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Researchers have been focusing on perceptual characteristics of autism spectrum disorder (ASD) in terms of sensory hyperreactivity. Previously, we demonstrated that temporal resolution, which is the accuracy to differentiate the order of two successive vibrotactile stimuli, is associated with the severity of sensory hyperreactivity. We currently examined whether an increase in the perceptual intensity of a tactile stimulus, despite its short duration, is derived from high temporal resolution and high frequency of sensory temporal summation. Twenty ASD and 22 typically developing (TD) participants conducted two psychophysical experimental tasks to evaluate detectable duration of vibrotactile stimulus with same amplitude and to evaluate temporal resolution. The sensory hyperreactivity was estimated using self-reported questionnaire. There was no relationship between the temporal resolution and the duration of detectable stimuli in both groups. However, the ASD group showed severe sensory hyperreactivity in daily life than TD group, and the ASD participants with severe sensory hyperreactivity tended to have high temporal resolution, not high sensitivity of detectable duration. Contrary to the hypothesis, there might be different processing between temporal resolution and sensitivity for stimulus detection. We suggested that the atypical temporal processing would affect to sensory reactivity in ASD. [ABSTRACT FROM AUTHOR]

Background: Existing evidence indicates that atypical sensory reactivity is a core characteristic of autism, and has been linked to both anxiety (and its putative infant precursor of fearfulness) and repetitive behaviours. However, most work has used cross‐sectional designs and not considered the differential roles of hyperreactivity and hyporeactivity to sensory inputs, and is thus limited in specificity. Methods: 161 infants with and without an elevated likelihood of developing autism and attention‐deficit hyperactivity disorder (ADHD) were followed from 10 to 36 months of age. Parents rated an infant precursor of later anxiety (fearfulness) using the Infant Behaviour Questionnaire at 10 and 14 months, and the Early Childhood Behavioural Questionnaire at 24 months, and sensory hyperreactivity and hyporeactivity at 10, 14 and 24 months using the Infant Toddler Sensory Profile. Domains of autistic traits (restrictive and repetitive behaviours; RRB, and social communication interaction, SCI) were assessed using the parent‐rated Social Responsiveness Scale at 36 months. Cross‐lagged models tested (a) paths between fearfulness and hyperreactivity at 10–24 months, and from fearfulness and hyperreactivity to later autism traits, (b) the specificity of hyperreactivity effects by including hyporeactivity as a correlated predictor. Results: Hyperreactivity at 14 months was positively associated with fearfulness at 24 months, and hyperreactivity at 24 months was positively associated with SCI and RRB at 36 months. When hyporeactivity was included in the model, paths between hyperreactivity and fearfulness remained, but paths between hyperreactivity and autistic traits became nonsignificant. Conclusions: Our findings indicate that alterations in early sensory reactivity may increase the likelihood of showing fearfulness in infancy, and relate to later social interactions and repetitive behaviours, particularly in individuals with a family history of autism or ADHD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these supra-modal traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a general response pattern factor for each supra-modal construct and determine the added value of modality-specific response pattern scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many real-world sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

Rats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long ‘22-kHz’ vocalizations (>300 ms, 32 kHz), often frequency-modulated, in appetitive situations. Here, we describe aversive vocalizations emitted at a higher pitch by male Wistar and spontaneously hypertensive rats (SHR) in an intensified aversive state – prolonged fear conditioning. These calls, which we named ‘44-kHz’ vocalizations, are long (>150 ms), generally at a constant frequency (usually within 35–50-kHz range) and have an overall spectrographic image similar to 22-kHz calls. Some 44-kHz vocalizations are comprised of both 22-kHz-like and 44-kHz-like elements. Furthermore, two separate clustering methods confirmed that these 44-kHz calls can be separated from other vocalizations. We observed 44-kHz calls to be associated with freezing behavior during fear conditioning training, during which they constituted up to 19.4% of all calls and most of them appeared next to each other forming uniform groups of vocalizations (bouts). We also show that some of rats’ responses to the playback of 44-kHz calls were more akin to that of aversive calls, for example, heart rate changes, whereas other responses were at an intermediate level between aversive and appetitive calls. Our results suggest that rats have a wider vocal repertoire than previously believed, and current definitions of major call types may require reevaluation. We hope that future investigations of 44-kHz calls in rat models of human diseases will contribute to expanding our understanding and therapeutic strategies related to human psychiatric conditions.

Introduction The nonspecific hyperreactivity of rhinitis has been attributed to neurotrophins activating sensory nerves and inflammatory cells. The relationship between these markers and the intensity of the symptoms is not well established and few studies have evaluated individuals with idiopathic rhinitis. Objective The present study aims to evaluate whether perivascular innervation and nerve growth factor (NGF) are related to the intensity of the clinical conditions in allergic rhinitis (AR) and idiopathic rhinitis (IR). Methods A total of 15 patients with AR and 15 patients with IR with the indication for inferior turbinectomy (associated or not with septoplasty) were selected. The patients received a score according to their signs and symptoms. After the surgery, we quantified eosinophils, mast cells, NGF, and nerve fibers in the nasal turbinate. Results The score of the signs and symptoms was higher in the AR group. Nerve growth factor was found in the cytoplasm of inflammatory cells in the submucosa in greater quantity in the AR group. The nerve fibers were distributed throughout the tissue, mainly in the subepithelial, glandular, and vascular regions, and there was no difference between the groups. Greater perivascular innervation was associated with a higher signs and symptoms score. Conclusions We concluded that these findings suggest that the NGF produced by submucosal inflammatory cells stimulates increased perivascular innervation in rhinitis, thus directly reflecting in more intense clinical conditions, especially in AR. [ABSTRACT FROM AUTHOR]

Objective:Transection or ablation of the posterior nasal nerve (TRPN) has been described as an adjunctive tool to reduce the symptoms of intractable allergic rhinitis (AR). The procedure, however, requires surgical skill and carries the risk of bleeding from the sphenopalatine artery. The aim of the present study is to describe radiofrequency ablation of the peripheral branches of the posterior nasal nerves within the inferior turbinates (RAPN) as an effective easier alternative to TRPN.Methods:The procedure was performed on 24 patients with intractable AR. Nasal reactivity was tested by cold dry air (CDA) provocation before and 12 months after the radiofrequency procedure. Visual analog scale and acoustic rhinometry were used to measure the changes in nasal reactivity subjectively and objectively.Results:Worsening of nasal symptoms following CDA provocation had significantly decreased after the RAPN procedure. Likewise, postoperative decrease in nasal volumes and minimal cross-sectional areas after CDA provocation were significantly less than the corresponding preoperative values.Conclusion:RAPN effectively reduces nasal reactivity in patients with AR. The procedure is simple, minimally invasive, and can be performed under local or general anesthesia.

Metabolic syndrome (MS) is a serious medical and social problem due to its high prevalence, lack of common approaches to diagnosis and treatment. Prevention of food dysadaptation reactions and the studies of control mechanisms of immune tolerance to food antigens is of special scientific interest, thus providing available anti-inflammatory tools for correcting increased permeability of the intestinal epithelium and vascular endothelium associated with development of MS. Nutritional dysadaptation occurs due to inappropriate diet being mediated by the geno-phenotypic characteristics of digestive enzymes and immune system which control the efficiency of food digestion.Immunological control of digestion, including dynamic maintenance of tolerance to food antigens, is carried out at two levels of immune system: innate response with functional involvement of microbiota, and adaptive response, represented by cellular and humoral mechanisms associated with molecular epitopes and critical mass of persistent food antigens which are present in immunologically competent areas of small intestine, due to changing permeability of intestinal barrier and transcytosis processes. Patients and methods: aiming for assessment of the diet contribution to the immuno-biochemical and rheological imbalance in people with increased body weight, 170 volunteers of both sexes aged 20-55 years were examined, depending on the body mass index: > 27.0 kg/m2 (clinical group, n = 120), and those with BMI of < 25.0 kg/m2 (control group, n = 50). We have revealed statistically significant increase of multiple parameters in the clinical group, i.e., concentration of IL-6, IL-17, cholesterol, glucose, glycosylated hemoglobin, insulin, indices of insulin resistance and atherogenicity. Increased levels of specific IgG antibodies to a number of food antigens were found in the subjects in the clinical group. In the course of our study, a statistically significant relationships was found between total numbers of platelets (p < 0.05; r = 0.213), erythrocytes (p < 0.05; r = -0.211), mean erythrocyte volume (MCV) (p < 0, 05; r = 0.339), and the concentration of IgG to casein in the blood, as well as a correlation between the levels of sIgG to soybeans and the number of platelets (p < 0.05; r = 0.231). At the same time, some associations were found between the established values of IgG to casein pAG, and the risk of developing atherogenic changes (atherogenicity index > 3) being significant at OR = 2.68 (1.33-5.42), as well as between IgG values to casein pAG (OR = 8.9 (2.6-30.5)), to soybean pAG (OR = 5.6 (1.8-16.7)), to gluten pAG ((F = 0.00359. p < 0.05), and increased body mass index.The results obtained were interpreted as a possible impairment of food tolerance for a number of food antigens in individuals with high body mass index, due to the revealed correlations between concentrations of IgG to food antigens, imbalance of pro-inflammatory cytokines, rheological and metabolic parameters. These data may be used as biomarkers suggesting higher risk of evolving metabolic syndrome.

Introduction and Methods: This study examined 85 parental‐reports with 85 self‐reports of autistic symptoms with the 84‐item Coolidge Autistic Symptom Survey (CASS). The CASS covers all of the diagnostic criteria for autism spectrum disorder (ASD) in the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5), as no studies to date have compared the self‐reports of individuals with autism with parent‐ or significant‐other‐reports of those individuals using the complete DSM‐5. Results: The CASS‐Parental‐Report and CASS‐Self‐Report exhibited excellent internal reliability (α = 0.97 and 0.96, respectively). There was support for the hypothesis that parental‐reports and self‐reports would be similar (r = 0.66, p < 0.001). Discussion: In conclusion, the CASS should be considered a promising tool for assessing autistic symptoms from both parent‐ and self‐perspectives. [ABSTRACT FROM AUTHOR]

Objective: Transection or ablation of the posterior nasal nerve (TRPN) has been described as an adjunctive tool to reduce the symptoms of intractable allergic rhinitis (AR). The procedure, however, requires surgical skill and carries the risk of bleeding from the sphenopalatine artery. The aim of the present study is to describe radiofrequency ablation of the peripheral branches of the posterior nasal nerves within the inferior turbinates (RAPN) as an effective easier alternative to TRPN. Methods: The procedure was performed on 24 patients with intractable AR. Nasal reactivity was tested by cold dry air (CDA) provocation before and 12 months after the radiofrequency procedure. Visual analog scale and acoustic rhinometry were used to measure the changes in nasal reactivity subjectively and objectively. Results: Worsening of nasal symptoms following CDA provocation had significantly decreased after the RAPN procedure. Likewise, postoperative decrease in nasal volumes and minimal crosssectional areas after CDA provocation were significantly less than the corresponding preoperative values. Conclusion: RAPN effectively reduces nasal reactivity in patients with AR. The procedure is simple, minimally invasive, and can be performed under local or general anesthesia. [ABSTRACT FROM AUTHOR]

Abstract Since the outbreak of the novel coronavirus disease (COVID-19), the therapeutic and management options to reduce the burden of the COVID-19 disease are under investigation. IVIG therapy is used as an effective treatment for immunodeficient patients and patients with inflammatory or autoimmune conditions. The therapeutic effect of IVIG in COVID-19 patients has been investigated. But, the results are controversial and some studies reported no benefit of IVIG therapy. More clinical trials on the effect of IVIG therapy in COVID-19 patients should be performed to establish a certain conclusion about IVIG effectiveness.

In mice, rats, and rabbits, vigorous jumping and hyperexcitability occur at the popcorn stage of postnatal development. In view of subcortical structures appearing before cortical ones, the trait is deemed to occur at the maturation time of ascending excitatory projections from the brainstem and to disappear at the maturation time of descending inhibitory projections from the forebrain. There is evidence that the popcorn stage may be due in part to the lack of a cholinergic influence on dopamine systems. Based mostly on results found in adult mice and rats, there may also be a role for cortico-subcortical systems that include the cerebellum and basal ganglia requiring the influence of biogenic amines, glutamate, and endocannabinoids. [ABSTRACT FROM AUTHOR]

Background: Sensory processing issues are among the key diagnostic criteria for autism spectrum disorder (ASD). As altered sensory processing causes autistic children to react differently to sensory experiences and has a profound impact on their development, affecting their learning ability, social interaction, and ability to adapt to a new environment, there is a need to recognize and address these issues in children diagnosed with ASD during assessments and interventions. This study aimed to identify the patterns of sensory issues and their impact, and selected correlates among autistic children attending a center for neurodevelopmental disorders in northern Sri Lanka., Methods: This institution-based, descriptive, cross-sectional study was conducted at a center for neurodevelopmental disorders in Jaffna among 100 children diagnosed with ASD. The sociodemographic details of the child, and scores of the Childhood Autism Rating Scale second edition (CARS™ 2), Sensory Profile™ 2, and a locally developed Behavioral Checklist were extracted from the records available at the center. Data were analyzed using R statistical computing software (R Foundation for Statistical Computing, Vienna, Austria) using general linear models., Results: All the children in this study had at least one sensory issue, with 50% having visual processing issues. The severity of ASD increased as auditory processing issues increased. Behavioral issues, in general, increased significantly with increasing auditory and visual processing issues. Repetitive behaviors significantly increased with increasing auditory processing issues, while problems with self-regulation increased significantly with increasing visual and movement processing issues. Conduct-related issues were found to increase significantly with increasing movement and visual processing issues, and attentional response issues were found to increase significantly with increasing auditory, visual, and touch processing issues., Conclusion: The high prevalence of sensory issues in autistic children and its impact on the severity of ASD and behavioral issues are reiterated in this study. These results emphasize the importance of including interventions targeting sensory issues with the routine therapy for ASD., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Ethics Review Committee of the Faculty of Medicine, University of Jaffna issued approval J/ERC/22/143/NDR/0285. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sivapalan et al.)

Complexes of IL-2 and JES6-1 mAb (IL-2/JES6) provide strong sustained IL-2 signal selective for CD25+ cells and thus they potently expand Treg cells. IL-2/JES6 are effective in the treatment of autoimmune diseases and in protecting against rejection of pancreatic islet allografts. However, we found that IL-2/JES6 also dramatically increase sensitivity to LPS-mediated shock in C57BL/6 mice. We demonstrate here that this phenomenon is dependent on endogenous IFN-γ and T cells, as it is not manifested in IFN-γ deficient and nude mice, respectively. Administration of IL-2/JES6 leads to the emergence of CD25+Foxp3-CD4+ and CD25+Foxp3-CD8+ T cells producing IFN-γ in various organs, particularly in the liver. IL-2/JES6 also increase counts of CD11b+CD14+ cells in the blood and the spleen with higher sensitivity to LPS in terms of TNF-α production and induce expression of CD25 in these cells. These findings indicate safety issue for potential use of IL-2/JES6 or similar IL-2-like immunotherapeutics.

Since the outbreak of the novel coronavirus disease (COVID-19), the therapeutic and management options to reduce the burden of the COVID-19 disease are under investigation. IVIG therapy is used as an effective treatment for immunodeficient patients and patients with inflammatory or autoimmune conditions. The therapeutic effect of IVIG in COVID-19 patients has been investigated. But, the results are controversial and some studies reported no benefit of IVIG therapy. More clinical trials on the effect of IVIG therapy in COVID-19 patients should be performed to establish a certain conclusion about IVIG effectiveness. [ABSTRACT FROM AUTHOR]

Objective: Determine effects on respiratory health of firefighters attending a catastrophic wildfire. Methods: Within the Alberta Administrative Health Database, we identified five community-based controls for each firefighter in a cohort of 1234 deployed to the 2016 Fort McMurray fire. Spirometry records were identified and a stratified sample assessed clinically. We estimated PM2.5 particles exposure. Results: Firefighters had an increased risk of asthma consultation post-fire (OR new onset asthma = 2.56; 95%CI 1.75 to 3.74). Spirometry showed decreased FEV1 and FVC with increasing exposure. In the clinical assessment, 20% had a positive MCT and 21% BWT. Those with ongoing fire-related symptoms had a higher concurrence of positive MCT and BWT (OR = 4.35; 95%CI 1.11 to 17.12). Lower diffusion capacity related to higher exposure. Conclusions: Massive exposures during a wildfire are associated with non-resolving airways damage. [ABSTRACT FROM AUTHOR]

Sublethal exposure to imidacloprid and other neonicotinoid insecticides may affect the neurological functions of birds. As such, behavior may be compromised. Here, we tested experimentally the effects of 1 and 6 mg/kg bw of imidacloprid on the antipredator behavioral responses of the red-legged partridge ( Alectoris rufa ) to simulated predator threats. Sixty-six partridges were challenged in groups or individually to intra- and interspecific alarm calls, to a raptor silhouette (aerial predation risk), and to a fox model (terrestrial predation risk). Antipredator behaviors were recorded as active (escape, active vigilance) and passive (passive vigilance, crouching, and freezing) responses. Latency in response to the stimuli, percentage of individuals who responded, response duration, speed of active responses, and vocalizations were measured. In experiments with partridges in the group, crouching against simulated predation risk lasted less time in birds treated with 6 mg a.i./kg bw than in control birds. In the experiments with individual partridges, passive vigilance against the intraspecific alarm lasted longer in birds treated with 6 mg a.i./kg bw than in control birds. The observed hyperreactivity to the predatory threat after a sublethal imidacloprid exposure can have consequences on survival under field conditions, where predation is a main driver of population dynamics.

Objective: Starting from the controversial results showed by empirical research on Linehan’s Biosocial model of Borderline Personality Disorder (BPD), this study aims to empirically evaluate Linehan’s conceptualization of emotional hypersensitivity and hyperreactivity, as well as to investigate the role of pre-existing emotional states in BPD altered physiological responsivity. Methods: We asked 24 participants (BPD = 12; Healthy Controls = 12) to complete a self-reported questionnaire (Positive and Negative Affect Schedule) in order to assess their pre-task affective state. Subsequently, 36 emotional pictures from four valence categories (i.e. erotic, negative, positive, neutral) were administered while assessing participants self-reported and electrodermal responses. Results: BPD patients showed higher levels of pre-task negative affectivity as well as an enhanced physiological response to neutral stimuli. No main BPD group effect was found for the physiological data. Moreover, pre-task negative affectivity levels were exclusively related to physiological responses among BPD subjects. Discussion: Our findings supported the hypersensitivity hypothesis operationalized as an enhanced responsiveness to non-emotional cues. Hyperreactivity assumption was not supported. Conversely, our study revealed heightened physiological responses in relation to pre-existent negative emotional states in BPD. We discussed our results in the context of the putative pathological processes underlying BPD.

• IFRD1 was downregulated in asthma pathogenesis. • IFRD1 overexpression alleviated airway inflammation in OVA-induced mice. • IFRD1 overexpression attenuated LPS-induced effects on HBE cells. • IFRD1 regulated LPS-induced asthmatic responses via NF-κB pathway. Asthma is a chronic respiratory disease which is susceptible to children and causes great harm to them. Recently, Interferon-related developmental regulator 1 (IFRD1) was proved to be participant in regulating lung diseases, and its abnormal expression was shown in pathological airway tissues. Our study aimed to demonstrate the role and modulatory mechanism of IFRD1 in the pathogenesis of asthma. First, we evaluated the expression of IFRD1 in the lungs of asthmatic patients. C57BL/6 mice and human bronchial epithelioid (HBE) cells were respectively induced by ovalbumin (OVA) and lipopolysaccharide (LPS) to construct asthma models in vivo and in vitro. Using adenovirus and pcDNA vectors, we carried out overexpression assays on mice and cell models. Additionally, the potential mechanism of IFRD1 on regulating asthma process was elucidated by targeting NF-κB pathway. The results showed that IFRD1 was significantly down-regulated in asthma lung tissues, as well as the in vivo and in vitro models of asthma. Besides, OVA induced the inflammation responses and hyperreactivity of airway in mice, and LPS also caused inflammatory cytokine secretion and apoptosis of HBE cells, while cell viability was inhibited. However, IFRD1 overexpression dramatically reversed the effects of OVA and LPS. We subsequently discovered that the NF-κB pathway was activated in asthmatic cells, and NF-κB signaling activation was involved in IFRD1 regulated asthma responses of HBE cells. In conclusion, our study indicated that IFRD1 inhibited the asthmatic responses of airway via the NF-κB pathway inactivation. The evidence presented herein might provide a novel sight for asthma therapy. [ABSTRACT FROM AUTHOR]

Asthma is a chronic debilitating airway disease affecting millions of people worldwide. Although largely thought to be a disease of the first world, it is now clear that it is on the rise in many middle- and lower-income countries. The disease is complex, and its etiology is poorly understood, which explains failure of most treatment strategies. We know that in children, asthma is closely linked to poor lung function in the first 3-years of life, when the lung is still undergoing post-natal alveolarization phase. Epidemiological studies also suggest that environmental factors around that age do play a critical part in the establishment of early wheezing which persists until adulthood. Some of the factors that contribute to early development of asthma in children in Western world are clear, however, in low- to middle-income countries this is likely to differ significantly. The contribution of fungal species in the development of allergic diseases is known in adults and in experimental models. However, it is unclear whether early exposure during perinatal or post-natal lung development influences a protective or promotes allergic asthma. Host immune cells and responses will play a crucial part in early development of allergic asthma. How immune cells and their receptors may recognize fungi and promote allergic asthma or protect by tolerance among other immune mechanisms is not fully understood in this early lung development stage. The aim of this review is to discuss what fungal species are present during early exposure as well as their contribution to the development of allergic responses. We also discuss how the host has evolved to promote tolerance to limit hyper-responsiveness to innocuous fungi, and how host evasion by fungi during early development consequentially results in allergic diseases.

We investigated the effects of prior stress on rats’ responses to 50-kHz (appetitive) and 22-kHz (aversive) ultrasonic playback. Rats were treated with 0, 1, 6 or 10 shocks (1 s, 1.0 mA each) and were exposed to playbacks the following day. Previous findings were confirmed: (i) rats moved faster during 50-kHz playback and slowed down after 22-kHz playback; (ii) they all approached the speaker, which was more pronounced during and following 50-kHz playback than 22-kHz playback; (iii) 50-kHz playback caused heart rate (HR) increase; 22-kHz playback caused HR decrease; (iv) the rats vocalized more often during and following 50-kHz playback than 22-kHz playback. The previous shock affected the rats such that singly-shocked rats showed lower HR throughout the experiment and a smaller HR response to 50-kHz playback compared to controls and other shocked groups. Interestingly, all pre-shocked rats showed higher locomotor activity during 50-kHz playback and a more significant decrease in activity following 22-kHz playback; they vocalized more often, their ultrasonic vocalizations (USV) were longer and at a higher frequency than those of the control animals. These last two observations could point to hypervigilance, a symptom of post-traumatic stress disorder (PTSD) in human patients. Increased vocalization may be a valuable measure of hypervigilance used for PTSD modeling.

Highlights • BPD patients cry more often than non-patients, while their crying proneness and dealing with crying were not different, which suggests greater exposure to emotional situations • BPD patients also seem less aware of the interpersonal impact of their crying than non-patients. • No differences were found in crying variables between BPD patients and Cluster C-PD's. • The results of this study thus emphasize the non-specificity of the findings of crying in BPD patients. Abstract Emotion dysregulation and hyperreactivity are considered central features of Borderline Personality Disorder (BPD). We assumed that such emotion dysregulation is also reflected in increased crying behavior of these patients and, consequently, hypothesized that BPD patients (N = 62), compared to Cluster C personality disorder patients (Cluster C-PD; N = 25) and non-patients (N = 54), would show higher scores on crying measures. To evaluate crying behavior, we used a set of specially designed tools. Compared to non-patients, BPD patients showed the anticipated higher crying frequency despite a similar crying proneness and ways of dealing with tears. They also reported less awareness of the influence of crying on others. However, Cluster C-PD patients showed a very similar pattern of findings. Overall, our results suggest that the increased crying of BPD patients likely results from environmental factors or the misperception of situations, rather than from stable traits. Remarkable is that the observed discrepancies in crying behavior compared to non-patients seem to be similar for Cluster-C PDs and BPD. [ABSTRACT FROM AUTHOR]

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Graphical abstract Abstract The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy. [ABSTRACT FROM AUTHOR]

A case of dilated cardiomyopathy complicated with complete left bundle branch block was reported. After admission, the patient was treated with cardiotonic, dilatation, diuresis, inhibition of myocardial remodeling, improvement of myocardial metabolism and so on. The patient was with recurrent ventricular fibrillation during hospitalization and poor heart function, and the patient's symptoms improved significantly after CRT-D (cardiac resynchronization therapy-defibrillator) implantation. Followed up for nearly 2 years, echocardiography showed that left ventricular end diastolic dimension reduced from 70mm to 42 mm, left atrium dimension reduced from 34 mm to 30 mm, and left ventricular ejection fraction increased from 0.35 to 0.62. The patient was generally in good condition and no restrictions on daily activities, which was the CRT-D hyperreactivity. The reason for this patient's hyperreactivity might be that CRT-D has corrected the progressive enlargement of the heart caused by conduction block. [ABSTRACT FROM AUTHOR]

In the French veterinary psychiatry model, the canine version of attention deficit hyperactivity disorder is called Hypersensitivity-Hyperactivity Syndrome (HSHA) and it includes two stages, depending on the symptom severity. Since methylphenidate is not authorized for veterinary use in France, HSHA dogs are commonly treated with 2 to 4 mg/kg Fluoxetine associated with behavioral modifications. Thus, the aim of this study was to analyze the long-term outcome of this approach. Twenty-four dogs diagnosed with HSHA were included. For each dog, 42 descriptive data were analyzed. Primary reasons for consulting were variable if the dogs had an additional behavioral diagnosis (i.e. 33% of the dogs): complaints were linked to the comorbid diagnosis (e.g. bite on strangers, people phobia), whereas they were linked to autocontrol deficiency for the dogs diagnosed with HSHA only (e.g. destructive, mouth, jumps on people). HSHA affection deeply alters the dog-human bond, as severe cases often lead owners to think about euthanasia or rehoming (12% for stage 1, but 83% for stage 2). Neither the possibility to have access to a garden nor the quantity of daily exercise were linked to HSHA stages (respectively, fisher's exact test, p=0.69, and Kruskal-Wallis, p=0.88). Eighty-three percent of the dogs attended training classes before consulting, with no noticeable improvement (mean training improvement score 1.7/10). In addition, training seemed even less efficient on severe cases, i.e. stage 2 dogs (Kruskall-Wallis, p<0.03). After two months of high dose Fluoxetine (2 to 4 mg/kg), the average score of improvement given by owners was 7.2/10 compared to 0/10 at start. No long-term adverse effect was reported. A HSHA clinical score (0 to 5 scale) was built to better categorize the dogs and to conduct the follow-up. The HSHA clinical score was correlated to Fluoxetine dose (Pearson correlation, p<0.01) and duration (Pearson correlation, p<0.05). A successful weaning from treatment was possible for 54% of the dogs. These results suggest that HSHA spectrum can range from mild clinical signs to widely pervasive and invalidating ones. Starting the treatment as early as possible seems determinant for the welfare of the dog and for the dog-owner relationship, but doesn't allow a shorter treatment (Kruskall-Wallis, p=0.84) or more chances for a weaning (Fisher's exact test, p=0.88). However, high dose Fluoxetine associated with behavioral modifications appear to be useful and well tolerated to treat this complex syndrome. [ABSTRACT FROM AUTHOR]

Atherothrombotic complications are important causes of morbidity and mortality in diabetic patients. Diabetes has been considered to be a prothrombotic status. Several factors contribute to the prothrombotic condition, such as increasing coagulation, impaired fibrinolysis, endothelial dysfunction, and platelet hyperreactivity. Among the factors that contribute to the prothrombotic status in diabetes, altered platelet function plays a crucial role. Although understanding platelet function abnormalities in diabetes still remains as a challenge, more attention should be focused on platelet function for effective management and the prediction of atherothrombotic events in diabetic patients. This review will provide an overview on the current status of knowledge of platelet function abnormalities and clinical marker of platelet hyperreactivity in patients with diabetes.

Background As asthma-like symptoms are common in CF, we evaluated reversible airway obstruction and associated characteristics. Methods Retrospective analysis of charts including spirometry and bronchodilator response. Results Of 190 CF patients (103 at Schneider's, 87 at Hadassah), aged 14.4 (4–76) years, median (range), 39% had reversible obstruction (ΔFEV 1 % predicted ≥ 12%), associated with younger age (p = 0.01) and severe genotype (p = 0.02). There was no association with family history of asthma, serum IgE, blood eosinophils, pancreatic status, FEV 1 < 40% predicted, Aspergillus or pseudomonas infection. Of patients with reversible obstruction, 74% were on bronchodilator and 68% on inhaled corticosteroid therapy but 54% and 57% respectively receiving these therapies did not have reversible obstruction. Conclusions Reversible airway obstruction is common in CF, more frequent in younger patients and with severe genotype, with no correlation to markers of atopy or CF clinical severity. Bronchodilator and inhaled corticosteroid therapies are commonly prescribed even without reversible obstruction. [ABSTRACT FROM AUTHOR]

Background: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 ( Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. Methods: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. Results: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. Conclusions: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. [ABSTRACT FROM AUTHOR]

Se realizó una revisión que abarca los aspectos más importantes de la fisiología y genética del gen de la sintasa del óxido nítrico 1 así como su participación en la patogénesis del asma. El asma es una enfermedad común y compleja, caracterizada por obstrucción de las vías aéreas, hiperreactividad bronquial y en muchos casos atopia. Su causa aún no esta bien definida, pero se conoce que está influenciada por factores genéticos y ambientales. Para tratar de esclarecer la fuente precisa de la enfermedad, se realizan análisis de genes candidatos y al nivel ambiental la influencia de los alergenos de ácaros y otros factores de riesgo en el desarrollo de asma. Dentro de los genes candidatos, el gen de la sintasa del óxido nítrico 1 ha cobrado gran interés por su amplio papel en la patogénesis del asma, porque actúa como un neurotransmisor y broncodilatador que provoca una hiperrespuesta en las vías aéreasA review of the most important aspects of physiology and genetics of type 1 nitric oxide synthase gene as well as its involvement in asthma pathogenesis was made. Asthma is a common and complex disease characterized by obstruction of airways, bronchial hyperreactivity and in many cases atopy. The fundamental cause of this disease is not yet well defined but it is known that genetic and environmental factors have their bearing on it. To clarify the exact origin of this disease, candidate genes, the influence of mite allergens at environmental level and other risk factors for asthma were all analyzed. Among candidate genes, type 1 nitric oxide synthase gene has aroused great interest due to its extensive role in asthma pathogenesis becuase it acts as a neurotransmitter and bronchodilator that provides hyperresponse in airways

Background This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats. Methods Long Evans wild type ( n = 9) and orl ( n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting β 2 -adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed. Results The methacholine concentration–response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. β 2 -Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats. Conclusion orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR. [ABSTRACT FROM AUTHOR]

Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/ xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness. [ABSTRACT FROM AUTHOR]

Migraine headaches are associated with sensory hyperreactivity and anxiety in the general population, but it is unknown whether this is also the case in autism spectrum disorders. This pilot study asked parents of 81 children (aged 7–17 years) with autism spectrum disorders to report their child’s migraine occurrence, sensory hyperreactivity (Sensory Over-Responsivity Inventory), and anxiety symptoms (Spence Child Anxiety Scale). Children with autism spectrum disorders who experienced migraine headaches showed greater sensory hyperreactivity and anxiety symptomatology (p < 0.01; medium effect size for both) than those without migraines. Sensory hyperreactivity and anxiety symptomatology were additionally correlated (ρ = 0.31, p = 0.005). This study provides preliminary evidence for a link between migraine headaches, sensory hyperreactivity, and anxiety symptomatology in autism spectrum disorders, which may suggest strategies for subtyping and exploring a common pathogenesis. [ABSTRACT FROM PUBLISHER]

Epidemiologic studies suggest that increased concentrations of airborne spores of Aspergillus fumigatus closely relate to asthma aggravation. Chronic exposure to A. fumigatus aggravates airway inflammation, remodeling, and airway hyperresponsiveness in asthmatic rats. The effects of chronic exposure to A. fumigatus on epidermal growth factor receptor (EGFR) expression in the airway epithelial cells of asthmatic rats remain unclear. This study aimed to investigate the effects of chronic exposure to A. fumigatus on injury and shedding of airway epithelium, goblet cell metaplasia, and EGFR expression in the airway epithelial cells of asthmatic rats. A rat model of chronic asthma was established using ovalbumin (OVA) sensitization and challenge. Rats with chronic asthma were then exposed to long-term inhalation of spores of A. fumigatus, and the dynamic changes in injury and shedding of airway epithelium, goblet cell metaplasia, and EGFR expression were observed and analyzed. Chronic exposure to A. fumigatus could aggravate airway epithelial cell damage, upregulate the expression of EGFR and its ligands EGF and TGF-α, promote goblet cell metaplasia, and increase airway responsiveness in rats with asthma. Chronic exposure to A. fumigatus upregulates the expression of EGFR and its ligands in asthmatic rats. The EGFR pathway may play a role in asthma aggravation induced by exposure to A. fumigatus. [ABSTRACT FROM AUTHOR]

Background: People with autism spectrum disorders (ASD) are known to have enhanced auditory perception, however, acoustic startle response to weak stimuli has not been well documented in this population. The objectives of this study are to evaluate the basic profile of acoustic startle response, including peak startle latency and startle magnitude to weaker stimuli, in children with ASD and typical development (TD), and to evaluate their relationship to ASD characteristics. Methods: We investigated acoustic startle response with weak and strong acoustic stimuli in 12 children with ASD and 28 children with TD, analyzing the relationship between startle measures and quantitative autistic traits assessed with the Social Responsiveness Scale (SRS). The electromyographic activity of the left orbicularis oculi muscle to acoustic stimuli of 65 to 115 dB sound pressure level (SPL), in increments of 5 dB, was measured to evaluate acoustic startle response. The average eyeblink magnitude for each acoustic stimuli intensity and the average peak startle latency of acoustic startle response were evaluated. Results: The magnitude of the acoustic startle response to weak stimuli (85 dB or smaller) was greater in children with ASD. The peak startle latency was also prolonged in individuals with ASD. The average magnitude of the acoustic startle response for stimulus intensities greater than 85 dB was not significantly larger in the ASD group compared with the controls. Both greater startle magnitude in response to weak stimuli (particularly at 85 dB) and prolonged peak startle latency were significantly associated with total scores, as well as several subscales of the SRS in the whole sample. We also found a significant relationship between scores on the social cognition subscale of the SRS and the average magnitude of the acoustic startle response for stimulus intensities of 80 and 85 dB in the TD group. Conclusions: Children with ASD exhibited larger startle magnitude to weak stimuli and prolonged peak startle latency. These startle indices were related to several characteristics of ASD. A comprehensive investigation of acoustic startle response, including the magnitude of startle responses to weak stimuli and peak startle latency, might further our understanding of the neurophysiological impairments underlying ASD. [ABSTRACT FROM AUTHOR]

The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88 mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88 mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function. [ABSTRACT FROM AUTHOR]

Abstract: Adenosine participates to asthma physiopathology by signaling through more than just one receptor subtype. Defining the role of each receptor is complicated by evidence that often results obtained on rodents do not coincide with human studies, but what emerges is that an important condition to establish hyperresponsiveness to adenosine in any species of sensitized animals is the exposure to allergen; this feature appears to be very similar to the human situation, since allergic humans regularly undergo exposure to allergen. Furthermore, A2B in humans, but A3 receptor in rodents, would mediate, indirectly, the bronchoconstriction in response to adenosine and would play the main role in adenosine-induced airway inflammation and airway hyperreactivity. On the other hand, A1 receptor over-expressed on asthmatic airways would mediate a direct adenosine bronchoconstrictor effect. Antagonists and agonists to adenosine receptors have been considered as antiasthmatic drugs but often their development has been limited by unwanted effects. Preventing adenosine accumulation in airways should be considered as a novel promising antiasthmatic strategy. [Copyright &y& Elsevier]

Background Nasal hyperreactivity is the symptomatic expression of vasomotor rhinitis. This study describes a typical nasal reaction, represented by a 'volley of sneezes' found in some patients during nasal endoscopy, and to assess the possible correlation between hyperreactivity and a particular clinical and cytological condition. Methods We studied 671 rhinological subjects, 344 male, mean age 35.7 ± 13.76 standard deviation (SD) years. All were submitted to medical histories and clinical and instrumental investigations (skin prick test, nasal endoscopy, and nasal cytology). While performing endoscopy, particular attention was paid to the possible signs of nasal hyperreactivity, in particular 'volley of sneezes' both during and immediately after the diagnostic procedure. Results Out of 671 endoscopies performed, 130 (17.1%) patients presented signs of hyperreactivity during and/or immediately after nasal endoscopy. The ratio of positive vasomotor reaction was 10.6% in the nasal polyposis (NP) group, 19% in the allergic rhinitis (AR) group, 70.6% ( p < 0.01) in nonallergic rhinitis with mast cells (NARMA), 76% ( p < 0.01) in nonallergic rhinitis with eosinophils and mast cells (NARESMA), and 83% ( p < 0.01) in nonallergic rhinitis with eosinophils (NARES). In the AR subjects hyperreactivity was more frequent during the pollen season, compared to the period of absence of pollen (87.5% vs 12%). Conclusion The onset of hyperreactivity (sneezing) can be considered an important 'sign' in nasal symptomatology, whose sensitivity and specificity for nonallergic 'cellular' rhinitis are 79% and 93%, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Airway hyperreactivity is characterized by increased responsiveness to bronchoconstrictor stimuli and it is hallmark of asthma. Adenosine is an ubiquitous signaling nucleoside resulting from ATP catabolism, whose extracellular levels increase following cellular damage or stress. Adenosine plays a role in asthma; asthmatics, but not normal subjects, present bronchoconstriction following inhalation of adenosine or of its precursor, adenosine-5′-monophosphate, most likely via adenosine A2B receptor on mast cells. However, the mechanism underling the increased airway smooth muscle sensitivity to adenosine in asthmatics remains to be elucidated. Early experimental studies suggested the involvement of A1 receptor; this hypothesis has been confirmed by more recent studies on guinea pigs and is corroborated by the finding of an increased adenosine A1 expression on asthmatic bronchial tissues. Brown Norway rats, the strain usually used to assess asthma models, develop hyperresponsiveness to adenosine 3h following allergen challenge, but not 24h thereafter, without involvement of A1 receptor. Here, we investigated the role of adenosine A1 receptor in sensitized Wistar rats showing airway hyperresponsiveness 24h following allergen challenge. We found that on bronchi of sensitized Wistar rats challenged with allergen there is an increased adenosine A1 receptor expression on smooth muscle that is responsible for hyperresponsiveness to adenosine and ovalbumin. [Copyright &y& Elsevier]

Background: Airway mucus hypersecretion is associated with increased morbidity and mortality in patients with asthma. Chronic Aspergillus fumigatus ( A. fumigatus) exposure leads to aggravation of airway inflammation and remodeling, including goblet cell hyperplasia (GCH) and mucus hypersecretion in a rat model of asthma. The effects of chronic A. fumigatus exposure on the expression of airway mucin 5AC (MUC5AC) are unknown. Methods: The rat model of chronic asthma was set up by systemic sensitization and repeated challenge to ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. The changes of MUC5AC expression, the extent of GCH, and airway hyperreactivity (AHR) were measured after exposure to the fungus. Results and Conclusions: Chronic exposure to A. fumigatus upregulates the expression of MUC5AC, and induces GCH in the airways of asthma rats, and the remodeling changes of the airway epithelium was positively correlated with AHR. Upregulation of MUC5AC and induction of GCH may be mechanisms by which chronic A. fumigatus exposure promotes the progression of asthma. [ABSTRACT FROM AUTHOR]

Background: Repaglinide is an FDA-approved treatment for type 2 diabetes mellitus. The anti-inflammatory effect of repaglinide in the absence of diabetes has not been reported previously. It is the objective of this set of studies to investigate the potential anti-inflammatory effects of repaglinide. Method: The in vivo anti-inflammatory effects of repaglinide were studied in two different models of delay type hyperreactivity (DTH) response induced by sheep red blood cells (sRBC) and 2,5′-dinitrofluorobenzene (DNFB), and in two different rodent models of lipopolysaccharide (LPS) challenge. Results: In mice systemically sensitized with sRBC, which subsequently received a local injection of sRBC in the footpad, local swelling occurred within 24 h after challenge. Repaglinide was efficacious in attenuating this response. In an orthogonal DTH model using DNFB as the antigen, the animals received topical sensitization with DNFB on their shaved backs, followed by topical challenge on the left ears. Repaglinide efficaciously downregulated the resulting ear swelling response. In mice challenged systemically or intratracheally with LPS, repaglinide significantly decreased serum tumor necrosis factor α level and bronchial alveolar lavage fluid MCP-1 levels, respectively. Conclusion: This set of data suggests novel anti-inflammatory effects of repaglinide in nondiabetic animals. However, the high dose required for an efficacious effect would make this application impractical in the clinic. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A lack of habituation in visual-evoked potentials (VEPs) is the main abnormality observed in migraineurs. However, no study of steady-state VEPs has yet evaluated pattern-reversal stimuli with respect to habituation behavior or spatial frequency. The aim of this study was to clarify habituation behavior in migraineurs between attacks and to establish characteristics of VEPs in these patients. Steady-state VEPs were sequentially recorded as checkerboard patterns in four consecutive blocks from 12 patients with migraine without aura (MO), 12 patients with migraine with aura (MA), and 12 healthy controls (HC) at four spatial frequencies of 0.5, 1.0, 2.0, and 4.0 cycles per degree (cpd) with a stimulus rate of 7.5 Hz (15 reversal/s). VEP amplitudes were consistently higher in migraineurs. However, habituation was not demonstrated in HCs, and migraineurs did not reveal a clear lack of habituation. MAs exhibited high-amplitude VEPs, depending on spatial frequency. In the MA patients, amplitude differences reached statistical significance at 2.0 cpd. The sequential amplitude changes at 0.5 cpd were significantly different in MAs compared with HCs. Migraine patients exhibited high-amplitude VEPs, which were dependent on spatial frequency, and may be related to altered excitability in pre-cortical and cortical visual processing. [ABSTRACT FROM AUTHOR]

Background The intestinal mucosa of patients with inflammatory bowel diseases (IBD) characteristically shows a high degree of inflammation when compared to healthy subjects. This appears to be attributable to an imbalance in local reactivity of inflammatory cells. In the present study, we tested the hypothesis that immune cells from patients with IBD are less sensitive to anti-inflammatory agents in the gut as exemplified by the short-chain fatty acid (SCFA) n-butyrate. Material and methods Peripheral blood mononuclear cells (PBMC) of patients with IBD (22 Crohn's Disease, CD; 9 Ulcerative Colitis, UC) and 20 healthy individuals were stimulated through TLR-4 and TLR-2 engagement, respectively, and the anti-inflammatory activity of n-butyrate (0·06-1 mM) on cytokine production (IL-1β, IL-10, IL-12 / 23p40, TNF-α) was assessed. Inhibition curves were generated, and effective doses (ED20-ED80) were determined. Results Hyperresponsiveness to TLR-2 activation reflected by increased IL-12 / 23p40 and TNF-α production was observed in patients with IBD. To inhibit the release of IL-12 / 23p40 from PBMC after activation via TLR2- agonists, higher concentrations of n-butyrate were required in patients with IBD , when compared to healthy subjects. With regard to TLR-4 activation, PBMC from patients with IBD and controls were equally responsive to the immunoregulatory effects of n-butyrate. Further analysis revealed that the impaired sensitivity of PBMC to the anti-inflammatory action of n-butyrate was independent from hyperreactivity of immunocompetent cells. Conclusions Impaired sensitivity to the inhibitory action of n-butyrate in IBD may constitute a determinant in the pathogenesis of these inflammatory diseases. [ABSTRACT FROM AUTHOR]