Purification, structure determination and synthesis of covalitoxin-II, a short insect-specific neurotoxic peptide from the venom of the Coremiocnemis validus (Singapore tarantula).
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Spider venoms contain toxins that specifically immobilize and kill insects. We report the purification and characterization of a new insect-specific toxin named covalitoxin-II (Cvtx-II; mass, 3406. 24+/-0.64), from Coremiocnemis validus (Singapore tarantula) venom. The complete 31 amino acid sequence of Cvtx-II has been determined and it shows less than 40% identity with spider toxins. However, Cvtx-II has conserved cystine motif analogous to other spider and omega-conotoxins. Cvtx-II was chemically synthesized and identified with the native Cvtx-II. Synthetic Cvtx-II induced insect-specific non-lethal excitatory activity when injected into crickets, but not in cockroaches and mice. (+info)
Coupling of peripheral tolerance to endogenous interleukin 10 promotes effective modulation of myelin-activated T cells and ameliorates experimental allergic encephalomyelitis.
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Several immune-based approaches are being considered for modulation of inflammatory T cells and amelioration of autoimmune diseases. The most recent strategies include simulation of peripheral self-tolerance by injection of adjuvant free antigen, local delivery of cytokines by genetically altered T cells, and interference with the function of costimulatory molecules. Although promising results have been obtained from these studies that define mechanisms of T cell modulation, efficacy, practicality, and toxicity, concerns remain unsolved, thereby justifying further investigations to define alternatives for effective downregulation of aggressive T cells. In prior studies, we demonstrated that an immunoglobulin (Ig) chimera carrying the encephalitogenic proteolipid protein (PLP)1 peptide corresponding to amino acid sequence 139-151 of PLP, Ig-PLP1, is presented to T cells approximately 100-fold better than free PLP1. Here, we demonstrate that aggregation endows Ig-PLP1 with an additional feature, namely, induction of interleukin (IL)-10 production by macrophages and dendritic cells, both of which are antigen-presenting cells (APCs). These functions synergize in vivo and drive effective modulation of autoimmunity. Indeed, it is shown that animals with ongoing active experimental allergic encephalomyelitis dramatically reduce the severity of their paralysis when treated with adjuvant free aggregated Ig-PLP1. Moreover, IL-10 displays bystander antagonism on unrelated autoreactive T cells, allowing for reversal of disease involving multiple epitopes. Therefore, aggregated Ig-PLP1 likely brings together a peripheral T cell tolerance mechanism emanating from peptide presentation by APCs expressing suboptimal costimulatory molecules and IL-10 bystander suppression to drive a dual-modal T cell modulation system effective for reversal of autoimmunity involving several epitopes and diverse T cell specificities. (+info)
A temperature-sensitive paralytic mutant defines a primary synaptic calcium channel in Drosophila.
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Neurotransmission at chemical synapses involves regulated exocytosis of neurotransmitter from the presynaptic terminal. Neurotransmitter release is thought to be triggered by calcium influx through specific classes of voltage-gated calcium channels. Here we report genetic and functional analysis implicating a specific calcium channel gene product in neurotransmitter release. We have isolated a temperature-sensitive paralytic allele of the Drosophila calcium channel alpha1 subunit gene, cacophony (cac). This mutant, referred to as cac(TS2), allows functional analysis of synaptic transmission after acute perturbation of a specific alpha1 subunit. Electrophysiological analysis at neuromuscular synapses revealed that neurotransmitter release in cac(TS2) is markedly reduced at elevated temperatures, indicating that cac encodes a primary alpha1 subunit functioning in synaptic transmission. These observations further define the molecular basis of voltage-gated calcium entry at synapses and provide a new starting point for further genetic analysis of synaptic mechanisms. (+info)
Synthesis of virus-specific high-mobility DNA after temperature upshift of SC-1 cells chronically infected with moloney murine leukemia virus mutant ts1.
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Premature termination products of reverse transcription that consist physically of viral minus-sense single-stranded DNA that is shorter than one long terminal repeat and partial DNA duplexes are dramatically increased in the central nervous system (CNS) of FVB/N mice that are infected by ts1, a temperature-sensitive mutant of Moloney murine leukemia virus. Due to their migration in agarose gels, these incomplete physical forms of DNA have been designated high-mobility (HM) DNA. In non-CNS tissues, the level of HM DNA is either low or not detectable. In order to determine the conditions that are necessary for the synthesis of HM DNA in vivo, we have characterized the physical forms of HM DNA that were synthesized in vitro in chronically infected SC-1 cells after temperature upshift. At the permissive temperature of 34 degrees C, the chronically infected SC-1 cells did not synthesize HM DNA. After temperature upshift of the cultured cells from 34 to 37 degrees C, the chronically infected SC-1 cells developed extremely high levels of HM DNA. Following temperature downshift of the cultured cells from 37 to 34 degrees C, a decrease in the level of HM DNA and an increase in the level of unintegrated linear proviral DNA occurred simultaneously. These results suggested that the accumulation of HM DNA both in vitro and in vivo may be the result of superinfection. (+info)
Complications from regional anaesthesia for carotid endarterectomy.
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The complications of carotid endarterectomy (CEA) under cervical plexus blockade have yet to be fully evaluated. Two different cases are presented; both patients suffered sudden collapse following superficial and deep cervical plexus block in preparation for CEA. The causes, presenting signs and differential diagnoses are discussed. The safest cervical plexus anaesthetic block technique has not yet been established. (+info)
Meralgia paresthetica, the elusive diagnosis: clinical experience with 14 adult patients.
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OBJECTIVE: To discuss the diagnosis and treatment of meralgia paresthetica as reported in the literature and as experienced by the author. SUMMARY BACKGROUND DATA: Meralgia paresthetica is a mononeuropathy of the lateral femoral cutaneous nerve that can lead to significant disability when the diagnosis and treatment is delayed or missed. This condition is relatively common but is frequently mistaken for other disorders. METHODS: Fifteen cases of meralgia paresthetica were identified in 14 patients in a private surgical practice during a 4-year period. All patients were initially treated conservatively and seven patients subsequently underwent surgical treatment. Follow-up ranged from 3 to 6 years. RESULTS: Conservative management consisting of local analgesics, steroids, nonsteroidal antiinflammatories, rest, and reduction or elimination of aggravating factors yielded long-lasting improvement in five patients with meralgia paresthetica. Nine patients with 10 cases of meralgia paresthetica did not benefit in the long term from conservative management. Seven of these patients, representing eight cases of meralgia paresthetica, ultimately opted for surgical management, and all obtained good long-term relief of symptoms. CONCLUSION: Surgical management of meralgia paresthetica is a viable option for patients in whom medical management fails. Based on the published literature and the author's experience, a rationale is presented for determining the appropriate surgical management of these patients. (+info)
Monoparesis. Complication of constant positive airways pressure.
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Erb's palsy has been observed in 2 infants who had been treated with constant positive airways pressure for idiopathic respiratory distress syndrome. Both infants made complete neurological recovery from what was thought to be an acquired injury from the neck seal. (+info)
Natural genetic exchanges between vaccine and wild poliovirus strains in humans.
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In a previous study of poliovirus vaccine-derived strains isolated from patients with vaccine-associated paralytic poliomyelitis (VAPP) (9, 11), we reported that a high proportion (over 50%) of viruses had a recombinant genome. Most were intertypic vaccine/vaccine recombinants. However, some had restriction fragment length polymorphism (RFLP) profiles different from those of poliovirus vaccine strains. We demonstrate here that five such recombinants, of 88 VAPP strains examined, carried sequences of wild (nonvaccine) origin. To identify the parental wild donor of these sequences, we used RFLP profiles and nucleotide sequencing to look for similarity in the 3D polymerase-coding region of 61 wild, cocirculating poliovirus isolates (43 type 1, 16 type 2, and 2 type 3 isolates). In only one case was the donor identified, and it was a wild type 1 poliovirus. For the other four vaccine/wild recombinants, the wild parent could not be identified. The possibility that the wild sequences were of a non-poliovirus-enterovirus origin could not be excluded. Another vaccine/wild recombinant, isolated in Belarus from a VAPP case, indicated that the poliovirus vaccine/wild recombination is not an isolated phenomenon. We also found wild polioviruses (2 of 15) carrying vaccine-derived sequences in the 3' moiety of their genome. All these results suggest that genetic exchanges with wild poliovirus and perhaps with nonpoliovirus enteroviruses, are also a natural means of evolution for poliovirus vaccine strains. (+info)