Pain mechanisms in hereditary palmoplantar keratodermas.

BACKGROUND: Palmoplantar keratodermas (PPKs) are a heterogeneous group of skin disorders characterized by thickening of the epidermis on the palms of the hands and soles of the feet. Individuals with PPKs report varying degrees of palmoplantar pain that can severely affect quality of life. OBJECTIVES: To provide an overview of the scope of pain in hereditary PPKs and highlight candidate mechanisms underlying this pain. METHODS: In this review, we discuss several forms of hereditary PPKs, with a focus on the incidence, nature, candidate underlying mechanisms and treatment of pain in these conditions. We also synthesize this information with current understanding of the mechanisms contributing to pathological pain in other conditions. RESULTS: Pain is a major problem for many, but not all individuals with hereditary PPK. This pain remains poorly understood, inconsistently reported and inadequately treated. The heterogeneity of pain prevalence and presentations across the many forms of PPK suggests that there may exist corresponding heterogeneity in the cellular and molecular mechanisms that drive and shape PPK-associated pain. Some candidate mechanisms include structural (e.g. fissures and blisters), infectious and immune/inflammatory processes. However, a growing body of evidence also supports the occurrence of localized neuropathic alterations in the affected skin of individuals with PPK, which might contribute to their pain. CONCLUSIONS: Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to prevention and treatment of pain in individuals with PPK. What's already known about this topic? Pain is a prominent symptom in hereditary palmoplantar keratodermas (PPKs). Pain in patients with PPK can be difficult to treat. Pain mechanisms in PPKs are poorly understood. What does this study add? This study defines multiple potential sources of pain in PPK, including both structural lesions (fissures, blisters) and specific cell types. This review highlights the variability of pain among several forms of hereditary PPK. This study provides mechanistic insights into how neuropathic and inflammatory mechanisms might contribute to pain in some forms of PPK.

When crust comes of age: on the chemical evolution of Archaean, felsic continental crust by crustal drip tectonics.

The secular evolution of the Earth's crust is marked by a profound change in average crustal chemistry between 3.2 and 2.5 Ga. A key marker for this change is the transition from Archaean sodic granitoid intrusions of the tonalite-trondhjemite-granodiorite (TTG) series to potassic (K) granitic suites, akin (but not identical) to I-type granites that today are associated with subduction zones. It remains poorly constrained as to how and why this change was initiated and if it holds clues about the geodynamic transition from a pre-plate tectonic mode, often referred to as stagnant lid, to mobile plate tectonics. Here, we combine a series of proposed mechanisms for Archaean crustal geodynamics in a single model to explain the observed change in granitoid chemistry. Numeric modelling indicates that upper mantle convection drives crustal flow and subsidence, leading to profound diversity in lithospheric thickness with thin versus thick proto-plates. When convecting asthenospheric mantle interacts with lower lithosphere, scattered crustal drips are created. Under increasing P-T conditions, partial melting of hydrated meta-basalt within these drips produces felsic melts that intrude the overlying crust to form TTG. Dome structures, in which these melts can be preserved, are a positive diapiric expression of these negative drips. Transitional TTG with elevated K mark a second evolutionary stage, and are blends of subsided and remelted older TTG forming K-rich melts and new TTG melts. Ascending TTG-derived melts from asymmetric drips interact with the asthenospheric mantle to form hot, high-Mg sanukitoid. These melts are small in volume, predominantly underplated, and their heat triggered melting of lower crustal successions to form higher-K granites. Importantly, this evolution operates as a disseminated process in space and time over hundreds of millions of years (greater than 200 Ma) in all cratons. This focused ageing of the crust implies that compiled geochemical data can only broadly reflect geodynamic changes on a global or even craton-wide scale. The observed change in crustal chemistry does mark the lead up to but not the initiation of modern-style subduction.This article is part of a discussion meeting issue 'Earth dynamics and the development of plate tectonics'.

Preparing Emergency Physicians for Acute Disaster Response: A Review of Current Training Opportunities in the US.

Study Objective This study aimed to review available disaster training options for health care providers, and to provide specific recommendations for developing and delivering a disaster-response-training program for non-disaster-trained emergency physicians, residents, and trainees prior to acute deployment. METHODS: A comprehensive review of the peer-reviewed and grey literature of the existing training options for health care providers was conducted to provide specific recommendations. RESULTS: A comprehensive search of the Pubmed, Embase, Web of Science, Scopus, and Cochrane databases was performed to identify publications related to courses for disaster preparedness and response training for health care professionals. This search revealed 7,681 unique titles, of which 53 articles were included in the full review. A total of 384 courses were found through the grey literature search, and many of these were available online for no charge and could be completed in less than six hours. The majority of courses focused on management and disaster planning; few focused on clinical care and acute response. CONCLUSION: There is need for a course that is targeted toward emergency physicians and trainees without formal disaster training. This course should be available online and should utilize a mix of educational modalities, including lectures, scenarios, and virtual simulations. An ideal course should focus on disaster preparedness, and the clinical and non-clinical aspects of response, with a focus on an all-hazards approach, including both terrorism-related and environmental disasters. Hansoti B , Kellogg DS , Aberle SJ , Broccoli MC , Feden J , French A , Little CM , Moore B , Sabato J Jr. , Sheets T , Weinberg R , Elmes P , Kang C . Preparing emergency physicians for acute disaster response: a review of current training opportunities in the US. Prehosp Disaster Med. 2016;31(6):643-647.

Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells.

Tumor-associated angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate here that the critical step in establishing the angiogenic capability of human tumor cells is the repression of a key secreted anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. In transformed epithelial cells, a signaling pathway leading from Ras to Tsp-1 repression induces the sequential activation of PI3 kinase, Rho and ROCK, leading to activation of Myc through phosphorylation, thereby enabling Myc to repress Tsp-1 transcription. In transformed fibroblasts, however, the repression of Tsp-1 can be achieved by an alternative mechanism involving inactivation of both p53 and pRb. We thus describe novel mechanisms by which the activation of oncogenes in epithelial cells and the inactivation of tumor suppressors in fibroblasts permits angiogenesis and, in turn, tumor formation.

Venoarterial extracorporeal membrane oxygenation for the management of massive amlodipine overdose.

A 50-year-old man was admitted to the intensive care unit with respiratory failure and shock after suffering a massive overdose of amlodipine, lisinopril and hydrochlorothiazide. Despite mechanical ventilation, vasopressors, calcium gluconate, hyperinsulinemia-euglycemia therapy, methylene blue and intravenous fat emulsion, the patient's respiratory and hemodynamic status deteriorated. Venoarterial extracorporeal membrane oxygenation (ECMO) was initiated to provide cardiopulmonary support in the setting of profound respiratory failure and refractory shock. The patient was placed on ECMO 19 hours after arrival to the hospital, after which vasopressor and ventilatory requirements decreased significantly. The patient was decannulated from ECMO after 8 days and was discharged home after a 56-day hospitalization. Early institution of ECMO should be considered for the management of respiratory failure and refractory shock in the setting of calcium channel blocker overdose when medical therapies are insufficient.

The distribution of phosphodiesterase 2A in the rat brain.

The phosphodiesterases (PDEs) are a superfamily of enzymes that regulate spatio-temporal signaling by the intracellular second messengers cAMP and cGMP. PDE2A is expressed at high levels in the mammalian brain. To advance our understanding of the role of this enzyme in regulation of neuronal signaling, we here describe the distribution of PDE2A in the rat brain. PDE2A mRNA was prominently expressed in glutamatergic pyramidal cells in cortex, and in pyramidal and dentate granule cells in the hippocampus. Protein concentrated in the axons and nerve terminals of these neurons; staining was markedly weaker in the cell bodies and proximal dendrites. In addition, in both hippocampus and cortex, small populations of non-pyramidal cells, presumed to be interneurons, were strongly immunoreactive. PDE2A mRNA was expressed in medium spiny neurons in neostriatum. Little immunoreactivity was observed in cell bodies, whereas dense immunoreactivity was found in the axon tracts of these neurons and their terminal regions in globus pallidus and substantia nigra pars reticulata. Immunostaining was dense in the medial habenula, but weak in other diencephalic regions. In midbrain and hindbrain, immunostaining was restricted to discrete regions of the neuropil or clusters of cell bodies. These results suggest that PDE2A may modulate cortical, hippocampal and striatal networks at several levels. Preferential distribution of PDE2A into axons and terminals of the principal neurons suggests roles in regulation of axonal excitability or transmitter release. The enzyme is also in forebrain interneurons, and in mid- and hindbrain neurons that may modulate forebrain networks and circuits.

Bitter taster status predicts susceptibility to vection-induced motion sickness and nausea.

BACKGROUND: Sensitivity to bitter taste and susceptibility to nausea are both protective mechanisms that guard against toxin ingestion, and both these traits vary within and between populations. Thus, we postulated that they may have co-evolved, such that they are associated. METHODS: Bitter taster status was determined in 40 subjects (13 men, 27 women) by measuring the differential perceived taste intensity between salt and n-propylthiouracil using a labeled magnitude scale; susceptibility to vection-induced motion sickness and nausea was assessed using an optokinetic drum, a validated multi-symptom scoring scale, and electrogastrography. KEY RESULTS: Taster status distribution was 25% non-tasters (NT), 40% tasters (T), and 35% supertasters (ST). Gender had no impact on this distribution, but females had a higher mean maximum symptom score than males (12.4 ± 1.4 vs 7.3 ± 2.0). Non-tasters displayed a faster and larger increase in mean symptom scores, had a higher percentage of subjects with high maximum symptom scores, and had a higher mean maximum score than T or ST, (14.8 ± 2.6 vs 7.1 ± 1.8, vs 9.8 ± 2.0). Taster status did not affect the gastric myoelectric frequency response to vection. CONCLUSIONS & INFERENCES: Non-tasters are more susceptible to vection-induced motion sickness and nausea than T or ST, suggesting these two traits may have co-evolved in a reciprocal manner: in environments where the NT trait conferred an evolutionary advantage by enabling intake of fruits and vegetables containing bitter, yet beneficial, phytonutrients, increased nausea susceptibility may have arisen to maintain protection against ingested toxins.

The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function.

Disrupted in schizophrenia 1 (DISC1), a genetic risk factor for multiple serious psychiatric diseases including schizophrenia, bipolar disorder and autism, is a key regulator of multiple neuronal functions linked to both normal development and disease processes. As these diseases are thought to share a common deficit in synaptic function and architecture, we have analyzed the role of DISC1 using an approach that focuses on understanding the protein-protein interactions of DISC1 specifically at synapses. We identify the Traf2 and Nck-interacting kinase (TNIK), an emerging risk factor itself for disease, as a key synaptic partner for DISC1, and provide evidence that the DISC1-TNIK interaction regulates synaptic composition and activity by stabilizing the levels of key postsynaptic density proteins. Understanding the novel DISC1-TNIK interaction is likely to provide insights into the etiology and underlying synaptic deficits found in major psychiatric diseases.

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence.

Approximately 20% of tumors contain activating mutations in the RAS family of oncogenes. As tumors progress to higher grades of malignancy, the expression of oncogenic RAS has been reported to increase, leading to an oncogene-induced senescence (OIS) response. Evasion of this senescence barrier is a hallmark of advanced tumors indicating that OIS serves a critical tumor-suppressive function. Induction of OIS has been attributed to either RAS-mediated production of reactive oxygen species (ROS) or to induction of a DNA damage response (DDR). However, functional links between these two processes in triggering the senescent phenotype have not been explicitly described. Our previous work has shown that, in cultured untransformed cells, preventing elimination of oxidized guanine deoxyribonucleotides, which was achieved by suppressing expression of the cellular 8-oxo-dGTPase, human MutT homolog 1 (MTH1), sufficed to induce a DDR as well as premature senescence. Here, we demonstrate that overexpression of MTH1 can prevent the oncogenic H-RAS-induced DDR and attendant premature senescence, although it does not affect the observed elevation in ROS levels produced by RAS oncoprotein expression. Conversely, we find that loss of MTH1 preferentially induces an in vitro proliferation defect in tumorigenic cells overexpressing oncogenic RAS. These results indicate that the guanine nucleotide pool is a critical target for intracellular ROS produced by oncogenic RAS and that RAS-transformed cells require robust MTH1 expression to proliferate.

A plasma membrane Ca2+ ATPase isoform at the postsynaptic density.

Most excitatory input in the hippocampus impinges on dendritic spines. Entry of Ca(2+) into spines through NMDA receptors can trigger a sequence of biochemical reactions leading to sustained changes in synaptic efficacy. To provide specificity, dendritic spines restrict the diffusion of Ca(2+) signaling and downstream molecules. The postsynaptic density (PSD) (the most prominent subdomain within the spine) is the site of Ca(2+) entry through NMDA receptors. We here demonstrate that Ca(2+) can also be removed via pumps embedded in the PSD. Using light- and electron-microscopic immunohistochemistry, we find that PMCA2w, a member of the plasma membrane Ca(2+)-ATPase (PMCA) family, concentrates at the PSD of most hippocampal spines. We propose that PMCA2w may be recruited into supramolecular complexes at the postsynaptic density, thus helping to regulate Ca(2+) nanodomains at subsynaptic sites. Taken together, these results suggest a novel function for PMCAs as modulators of Ca(2+) signaling at the synapse.

Spatial organization of cofilin in dendritic spines.

Synaptic plasticity is associated with morphological changes in dendritic spines. The actin-based cytoskeleton plays a key role in regulating spine structure, and actin reorganization in spines is critical for the maintenance of long term potentiation. To test the hypothesis that a stable pool of F-actin rests in the spine "core," while a dynamic pool lies peripherally in its "shell," we performed immunoelectron microscopy in the stratum radiatum of rat hippocampus to elucidate the subcellular distribution of cofilin, an actin-depolymerizing protein that mediates reorganization of the actin cytoskeleton. We provide direct evidence that cofilin in spines avoids the core, and instead concentrates in the shell and within the postsynaptic density. These data suggest that cofilin may link synaptic plasticity to the actin remodeling that underlies changes in spine morphology.

The evolving portrait of cancer metastasis.

The phenomenon of cancer metastasis remains poorly understood. We discuss here various conceptual frameworks that attempt to rationalize the mechanisms by which tumors acquire metastatic ability. Portrayal of cancer as a somatic Darwinian process occurring within a tissue fails to fully explain the phenomenon of metastatic competence. The biology of pre-neoplastic cells also complicates this picture, since the phenotypes of normal cellular precursors are clearly relevant to metastatic behavior following transformation. Recent experimental results help to shed light on these and other considerations regarding the molecular mechanisms of malignant progression.

Effects of a high polyunsaturated fat diet and vitamin E supplementation on high-density lipoprotein oxidation in humans.

Oxidative modification of high-density lipoproteins (HDL) impairs several biologic functions critical to its role in reverse cholesterol transport. We therefore investigated the effect of dietary polyunsaturated fat and vitamin E on the kinetics of HDL oxidation. Ten subjects were fed sequentially: a baseline diet in which the major fat source was olive oil; a high polyunsaturated fat diet in which the major fat source was safflower oil; and the safflower oil diet plus 800 I.U. vitamin E per day. Plasma lipoprotein levels, vitamin E content, fatty acid composition, and oxidation lag time and rate were determined after 3 weeks on each diet. The polyunsaturated fat diet increased the mean HDL(2) lag time from 45.8+/-12.5 to 83.3+/-11.6 min with no change in oxidation rate. Addition of vitamin E further increased the HDL(2) lag time to 115.6+/-4.4 min and decreased the HDL(2) oxidation rate 10-fold. Neither the polyunsaturated diet alone nor the diet with vitamin E supplementation had any effect on HDL(3) oxidation. We conclude that under conditions of controlled dietary fat intake, a high polyunsaturated fat intake does not increase the oxidation susceptibility of HDL subfractions, and that in this setting, vitamin E supplementation reduces the oxidation susceptibility of HDL(2). These data suggest that antioxidants could influence HDL function in vivo.

Substance P and nitric oxide signaling in cerebral cortex: anatomical evidence for reciprocal signaling between two classes of interneurons.

Parvalbumin-containing fast-spiking interneurons in the cerebral cortex exhibit widespread electrical coupling, as do somatostatin-containing low-threshold spiking interneurons. Besides the classical neurotransmitter gamma-aminobutyric acid, these cortical interneurons may also release various neuropeptides including substance P (SP), as well as the freely diffusible messenger nitric oxide (NO). To investigate whether these two networks of interneurons might interact via these nonclassical messengers, we performed immunocytochemistry for SP and NO signaling pathways in rat somatic sensory cortex. SP was found in a subset of parvalbumin-positive cells concentrated in layers IV and V, whereas its receptor, NK1, was found in a subset of somatostatin-containing neurons (and also, at much lower levels, in a disjoint subset of parvalbumin-containing neurons). Only 4% of SP-containing axon terminals were apposed to NK1-positive dendrites, suggesting that in the cerebral cortex, SP may act predominantly as a paracrine neuromediator. Nitric oxide synthase-I (NOS-I), the synthetic enzyme for NO, was found almost exclusively in NK1-positive neurons; 95% of intensely somatostatin/NK1-positive neurons were also positive for NOS-I, and 94% of NOS-positive neurons were also positive for NK1. Immunoreactivity for soluble guanylyl cyclase (the NO receptor) was at high levels in the apical dendrites of layer V pyramidal neurons and in parvalbumin/SP-positive neurons. These data point to a novel reciprocal chemical interaction between two inhibitory networks in the rat neocortex.

Derivation of human tumor cells in vitro without widespread genomic instability.

The majority of adult human epithelial cancers exhibit evidence of genetic instability, and it is widely believed that the genetic instability manifested by aneuploidy or microsatellite instability plays an essential role in the genesis of these tumors. Indeed, most experimental models of cancer also show evidence of genomic instability. The resulting genetic chaos, which has widespread effects on many genes throughout the genome, confounds attempts to determine the precise cohort of genetic changes that are required for the transformation of normal human cells to a tumorigenic state. Here we show that genetic transformation of human kidney epithelial cells can occur in the absence of extensive aneuploidy, chromosomal translocations, and microsatellite instability. These observations demonstrate that the in vitro oncogenic transformation of human cells can proceed without widespread genomic instability.

hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.

DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis. We show here that the protein product of the gene hSIR2(SIRT1), the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue, modification of which has been implicated in the activation of p53 as a transcription factor. Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53. In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity. We propose that hSir2 is involved in the regulation of p53 function via deacetylation.

Biochemical and morphological characterization of an intracellular membrane compartment containing AMPA receptors.

AMPA receptors cycle rapidly in and out of the postsynaptic membrane, while NMDA receptors are relatively immobile. Changing the distribution of AMPA receptors between intracellular and surface synaptic pools is an important means of controlling synaptic strength. However, little is known about the intracellular membrane compartments of neurons that contain AMPA receptors. Here we describe biochemical and morphological characteristics of an intracellular pool of AMPA receptors in rat brain. By velocity gradient centrifugation of microsomal light membranes from rat brain, we identified a membrane fraction enriched for AMPA receptor subunits GluR2/3 but lacking NMDA receptors. This membrane compartment sedimented more slowly than synaptosomes but faster than synaptic vesicles and cofractionated with GRIP, PICK-1 and syntaxin-13. Morphological examination of this fraction revealed round and tubular vesicles ranging from approximately 50 to 300 nm in diameter. Immunocytochemistry of cultured hippocampal neurons showed that a significant portion of AMPA receptors colocalized with syntaxin-13 (a SNARE protein associated with tubulovesicular recycling endosomes) and with transferrin receptors. Taken together, these results suggest that a pool of intracellular GluR2/3 resides in a syntaxin 13-positive tubulovesicular membrane compartment, which might serve as a reservoir for the dendritic recycling of AMPA receptors.