Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 7 Articles
Background: Spontaneous autoimmune peripheral neuropathy including Guillain-Barr�© Syndrome (GBS) represents\r\nas one of the serious emergencies in neurology. Although pathological changes have been well documented,\r\nmolecular and cellular mechanisms of GBS are still under-explored, partially due to short of appropriate animal\r\nmodels. The field lacks of spontaneous and translatable models for mechanistic investigations. As GBS is preceded\r\noften by viral or bacterial infection, a condition can enhance co-stimulatory activity; we sought to investigate the\r\ncritical role of T cell co-stimulation in this autoimmune disease.\r\nResults: Our previous study reported that transgene-derived constitutive expression of co-stimulator B7.2 on antigen\r\npresenting cells of the nervous tissues drove spontaneous neurological disorders. Depletion of CD4 T cells in L31 mice\r\naccelerated the onset and increased the prevalence of the disease. In the current study, we further demonstrated that\r\nL31/CD4-/- mice exhibited both motor and sensory deficits, including weakness and paresis of limbs, numbness to\r\nmechanical stimuli and hypersensitivity to thermal stimulation. Pathological changes were characterized by massive\r\ninfiltration of macrophages and CD8 T cells, demyelination and axonal damage in peripheral nerves, while changes in\r\nspinal cords could be secondary to the PNS damage. In symptomatic L31/CD4-/- mice, the disruption of the blood\r\nneural barriers was observed mainly in peripheral nerves. Interestingly, the infiltration of immune cells was initiated in\r\npre-symptomatic L31/CD4-/- mice, prior to the disease onset, in the DRG and spinal roots where the blood nerve barrier\r\nis virtually absent.\r\nConclusions: L31/CD4-/- mice mimic most parts of clinical and pathological signatures of GBS in human; thus\r\nproviding an unconventional opportunity to experimentally explore the critical events that lead to spontaneous,\r\nautoimmune demyelinating disease of the peripheral nervous system....
Background: Arteriovenous malformations (AVMs) are a type of high-flow vascular malformations that most\r\ncommonly occurs in the head and neck. They are present at birth but are usually clinically asymptomatic until later\r\nin life. The pathogenesis of AVMs remains unclear and therapeutic approaches to AVMs are unsatisfied. In order to\r\nprovide a tool for studying the pathogenesis and therapies of this disease, we established and studied a xenograft\r\nanimal model of human AVMs.\r\nMethods: Fresh human AVMs specimens harvested from 4 patients were sectioned (5x5x5 mm) and xenografted\r\nsubcutaneously in 5 immunologically na�¯ve nude mice (Athymic Nude-Foxn1nu). Each mouse had four pieces\r\nspecimens in four quadrants along the back. The grafts were observed weekly for volume, color and texture. The\r\ngrafts were harvested at every 30 days intervals for histologic examination. All grafts (n = 20) were sectioned and\r\nstained for hematoxylin and eosin (H&E). Comparative pathologic evaluation of the grafts and native AVMs were\r\nperformed by two blinded pathologists. Immunohistochemical examination of human-specific nuclear antigen,\r\nvascular endothelial growth factor receptor-2 (VEGFR-2) and Ki-67 was performed.\r\nResults: Clinical characteristics and pathologic diagnosis of native human derived AVMs were confirmed. 85%\r\n(n = 17) of AVM xenografts survived although the sizes decreased after implantation. Histological examination\r\ndemonstrated numerous small and medium-size vessels and revealed structural characteristics matching the native\r\nAVMs tissue.76.5% (n = 13) of the surviving xenografts were positive for Ki-67 and human-specific nuclear antigen\r\nsuggesting survival of the human derived tissue, 52.9% (n = 9) were positive for VEGFR-2.\r\nConclusions: This preliminary xenograft animal model suggests that AVMs can survive in the nude mouse. The\r\npresence of human-specific nuclear antigen, VEGFR-2, and Ki-67 demonstrates the stability of native tissue qualities\r\nwithin the xenografts....
Background: Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) have varying degrees\r\nof salvageable myocardium at risk of irreversible injury. We hypothesized that a novel model of NSTE-ACS produces\r\nacute myocardial injury, measured by increased T2 cardiovascular magnetic resonance (CMR), without significant\r\nnecrosis by late gadolinium enhancement (LGE).\r\nMethods: In a canine model, partial coronary stenosis was created and electrodes placed on the epicardium.\r\nMyocardial T2, an indicator of at-risk myocardium, was measured pre- and post-tachycardic pacing.\r\nResults: Serum troponin-I (TnI) was not detectable in unoperated sham animals but averaged 1.97 �± 0.72 ng/mL\r\nin model animals. Coronary stenosis and pacing produced significantly higher T2 in the affected vs. the remote\r\nmyocardium (53.2 �± 4.9 vs. 43.6 �± 2.8 ms, p < 0.01) with no evident injury by LGE. Microscopy revealed no significant\r\nirreversible cellular injury. Relative respiration rate (RRR) of affected vs. remote myocardial tissue was significantly\r\nlower in model vs. sham animals (0.72 �± 0.07 vs. 1.04 �± 0.07, p < 0.001). Lower RRR corresponded to higher final\r\nTnI levels (R2 = 0.83, p = 0.004) and changes in CaMKIID and mitochondrial gene expression.\r\nConclusions: A large animal NSTE-ACS model with mild TnI elevation and without ST elevation, similar to the\r\nhuman syndrome, demonstrates signs of acute myocardial injury by T2-CMR without significant irreversible damage.\r\nReduced tissue respiration and associated adaptations of critical metabolic pathways correspond to increased\r\nmyocardial injury by serum biomarkers in this model. T2-CMR as a biomarker of at-risk but salvageable myocardium\r\nwarrants further consideration in preclinical and clinical studies of NSTE-ACS...
Background: Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However,\r\nthe dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly\r\nunderstood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma\r\nmodel and studied how pharmacological intervention affects these processes.\r\nMethods: Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and\r\npresence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of\r\nbronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth\r\nmuscle thickening.\r\nResults: Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and\r\nsmooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and\r\ncollagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only\r\nobserved after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the\r\ndevelopment of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth\r\nmuscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy\r\nwas discontinued.\r\nConclusions: Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces\r\nreversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in\r\ninhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective\r\nin preventing smooth muscle hypertrophy....
Background: Changes in glucocorticoid receptors (GRs) have been implicated in the pathogenesis of stress related\r\npsychiatric disorders such as depression and post-traumatic stress disorder (PTSD). Abnormal adaptation of the\r\nstress-response system following traumatic stress can lead to an altered hypothalamic-pituitary-adrenal axis that\r\nmay contribute to PTSD development. Indeed, elevated GR expression in the hippocampus and prefrontal cortex\r\nlinked to PTSD-like characteristics have been reported in the validated animal model of PTSD, single-prolonged\r\nstress. These findings implicate increased levels of GRs in the development of post-traumatic psychopathology and\r\nsuggest that exploration of GR-targeted interventions may have potential for PTSD prevention. Early handling\r\nduring the neonatal phase alters GR expression and is proposed to confer resilience to stress. We therefore\r\nexamined the effects of combined early handling and single prolonged stress treatments on GR expression.\r\nMethods: Timed pregnant dams gave birth to pups that were subjected to early handling (n = 11) or control\r\n(n = 13) procedures during the neonatal phase. At postnatal day 45 animals underwent single prolonged stress or a\r\ncontrol procedure. Rats were euthanized one day later and GR levels were assayed using western blot\r\nelectrophoresis.\r\nResults: Single prolonged stress exposure enhanced GR expression in the hippocampus and prefrontal cortex. Early\r\nhandling treatment protected against single prolonged stress-induced enhancement of GR expression in the\r\nprefrontal cortex, but not in the hippocampus.\r\nConclusions: These data are a first step in highlighting the importance of targeting GR systems in prevention/\r\nresilience and may suggest that preventive strategies targeting GR upregulation might be particularly effective\r\nwhen prefrontal rather than hippocampal GRs are the target....
Background: Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia\r\nusing growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular\r\nendothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients\r\nto the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched\r\nwith VEGF liposomes on the hair growth stimulation and its toxicological aspects.\r\nMethods: Mesocricetus auratus were randomly divided into three groups. Control group was treated with\r\nAristoflexW gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical,\r\nhematological and histological analyses were done.\r\nResults: At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by\r\nhair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair\r\nof the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological\r\nresults had shown that VEGF was not 100% inert.\r\nConclusions: VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity....
Background: Heliox has a lower density and higher diffusion capacity compared to\r\noxygen-in-air. We hypothesized that heliox ventilation allows for a reduction in\r\nminute volume ventilation and inspiratory pressures needed for adequate gas\r\nexchange in an animal model of an acute lung injury.\r\nMethods: After intratracheal instillation of lipopolysaccharide (10 mg/kg), adult rats\r\nwere randomized to ventilation with either a gas mixture of helium/oxygen (50:50%)\r\nor oxygen/air (50:50%). They were mechanically ventilated according to the ARDSnet\r\nrecommendations with tidal volumes of 6 ml/kg and monitored with a\r\npneumotachometer. Bronchoalveolar lavage fluid was analyzed for markers of lung\r\ninjury, and embedded lung sections were histologically scored for lung injury.\r\nResults: Heliox limited the increase in driving pressures needed to achieve preset\r\ntidal volumes, with a concomitant decrease in loss of compliance. Heliox did neither\r\nallow for reduced minute volume ventilation in this model nor improve gas\r\nexchange. Also, heliox did not reduce lung injury.\r\nConclusions: Heliox modestly improved respiratory mechanics but did not improve\r\nlung injury in this rat model of acute respiratory distress syndrome....
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