL and 32 mg/dL at the end of the study (NS).
Conclusion: In adult female acne, supplementation with prebiotic FOS and GOS was associated with positive effects on glycemic and lipid metabolic parameters.
PMID: 30349341 [PubMed]
Palmar crease xanthomas in familial hypercholesterolemia
International Journal of Dermatology, EarlyView.
Treatment of primary non-metastatic melanoma at high-volume academic facilities is associated with improved long-term patient survival
Publication date: Available online 23 October 2018
Source: Journal of the American Academy of Dermatology
Author(s): Shayan Cheraghlou, George O. Agogo, Michael Girardi
Abstract
Background
Previous studies of cancer care have demonstrated improved long-term patient outcomes for those treated at high-volume centers. The influence of treatment center characteristics on outcomes for primary non-metastatic melanoma is not currently established.
Objective
We aimed to investigate the association of cancer treatment center case volume and academic affiliation on long-term patient survival for cases of primary non-metastatic melanoma.
Methods
US adult melanoma cases diagnosed from 2004-2014 in the NCDB were identified. Hospitals were grouped by yearly case volume quartile: bottom quartile, middle quartiles, and top quartile.
Results
Facility case volume was significantly associated with long-term patient survival (p<0.0001). Five-year survival was 76.8%, 81.9%, and 86.4% respectively for patients treated at institutions in the bottom, middle, and top quartiles of case volume respectively. On multivariate analysis, treatment at both middle-quartile (HR 0.834;95% CI 0.778-0.895) and top-quartile (HR 0.691;95% CI 0.644-0.741) volume centers was associated with improved survival relative to bottom-quartile volume hospitals. Academic affiliation was associated with improved outcomes for top-quartile but not middle-quartile volume facilities.
Limitations
Disease-specific survival was not available.
Conclusions
Treatment at a high-volume facility is associated with improved long-term patient survival for melanoma. High-volume academic centers have improved patient outcomes compared to other high-volume centers.
Brote de psoriasis en placas y edema periférico en un paciente tratado con atezolizumab
Publication date: Available online 23 October 2018
Source: Actas Dermo-Sifiliográficas
Author(s): J. Santos-Juanes, P. Munguía Calzada, C. Álvarez Fernández
Are childhood flexural comedones hamartomas? A single institution experience
JDDG: Journal der Deutschen Dermatologischen Gesellschaft, EarlyView.
Level of knowledge among pharmacists regarding anaphylaxis and the use of epinephrine autoinjectors
JDDG: Journal der Deutschen Dermatologischen Gesellschaft, EarlyView.
Asymptomatic perianal papules in a 75‐year‐old man
Clinical and Experimental Dermatology, EarlyView.
Delayed angioedema of the unilateral tongue associated with angiotensin II receptor blocker in a patient with polypharmacy
Australasian Journal of Dermatology, EarlyView.
Volume outlier benchmark proposal for Australian Mohs surgery
Australasian Journal of Dermatology, EarlyView.
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Publication date: Available online 25 July 2018 Source: Journal of Photochemistry and Photobiology B: Biology Author(s): Marco Ballestr...
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