Repetitive Insults Research Articles

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy.

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress. Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

Drosophila melanogaster as a model to study age and sex differences in brain injury and neurodegeneration after mild head trauma.

Repetitive physical insults to the head, including those that elicit mild traumatic brain injury (mTBI), are a known risk factor for a variety of neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), and chronic traumatic encephalopathy (CTE). Although most individuals who sustain mTBI typically achieve a seemingly full recovery within a few weeks, a subset experience delayed-onset symptoms later in life. As most mTBI research has focused on the acute phase of injury, there is an incomplete understanding of mechanisms related to the late-life emergence of neurodegeneration after early exposure to mild head trauma. The recent adoption of Drosophila-based brain injury models provides several unique advantages over existing preclinical animal models, including a tractable framework amenable to high-throughput assays and short relative lifespan conducive to lifelong mechanistic investigation. The use of flies also provides an opportunity to investigate important risk factors associated with neurodegenerative conditions, specifically age and sex. In this review, we survey current literature that examines age and sex as contributing factors to head trauma-mediated neurodegeneration in humans and preclinical models, including mammalian and Drosophila models. We discuss similarities and disparities between human and fly in aging, sex differences, and pathophysiology. Finally, we highlight Drosophila as an effective tool for investigating mechanisms underlying head trauma-induced neurodegeneration and for identifying therapeutic targets for treatment and recovery.

Systemic Activin Is Elevated in Patients With Severe Alcoholic Hepatitis.

Systemic Activin Is Elevated in Patients With Severe Alcoholic Hepatitis.

Constrictive Entrapment Neuropathies of a Limb Secondary to Restraint Strapping: A Case Report

Rationale: Entrapment neuropathies are peripheral nerve disorders at specific anatomical locations. They may be caused by trauma in a manner of sprains or bone fracture, but it is often caused by repetitive insults or compression of nerves as they travel through a narrow anatomic space. Pregnancy and pre-existing comorbidities such as diabetes, obesity, cancer, or autoimmune diseases may also cause nerve entrapment. Objective: To highlight the case of a 52-year-old female developing right foot dysesthesia and weakness after continuous restraint strapping from her previous hospitalization. Case: Here we have the case of a 52-year-old Filipino female consulted because of right foot dysesthesia, allodynia, and mild weakness. She had a history of bipolar disorder and recent onset of acute psychosis and overdosing with her irregularly taken maintenance olanzapine tablets. She was put on restraint strapping of the right lower limb in her one-week hospital stay. This resulted in developing restraint marks on her right ankle accompanied by difficulty walking on heels and toes, spontaneous dysesthesia, and touch allodynia of her entire right foot. An electrodiagnosis yielded right lower limb focal neuropathies involving the right fibular nerve, right tibial nerve, right superficial fibular, and right sural nerves. The prescribed amitriptyline and gabapentin for 6 months led to gradual improvement of neuropathic pain. Discussion and Summary: Our case exemplifies focal limb neuropathies from entrapment due to restraint strapping. Electrodiagnostic confirmation of neuropathies of the same limb sensory and motor nerves was mandated to corroborate clinical neuropathic pain and after ruling out other causes of entrapment neuropathies. Prolonged use of neuropathic pain medications were needed to attain relief in this present case. Restrictive strapping is an iatrogenic cause of entrapment neuropathy that is preventable, had there been proper medical attention applied.

The Hexosamine Biosynthetic Pathway Links Innate Inflammation With Epithelial-Mesenchymal Plasticity in Airway Remodeling.

Disruption of the lower airway epithelial barrier plays a major role in the initiation and progression of chronic lung disease. Here, repetitive environmental insults produced by viral and allergens triggers metabolic adaptations, epithelial-mesenchymal plasticity (EMP) and airway remodeling. Epithelial plasticity disrupts epithelial barrier function, stimulates release of fibroblastic growth factors, and remodels the extracellular matrix (ECM). This review will focus on recent work demonstrating how the hexosamine biosynthetic pathway (HBP) links innate inflammation to airway remodeling. The HBP is a core metabolic pathway of the unfolded protein response (UPR) responsible for protein N-glycosylation, relief of proteotoxic stress and secretion of ECM modifiers. We will overview findings that the IκB kinase (IKK)-NFκB pathway directly activates expression of the SNAI-ZEB1 mesenchymal transcription factor module through regulation of the Bromodomain Containing Protein 4 (BRD4) chromatin modifier. BRD4 mediates transcriptional elongation of SNAI1-ZEB as well as enhancing chromatin accessibility and transcription of fibroblast growth factors, ECM and matrix metalloproteinases (MMPs). In addition, recent exciting findings that IKK cross-talks with the UPR by controlling phosphorylation and nuclear translocation of the autoregulatory XBP1s transcription factor are presented. HBP is required for N glycosylation and secretion of ECM components that play an important signaling role in airway remodeling. This interplay between innate inflammation, metabolic reprogramming and lower airway plasticity expands a population of subepithelial myofibroblasts by secreting fibroblastic growth factors, producing changes in ECM tensile strength, and fibroblast stimulation by MMP binding. Through these actions on myofibroblasts, EMP in lower airway cells produces expansion of the lamina reticularis and promotes airway remodeling. In this manner, metabolic reprogramming by the HBP mediates environmental insult-induced inflammation with remodeling in chronic airway diseases.

The influence of preconditioning with low dose of LPS on paraquat-induced neurotoxicity, microglia activation and expression of \u03b1-synuclein and synphilin-1 in the dopaminergic system

BackgroundProlonged inflammation, oxidative stress, and protein aggregation are important factors contributing to Parkinson’s disease (PD) pathology. A known ROS generator, pesticide paraquat (PQ), was indicated as an environmental substance potentially increasing the incidence of PD and is used to model this disease. We investigated if a combination of inflammation and oxidative stress in subthreshold doses would exacerbate the modelled neuropathology.MethodsWe examined the late effects of acute or repeated peripheral inflammation induced by low dose of LPS (10 μg/kg, ip) on PQ toxicity in the rat nigrostriatal dopaminergic pathway, microglial activation markers and expression of major Lewy bodies proteins, α-synuclein and synphilin-1.ResultsWe observed that LPS increased, while PQ decreased body temperature and microglia CD11b expression in the SN. Single LPS pretreatment, 3 h before repeated weekly PQ injections (4×) slightly aggravated neuronal degeneration in the SN. Moreover, degeneration of dopaminergic neurons after weekly repeated inflammation itself (4×) was observed. Interestingly, repeated LPS administration combined with each PQ dose counteracted such effect. The expression of α-synuclein decreased after repeated LPS injections, while only combined, repeated LPS and PQ treatment lowered the levels of synphilin-1. Therefore, α-synuclein and synphilin-1 expression change was influenced by different mechanisms. Concomitantly, decreased levels of the two proteins correlated with decreased degeneration of dopaminergic neurons and with a normalized microglia activation marker.ConclusionsOur results indicate that both oxidative insult triggered by PQ and inflammation caused by peripheral LPS injection can individually induce neurotoxicity. Those factors act through different mechanisms that are not additive and not selective towards dopaminergic neurons, probably implying microglia. Repeated, but small insults from oxidative stress and inflammation when administered in significant time intervals can counteract each other and even act protective as a preconditioning effect. The timing of such repetitive insults is also of essence.

Axonal injury following mild traumatic brain injury is exacerbated by repetitive insult and is linked to the delayed attenuation of NeuN expression without concomitant neuronal death in the mouse.

Mild traumatic brain injury (mTBI) affects brain structure and function and can lead to persistent abnormalities. Repetitive mTBI exacerbates the acute phase response to injury. Nonetheless, its long‐term implications remain poorly understood, particularly in the context of traumatic axonal injury (TAI), a player in TBI morbidity via axonal disconnection, synaptic loss and retrograde neuronal perturbation. In contrast to the examination of these processes in the acute phase of injury, the chronic‐phase burden of TAI and/or its implications for retrograde neuronal perturbation or death have received little consideration. To critically assess this issue, murine neocortical tissue was investigated at acute (24‐h postinjury, 24hpi) and chronic time points (28‐days postinjury, 28dpi) after singular or repetitive mTBI induced by central fluid percussion injury (cFPI). Neurons were immunofluorescently labeled for NeuroTrace and NeuN (all neurons), p‐c‐Jun (axotomized neurons) and DRAQ5 (cell nuclei), imaged in 3D and quantified in automated manner. Single mTBI produced axotomy in 10% of neurons at 24hpi and the percentage increased after repetitive injury. The fraction of p‐c‐Jun+ neurons decreased at 28dpi but without neuronal loss (NeuroTrace), suggesting their reorganization and/or repair following TAI. In contrast, NeuN+ neurons decreased with repetitive injury at 24hpi while the corresponding fraction of NeuroTrace+ neurons decreased over 28dpi. Attenuated NeuN expression was linked exclusively to non‐axotomized neurons at 24hpi which extended to the axotomized at 28dpi, revealing a delayed response of the axotomized neurons. Collectively, we demonstrate an increased burden of TAI after repetitive mTBI, which is most striking in the acute phase response to the injury. Our finding of widespread axotomy in large fields of intact neurons contradicts the notion that repetitive mTBI elicits progressive neuronal death, rather, emphasizing the importance of axotomy‐mediated change.

Inflammatory Molecules Released by Mechanically Injured Astrocytes Trigger Presynaptic Loss in Cortical Neuronal Networks.

Deformation, compression, or stretching of brain tissues cause diffuse axonal injury (DAI) and induce structural and functional alterations of astrocytes, the most abundant cell type in the brain. To gain further insight into the role of mechanically activated astrocytes on neuronal networks, this study was designed to investigate whether cytokines released by mechanically activated astrocytes can affect the growth and synaptic connections of cortical neuronal networks. Astrocytes were cultivated on elastic membranes and subjected to repetitive mechanical insults, whereas well-defined protein micropatterns were used to form standardized neuronal networks. GFAP staining showed that astrocytes were mechanically activated after two cycles of stretch and mesoscale discovery assays indicated that injured astrocytes released four major cytokines. To understand the role of these cytokines, neuronal networks were cultured with the supernatant of healthy or mechanically activated astrocytes, and the individual contribution of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) was studied. We found that the supernatant of two-cycle stretched astrocytes decreased presynaptic terminals and indicated that TNF-α must be considered a key player of the synaptic loss. Furthermore, our results indicate that cytokines released by injured astrocytes significantly modulate the balance between TNFR1 and TNFR2 receptors by enhancing R2 receptors. We demonstrated that TNF-α is not involved in this process, suggesting a predominant role of other secreted cytokines. Together, these results contribute to a better understanding of the consequences of repetitive astrocyte deformations and highlight the role of inflammatory signaling pathways in synaptic plasticity and modulation of TNFR1 and TNFR2 receptors.

Tobacco Use and Periodontal Disease-The Role of Microvascular Dysfunction.

Simple SummaryPeriodontal disease consists of a wide range of inflammatory conditions that affect the supporting apparatus of teeth, and is highly prevalent in adults worldwide. Tobacco use is currently recognized as the most important risk factor for periodontal disease as it negatively affects both disease evolution and therapeutic strategies. Given close contact with tobacco products, oral microcirculation becomes dysfunctional which, in turn, aggravates periodontal disease. This paper intends to provide a comprehensive review about the impact of tobacco use on oral microcirculation and the mechanisms underlying periodontal disease aggravation. Acute nicotine administration or tobacco use increases oral perfusion (gingiva, lip, tongue) of healthy subjects due to local irritation and increased blood pressure, which overcome neural- and endocrine-mediated vasoconstriction. Chronic tobacco use, particularly smoking, causes several morphological changes to oral microcirculation, namely, increased vascular density and tortuosity, despite a decrease in capillary diameter, and decreased perfusion due to the multiple vasoconstrictive insults. Periodontal disease involves considerable gingival inflammation and angiogenesis in non-smokers which, in chronic smokers, are considerably suppressed, in part due to local immune suppression and oxidative stress. Tobacco exposure, irrespective of form of use, causes long-term microvascular dysfunction which may not be completely reversible upon cessation, and increases the risk of complications due to the natural disease course or secondary to therapeutic strategies.Periodontal disease consists in highly prevalent wide-ranging inflammatory conditions that affect the supporting apparatus of teeth. Tobacco use is the most important risk factor for periodontal disease as it increases disease severity and periodontal surgery complications. Tobacco use is harmful for the vasculature by causing microvascular dysfunction, which is known to negatively affect periodontal disease. To the author’s knowledge this paper is the first comprehensive review on the mechanisms by which tobacco use affects oral microcirculation and impacts the pathophysiology of periodontal disease. In healthy subjects, acute nicotine administration or tobacco use (smoking/smokeless forms) increases the blood flow in the oral mucosa due to local irritation and increased blood pressure, which overcome neural- and endocrine-mediated vasoconstriction. Chronic tobacco smokers display an increased gingival microvascular density, which is attributed to an increased capillary recruitment, however, these microcirculatory units show higher tortuosity and lower caliber. These morphological changes, together with the repetitive vasoconstrictive insults, contribute to lower gingival perfusion in chronic smokers and do not completely regress upon smoking cessation. In periodontal disease there is considerable gingival inflammation and angiogenesis in non-smokers which, in chronic smokers, are considerably suppressed, in part due to local immune suppression and oxidative stress. Tobacco exposure, irrespective of the form of use, causes long-term microvascular dysfunction that increases the risk of complications due to the natural disease course or secondary therapeutic strategies.

Complementary NAD+ replacement strategies fail to functionally protect dystrophin-deficient muscle

BackgroundDuchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs).MethodsUsing a metabolomics-based approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38.ResultsAdministering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, nor improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery.ConclusionsIn the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, we found no evidence that either small molecule strategy is sufficient to restore muscle contractile function or confer protection from eccentric injury, undermining the modulation of NAD metabolism as a therapeutic approach for DMD.

Obstructive sleep apnoea and open heart surgery: a review of its incidence and impact to patients.

Obstructive sleep apnea (OSA) is a serious health disorder which contributes to cardiovascular complications, decreased work productivity, automobile accidents, and death. This condition is characterized by a temporary cessation of breathing resulting due to upper airway closure during a person's sleep. Strain to the heart caused by this repetitive hypoxic insult can lead to postoperative complications for patients undergoing heart surgery. Recognizing cardiac surgical patients with OSA is important. Early recognition and intervention such as use of BiPAP device can reduce the postoperative complications due to OSA. The aim of this study is to identify the incidence of unrecognized OSA in cardiac surgical patients. This is a retrospective analysis of a prospective data of the study which was done between July 2012 and July 2013 in University Malaya Medical Center. All patients undergoing elective cardiac surgery were recruited and the demographic data, questionnaire and the portable sleep study results were obtained. Patients were followed up till 30 days to record any complications. Data were entered in SPSS version 17 and analysis was done. The incidence of OSA was 61.4% and 43.5% were moderate to severe OSA. There was male predominance of OSA (79%) with a mean age of 60 years. OSA subjects had shorter inter-incisor distance (4.18±0.6 cm) and larger waistline (94.1±12.1 cm). The STOP-Bang questionnaire has a sensitivity of 75.8% in predicting apnoa-hypopnea index (AHI) ≥5/hour. OSA can be diagnosed with a simple screening questionnaire and a bedside portable sleep study. Cardiac patients diagnosed with OSA can be pre-emptively given extra attention in managing their postoperative care.

Implementation of a Generalized Vestibular Rehabilitation Approach.

Vestibular dysfunction is common in military populations as the result of traumatic brain injury, blast exposure, and/or repetitive acoustic insult. Vestibular rehabilitation (VR) has been proven to be an effective approach in the treatment of vestibular dysfunction. VR consists of a series of exercises prescribed on the basis of individual patient needs by a vestibular trained physical therapist (PT). A generalized approach to VR in a military setting could help widen the system capacity to take care of patients with vestibular symptoms, shorten waiting times for patients without impacting the burden on PTs. The rehabilitation team at the Warrior Recovery Center on Fort Carson, Colorado, developed a generalized approach in which a series of exercises were administered to individuals with vestibular dysfunction. The implementation of this approach was evaluated for quality improvement purposes and is presented below. We utilized a combined observational/survey approach to evaluate the patients' tolerance to a variety of exercises provocative of dizziness symptoms, their overall satisfaction with the intervention, the appropriateness of the allocated resources, and the providers' confidence with the treatment and its administration. Research staff members were present as observers in all therapy sessions during the 3-month implementation period and administered surveys to patients and clinical staff at pre-established time points. Descriptive analysis was performed to summarize observations and responses to surveys. Linear regression was utilized to evaluate if a reduction in the number of patient:provider interactions occurred over the course of the implementation period. A total of 25 therapy sessions took place during the implementation period. Each visit lasted an average of 56 minutes with 6 minutes allocated for set up, 45 minutes for intervention and 5 minutes for cleanup. The mean number of patients per session was 3 (Max 6, Min 1) with one staff member running the intervention 56% of the time and two staff members running the intervention 44% of the time. Exercise tolerance was at 99% and the need for one-on-one interactions between providers and patients was easily attained at a 3:1 patient:provider rate. Survey assessment demonstrated 100% patient satisfaction with the program and 100% provider confidence with treatment delivery. Generalized Vestibular Rehabilitation Treatment (GVRT) was successfully implemented at the Warrior Recovery Center at Fort Carson, Colorado. The individual exercises used during the interventions were challenging to patients yet well tolerated. Resource allocation was appropriate in terms of personnel, time, and equipment. Both the clinical staff and the patients felt comfortable with the therapy and subjectively found it to be effective. The project provided valuable information to clinical staff, administrators, and the organization.

Effect of mean ocular perfusion pressure on primary open angle glaucoma

Primary open angle glaucoma is the most common form of glaucoma and it remains asymptomatic until the late stage of the disease. The purpose of this study is to compare the mean ocular perfusion pressure with the primary open angle glaucoma. A total of 60 study subjects were divided into two following groups: a) newly diagnosed patients with primary open angle glaucoma (case) and b) age and sex-matched healthy volunteers (control). The intraocular pressure and blood pressure were measured 3 hourly from 8:00 am to 11:00 pm. The mean ocular perfusion pressure of the right eyes in untreated primary open angle glaucoma was 39.9 ± 7.5 mm Hg whereas it was 47.7 ± 7.7 mm Hg in the control. The odds ratio was 6.6 (95% CI, 2.1-20.5; p=0.002). The right eyes of untreated primary open angle glaucoma had 6.6 times more risk compared to the control group. The mean ocular perfusion pressure of left eyes in untreated primary open angle glaucoma was 39.9 ± 7.5 mm Hg and 48.6 ± 4.0 mm Hg in the control group. The odds ratio was 5.7 (95% CI, 1.8-17.5; p=0.004). The left eyes of untreated primary open angle glaucoma had 5.7 times more risk compared to control group. The findings revealed the evidence of vascular mechanism in glaucoma pathogenesis: Reduction of mean ocular perfusion pressure ≤48 mm Hg, may lead to daily repetitive ischemic insult to the optic nerve.

Intensity Specific Repetitive Mild Traumatic Brain Injury Evokes an Exacerbated Burden of Neocortical Axonal Injury.

Mild traumatic brain injury (mTBI) has been linked to enduring neurological damage following repetitive injury. Previously, we reported that intensity-specific, repetitive mTBI exacerbated microvascular and axonal damage in brainstem. For a more rigorous and global assessment, we assessed the burden of neocortical diffuse axonal injury (DAI) evoked by repetitive mTBI. Mice were subjected to mild central fluid percussion injuries at 1.4 and 1.6 atm with or without repetitive insult at a 3-hour interval and killed at 24 hours postinjury. Neocortical DAI within layer V was quantitatively assessed by double-labeling p-c-Jun and NeuN to identify both the axotomized and total neuronal population. Both confocal and electron microscopic findings revealed no apparent evidence of neuronal death. Repetitive mTBI of 1.6 atm group, but not of 1.4 atm group, demonstrated a significantly higher proportion of axotomized neurons. These results demonstrate that different intensities of mTBI induced different burdens of DAI after repetitive insult. Interestingly, the parallel loss of the righting reflex reflected differences in injury intensity, yet the duration of this reflex was not elongated by the repetitive insult. These data highlight some of the complex issues surrounding repetitive mTBI and its associated morbidity, mandating the need for continued exploration.

Aspergillus fumigatus viability drives allergic responses to inhaled conidia

BackgroundAspergillus fumigatus–induced allergic airway disease has been shown to involve conidial germination in vivo, but the immunological mechanisms remain uncharacterized. ObjectiveA subchronic murine exposure model was used to examine the immunological mediators that are regulated in response to either culturable or nonculturable A fumigatus conidia. MethodsFemale B6C3F1/N mice were repeatedly dosed via inhalation with 1 × 105 viable or heat-inactivated conidia (HIC), twice per week for 13 weeks (26 exposures). Control mice inhaled high-efficiency particulate arrestor–filtered air. The influence of A fumigatus conidial germination on the pulmonary immunopathological outcomes was evaluated by flow cytometry analysis of cellular infiltration in the airways, assessment of lung messenger RNA expression, quantitative proteomics, and histopathology of whole lung tissue. ResultsRepeated inhalation of viable conidia, but not HIC, resulted in allergic inflammation marked by vascular remodeling, extensive eosinophilia, and accumulation of alternatively activated macrophages (AAMs) in the murine airways. More specifically, mice that inhaled viable conidia resulted in a mixed TH1 and TH2 (IL-13) cytokine response. Recruitment of eosinophils corresponded with increased Ccl11 transcripts. Furthermore, genes associated with M2 or alternatively activated macrophage polarization (eg, Arg1, Chil3, and Retnla) were significantly up-regulated in viable A fumigatus–exposed mice. In mice inhaling HIC, CD4+ T cells expressing IFN-γ (TH1) dominated the lymphocytic infiltration. Quantitative proteomics of the lung revealed metabolic reprogramming accompanied by mitochondrial dysfunction and endoplasmic reticulum stress stimulated by oxidative stress from repetitive microbial insult. ConclusionOur studies demonstrate that A fumigatus conidial viability in vivo is critical to the immunopathological presentation of chronic fungal allergic disease.

Immune-regulating effects of exercise on cigarette smoke-induced inflammation.

Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus–capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic antioxidative capacity and several compensatory mechanisms in tissues such as an increased anabolic signaling in muscle or an increased compliance of the vascular system. Accordingly, regular exercise training seems to protect long-term smokers against some important negative local and systemic consequences of smoking. Data suggest that it seems to be important to start exercise training as early as possible.

Perinatal Hypoxia and Ischemia in Animal Models of Schizophrenia.

Intrauterine or perinatal complications constitute a major risk for psychiatric diseases. Infants who suffered from hypoxia–ischemia (HI) are at twofold risk to develop schizophrenia in later life. Several animal models attempt to reproduce these complications to study the yet unknown steps between an insult in early life and outbreak of the disease decades later. However, it is very challenging to find the right type and severity of insult leading to a disease-like phenotype in the animal, but not causing necrosis and focal neurological deficits. By contrast, too mild, repetitive insults may even be protective via conditioning effects. Thus, it is not surprising that animal models of hypoxia lead to mixed results. To achieve clinically translatable findings, better protocols are urgently needed. Therefore, we compare widely used models of hypoxia and HI and propose future directions for the field.

Region-specific alterations in astrocyte and microglia morphology following exposure to blasts in the mouse hippocampus.

Traumatic brain injury (TBI) is a serious public health concern, especially injuries from repetitive insults. The main objective of this study was to immunocytochemically examine morphological alterations in astrocytes and microglia in the hippocampus 48h following a single blast versus multiple blasts in adult C57BL/6 mice. The effects of ketamine and xylazine (KX), two common anesthetic agents used in TBI research, were also evaluated due to the confounding effect of anesthetics on injury outcome. Results showed a significant increase in hypertrophic microglia that was limited to the outer molecular layer of the dentate gyrus, but only in the absence of KX. Although the presence or absence of KX had no effect on astrocytes following a single blast, a significant decrease in astrocytic immunoreactivity was observed in the stratum lacunosum moleculare following multiple blasts in the absence of KX. The morphological changes in astrocytes and microglia reported in this study reveal region-specific differences in the absence of KX that could have significant implications for our interpretation of glial alterations in animal models of injury.

Postnatal hypoxia evokes persistent changes within the male rat's dopaminergic system.

Hypoxic insults occurring during the perinatal period remain the leading cause of permanent brain impairment. Severe cognitive and motor dysfunction, as seen in cerebral palsy, will occur in 4-10% of post-hypoxic newborns. Subtle cognitive impairment, apparent in disorders of minimal brain dysfunction will occur in >3 million post-hypoxic newborns. Analyses of post-hypoxic rodent brains reveal reduced extracellular levels of dopamine, a key neurotransmitter of vigilance, execute function, and behavior. The purpose of this study was to assess whether synaptic levels of dopamine could be enhanced in post-hypoxic, hypodopaminergic rats. Newborn male rats were exposed to subtle, repetitive hypoxic insults for 4-6h per day, during postnatal days 7-11. During adolescence, we quantified dopamine content within the caudate nuclei. We then determined whether extracellular dopamine levels could be increased by injecting the psychostimulant d-amphetamine. We next assessed whether the post-hypoxic rat's response to d-amphetamine would differentially impact place preference behavior when compared with littermate controls. Total tissue content of dopamine was significantly higher in post-hypoxic rats. Injection of d-amphetamine liberated that dopamine which subsequently enhanced extracellular levels. Post-hypoxic rats acquired conditioned place preference for d-amphetamine during the training days. During the testing day, total time spent in the amphetamine-pairing box did not differ between post-hypoxic and control littermates. Postnatally occurring hypoxic insults promote remodeling of the dopaminergic system resulting in increased intracellular sequestering of this monoamine. That sequestered dopamine can be released using the psychostimulant d-amphetamine, which did not promote a conditioned place preference any greater than was observed in non-hypoxic littermate controls.

Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells

Tubular epithelial cells (TECs) can be dedifferentiated by repetitive insults, which activate scar-producing cells generated from interstitial cells such as fibroblasts, leading to the accumulation and deposition of extracellular matrix molecules. The dedifferentiated TECs play a crucial role in the development of renal fibrosis. Therefore, renal fibrosis may be attenuated if dedifferentiated TECs are converted back to their normal state (re-epithelialization). However, the mechanism underlying the re-epithelialization remains to be elucidated. In the present study, TGF-β1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-β1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1β) was identified as a candidate molecule involved in inducing re-epithelialization by means of DNA microarray and biological network analysis. In functional validation studies, the re-epithelialization by TGF-β1 removal was abolished by HNF-1β knockdown. Furthermore, the ectopic expression of HNF-1β in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-β/Smad signaling, even in the presence of TGF-β1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1β expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1β downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1β suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1β in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.