Effect of subarachnoid bupivacaine block on anesthetic requirements for thiopental in rats

BACKGROUND: Subarachnoid bupivacaine blockade has been reported to reduce thiopental and midazolam hypnotic requirements in patients. The purpose of this study was to examine if local anesthetically induced lumbar intrathecal blockade would reduce thiopental requirements for blockade of motor responses to noxious and nonnoxious stimuli in rats. METHODS: After intrathecal and external jugular catheter placement, rats were assigned randomly to two groups in a crossover design study, with each rat to receive either 10 microl of 0.75% bupivacaine or 10 microl of normal saline intrathecally. The doses of intravenously administered thiopental required to ablate the eyelid reflex, to block the withdrawal reflex of a front limb digit, and to block the corneal reflex were compared. In two separate groups of animals, hemodynamic parameters and concentrations of thiopental in the brain were compared between intrathecally administered bupivacaine and saline. RESULTS: The thiopental dose required to block the described responses was decreased with intrathecally administered bupivacaine versus intrathecally administered saline from (mean +/- SD) 40 +/- 5 to 24 +/- 4 mg/kg (P < 0.001) for the eyelid reflex, from 51 +/- 6 to 29 +/- 6 mg/kg (P < 0.005) for front limb withdrawal, and from 67 +/- 8 to 46 +/- 8 mg/kg (P < 0.01) for the corneal reflex. The concentration of thiopental in the brain at the time of corneal reflex blockade for the group given bupivacaine was significantly lower than in the group given saline (24.1 vs. 35.8 microg/g, P = 0.02). CONCLUSION: This study demonstrates that lumbar intrathecally administered local anesthetic blockade decreases anesthetic requirements for thiopental for a spectrum of end points tested. This effect is due neither to altered pharmacokinetics nor to a direct action of the local anesthetic on the brain; rather, it is most likely due to decreased afferent input.     

Conserved cis- and trans-acting determinants for replication initiation and regulation of replication fork movement in tetrahymenid species

The rDNA minichromosomes of Tetrahymena thermophila and Tetrahymena pyriformis share a high degree of sequence similarity and structural organization. The T.thermophila 5' non-transcribed spacer (5' NTS) is sufficient for replication and contains three repeated sequence elements that are conserved in T.pyriformis , including type I elements, the only known determinant for replication control. To assess the role of conserved sequences in replication control, structural and functional studies were performed on T.pyriformis rDNA. Similar to T.thermophila , replication initiates exclusively in the 5' NTS, localizing to a 900 bp segment. Elongating replication forks arrest transiently at one site which bears strong similarity to a tripartite sequence element present at fork arrest sites in T.thermophila rDNA. An in vitro type I element binding activity indistinguishable from the T.thermophila protein, ssA-TIBF, was detected in T.pyriformis extracts. The respective TIBF proteins bind with comparable affinity to type I elements from both species, suggesting that in vivo recognition could cross species boundaries. Despite these similarities, the T.pyriformis 5' NTS failed to support replication in transformed T.thermophila cells, suggesting a more complex genetic organization than previously realized.     

The Australian brushtail possum (Trichosurus vulpecula) gonadotrophin alpha-subunit: analysis of cDNA sequence and pattern of expression

Substantial evidence has accumulated to suggest that in the near future implementation of the veto-cell-suppressor concept in the treatment of kidney allograft recipients might lead to the establishment of life-long specific allograft tolerance in the absence of further immunosuppressive therapy. Veto suppression prevents the generation of antigen-specific T-helper and cytotoxic T lymphocytes in vitro provided that the T-lymphocyte precursors specifically recognize antigenic peptides associated with the major histocompatibility complex molecules class II and class I, respectively, expressed on the surface of the veto-active cell. Data from a large number of experimental and clinical studies strongly indicate that veto-active cells function in vivo and are capable of preventing allograft rejection. Thus, donor-cell-mediated veto activity is the most likely explanation for the well-known graft tolerizing effect of pretransplant donor blood transfusions in kidney graft recipients. A prerequisite for a veto-active environment in vivo is the establishment of lymphoid microchimerism, in which veto-active donor and recipient cells mutually downregulate potential alloaggression.     

Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells

The mouse shaker-1 locus, Myo7a, encodes myosin VIIA and mutations in the orthologous gene in humans cause Usher syndrome type 1B or non-syndromic deafness. Myo7a is expressed very early in sensory hair cell development in the inner ear. We describe the effects of three mutations on cochlear hair cell development and function. In the Myo7a816SB and Myo7a6J mutants, stereocilia grow and form rows of graded heights as normal, but the bundles become progressively more disorganised. Most of these mutants show no gross electrophysiological responses, but some did show evidence of hair cell depolarisation despite the disorganisation of their bundles. In contrast, the original shaker-1 mutants, Myo7ash1, had normal early development of stereocilia bundles, but still showed abnormal cochlear responses. These findings suggest that myosin VIIA is required for normal stereocilia bundle organisation and has a role in the function of cochlear hair cells.     

Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices

STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy, nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.     

Circulating plasma prekallikrein and tissue kallikrein in normotensive and hypertensive humans: effects of angiotensin II infusion

Kinins lower blood pressure but the stimuli leading to kinin generation and their origin are less well known. We administered angiotensin II in graded infusion doses to patients with primary hypertension and normotensive controls to study the effects of on circulating kallikreins. Angiotensin II infusion did not significantly alter plasma prekallikrein or tissue kallikrein levels and the plasma levels and their changes did not correlate with blood pressure levels or changes. In the normotensive group prekallikrein levels and renin activity correlated negatively with urinary sodium and chloride excretion during basal conditions and partially during the infusion. U-tissue kallikrein concentration increased in the normotensive group. Thus, acute elevation of blood pressure induced by angiotensin II does not activate the circulating kallikrein-kinin systems. Data rather indicate that the circulating kallikrein-kinin systems may be related to alterations in volume and sodium balance and that these mechanisms may be altered in primary hypertension.