Incorrectly sited PEEP valve.
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Equipment Design↗
Biomedical subjects
C Brosnan
Publications and source records attributed to C Brosnan.
Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: enhanced in vivo potency of encephalitogenic peptides.
T cell epitope peptides derived from proteolipid protein (PLP139-151) or myelin basic protein (MBP86-100) induce experimental autoimmune encephalomyelitis (EAE) in "susceptible" strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, "resistant" to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 microg of the PLP139-151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.
Animals↗
Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism.
Signaling by extracellular nucleotides through P2 purinergic receptors affects diverse macrophage functions; however, its role in regulating antimicrobial radicals during bacterial infection has not been investigated. Mycobacterium tuberculosis-infected macrophages released ATP in a dose-dependent manner, which correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized ATP, blocked NO synthase (NOSII) up-regulation and NO production induced by infection with M. tuberculosis or bacille Calmette-Guérin, or treatment with LPS or TNF-alpha. Oxidized ATP also inhibited oxygen radical production and activation of NF-kappaB and AP-1 in response to infection and inhibited NO-dependent killing of bacille Calmette-Guérin by macrophages. Experiments using macrophages derived from P2X7 gene-disrupted mice ruled out an essential role for P2X7 in NOSII regulation. These data demonstrate that P2 receptors regulate macrophage activation in response to bacteria and proinflammatory stimuli, and suggest that extracellular nucleotides released from infected macrophages may enhance production of oxygen radicals and NO at sites of infection.
Adenosine Triphosphate↗
Complications of treatment: pulmonary embolism following craniotomy for meningioma.
We present two case reports of patients who suffered a pulmonary embolism (PE) in the week following surgery for removal of a meningioma. Both patients were anticoagulated in the first week following surgery, and as a result, both suffered intracerebral bleeds requiring further surgery. An inferior vena caval (IVC) filter was then used in both patients to prevent further embolic events. Following our experience, we believe that it is dangerous to use intravenous anticoagulation within 6 days of cranial surgery for removal of a meningioma. We have reviewed the literature concerning the present guidelines for thromboembolic prophylaxis in patients requiring neurosurgery and believe that consideration of subcutaneous low-molecular-weight heparin should now be given to all patients requiring craniotomy for removal of a meningioma.
Anticoagulants↗
Regional analgesia in early active labour: combined spinal epidural vs. epidural.
We randomly allocated 93 women in early active labour and requesting epidural analgesia to receive either epidural (n = 48) or combined spinal-epidural analgesia (n = 45). For epidural analgesia 15 ml of bupivacaine 0.1% with 75 micrograms of fentanyl were injected into the epidural space. For combined spinal-epidural analgesia 1 ml of bupivacaine 0.25% with 25 micrograms of fentanyl were injected into the subarachnoid space. For both groups subsequent top-ups of 10 ml of bupivacaine 0.1% with fentanyl 20 micrograms were given using a lightweight patient-controlled epidural analgesia (PCEA) pump with a lockout time of 30 min. We assessed analgesia and the degree of motor blockade and found no significant differences in pain or maternal satisfaction scores between the two groups. The time to first top-up was significantly longer in the epidural group than in the CSE group (p = 0.01). The combined spinal-epidural group had significantly greater motor blockade at 30 min than the epidural group (p = 0.01), but there was no difference after this. The PCEA machine failed completely twice and temporarily many times. We conclude that the combined spinal-epidural technique confers no advantages in early active labour. Also, a lightweight PCEA pump needs to be more reliable before we can recommend its use.
Adult↗
Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice.
Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.
Animals↗
The effect of a toothguard on the difficulty of intubation.
Dental damage is the most common reason for complaints against anaesthetists. The purpose of this study was to investigate the common belief that the use of a toothguard at the time of intubation causes intubation to be more difficult. We studied 80 patients, half of whom were intubated with a toothguard in situ and the other half intubated without a toothguard. The time taken from mouth opening to successful passage of the tracheal tube through the vocal cords was measured. In the toothguard group, the recorded time also included the time taken to insert the toothguard. The median time to intubation in the group with a toothguard was 24 s and the median time to intubation in the group without a toothguard was 17 s. The difference of 7 s in the time to intubation was statistically significant (p = 0.0003). As the recorded times also included the time taken to insert the toothguard, we do not regard this result to be clinically significant and believe that anaesthetists should think carefully before disregarding this simple protective device.
Adolescent↗
IL-10 fails to abrogate experimental autoimmune encephalomyelitis.
Mice adoptively-sensitized to develop chronic relapsing experimental autoimmune encephalomyelitis (EAE), a model for the human demyelinating condition, multiple sclerosis (MS), were given injections of recombinant human IL-10 at various timepoints post-sensitization in an attempt to abrogate disease development. IL-10 is a Th2 immunomodulatory cytokine with known down-regulatory effects upon Th1 responses and macrophages. Contrary to a previous report on EAE and the predicted outcome, after repeated experiments, IL-10 was found to elicit a worsening or no effect upon EAE in the mouse. Animals were studied clinically, histopathologically and immunocytochemically. On no occasion was disease ameliorated by IL-10. Pretreatment with IL-10 of lymph node cells used to transfer EAE had no effect upon disease outcome, indicating that the cells were already committed effectors. Administration of anti-IL-10 monoclonal antibody before onset of signs had no effect when given early post-sensitization and caused marked worsening when given immediately before onset of signs. In the context of this autoimmune demyelinating model, these results suggest that IL-10 alone is insufficient to reverse the effector response and indeed may serve to enhance the cascade of events in EAE.
Adoptive Transfer↗
Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity.
BACKGROUND: The reverse transcriptase inhibitor, 2',3'-dideoxycytidine (ddC), causes a dose-limiting peripheral neuropathy in humans, the mechanism of which is unknown. Rabbits given ddC develop peripheral myelinopathy and axonopathy, but it has not been determined if either the myelin or axonal changes are primary or if they occur concurrently. EXPERIMENTAL DESIGN: To characterize sequential development of the ddC-induced neuropathy, 40 rabbits were given either vehicle or ddC by oral intubation at a dose of 35 mg/kg per day for 24 weeks. Electrophysiologic studies, pathologic examination of peripheral and central nervous system and skeletal muscle, and biochemical analysis of the sciatic nerve were performed at baseline (electrophysiology only) and after 8, 12, 16, 20, and 24 weeks of treatment. RESULTS: Neuropathologic changes in peripheral nerves were first evident at 16 weeks and were more pronounced at 20 and 24 weeks; onset of paresis occurred at week 20, whereas clear electrophysiologic deficits were seen only at week 24. Electrophysiologic changes were prolonged F-waves (measure of proximal motor conduction) and minor changes in distal conduction measurements. Pathologic changes included myelin splitting, intramyelinic edema, demyelination, and remyelination of the largest diameter nerve fibers in the ventral root and sciatic nerve. Axonal degeneration and reduction in axonal diameter were seen. Enlarged mitochondria with abnormal ultrastructure were present in Schwann cells of those animals with a myelinopathy. Mitochondrial abnormalities or other signs of degeneration were not seen in neurons of the dorsal root ganglia or in skeletal muscle. Significant changes were not present in myelin protein composition, myelin lipid composition, or activity of the myelin-specific enzyme 2',3'-cyclic nucleotide 3'-phosphohydrolase. Major reductions in levels of protein zero (P0, the homophilic adhesion protein of myelin) were not seen; however, the turnover rate of P0 was reduced as P0 messenger RNA expression in ddC-treated sciatic nerves decreased to 30 to 50% of control values. CONCLUSIONS: The peripheral neuropathy caused by ddC in rabbits is characterized as a myelinopathy of the proximal portion of the nerve fibers and as an axonopathy involving both proximal and distal fibers. The myelinopathy was associated with enlarged and abnormally shaped mitochondria in Schwann cells and is consistent with an effect of ddC on structure and function of Schwann cell mitochondria. Altered Schwann cell metabolism was evident by reduced levels of P0 messenger RNA, loss of homophilic myelin adhesion at the intraperiod line, and subsequent intramyelinic edema. Because axonal degeneration occurred concurrently with the myelin changes, it could not be determined if axonal changes were secondary to serve myelinic edema or if they represented a primary effect of ddC on neurons.
Animals↗
Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease.
Microglia are associated with central nervous system (CNS) pathology of both Alzheimer's disease (AD) and the acquired immunodeficiency syndrome (AIDS). In AD, microglia, especially those associated with amyloid deposits, have a phenotype that is consistent with a state of activation, including immunoreactivity with antibodies to class II major histocompatibility antigens and to inflammatory cytokines (interleukin-1-beta and tumor necrosis factor-alpha). Evidence from other studies in rodents indicate that microglia can be activated by neuronal degeneration. These results suggest that microglial activation in AD may be secondary to neurodegeneration and that, once activated, microglia may participate in a local inflammatory cascade that promotes tissue damage and contributes to amyloid formation. In AIDS, microglia are the primary target of retroviral infection. Both ramified and ameboid microglia, in addition to multinucleated giant cells, are infected by the human immunodeficiency virus (HIV-1). The mechanism of microglial infection is not known since microglia lack CD4, the HIV-1 receptor. Microglia display high affinity receptors for immunoglobulins, which makes antibody-mediated viral uptake a possible mechanism of infection. In AIDS, the extent of active viral infection and cytokine production may be critically dependent upon other factors, such as the presence of coinfecting agents. In the latter circumstance, very severe CNS pathology may emerge, including necrotizing lesions. In other circumstances, HIV infection of microglia probably leads to CNS pathology by indirect mechanisms, including release of viral proteins (gp120) and toxic cytokines. Such a mechanism is the best hypothesis for the pathogenesis of vacuolar myelopathy in adults and the diffuse gliosis that characterizes pediatric AIDS, in which very little viral antigen can be detected.
Acquired Immunodeficiency Syndrome↗
Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity.
The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose-dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC-treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment-related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.
Administration, Oral↗
Ultrastructure of peripheral neuropathy induced in rabbits by 2',3'-dideoxycytidine.
The nucleoside analogue, 2',3'-dideoxycytidine (ddC), an inhibitor of human immunodeficiency virus reverse transcriptase, mediates virologic and immunologic improvements in acquired immunodeficiency syndrome patients. However, in clinical studies ddC treatment is associated with a dose-limiting peripheral neuropathy. The purpose of this study was to characterize the ultrastructural features of the peripheral neuropathy induced in rabbits. Rabbits received 0, 10, 50, or 100 mg/kg/day of ddC for 18 weeks. A prominent ultrastructural change induced by ddC in sciatic nerve and ventral root was separation of myelin lamellae at the intraperiod line and vacuolation and fragmentation of myelin sheaths. Many demyelinated and remyelinated axons were observed. Although pathologic alterations in Schwann cells were evident by the presence of lipid droplets and myelin figures, their formation was not considered a primary event. Axons containing abnormal cytoplasmic components were occasionally observed. Other changes included redundance of Schwann cell basal lamina and the presence of lipid droplets and/or myelin figures within endoneurial fibroblasts and macrophages. The results of this study indicate that ddC induces a myelinopathy in rabbits characterized by myelin splitting and intramyelinic edema and an axonopathy that may be secondary to the myelin changes.
Animals↗
Gangliosides improve the outcome of experimental allergic neuritis (EAN).
The effect of gangliosides on the clinical expression of experimental allergic neuritis (EAN), a PNS counterpart of experimental allergic encephalomyelitis (EAE), was tested in Lewis rats sensitized with bovine intradural root myelin in complete Freund's adjuvant (CFA). A mixture of bovine brain gangliosides (GM1, GD1a, GD1b, GT1b) was injected intramuscularly at a daily dose of 20 mg per kg beginning 6 days post inoculation. The results show that GA treatment considerably reduces the incidence of mortality, delays its occurrence, and reduces the severity of clinical scores when either the whole population or survivors only are considered. Benefit from GA treatment appeared roughly proportional to disease severity. The neuronotrophic and anti-inflammatory effects possibly play a role in GA protecting effect.
Analysis of Variance↗
Failure to thrive: a dilemma for the community health nurse.
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Community Health Nursing↗
Infection of organotypic cultures of spinal cord and dorsal root ganglia with Trypanosoma cruzi.
Although the involvement of the nervous system in Chagas' disease is well described, the mechanism of the neuronal destruction is unclear. Immunologic, toxic mechanisms and direct invasion have been advocated. Organotypic cultures of spinal cord and dorsal root ganglion derived from Swiss outbred mice were infected with the Brazil strain of Trypanosoma cruzi. Light microscopic and ultrastructural studies were performed at regular intervals. It was found that trypomastigotes were rapidly taken up by glial and other supporting cells. Neurons were rarely parasitized and demyelination was not evident. Loss of several cytoskeletal components was seen. Dendrites were swollen and axons lost their normal filamentous structures but synaptic membranes remained intact. Mitochondrial swelling was evident even in nonparasitized neurons from infected cultures. By 7-10 days of infection the majority of neurons lost their typical morphology and were eventually destroyed by mechanisms other than direct parasite invasion. Organotypic cultures exposed to T. cruzi-conditioned medium exhibited no change in morphology. Since neurons were found only rarely to be parasitized, it is suggested that neuronal destruction is an indirect result of the parasitism of supporting cells such as glial cells and macrophages.
Animals↗
Nickel induction of Rosenthal fibers in rat brain.
Nickel wire implants into the central nervous system of Lewis rats induces the formation of structures morphologically similar to Rosenthal fibers. The nickel-induced lesions are similar to those seen in Alexander's disease and other human conditions in which Rosenthal fibers are found. This is the first report on the induction of Rosenthal fibers in animals. It might be used to design animal models to study Rosenthal fiber formation and possibly Alexander's disease.
Animals↗
Abnormal tubulin aggregates induced by zinc sulfate in organotypic cultures of nerve tissue.
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Animals↗
Notes on the pathogenesis of multiple sclerosis.
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Animals↗