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The functional role of beta-adrenoceptor subtypes in mediating relaxation of pig urethral smooth muscle.
PURPOSE: The predominant beta-adrenoceptor subtype present in the bladder and urethra is beta3-adrenoceptors. We investigated the role of beta-adrenoceptors in mediating relaxation of the in vitro female pig urethra. MATERIALS AND METHODS: Circular strips of urethral tissues were pre-contracted with KCl. Concentration-relaxation curves (CRCs) to beta-adrenoceptor agonists were obtained in the absence and presence of antagonists. RESULTS: The nonselective beta-agonist isoproterenol in 30 animals and the beta3-adrenoceptor agonist BRL37344 in 4 relaxed with high potency (pEC50 7.2 and 8.1, respectively), while the beta2-adrenoceptor agonist salbutamol in 6 had low potency (pEC50 6.1). Mean maximal relaxation responses of BRL37344 and salbutamol relative to maximal isoproterenol responses were 89.8% and 76.7%, respectively. Propranolol (10 to 100 nM) in 18 animals antagonized CRCs to isoproterenol with high affinity (apparent pKB 8.6) but the Schild plot had a slope that was significantly less than unity (0.68, p <0.01). High concentrations of the beta1-antagonist CGP20712A (3 to 30 microM) in 12 animals had no effect on responses to isoproterenol. The beta2-antagonist ICI118551 (30 to 300 nM) in 25 animals antagonized responses to isoproterenol with high affinity (apparent pKB 8.03) with a Schild slope not different from unity (0.79). The beta3-antagonist SR59230A (10 to 100 nM) in 12 animals antagonized CRCs to isoproterenol with an apparent pKB of 7 and with a Schild slope that was again significantly less than unity (0.62, p <0.01), indicating that responses to isoproterenol are mediated by more than 1 beta-adrenoceptor subtype. According to the Schild plot of unity ICI118551 (3 to 30 nM) in 18 animals competitively antagonized responses to salbutamol with high affinity (pA2 8.5). CONCLUSIONS: In the pig urethra beta-adrenoceptor mediated relaxations to isoproterenol are mediated via beta2 and beta3-adrenoceptors, while responses to beta2-adrenoceptor agonists such as salbutamol appear to be mediated only via beta2-adrenoceptors.
Characteristics of adenosine triphosphate [corrected] release from porcine and human normal bladder.
PURPOSE: Although the sensory and motor roles of the purinergic system in the bladder are well proven in animal species, there is increasing evidence that it may have an important role in humans. In addition, it may be important in the pathophysiology of bladder dysfunction. We established the level of adenosine triphosphate (ATP) release from porcine and normal human bladders. MATERIALS AND METHODS: Bladder strips from patients with a urodynamically proven stable bladder undergoing surgery for stress incontinence and those undergoing cystectomy for cancer with no lower urinary tract symptoms were subjected to varying degrees of stretch (up to 50%) and electric field stimulation (10 to 40 Hz). A luciferase assay was used to quantify ATP release. RESULTS: Significantly increased ATP release over baseline was induced by mechanical and electrical stimulation (each p <0.05). Mean ATP release +/- SE from porcine bladders (38.2 +/- 1.9 pM/gm tissue following stretch and 19.9 +/- 6.5 pM/gm following electrical stimulation) was comparable to the release from human bladders (26.1 +/- 2.4 pM/gm tissue following stretch and 29.9 +/- 1.0 pM/gm following electrical stimulation). The main source of ATP release was the urothelium and not the muscle (p <0.05). This ATP release following stretch was not tetrodotoxin sensitive. CONCLUSIONS: The characteristics of ATP release from porcine and human bladders are similar and, therefore, the pig is a good model for humans. The main source of ATP release is urothelium from predominantly nonneuronal sources. This study supports a sensory role for ATP. An increased role for this purinergic neurotransmission may result in functional motor as well as sensory bladder disorders.
Recent advances in basic science for overactive bladder.
PURPOSE OF REVIEW: Detrusor overactivity is a relatively common yet embarrassing symptom complex with significant impact on quality of life. The mainstay of current pharmacological treatment involves the use of muscarinic receptor antagonists, but their therapeutic effectiveness is limited by a combination of limited efficacy and troublesome side effects and has recently been challenged by Herbison et al. Recognition of the limitations of existing therapy has started the search for pharmacotherapeutic agents acting on alternative pathways underlying detrusor overactivity with the intention of improving storage symptoms of urgency, frequency and urge incontinence. RECENT FINDINGS: Recent research has suggested that several transmitters may modulate bladder storage. However, no agents currently available, acting via mechanisms other than muscarinic receptors have entered clinical practice so far. It is clear that far from being a passive container for urine, the urothelium is a crucial area within the bladder wall and its functions are complex and only now beginning to be appreciated. The release of several neurotransmitters from urothelium in response to distension and its action on receptors on sensory neurons is being increasingly recognized. The role for this afferent stimulation on the micturition reflex is gradually gaining importance in the pathophysiology of detrusor overactivity. SUMMARY: In this article, the recent developments in basic science related to the pathogenesis and pharmacological basis for future drug targets for effective management of overactive bladder are discussed.
Cubitus varus: significant factors.
For better understanding of the etiology of "post-supracondylar fracture cubitus varus," an in vitro anatomic experiment was performed. Elbow models were precisely photographed in 256 combinations of 10 degrees increments of varus angulation, posterior angulation, internal rotation, and/or flexion contracture. Varus angulation was the most important single factor contributing to deformity. Addition of flexion contracture or posterior angulation to a given varus angulation decreased apparent deformity, whereas addition of internal rotation worsened the deformity. Control of varus angulation in the clinical setting, by whatever method, should minimize post-supracondylar fracture cubitus varus.
Short arm plaster cast for distal pediatric forearm fractures.
Ten years' clinical experience with below-elbow plaster cast treatment of distal one third pediatric forearm fractures was subjected to an independent retrospective radiographic review. In the study population of 761 fractures, no significant displacement occurred while the forearm remained in plaster. The average angulation change was 4.5 degrees (SD +/- 2.2 degrees). In each angulation change > 5 degrees, poor cast molding was evident, as reflected by a high "cast index" (p < 0.01). Although this technique is technically demanding, excellent results are obtained in all distal pediatric forearm fractures if proper cast molding is used.
Phylogeny of the genus flavivirus using complete coding sequences of arthropod-borne viruses and viruses with no known vector.
Attempts to define the evolutionary relationships and origins of viruses in the genus Flavivirus are hampered by the lack of genetic information particularly amongst the non-vectored flaviviruses. Using a novel protocol for sequence determination, the first complete coding sequence of St Louis encephalitis virus and those of two representative non-vectored flaviviruses, Rio Bravo (isolated from bat) and Apoi (isolated from rodent), are reported. The encoded polyproteins of Rio Bravo and Apoi virus are the smallest described to date within the genus FLAVIVIRUS: The highest similarities with other flaviviruses were found in the NS3 and NS5 genes. The proteolytic cleavage sites for the viral serine protease were highly conserved among the flaviviruses completely sequenced to date. Comparative genetic amino acid alignments revealed that p-distance cut-off values of 0.330-0.470 distinguished the arthropod-borne viruses according to their recognized serogroups and Rio Bravo and Apoi virus were assigned to two distinct non-vectored virus groups. Within these serogroups, cladogenesis based on the complete ORF sequence was similar to trees based on envelope and NS5 sequences. In contrast, branching patterns at the deeper nodes of the tree were different from those reported in the previous study of NS5 sequences. The significance of these observations is discussed.
Phylogeny of the genus flavivirus using complete coding sequences of arthropod-borne viruses and viruses with no known vector
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Sequences of flavivirus-related RNA viruses persist in DNA form integrated in the genome of Aedes spp. mosquitoes.
Flavivirus-related sequences have been discovered in the dsDNA genome of Aedes albopictus and Aedes aegypti mosquitoes, demonstrating for the first time an integration into a eukaryotic genome of a multigenic sequence from an RNA virus that replicates without a recognized DNA intermediate. In the Aedes albopictus C6/36 cell line, an open reading frame (ORF) of 1557 aa with protease/helicase and polyprotein processing domains characteristic of flaviviruses was identified. It is closely related to NS1-NS4A genes of the Cell Fusing Agent and Kamiti River virus and the corresponding mRNAs were detected. Integrated sequences homologous to the envelope, NS4B and polymerase genes of flaviviruses were identified. Overall, approximately two-thirds of a flavivirus-like genome were characterized. In the Aedes aegypti A20 cell line, a 492 aa ORF related to the polymerase of the Cell Fusing Agent and Kamiti River virus was identified. These flavivirus-related integrated DNA sequences were detected in laboratory-bred and wild Aedes albopictus and Aedes aegypti mosquitoes, demonstrating that their discovery is not an artefact resulting from the manipulation of mosquito cell lines, since they exist under natural conditions. This finding has major implications regarding evolution, as it represents an entirely different mechanism by which genetic diversity may be generated in eukaryotic cells distinct from accepted processes.
Isolation of a new strain of the flavivirus cell fusing agent virus in a natural mosquito population from Puerto Rico.
The genus Flavivirus contains approximately 70 single-stranded, positive-sense RNA viruses that are mosquito-borne, tick-borne or have no known vector. Two discoveries support previous suggestions of the existence of a large number of unsampled flaviviruses: (i) a new flavivirus, Kamiti River virus, was recently isolated from Kenyan mosquitoes, and (ii) sequences with high similarity to those of flaviviruses have been found integrated into the genome of Aedes mosquitoes, suggesting a past infection with a virus (or viruses) that has yet to be discovered. These sequences were related most closely to a flavivirus that infects insects alone, cell fusing agent virus (CFAV). CFAV was originally isolated in the laboratory from an Aedes aegypti cell line. To date, this virus had not been found in the wild. In the present study, over 40 isolates of a novel strain of CFAV were discovered from mature mosquitoes sampled from the wild in Puerto Rico. The viral strain was present in a range of mosquito species, including Aedes aegypti, Aedes albopictus and Culex sp., from numerous locations across the island and, importantly, in mosquitoes of both sexes, suggesting vertical transmission. Here, results from viral screening, and cell culture and molecular identification of the infected mosquitoes are presented. Experimental-infection tests were also conducted by using the original CFAV strain and a highly efficient reverse-transcription mechanism has been documented, in which initiation of copying occurs at the 3' terminus of either the genomic RNA or the intermediate of replication, potentially elucidating the mechanism by which flaviviral sequences may have integrated into mosquito genomes.
Kappa chain monoallelic demethylation and the establishment of allelic exclusion.
Allelic exclusion in kappa light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional kappa light chain on the surface of the B cell leads to an intracellular signal that down-regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a feedback mechanism clearly plays a role in the maintenance of allelic exclusion, here we provide evidence suggesting that the initial establishment of allelic exclusion involves differential availability of the two kappa alleles for rearrangement. Analysis of kappa+ B-cell populations and of individual kappa+ B cells that have rearranged only one allele demonstrates that in these cells, critical sites on the rearranged allele are unmethylated, whereas the nonrearranged allele remains methylated. This pattern is apparently generated by demethylation that is initiated at the small pre-B cell stage, on a single allele, in a process that occurs prior to rearrangement and requires the presence in cis of both the intronic and 3' kappa enhancers. Taken together with data demonstrating that undermethylation is required for rearrangement, these results indicate that demethylation may actually underly the process of allelic exclusion by directing the initial choice of a single kappa allele for rearrangement.
An epigenetic state associated with areas of gene duplication.
Asynchronous DNA replication is an epigenetically determined feature found in all cases of monoallelic expression, including genomic imprinting, X-inactivation, and random monoallelic expression of autosomal genes such as immunoglobulins and olfactory receptor genes. Most genes of the latter class were identified in experiments focused on genes functioning in the chemosensory and immune systems. We performed an unbiased survey of asynchronous replication in the mouse genome, excluding known asynchronously replicated genes. Fully 10% (eight of 80) of the genes tested exhibited asynchronous replication. A common feature of the newly identified asynchronously replicated areas is their proximity to areas of tandem gene duplication. Testing of other clustered areas supported the idea that such regions are enriched with asynchronously replicated genes.
The T4 glycoprotein is a cell-surface receptor for the AIDS virus.
Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells.
Molecular biology of smell: expression of the multigene family encoding putative odorant receptors.
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Dscam-mediated self- versus non-self-recognition by individual neurons.
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A mathematical model of the vagus-heart period system in the cat.
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Organizational theory and the stages of risk communication.
The evolution of risk communication has been described as a series of communication strategies. This article suggests that organizational theory provides another dimension to understanding the evolution of risk communication, and that risk communication can be seen as an organizational adaptation of chemical manufacturers to external pressure. Following the tragedy in Bhopal the chemical manufacturing sector's loss of legitimacy led to destabilization of its authority and to increased uncertainty in its external environment. Risk communication was one means to increase legitimacy, thereby decreasing uncertainty and potential impact on resources. However, although risk communication may evolve from crises of legitimacy, the concept of "isomorphism"--conformance to norms within a corporate sector--predicts this need not be the case.
Risk communication is a key to dealing effectively with bioterrorism.
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