ABSTRACT
To date, there are only a few, non-evidence based, cerebroprotective therapeutic strategies for treatment and, accordingly, for prevention of secondary brain injuries following severe closed head trauma. In order to develop new therapy strategies, existing realistic animal models need to be advanced. The objective is to bridge standardized small animal models and actual patient medical care, since the results of experimental small animal studies often cannot be transferred to brain-injured humans. For improved standardization of high-velocity trauma, new trauma devices for initiating closed traumatic brain injury in sheep were developed. The following new devices were tested: 1. An anatomically shaped rubber bolt with an integrated oscillation absorber for prevention of skull fractures; 2. Stationary mounting of the bolt to guarantee stable experimental conditions; 3. Varying degrees of trauma severity, i. e., mild and severe closed traumatic brain injury, using different cartridges; and 4. Trauma analysis via high-speed video recording. Peritraumatic measurements of intracranial pressure, brain tissue pH, brain tissue oxygen, and carbon dioxide pressure, as well as neurotransmitter concentrations were performed. Cerebral injuries were documented with magnetic resonance imaging and compared to neuropathological results. Due to the new trauma devices, skull fractures were prevented. The high-speed video recording documented a realistic trauma mechanism for a car accident. Enhancement of extracellular glutamate, aspartate, and gamma amino butyric acid concentrations began 60 min after the trauma. Magnetic resonance imaging and neuropathological results showed characteristic injury patterns of mild, and severe, closed traumatic brain injury. The severe, closed traumatic brain injury group showed diffuse axonal injuries, traumatic subarachnoid hemorrhage, and hemorrhagic contusions with inconsistent distribution among the animals. The model presented here achieves a gain in standardization of severe, closed traumatic brain injury by increasing approximation to reality. The still existent heterogeneity of brain pathology mimics brain changes observed in patients after high-energy trauma. This model seems to close the gap between experimental small animal models and clinical studies. However, further investigations are needed to evaluate if this model can be used for testing new therapeutic strategies for these patients.
Subject(s)
Brain Injuries/pathology , Head Injuries, Closed/pathology , Animals , Aspartic Acid/metabolism , Brain/metabolism , Brain/pathology , Brain Injuries/metabolism , Carbon Dioxide/metabolism , Disease Models, Animal , Electron Spin Resonance Spectroscopy , Glutamic Acid/metabolism , Head Injuries, Closed/metabolism , Humans , Image Processing, Computer-Assisted , Intracranial Pressure , Magnetic Resonance Imaging , Oxygen Consumption , Sheep , Sheep, Domestic , gamma-Aminobutyric Acid/metabolismABSTRACT
A new remote-controlled interface-type chamber was designed in order to conduct experiments in brain slices involving gas, fluid, and temperature changes with as little tissue manipulation as possible. The chamber allows for extremely quick changes between different fluid and/or gaseous phases and for active cooling as well as heating by using a set of electromechanical valves and Peltier elements. The design drawings are complemented by exemplary tests of temperature and gas changes, and electrophysiological recordings of slices manipulated with gas and fluid alterations were used to test the efficacy and accuracy of the design. Changing between normoxia and anoxia needs less than 30 s, while the readjustment of the chamber to a new, preset temperature is accomplished in about 1 min. Supplementary data provide a proposal for the electronic circuit diagram. This chamber design should simplify data acquisition in interface environments.
Subject(s)
Diffusion Chambers, Culture/instrumentation , Diffusion Chambers, Culture/methods , Electrophysiology/instrumentation , Electrophysiology/methods , Animals , Hippocampus/physiology , Hypoxia , Rats , Rats, Wistar , TemperatureABSTRACT
BACKGROUND: The therapeutic use of pure oxygen, even under hyperbaric conditions, has been well established for about 50 years, whereas the discovery of oxygen occurred 250 years earlier. Many neurosurgical patients suffer from brain tissue damage, due to reduced blood flow, obstructive vessel disease, or as a result of traumatic brain injury. METHODS AND RESULTS: The application of pure oxygen in these patients is the only method of increasing the O(2) concentration in tissue with impaired blood supply and can minimize secondary impairment of brain tissue. DISCUSSION: In this brief historical overview we focus on the development and evidence of hyperbaric oxygenation in this specific field of insufficient oxygen supply to the central neural tissue. CONCLUSION: With the use of modern biological methods and new study designs, HBO has a place in evidence-based treatment of patients with neural tissue damage.
Subject(s)
Hyperbaric Oxygenation/history , Hypoxia, Brain/history , Neurosurgical Procedures/history , Brain/metabolism , Brain/physiopathology , Brain Injuries/metabolism , Brain Injuries/physiopathology , Brain Injuries/therapy , Decompression Sickness/therapy , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , History, Ancient , Hyperbaric Oxygenation/methods , Hypoxia, Brain/therapy , Neurosurgical Procedures/methods , Oxygen/metabolism , Oxygen Consumption/physiology , Stroke/metabolism , Stroke/physiopathology , Stroke/therapyABSTRACT
While the vasomotor effects of pCO(2) modulation are well documented, the influence of the carbon dioxide-bicarbonate system on the ischemia tolerance of brain tissue itself is controversial. Guinea-pig hippocampal tissue was subjected to ischemia simulation in an interface environment and examined electrophysiologically. Characteristics of anoxic depolarization as well as the postischemic recovery of evoked potentials were registered. During ischemia simulation, pH was changed and afterwards restored to 7.4. pH of 7.6 (n=6), and 7.8 (n=6) were adjusted by increasing bicarbonate concentration without changing pCO(2), while pH 8.2 was reached either with normal pCO(2) (n=8) or with zero CO(2) (n=9). pH 7.1 was created by doubling pCO(2) (n=22) or reducing bicarbonate (n=21), while acid pH of 6.9 (high pCO(2) and low bicarbonate) led to erratic measurements in the interface setup. Alkalotic conditions did not improve electrophysiological stability of the tissue, and pH 8.2 impeded the recovery of evoked potentials. Hypercarbic pH 7.1 led to significantly longer latency of depolarization while the same pH with lowered bicarbonate did not. Evoked potentials, however, recovered only partially after ischemia at hypercarbic pH 7.1. Once the tissue had recovered from anoxic depolarization at control pH, hypercarbic acidosis did not have any further protective effect when ischemia simulation was repeated (n=12). These results do not strengthen the concept of hyperventilation in intensive care, while they suggest a potential of hypercarbia within broader strategies delaying the onset of secondary brain damage.
Subject(s)
Bicarbonates/metabolism , Carbon Dioxide/metabolism , Evoked Potentials/physiology , Hippocampus/physiology , Hypoxia/physiopathology , Acidosis/physiopathology , Alkalosis/physiopathology , Animals , Electric Stimulation/methods , Guinea Pigs , In Vitro Techniques , Partial Pressure , Reaction Time/physiologyABSTRACT
AIMS: The polycomb factor BMI-1 has recently been implicated in tumorigenesis of the central nervous system in several experimental animal models. However, the significance of BMI-1 in human glioma has not been investigated. Here we describe expression of the polycomb protein BMI-1 and its downstream targets p16(Ink4a) and MDM2 in both high- and low-grade human glioma. METHODS: Tumour samples were collected from 305 adult patients treated for primary grades 2-4 gliomas between 1980 and 2006 in Finland and Germany. BMI-1, p16 and MDM2 expression was evaluated using immunohistochemistry in representative paraffin-embedded tumour tissue. The significance of observed immunoreactivity, age at onset, gender, histopathological findings and proliferative index was analysed in univariate and multivariate survival models. RESULTS: BMI-1 was expressed in all histologic types of diffuse gliomas. We found a significant correlation (P = 0.007) between the frequency of BMI-1 immunoreactive tumour cells and poor survival in World Health Organization grades II-III oligodendrogliomas and oligoastrocytomas (n = 62). The median survival of patients grouped by low, intermediate or high frequency of BMI-1 immunoreactive tumour cells was 191 months, 151 months and 68 months, respectively. This association was also significant in the Cox multivariate regression model. Nuclear p16 immunopositivity predicted better survival in astrocytomas and an inverse correlation between p16 expression and the Ki-67 mitotic index was also observed. CONCLUSIONS: BMI-1 is found in all histological types of gliomas and the relative protein expression of BMI-1 is a novel independent prognostic marker in oligodendroglial tumours.
Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/metabolism , Glioma/metabolism , Nuclear Proteins/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Repressor Proteins/biosynthesis , Adolescent , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Female , Gene Expression , Glioma/mortality , Glioma/pathology , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Polycomb Repressive Complex 1 , Proto-Oncogene Proteins c-mdm2/biosynthesisABSTRACT
Four feline cases of bilateral eyelid coloboma were treated with injectable subdermal collagen and a modified Stades technique. This new technique was found to be easy to perform and the long-term results appear to be similar to other published reports.
Subject(s)
Cat Diseases/surgery , Collagen/administration & dosage , Coloboma/veterinary , Eyelids/abnormalities , Animals , Cat Diseases/pathology , Cats , Coloboma/surgery , Eyelids/surgery , Female , Injections/veterinary , Male , Ophthalmologic Surgical Procedures/veterinarySubject(s)
Orbital Neoplasms/veterinary , Animals , Autopsy/veterinary , Diagnosis, Differential , Dogs , Female , Magnetic Resonance Imaging/veterinary , Neoplasm Invasiveness , Orbital Diseases/diagnosis , Orbital Diseases/veterinary , Orbital Neoplasms/diagnosis , Orbital Neoplasms/pathology , PrognosisSubject(s)
Adenocarcinoma/veterinary , Dog Diseases/pathology , Orbital Neoplasms/veterinary , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Animals , Dog Diseases/diagnosis , Dog Diseases/surgery , Dogs , Female , Orbital Neoplasms/pathology , Orbital Neoplasms/surgery , Palliative Care , Retinal Detachment/etiology , Retinal Detachment/veterinarySubject(s)
Choristoma/veterinary , Corneal Ulcer/veterinary , Guinea Pigs , Rodent Diseases/diagnosis , Uveitis/veterinary , Animals , Calcinosis/etiology , Calcinosis/veterinary , Choristoma/etiology , Corneal Ulcer/complications , Corneal Ulcer/diagnosis , Male , Rats , Rodent Diseases/pathology , Uveitis/etiologyABSTRACT
Ten cases of uni- or bilateral restrictive ventromedial strabismus in young dogs of different breeds are reported. Clinically, abnormalities were restricted to the extraocular muscles with sparing of the masticatory muscles and limb muscles. This was supported in some cases by imaging studies, electrophysiology, and immunocytochemical assay for antibodies against type 2M fibers. Histologically, there was variable lymphocytic plasmacytic mononuclear cell infiltration and fibrosis. This disorder is similar in many aspects to chronic masticatory myositis with focal myositis and subsequent fibrosis. Surgical correction may restore eye position and vision.
ABSTRACT
Nimodipine and dimethyl sulfoxide (DMSO) were tested (alone and in combination) regarding their ability to increase hypoxic tolerance of brain slices under 'hypoxic' (deprivation of oxygen) or 'ischemic' (hypoxia+withdrawal of glucose) conditions. Direct current (DC) and evoked potentials were recorded in the CA1 region of hippocampal slices of adult guinea pigs. After induction of hypoxia or ischemia, the latency of anoxic terminal negativity (ATN) of the DC potential was determined during superfusion with artificial cerebrospinal fluid alone (aCSF), and during superfusion with aCSF containing DMSO [0.1% (14.1 mmol/l) and 0.4% (56.3 mmol/l)] with the addition of nimodipine (40 micromol/l). Latencies of ATN with first hypoxia were 6.7+/-3.7 min in the control group, 9. 3+/-4.2 min in the 0.4% DMSO group and 12.3+/-5.5 min (P=0.007) in the nimodipine/0.4% DMSO group. Latencies of ATN with first ischemia were 2.9+/-2 min in the control group, 4.1+/-1.6 min in the 0.1% DMSO group, 7.1+/-3.9 min in the 0.4% DMSO group (P=0.006), 5.3+/-1. 5 min in the nimodipine/0.1% DMSO group and 7.6+/-3 min (P<0.001) in the nimodipine/0.4% DMSO group. DMSO (0.4%), either alone or in combination with nimodipine, increase the latency of the ATN after acute onset of hypoxia and ischemia.
Subject(s)
Brain/drug effects , Dimethyl Sulfoxide/pharmacology , Hypoxia-Ischemia, Brain/prevention & control , Nimodipine/pharmacology , Animals , Brain/physiology , Brain/physiopathology , Brain Ischemia/prevention & control , Evoked Potentials/drug effects , Guinea Pigs , Hypoxia, Brain/prevention & control , Hypoxia-Ischemia, Brain/physiopathology , In Vitro Techniques , Membrane Potentials/drug effects , Nerve Endings/drug effects , Nerve Endings/physiology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Reaction TimeSubject(s)
Dog Diseases/diagnosis , Scleritis/veterinary , Uveitis/veterinary , Adrenal Cortex Hormones/therapeutic use , Animals , Azathioprine/therapeutic use , Dog Diseases/drug therapy , Dogs , Female , Immunosuppressive Agents/therapeutic use , Scleritis/diagnosis , Scleritis/drug therapy , Uveitis/diagnosisSubject(s)
Conjunctivitis/veterinary , Dog Diseases/diagnosis , Eye Neoplasms/veterinary , Scleral Diseases/veterinary , Animals , Biopsy , Conjunctivitis/etiology , Diagnosis, Differential , Dog Diseases/pathology , Dog Diseases/surgery , Dogs , Eye Neoplasms/diagnosis , Eye Neoplasms/pathology , Eye Neoplasms/surgery , Female , Hyperemia/etiology , Hyperemia/veterinary , Ophthalmoscopy/methods , Ophthalmoscopy/veterinary , Scleral Diseases/etiologyABSTRACT
Dimethyl sulfoxide (DMSO), which is widely used as a solvent for a variety of drugs, was used in the present study to investigate its ability to increase the hypoxic tolerance of brain tissue in vitro. DC-potentials and evoked potentials (EP, Schaffer collateral stimulation) were recorded in the CA1 region of hippocampal slices from adult guinea pigs. The latencies of the negative DC-potential shift (anoxic terminal negativity, ATN) after onset of hypoxia (95% N2, 5% CO2) were determined during superfusion with artificial cerebrospinal fluid (aCSF) or DMSO 0.4% dissolved in aCSF, respectively. The latencies of ATN were increased by DMSO application from 7.5+/-0.9 min (mean +/- SEM) under control conditions (n = 38) to 11.1+/-1.3 min with DMSO (n = 22, P < 0.01). These results demonstrate a neuroprotective effect of DMSO.
Subject(s)
Dimethyl Sulfoxide/pharmacology , Free Radical Scavengers/pharmacology , Hippocampus/physiology , Hypoxia, Brain/physiopathology , Reaction Time/drug effects , Animals , Evoked Potentials/drug effects , Female , Guinea Pigs , Hippocampus/drug effects , Hypoxia/physiopathology , Male , Membrane Potentials/drug effects , Organ Culture Techniques , Osmolar Concentration , Oxygen/physiologyABSTRACT
To estimate whether mild hypothermia during repetitive hypoxia provides a neuroprotective effect on brain tissue, hippocampal slice preparations were subjected to repetitive hypoxic episodes under different temperature conditions. Slices of guinea pig hippocampus (n=40) were placed at the interface of artificial cerebrospinal fluid (aCSF) and gas (normoxia: 95% O2, 5% CO2; hypoxia: 95% N2, 5% CO2). Evoked potentials (EP) and direct current (DC) potentials were recorded from hippocampal CA1 region. Slices were subjected to two repetitive hypoxic episodes under the following temperature conditions: (A) 34 degrees C/34 degrees C, (B) 30 degrees C/30 degrees C and (C) 34 degrees C/30 degrees C. Hypoxic phases lasted until an anoxic terminal negativity (ATN) occurred. The recovery after first hypoxia lasted 30 min. Tissue function was assessed regarding the latency of ATN and the recovery of evoked potentials. The ATN latencies with protocol A (n = 25) for the first and second hypoxia were 5.9+/-1.3 min (mean+/-S.E.M., 1st hypoxia) and 2.4+/-0.9 min (2nd hypoxia), with protocol B the latencies (n = 7) were significantly longer: 25.2+/-7.1 min and 15.6+/-7.7 min. With protocol C (n=8), the latencies were 5.6+/-1.8 and 3.3+/-0.5 min. No differences were seen in the recovery of the EPs with protocols A-C. Our results suggest that a mild hypothermia is only neuroprotective if applied from an initial hypoxia onwards.