Human Hypersensitivity Research Articles

Pinprick-induced gamma-band oscillations are not a useful electrophysiological marker of pinprick hypersensitivity in humans

ObjectiveThis study aimed to investigate scalp gamma-band oscillations (GBOs) induced by mechanical stimuli activating skin nociceptors before and after the induction of mechanical hypersensitivity using high-frequency electrical stimulation (HFS) of the skin. MethodsIn twenty healthy volunteers, we recorded the electroencephalogram during robot-controlled mechanical pinprick stimulation (512 mN) applied at the right ventral forearm before and after HFS. ResultsHFS induced a significant increase in mechanical pinprick sensitivity, but this increased pinprick sensitivity was, at the group level, not accompanied by a significant increase in GBOs. Visual inspection of the individual data revealed that possible GBOs were present in eight out of twenty participants (40%) and the frequency of these GBOs varied substantially across participants. ConclusionsBased on the low number of participants showing GBOs we question the (clinical) utility of mechanically-induced GBOs as an electrophysiological marker of pinprick hypersensitivity in humans. SignificanceMechanical pinprick-induced scalp GBOs are not useful for evaluating mechanical pinprick hypersensitivity in humans.

Effect of the chiral blocks of functionalized fullerene on levofloxacin enantioselective voltammetric sensing

Antibiotics are one of the most important bioactive and chemotherapeutic groups of compounds. However, as a result of their excessive consumption for human treatment, veterinary and food industries, it can lead to direct toxic effects, pathogen resistance and allergic hypersensitivity in humans. The situation calls for developing sensitive and selective techniques for antibiotics analysis to monitor their appropriate use, public health, and new drugs design. In this study the glassy carbon voltammetric sensors (GCE) based on layer-by-layer deposited graphene oxide (rGO) and functionalized fullerene (C60) were proposed for the levofloxacin (Lev: S-(–)-Ofloxacin) sensing. Since Lev is an optically active substance, it can be assumed that the sensitive layer of sensor with chiral selector will selectively interact with the antibiotic through various intermolecular interactions. Therefore, a number of selectors with different optical center configurations were obtained and studied, such as S/R-2-chloro-N-(1-phenylethyl)acetamide fullerene (S/R-C60AA), and S/R-N,N'-bis(1-phenylethyl)malonamide fullerene (S/R-C60MA). The structure of obtained selectors was confirmed by NMR and IR spectroscopy, polarimetric studies were carried out. The proposed sensors were characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) using standard redox probe. Morphological studies were carried out by scanning electron microscopy (SEM). Possible binding sites between Lev and selectors were revealed by computational studies. Some patterns of changes in the electrochemical behavior of Lev depending on the composition of the sensitive layer of the sensor were obtained by differential pulse voltammetry (DPV). Quantitative determination of Lev was carried out using sensor GCE/rGO/S-C60AA. Calibration plot was found to be linear in two ranges, such as 1.0·10−6–3.0·10−5 M and 3.0·10−5–5.0·10−4 M with sensitivity values of 82.14 and 58.71 μA/mM, respectively. The limits of detection and quantitation were calculated to be 3.7·10−8 M and 1.2·10−7 M, respectively (according to 3Sb/m and 10Sb/m). The developed sensor has a simple design, good analytical and operational characteristics compared to some previous reports in the literature. In addition, the sensor was successfully tested for Lev quantification in real samples of biological fluids and pharmaceutical formulations with a good recovery percentage ranged in 91.5–104.4 %.

Light-Touch-Induced Afterdischarge Firing in the Superficial Spinal Dorsal Horn Neurons in Hairless Mice with Irritant Contact Dermatitis.

The skin is an important barrier that protects against invasion by foreign substances, including irritants and harmful microorganisms, and holds water in the body. Washing the skin with cleansers and shampoos containing anionic surfactants, for example sodium dodecyl sulfate (SDS), is important for maintaining skin homeostasis. However, surfactants can cause dermatitis, cutaneous hypersensitivity (e.g., alloknesis), and pruritus in humans. Our previous studies revealed an alloknesis response in the skin with SDS-induced dermatitis in C57BL/6 mice. In addition, we found that alloknesis responses and afterdischarge responses following stimulation with light touch are related because they are observed contemporaneously. In this study, we used Hos:HR-1 hairless mice to establish a mouse model to evaluate long-term drug application for alloknesis responses. Alloknesis was observed in HR-1 mice with SDS-induced dermatitis. The mean number of c-Fos (a marker of neural activity) immunopositive neurons was increased in the lamina 1-2 (L1-2) spinal dorsal horn, but not in L3-4, of SDS-treated HR-1 mice compared to vehicle-treated mice. We also discovered that afterdischarge responses were observed in neurons in L1-2. There was also a correlation between the intensity of the afterdischarge responses and depth of the recording site. Thus, the following were suggested: 1) neurons that mediate these afterdischarge responses are located on the superficial layer of the spinal cord; 2) afterdischarge responses can be an index of alloknesis responses, and 3) the mouse model of SDS-induced dermatitis is an appropriate alloknesis model.

Anisakis typica (DIESING, 1860), DOMINANT ANISAKID NEMATODE PRESENT IN SHORTFIN SCAD, Decapterus macrosoma (BLEEKER, 1851) FROM TERENGGANU WATERS, MALAYSIA

Anisakid (Anisakis spp.) nematode is a fish-borne parasite that can cause zoonotic disease, Anisakiasis and IgE hypersensitivity in humans. Thus, the ecology and epidemiology of Anisakis nematode are important to control this zoonotic infection. Although Anisakis larvae have been reported in Malaysia, it has not been studied through morphological characteristics and molecular analyses. The objective of this study was to identify the Anisakis species and its infection status in Decapterus macrosoma from Terengganu waters, Malaysia. All Anisakis larvae found were morphologically similar to each other and identified as Anisakis typica. High infection level (P = 100%, M.I. = 23.31±17.26) of A. typica was found in D. macrosoma. There was a bioaccumulation of A. typica in D. macrosoma, showing significant correlation of body weight (p = 0.05) and total body length (p = 0.02) with the amount of A. typica present in D. macrosoma. Interestingly, the gonad was the specific site of infection of A. typica in D. macrosoma, where the intensity of A. typica was significantly (p < 0.003) higher than other visceral organs. Therefore, the migration of A. typica depended on the fatty tissue of the organ.

Residuos de antimicrobianos encontrados en aves de corral comercializadas en tiendas minoristas de la zona Metropolitana de Guadalajara, Jalisco

The increased demand to produce large quantities of meat and animal products for human consumption has promoted the indiscriminate use of antimicrobials. The increased use of these substances in the production of poultry, has negative consequences on Public Health due to the fact that the accumulation of antimicrobial residues in the organs and tissues of poultry might reach the consumer. The presence of antimicrobial residues can cause problems of hypersensitivity in humans, or the emergence of antimicrobial resistant pathogens. The purpose of this work was to assess the presence of antimicrobial residues in kidney and muscle tissue of poultry, commercialized in four municipalities of the Metropolitan Area of Guadalajara, Jalisco. The results show that kidney samples had a higher number of positive results compared to muscle tissue. Inhibitors of the folate pathway (sulfamethazine) were the antimicrobials with the highest number of positive results in kidney samples. In contrast, in muscle tissue, β-Lactam (penicillin) were the antimicrobials with the highest number of positive samples. Regarding the analysis of the results by municipalities, it was observed that one of them showed a greater number of positive samples for all the classes of antimicrobials evaluated. This work shows the presence of antimicrobial residues in kidney and muscle tissues of poultry, commercialized in retail sites. Therefore, it is necessary to increase efforts to monitor and control the use of antimicrobial in poultry farms.

Food Color Additives and Health Interaction

Colorants, which have an important place in food additives, are defined by the International Food Codex Commission as "a substance that regulates the color of food or is added to give color". The Joint FAO/WHO Expert Committee on Food Additives (JECFA) affiliated with the Codex Alimentarius Commission (CAC) formed by the World Health Organization (WHO) and the Food Agriculture Organization (FAO) as part of the United Nations (UN) organization, is an authority that makes suggestions and recommendations on all matters concerning the additives. Different opinions have emerged in studies evaluating food additives in terms of health risks involved. In various studies investigating colorants in foods, it has been reported that the permitted colorants are used in high amounts and also that non-permitted colorants are encountered. In various epidemiological studies, it is stated that colorants cause diseases such as asthma, hypersensitivity, skin rashes, premature childbirth, migraine, cancer, thyroid, tumor, and chromosome damage in humans.

The Modified THP-1 Activation Assay for the In Vitro Identification of Drug-Inducing Systemic Hypersensitivity.

The development of new low molecular weight drugs has many chances of failure and is an expensive process. Currently, there are no screening methods and/or models to assess the hazard of hypersensitivity reactions to drugs (DHRs) in the preclinical phase. DHRs represent 6–15% of adverse drug reactions. Although rare, DHRs represent a serious health problem for predisposed individuals, resulting, in some cases, in life-threatening pathologies. To date, there are no in vitro or in vivo sensitive models able to predict the sensitizing potential of drugs in the preclinical tests, and these reactions are highlighted only after the drug has been placed on the market, affecting both population and public health. This article describes a novel approach methodology for the study of the sensitizing potential of drugs based on the use of the human promyelocytic cell line THP-1 as a surrogate for dendritic cells. The method is based on the upregulation of specific surface markers (CD86 and CD54) and on the production of IL-8. In our experience, the THP-1 activation assay allowed the correct identification of drugs known to induce systemic hypersensitivity in humans, including the one associated with specific HLAs. This method may help to discover possible systemic hypersensitivity reactions early in the preclinical phase of drug development.

Synthesis and application of cationized cellulose for adsorption of anionic dyes

Synthetic dyes are commonly used in paper, printing, leather, food, and textile industries. Dyes are non-biodegradable and unstable in the environment causing allergies and hypersensitivity in humans even at low concentrations. Adsorption process is a simple and reliable popular method as it has been extensively used on a variety of contaminants. The availability and use of low-cost adsorbents such as natural cellulose makes it more favorable. In this study, cationized hemp cellulose was used as an adsorbent for the removal of methyl orange (MO), and sunset yellow (SY) from aqueous solutions. The cellulose was extracted from hemp fibers by alkali treatment using 4 %wt NaOH and bleached using 1.7% NaOCl2 in acetate buffer solution. Glycidyl trimethylammonium chloride (GTMAC) was used as a cationizing agent to functionalize cellulose (GT-cellulose). For adsorption studies, the influence of pH, adsorbent dosage, initial dye concentration, contact time, and temperature were investigated using batch experiments. After modification, cellulose showed enhanced adsorption capacity for removal of anionic dyes from aqueous solution. The equilibrium adsorption isotherm data were best described by Langmuir model. The maximum adsorption capacity for MO and SY onto GT-cellulose were found to be 76.9 mgg−1 and 44.9 mgg−1 respectively. The adsorption kinetics were best fit with pseudo-second order for both anionic dyes. The thermodynamic study showed that the adsorption processes for MO and SY were both endothermic and spontaneous in nature. From the resulted, cationized cellulose adsorbents could be effectively applied for removal of anionic dye from wastewater.

Sex-Dependent Effects on Liver Inflammation and Gut Microbial Dysbiosis After Continuous Developmental Exposure to Trichloroethylene in Autoimmune-Prone Mice.

Trichloroethylene (TCE) is a common environmental toxicant linked with hypersensitivity and autoimmune responses in humans and animal models. While autoimmune diseases are more common in females, mechanisms behind this disparity are not clear. Recent evidence suggests that autoimmunity may be increasing in males, and occupational studies have shown that TCE-mediated hypersensitivity responses occur just as often in males. Previous experimental studies in autoimmune-prone MRL+/+ mice have focused on responses in females. However, it is important to include both males and females in order to better understand sex-disparity in autoimmune disease. In addition, because of an alarming increase in autoimmunity in adolescents, developmental and/or early life exposures to immune-enhancing environmental pollutants should also be considered. Using MRL+/+ mice, we hypothesized that TCE would alter markers related to autoimmunity to a greater degree in female mice relative to male mice, and that TCE would enhance these effects. Mice were continuously exposed to either TCE or vehicle beginning at gestation, continuing during lactation, and directly in the drinking water. Both male and female offspring were evaluated at 7 weeks of age. Sex-specific effects were evident. Female mice were more likely than males to show enhanced CD4+ T cell cytokine responses (e.g., IL-4 and IFN-γ). Although none of the animals developed pathological or serological signs of autoimmune hepatitis-like disease, TCE-exposed female mice were more likely than males in either group to express higher levels of biomarkers in the liver related to regeneration/repair and proliferation. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure and were more prominent in females as compared to males. Thus, our expectations were correct in that young adult female mice developmentally exposed to TCE were more likely to exhibit alterations in immunological and gut/liver endpoints compared to male mice.

Associations between human leukocyte antigen polymorphisms and hypersensitivity to antiretroviral therapy in patients with human immunodeficiency virus: a meta-analysis

BackgroundHuman leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients.MethodsWe conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect.ResultsThe meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy.ConclusionsThe findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.

Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs

The increasing use in the last decade of PEGylated nanodrugs such as Doxil® has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.

Male-Specific Conditioned Pain Hypersensitivity in Mice and Humans

Pain memories are hypothesized to be critically involved in the transition of pain from an acute to a chronic state. To help elucidate the underlying neurobiological mechanisms of pain memory, we developed novel paradigms to study context-dependent pain hypersensitivity in mouse and human subjects, respectively. We find that both mice and people become hypersensitive to acute, thermal nociception when tested in an environment previously associated with an aversive tonic pain experience. This sensitization persisted for at least 24hr and was only present in males of both species. In mice,context-dependent pain hypersensitivity was abolished by castrating male mice, pharmacological blockade of the hypothalamic-pituitary-adrenal axis, or intracerebral or intrathecal injections of zeta inhibitory peptide (ZIP) known to block atypical protein kinase C (including the protein kinase Mζ isoform). In humans, men, but not women, self-reported higher levels of stress when tested in a room previously associated with tonic pain. These models provide a new, completely translatable means for studying the relationship between memory, pain, and stress.

Future developments and advances in disinfectants and application modes for use in departments, military units and medical facilities in a climate of the Arctic and Extreme North

There were performed test and development review concerning disinfection procedures in a climate of the Arctic and Extreme North, an assessment of their sophistication, and determination of possible ways to enhancement of efficiency. It was found that long-term low temperatures, geographical distance and hard-to-reach territories, weak natural self-regeneration mechanism of biocenosis, development of human hypersensitivity to infectious agents, congestion of personnel at camping and operation places define the urgency of creation of modern chemical and technical disinfectants which are effective in the north. The basic requirements to these disinfectants were formulated. Thus, process chemical solutions should not become frozen over a period that biocide effect takes; disinfectants to use in human presence should meet the operational criteria for sealable inhabited objects. Engineering tools should be equipped with productive snowmelters, heat-insulated rooms, all-terrain running gear, liquid fuel -powered cauldrons, heaters, electric power station. Promising directions of new disinfectants advancing and development were determined. It’s necessary to study infectious and parasitic morbidity in the Arctic and Extreme North, the causes and conditions governing its structure and dynamics, specificity of epidemic process. The establishment of special climate chambers with variable capacities for materials and goods disinfection mode development, including the use of engineering tools; it is essential to choose or develop the study methods of arctic climatic factors influence on test microorganisms, operating procedure behavior of disinfection, worked objects’ properties. The studies of microbial contamination specifics seemed perspective, both in the environment and within inhabited objects, under long-term exposure of low temperatures; the search of biocidic technologies and factors for making disinfectants, modes and methods of application; substantiation of disinfection procedures tactics. Instructional and methodological base preparing will allow to perform perspective studies and disinfection procedures in a climate of the Arctic and Extreme North in accordance with contemporary requirements.

Familial gestational hyperthyroidism caused by Val597ile mutant of TSH receptor gene with human chorionic gonadotropin hypersensitivity

Familial gestational hyperthyroidism caused by Val597ile mutant of TSH receptor gene with human chorionic gonadotropin hypersensitivity

Erratum: Lavergne, S.N. In Vitro Research Tools in the Field of Human Immediate Drug Hypersensitivity and Their Present Use in Small Animal Veterinary Medicine Vet. Sci. 2017, 4, 1.

Due to an error during production, the author, Lavergne S. Lavergne's name in the published paper [1] was incorrect.[...].

Rehabilitation modality and onset differentially influence whisker sensory hypersensitivity after diffuse traumatic brain injury in the rat.

As rehabilitation strategies advance as therapeutic interventions, the modality and onset of rehabilitation after traumatic brain injury (TBI) are critical to optimize treatment. Our laboratory has detected and characterized a late-onset, long-lasting sensory hypersensitivity to whisker stimulation in diffuse brain-injured rats; a deficit that is comparable to visual or auditory sensory hypersensitivity in humans with an acquired brain injury. We hypothesize that the modality and onset of rehabilitation therapies will differentially influence sensory hypersensitivity in response to the Whisker Nuisance Task (WNT) as well as WNT-induced corticosterone (CORT) stress response in diffuse brain-injured rats and shams. After midline fluid percussion brain injury (FPI) or sham surgery, rats were assigned to one of four rehabilitative interventions: (1) whisker sensory deprivation during week one or (2) week two or (3) whisker stimulation during week one or (4) week two. At 28 days following FPI and sham procedures, sensory hypersensitivity was assessed using the WNT. Plasma CORT was evaluated immediately following the WNT (aggravated levels) and prior to the pre-determined endpoint 24 hours later (non-aggravated levels). Deprivation therapy during week two elicited significantly greater sensory hypersensitivity to the WNT compared to week one (p < 0.05), and aggravated CORT levels in FPI rats were significantly lower than sham levels. Stimulation therapy during week one resulted in low levels of sensory hypersensitivity to the WNT, similar to deprivation therapy and naïve controls, however, non-aggravated CORT levels in FPI rats were significantly higher than sham. These data indicate that modality and onset of sensory rehabilitation can differentially influence FPI and sham rats, having a lasting impact on behavioral and stress responses to the WNT, emphasizing the necessity for continued evaluation of modality and onset of rehabilitation after TBI.

Characterization of short- and long-term mechanical sensitisation following surgical tail amputation in pigs

Commercial pigs are frequently exposed to tail mutilations in the form of preventive husbandry procedures (tail docking) or as a result of abnormal behaviour (tail biting). Although tissue and nerve injuries are well-described causes of pain hypersensitivity in humans and in rodent animal models, there is no information on the changes in local pain sensitivity induced by tail injuries in pigs. To determine the temporal profile of sensitisation, pigs were exposed to surgical tail resections and mechanical nociceptive thresholds (MNT) were measured in the acute (one week post-operatively) and in the long-term (either eight or sixteen weeks post-surgery) phase of recovery. The influence of the degree of amputation on MNTs was also evaluated by comparing three different tail-resection treatments (intact, ‘short tail’, ‘long tail’). A significant reduction in MNTs one week following surgery suggests the occurrence of acute sensitisation. Long-term hypersensitivity was also observed in tail-resected pigs at either two or four months following surgery. Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.

Abstract 470: Computational Identification of NKX2-5 Binding Sites and Downstream Gene Targets Using Transcription Factor Motif and Human Heart-specific Experimental Data

Background: While NKX2-5 plays pivotal roles in human cardiac development and disease, no ChIP-Seq studies of NKX2-5 in human cardiac tissues currently exist, resulting in an incomplete understanding of its direct gene targets. Modern computational methods which identify binding sites using transcription factor motif and tissue-specific experimental data can help to fill this knowledge gap. Objective: To use computational methods to identify likely NKX2-5 binding sites and downstream gene targets using human heart-specific experimental data. Methods: Human cardiomyocyte DNAse hypersensitivity data (2 replicates) were downloaded from the Encyclopedia of DNA Elements (ENCODE) database. The position weight matrix (PWM) representing the transcription factor motif of NKX2-5 was obtained from JASPAR. We applied the Protein Interaction Quantification (PIQ) algorithm to detect NKX2-5 binding sites using the PWM and DNAse hypersensitivity data as inputs. RNA-Seq data from 108 human heart-specific samples (atrial appendages and left ventricles) were downloaded from the Genotype-Tissue Expression (GTEx) database. Protein-coding genes significantly expressed in the heart (RPKM &lt;= 1 based on the GTEx RNA-Seq data) that were within 100kb of the predicted binding sites were then identified. Pathway analysis of these genes was performed using Ingenuity Pathway Analysis (IPA). Results: 1283 binding sites for NKX2-5 were discovered by PIQ. Of 12698 protein-coding, heart-expressed genes, 625 were within 100kb of these binding sites. The identified genes were highly enriched in physiologic categories like “Vasculogenesis” and “Development of Cardiovascular Tissue” (p = 2.36x10-9 and 2.31x10-8 respectively). Notable genes included: cardiac transcription factors (MEF2A, TBX20); growth factors (TGFB2, BMP2); muscle and ion channel function (ACTA2, BIN1), and; calcium signaling (CALM2, CAMK2D). Conclusion: By using computational analyses of transcription factor motif and human heart-specific experimental data, we have identified candidate downstream targets of NKX2-5. Future work will include validation studies in an external cohort and analysis of associations between these candidate genes and cardiac disease.

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice’s respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.

Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control

IntroductionChronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is...