Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders.

Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinson's Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways. Delta opioid agonists such as (D-Ala2, D-Leu5) enkephalin (DADLE) have been shown to promote neuronal survival and decrease apoptosis, resulting in a substantial amount of research for its application as a neurological therapeutic. Most notably, DADLE has demonstrated significant potential to reduce cell death following ischemic events. Current research is working to reveal the complex mechanisms of DADLE's neuroprotective properties. Ultimately, our knowledge of the DOR receptors and agonists has made the opioid system a promising target for therapeutic intervention in many neurological disorders.

Bronchial inflammation in seasonal allergic rhinitis with or without asthma in relation to natural exposure to pollen allergens.

BACKGROUND: Nasal inflammation in allergic rhinitis enhances bronchial Th2 driven inflammation and development of asthma. We assessed bronchial inflammation induced by natural allergen exposure during pollen season in patients with pollinosis with or without asthma to show the intensity of inflammation in asthma and rhinitis and possible persistence of inflammation in periods without allergen exposure. METHODS: Sputum was induced in 52 patients with seasonal allergic rhinitis without asthma, 38 patients with seasonal allergic rhinitis and seasonal asthma and 23 healthy volunteers. Sampling was performed 6-8 weeks before the expected beginning of symptoms, during symptomatic period and 6-8 weeks after the end of symptoms. Sputum ECP was measured by means of chemi-luminiscent immunometric assay and sputum cell counts were assessed by classical staining and immunocytochemistry. RESULTS: Sputum eosinophils were on the whole higher in both asthma and rhinitis compared to controls (p<0.001, p=0.003). The rise of eosinophils during pollen season compared with values out of pollen season was significant in asthma (classical staining) (p=0.014) and slightly apparent in rhinitis (immunocytochemistry) (p=0.073). The seasonal rise of sputum ECP was observed only in rhinitis (p=0.006). CONCLUSIONS: Inflammation of the lower airway in patients with allergic rhinitis with and without asthma has been confirmed by means of both sputum eosinophil count and sputum ECP level. Persistent inflammation of lower airway in periods without allergen exposure was proven in seasonal asthma. This may have implications for the therapy of seasonal allergic rhinitis with and without asthma in terms of promoting long-term anti-inflammatory treatment.

A radiologic correlation with the basic functional neuroanatomy of the brain.

Primary cortical areas for motor, sensory and sensitive functions are localized in certain areas of the brain cortex. In clinical practice, cross sectional imaging (computer tomography and magnetic resonance) is wildy used for diagnostics purpose, treatment planning and follow up of the patients. Accurate orientation in brain structures is necessary for the evaluation of radiological images. There are numerable landmark signs, which can be used for precise identification of important brain structures. In this review article, the mostly used anatomical landmarks are described and shown on the cross sectional images (magnetic resonance imaging) (Fig. 14, Ref. 25).

Percutaneous dilation tracheostomy versus surgical tracheostomy in critically ill patients.

OBJECTIVES: This study was done to compare surgical tracheostomy and percutaneous dilation tracheostomy in respect to their early postoperative complications in critically ill patients. METHODS: At a university hospital general intensive care unit, we studied 109 critically ill patients who underwent either elective surgical tracheostomy (n=63) or percutaneous dilation tracheostomy (n=46). The number and type of complications during operation and early postoperative period were recorded and compared. RESULTS: When comparing the perioperative period of surgical versus percutaneous dilation tracheostomy, we recorded 2 vs 0 complications (NS difference).Average durations of postoperative observation (time until decannulation, release or death) were 16.04 and 16.09 days in group 1 and group 2, respectively; the difference in time was insignificant. When comparing the surgical versus percutaneous groups we have found no significant difference in postoperative complications in respect of bleeding and leakage through the space between the cannula and the stoma (bleeding 2 (3.2 %) vs 3 (6.5 %), NS; leakage 6 (9.5 %) vs 4 (8.7 %), NS). A significant difference was found in infectious complications and disintegration of tracheostomy (inflammation 17 (27 %) vs 0 (0 %), p<0.001, disintegration 14 (22.2 %) vs 0 (0), p<0.001, total number of complications 39 (61.9 %) vs 7 (15.2 %), p<0.001). No other complications were recorded. CONCLUSION: Percutaneous dilation tracheostomy is an equally safe method compared with surgical tracheostomy. While posing the same perioperative risk, it requires neither the transport to the operating theater, nor the presence of the whole surgical team. In the early postoperative period, it significantly reduces the complications, mainly infections in a critically ill patient. The latter benefits make it a method of choice in elective tracheostomies at ICU (Tab. 2, Ref. 11).

SCOTOMAS IN THE VISUAL FIELD AS THE FIRST SIGN OF INTRACRANIAL EXPANSION. CASE REPORT.

The most common cause of visual field loss in ophthalmology is glaucoma. Other causes of visual field damage include local damage to the eye itself in intrabulbar or retrobulbar neuritis or injuries. However, they can also be caused by general diseases, e.g. in endocrine orbitopathy, toxic and nutritional neuropathy, or in diseases that are localized intracranially. Each of these findings in itself suggests the nature of the lesion, its intracranial location, lateral occurrence, as well as in which part of the visual pathway the lesion is located. The use of perimeter has therefore become the primary examination method, which is available, is not demanding and will quickly allow a diagnosis to be made. When found on a perimetric examination, it is necessary to indicate targeted imaging examinations, such as computed tomography or magnetic resonance imaging. The article describes a patient who was primarily examined at the Department of Ophthalmology, Faculty of Medicine, Comenius University and the University hospital of Bratislava. The patient reported visual field outages, and after subsequent computed tomography, she was interdisciplinary managed and surgery was done on at the Neurosurgical Department. After the operation, there was a significant improvement without a pathological finding on the perimeter.

Investigation of the osteitis deformans phases in snake vertebrae by double-pulse laser-induced breakdown spectroscopy.

Double-pulse laser-induced breakdown spectroscopy (DP-LIBS) was optimized for microspatial analyses of fossil and recent snake vertebrae. As complimentary techniques, solution analysis by inductively coupled plasma mass spectrometry and synchrotron radiation X-ray microtomography was utilized in order to determine the overall concentration of the selected elements in the samples and to visualize nondestructively the fossil sample microstructure, respectively. Elemental mapping of pathological bony tissue by DP-LIBS has been proven as a powerful tool for considering the osteitis deformans phases in fossil vertebrae.

Central and Peripheral Secondary Cell Death Processes after Transient Global Ischemia in Nonhuman Primate Cerebellum and Heart.

Cerebral ischemia and its pathological sequelae are responsible for severe neurological deficits generally attributed to the neural death within the infarcted tissue and adjacent regions. Distal brain regions, and even peripheral organs, may be subject to more subtle consequences of the primary ischemic event which can initiate parallel disease processes and promote comorbid symptomology. In order to characterize the susceptibility of cerebellar brain regions and the heart to transient global ischemia (TGI) in nonhuman primates (NHP), brain and heart tissues were harvested 6 months post-TGI injury. Immunostaining analysis with unbiased stereology revealed significant cell death in lobule III and IX of the TGI cerebellum when compared to sham cerebellum, coinciding with an increase in inflammatory and apoptotic markers. Cardiac tissue analysis showed similar increases in inflammatory and apoptotic cells within TGI hearts. A progressive inflammatory response and cell death within the cerebellum and heart of chronic TGI NHPs indicate secondary injury processes manifesting both centrally and peripherally. This understanding of distal disease processes of cerebral ischemia underscores the importance of the chronic aberrant inflammatory response and emphasizes the needs for therapeutic options tailored to target these pathways. Here, we discuss the protocols for characterizing the histopathological effects of transient global ischemia in nonhuman primate cerebellum and heart, with an emphasis on the inflammatory and apoptotic cell death processes.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

Mapping the intake of different elements in vegetal tissues by dual-energy X-ray imaging at DaPhine synchrotron light source.

This article reports on the first utilization of the soft X-ray beamline at the DaPhine synchrotron light source for mapping the intake of different elements in plant tissues. As a test, the method of dual-energy X-ray microradiography was applied to the investigation of the natural sulfur content in dried leaf and root samples. Our ultimate goal was to monitor the pollutant lead and its intake, which was added in controlled doses to the hydroponic medium of laboratory-controlled samples of vegetal species. The results obtained by the nondestructive X-ray radiographic analysis are compared to the values of concentrations determined by a standard chemical analysis utilizing atomic absorption spectroscopy. From this comparison the validity of the X-ray detection of heavy metals in biological samples has been confirmed. The superposition of the dual energy results on the simple planar radiography shows the representation of the pollutant intake directly on the sample structures. It should be pointed out that this method, developed here for plant root and leaves could be applied to any biological sample of interest, but the preparation and observation conditions necessitate different strategies according to the type of sample under analysis.

Neuroprotective and neuroregenerative potential of pharmacologically-induced hypothermia with D-alanine D-leucine enkephalin in brain injury.

Neurovascular disorders, such as traumatic brain injury and stroke, persist as leading causes of death and disability - thus, the search for novel therapeutic approaches for these disorders continues. Many hurdles have hindered the translation of effective therapies for traumatic brain injury and stroke primarily because of the inherent complexity of neuropathologies and an inability of current treatment approaches to adapt to the unique cell death pathways that accompany the disorder symptoms. Indeed, developing potent treatments for brain injury that incorporate dynamic and multiple disorder-engaging therapeutic targets are likely to produce more effective outcomes than traditional drugs. The therapeutic use of hypothermia presents a promising option which may fit these criteria. While regulated temperature reduction has displayed great promise in preclinical studies of brain injury, clinical trials have been far less consistent and associated with adverse effects, especially when hypothermia is pursued via systemic cooling. Accordingly, devising better methods of inducing hypothermia may facilitate the entry of this treatment modality into the clinic. The use of the delta opioid peptide D-alanine D-leucine enkephalin (DADLE) to pharmacologically induce temperature reduction may offer a potent alternative, as DADLE displays both the ability to cause temperature reduction and to confer a broad profile of other neuroprotective and neuroregenerative processes. This review explores the prospect of DADLE-mediated hypothermia to treat neurovascular brain injuries, emphasizing the translational steps necessary for its clinical translation.

Multifaceted Effects of Delta Opioid Receptors and DADLE in Diseases of the Nervous System.

BACKGROUND: The opioid system is considered a potential therapeutic target in a variety of neurological disorders. Delta opioid receptors (DORs) are broadly expressed in the brain, and their activation protects cells from hypoxic/ischemic insults by counteracting disruptions of ionic homeostasis and initiating neuroprotective pathways. The DOR agonist D-Ala2-D-Leu2-Enkephalin (DADLE) promotes neuronal survival, mitigates apoptotic pathways, and protects neurons and glial cells from ischemia-induced cell death, thus making DADLE a promising therapeutic option for stroke. The significant amount of research regarding DORs and DADLE in the last decades also suggests their potential in treating other neurological disorders. METHODS: This review compiled relevant literature detailing the role of DORs and agonists in central nervous system function and neuropathologies. RESULTS: Several studies demonstrate potential mechanisms implicating a key interaction between DORs and DADLE in conferring neuroprotective benefits. A better understanding of DOR function in disease-specific contexts is critical to transitioning DOR agonists into the clinic as a therapy for stroke and other neurological diseases. CONCLUSION: Evidence-based studies support the potential of the delta-opioid family of receptors and its ligands in developing novel therapeutic strategies for stroke and other brain disorders.

An update on intracerebral stem cell grafts.

INTRODUCTION: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.

Monitoring of the heavy-metal hyperaccumulation in vegetal tissues by X-ray radiography and by femto-second laser induced breakdown spectroscopy.

This article reports on the utilization of X-ray microradiography and laser induced breakdown spectroscopy (LIBS) techniques for investigation of the metal accumulation in different part of leaf samples. The potential of the LIBS-analysis for finding the proper plant species for phytoremediation is compared with the results of microradiography measurements at the HERCULES source at ENEA, Rome (Italy) and X-ray microradiography experiments at the ELETTRA Synchrotron, Trieste (Italy).

Translating regenerative medicine techniques for the treatment of epilepsy.

Epilepsy is considered a chronic neurological disorder and is accompanied by persistent and diverse disturbances in electrical brain activity. While antiepileptic pharmaceuticals are still the predominant treatment for epilepsy, the advent of numerous surgical interventions has further improved outcomes for patients. Despite these advancements, a subpopulation continues to experience intractable seizures which are resistant to current conventional and nonconventional therapeutic options. In this review, we begin with an introduction to the clinical presentation of epilepsy before discussing the clinically relevant laboratory models of epilepsy. Finally, we explore the implications of regenerative medicine - including cell therapy, neuroprotective agents, and electrical stimulation - for epilepsy, supplemented with our laboratory's data. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

Utilizing Delta Opioid Receptors and Peptides for Cytoprotection: Implications in Stroke and Other Neurological Disorders.

The opioid system has been elucidated as a potential target for therapy in a variety of neurological disorders including stroke. Delta opioid receptors have been revealed to pose an especially compelling biological function for new neuroprotective therapies. Two distinct therapeutic mechanisms have been characterized for delta opioid receptors, namely, these receptors aid in maintaining ionic homeostasis and initiate endogenous neuroprotective pathways. Specific agonists of delta opioid receptors, such as (D-Ala2, D-Leu5) enkephalin (DADLE), have displayed the ability to promote neuronal survival and mitigate apoptotic pathways. These findings have led to a significant amount of research on this molecule's potential as a neurotherapeutic. At the forefront of these efforts has been investigation into DADLE's ability to protect neurons and glial cells following ischemia. Additionally, current research is attempting to reveal the dynamic neuroprotective mechanisms that mediate DADLE's therapeutic benefits. This review article discusses the scientific evidence supporting the use of delta opioid family of receptors and ligands as a promising target for therapeutic intervention in neurological disorders, with emphasis on stroke.

Current functional status of Symbion total artificial heart recipients after transplantation.

This multicenter study examines long-term data from the five most experienced North American centers (> 8 total artificial heart [TAH] implants), investigating the functional status of 37 patients who received a Symbion TAH followed by a heart transplant (TX) with post-TX survival > or = 1 year. Primary indications for TAH use included acute cardiogenic shock in 38% (14/37) of patients and deterioration while on the TX waiting list in 35% (13/37). At the time of this study, 86% (32/37) of patients were alive, 94% of whom were functioning at a New York Heart Association (NYHA) classification of I (75% [24/32]) or II (19% [6/32]). NYHA classification before death was I for all five patients who died 40 +/- 17 (r = 14-58) months after transplant. Of the 32 surviving patients, 47% (15) were working, 16% (5) were retired, 12% (4) chose not to work, and 9% (3) were in school. The remaining 16% (5) were unable to work due to surgical limitations. After TX, significant infections occurred in 81% (26/32) of patients and rejection in 72% (23/32). At 1 year after TX, creatinine was within normal limits (< or = 1.4 mg/100 ml or 65-125 mol/L) for 41% (13/32) of patients, 1-2 times normal for 56% (18/32), and > 2 times normal for 3% (1/32). Although TAH is not required for most patients awaiting TX, the device allows excellent long-term functional status in patients otherwise at risk for death. No long-term problems related to the use of temporary mechanical circulatory support were found.

Registry report. Use of total artificial hearts: summary of world experience, 1969-1991.

Eleven models of total artificial hearts (TAHs) have been used for transient or permanent circulatory support in patients with failing hearts. From April 4, 1969 to July 1, 1991, 230 TAHs were used in 226 patients (four patients received a second TAH) at 39 centers worldwide. Five patients received a Symbion TAH as a permanent circulatory support device; the remaining 221 received TAHs as bridges to cardiac transplantation. The principal investigators received written requests for demographic and clinical information after each implant and annually thereafter to assess survival. The mean patient age (+/- SD) was 43 +/- 12 years (range, 13-69 years); 88% of patients were men. The primary indications for implantation were deterioration while on a transplant waiting list (34%) and acute cardiogenic shock (33%). The duration of implantation ranged from < 1 to 603 days; 65% received heart transplants. The incidence of infection and embolic events occurring during implantation times were 36% and 9%, respectively (stroke, 5%; transient ischemic attacks 4%). Most deaths were caused by sepsis (33%) and multiorgan failure (32%) during the implantation period; sepsis (36%) and rejection of the donor heart (19%) were responsible for most deaths in patients who died after transplantation. The 1 year survival rate was 37% for all patients receiving a device and 50% for those who received a transplanted organ. In the overall Symbion TAH population (187 patients), 40% survived 1 year and 56% of the transplanted group survived 1 year; 39 non-Symbion TAH implants resulted in one long-term survivor (3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of active and passive antibacterial immunization on skin allograft survival in rabbits.

The effect of active and passive antibacterial immunization on transplantation immunity was investigated in rabbits. Immunization with dead bacterial vaccines prepared from E. coli, Proteus mirabilis and Pseudmonas aeruginosa had no effect on skin allograft survival, whereas immunization with vaccines prepared from streptococcal and staphylococcal strains shortened allograft survival. Similar results were obtained with specific antisera against individual microbial species. Skin allografts survived in rabbits treated with antisera against E. coli, Proteus mirabilis and Pseudomonas aeruginosa in the same manner as in untreated controls, whereas allograft survival was shortened with antisera against streptococci or staphylococci. The possible mechanism of the stimulatory effect of Gram-positive cocci on transplantation immunity is discussed and the possibilities of using active and passive antibacterial immunication in clinical transplantation are considered.

Effect of cytomegalovirus antigen on skin allograft survival in rabbits.

In experiments on rabbits it was found that the subcutaneous injection of cytomegalovirus (CMV) antigen into the draining lymphatic area of the skin allograft caused a decrease in graft survival. The difference of experimental versus control grafts was statistically significant. The finding supports some clinical data regarding the increased incidence of rejection episodes during CMV infection.

Effects of various immunosuppressive drugs on the development of experimental renal infection in rats.

The effect of azathioprine, hydrocortisone and antihymocyte serum on the development of experimental colibacillary renal infection in rats was assessed by macroscopical findings in the kidneys, especially by determining the number of microbes in the infected organ, on day 7 after injection of the infectious agent. The greatest multiplication of bacteria and so the most pronounced macroscopical changes occurred after ALS treatment. There was statistically significant difference between ALS-treated group and the control group, whereas the differences between controls and the other experimental groups (Imuran, hydrocortisone) were non-significant.