Rectal and intravenous propranolol infusion to steady state: kinetics and beta-receptor blockade

The effects of intravenous propranolol infusion for 24 hr was compared with those of zero-order rectal administration by an osmotic delivery system in six healthy subjects. In plasma and urine, levels of propranolol, 4-OH-propranolol (4-OH-P), and conjugates were determined just before and at 6 hr and at 20 hr during drug administration. With the rectally applied osmotic delivery system providing zero-order release, fairly constant steady-state levels of propranolol in plasma were produced within 12 to 15 hr (four to five times elimination t1/2). The mean steady-state levels were 25 ng/ml after 1.1 micrograms/min/kg rectally and 60 ng/ml after 0.8 micrograms/min/kg IV. The mean rectal systemic availability was 33%; the elimination t1/2s for the two routes did not differ. The results of analysis of plasma for metabolites indicate that after rectal propranolol different metabolic pathways are followed and that there is partial avoidance of first-pass elimination. The isoproterenol challenge resulted in a reproducible assessment of beta-receptor blockade that was closely related to the propranolol concentration in plasma in all subjects and for both routes of administration. With rate-controlled release of propranolol from an osmotic delivery device, the rectal route provides an alternative to intravenous infusion to achieve constant steady-state propranolol concentrations. This may be useful for research purposes or during the perioperative period in surgical patients.     

Effects of intranasal cocaine on sympathetic nerve discharge in humans.

Cocaine-induced cardiovascular emergencies are mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, we recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. After lidocaine, blood pressure and sympathetic nerve discharge were unchanged. After cocaine, blood pressure increased abruptly and remained elevated for 60 min while sympathetic nerve discharge initially was unchanged and then decreased progressively over 60 min to a nadir that was only 2+/-1% of baseline (P < 0.05); however, plasma venous norepinephrine concentrations (n = 5) were unchanged up to 60 min after cocaine. Sympathetic nerve discharge fell more rapidly but to the same nadir when blood pressure was increased similarly with phenylephrine. When the cocaine-induced increase in blood pressure was minimized (nitroprusside), sympathetic nerve discharge did not decrease but rather increased by 2.9 times over baseline (P < 0.05). Baroreflex gain was comparable before and after cocaine. We conclude that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. Furthermore, sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences determines the net effect of cocaine on sympathetic discharge targeted to the human skeletal muscle circulation.     

Albuterol aerosol delivered via metered-dose inhaler to intubated pediatric models of 3 ages, with 4 spacer designs

OBJECTIVE: To determine the amount of albuterol, in various particle size ranges, delivered from a hydrofluoroalkane-propelled metered-dose inhaler (Airomir) in 3 models of pediatric intubation (ages 8 months, 4 years, and 16 years) using 4 types of aerosol reservoir: 3 spacers (ACE, AeroChamber HC MV, metal NebuChamber without 1-way valve) and 1 holding chamber (metal NebuChamber with 1-way valve). METHODS: Five reservoirs of each type were tested with albuterol sulfate delivered via metered-dose inhaler that delivers 100 microg of albuterol per actuation. Each reservoir was connected to an endotracheal tube (ETT) that corresponded to the given patient age (8 months = 4 French; 4 years = 5 French; 16 years = 7.5 French) and to a valved system that allowed connection of the ETT to a cascade impactor. Simulated tidal volumes representative of children of the given ages were passed through the reservoir. Both the cascade impactor and the ETT were enclosed within a 100% humidity, 37 degrees C environment. RESULTS: For the total amount of albuterol inhaled onto the impactor, and both the 1.1-4.7 microm and 1.1-3.3 microm inhaled fine-particle fractions, the NebuChamber-with-valve showed significantly greater drug delivery than the NebuChamber-without-valve, the AeroChamber HC MV, or the ACE (p < 0.001). Among the reservoirs without valves the NebuChamber showed significantly greater delivery than the AeroChamber HC MV or ACE (p < 0.001) for total drug deposition and for both the 1.1-4.7 microm and 1.1-3.3 microm fine-particle fractions. These results were consistent over all age groups. The AeroChamber HC MV had significantly greater delivery (total deposition) than the ACE (p < 0.001), except in the 4-year-old model. There were no significant differences between the AeroChamber HC MV and the ACE for either the 1.1-4.7 microm or the 1.1-3.3 microm fine-particle fraction. CONCLUSION: An aerosol reservoir with 1-way valve positioned between the spacer and the ETT improved the amount of inhaled albuterol 300-900%, compared to the other reservoirs.     

3D-Elaboration of postoperative CT data after liver resection: technique and utility

Objectives  3D reconstructions of CT data permit precise planning of liver surgery. To analyze the realisation of surgical plans 3D reconstructed postoperative CT data were evaluated. Method  Pre- and postoperative CT data were analyzed on a series of 15 liver resections (2 hemihepatectomies and 13 segmental resections) by 3D reconstruction of portal and hepatic veins. Virtual surgical resection plans were compared with 3D reconstructed postoperative CT data and clinical data. Results  Pre- and postoperative CT data as the basis for subsequent processing were of comparable quality. Detailed elaboration of data could be realized with an overall data processing and analyzation time of 120 min. The best correlation between calculated and actually measured liver resection volume was obtained by intersection volumes of portal and hepatic veins (k = 0.828, P < 0.000). However, portal and hepatic vein analysis revealed 9 and 12% of liver parenchyma with unplanned resection and 5 and 1% of unplanned residual tissue. No correlation with clinical data was found in this series. Conclusion  Volume calculation without consideration of vascular anatomy is less suited for precise assessment of surgical plan implementation in our study. Comparison of pre- and postoperative vascular structures with the aid of three-dimensionally reconstructed CT data is feasible. Unplanned resected and remained liver tissue can be identified. However, its clinical meaning for quantitative analysis of surgical plan implementation is questionable and should be investigated in larger series.     

Childhood victimization and pain in adulthood: a prospective investigation

Evidence of the relationship between childhood abuse and pain problems in adulthood has been based on cross-sectional studies using retrospective self-reports of childhood victimization. The objective of the current study was to determine whether childhood victimization increases risk for adult pain complaints, using prospective information from documented cases of child abuse and neglect. Using a prospective cohort design, cases of early childhood abuse or neglect documented between 1967 and 1971 (n = 676) and demographically matched controls (n = 520) were followed into young adulthood. The number of medically explained and unexplained pain complaints reported at follow-up (1989-1995) was examined. Assessed prospectively, physically and sexually abused and neglected individuals were not at risk for increased pain symptoms. The odds of reporting one or more unexplained pain symptoms was not associated with any childhood victimization or specific types (i.e. sexual abuse, physical abuse, or neglect). In contrast, the odds of one or more unexplained pain symptoms was significantly associated with retrospective self-reports of all specific types of childhood victimization. These findings indicate that the relationship between childhood victimization and pain symptoms in adulthood is more complex than previously thought. The common assumption that medically unexplained pain is of psychological origin should be questioned. Additional research conducting comprehensive physical examinations with victims of childhood abuse and neglect is recommended.     

Localization of 17beta-hydroxysteroid dehydrogenase and characterization of testosterone in the brain of the male frog.

Several enzymes involved in the formation of steroids of the pregnene and pregnane series have been identified in the brain, but the biosynthesis of testosterone has never been reported in the central nervous system. In the present study, we have investigated the distribution and bioactivity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) (EC 1.1.1.62; a key enzyme that is required for the formation of testosterone and estradiol) in the brain of the male frog Rana ridibunda. By using an antiserum against human type I placental 17beta-HSD, immunoreactivity was localized in a discrete group of ependymal glial cells bordering the telencephalic ventricles. HPLC analysis of telencephalon and hypothalamus extracts combined with testosterone radioimmunoassay revealed the existence of two peaks coeluting with testosterone and 5alpha-dihydrotestosterone. After HPLC purification, testosterone was identified by gas chromatography/mass spectrometry. Incubation of telencephalon slices with [3H]pregnenolone resulted in the formation of metabolites which coeluted with progesterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, and 5alpha-dihydrotestosterone. The newly synthesized steroid comigrating with testosterone was selectively immunodetected by using testosterone antibodies. These data indicate that 17beta-HSD is expressed in a subpopulation of gliocytes in the frog telencephalon and that telencephalic cells are capable of synthesizing various androgens, including dehydroepiandrosterone, androstenedione, testosterone, and 5alpha-dihydrotestosterone.     

Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.     

Immunoglobulin heavy chain constant region variants in rheumatoid arthritis.

Polymorphisms within the immunoglobulin heavy chain constant region at switch (S)mu and S alpha 1 loci were studied in patients with rheumatoid arthritis (RA) and controls in parallel with Gm and A2m allotyping. S mu and S alpha 1 restriction fragment length polymorphisms were defined using a S mu probe which was hybridised to SstI digests of DNA extracted from circulating white cells. There were no differences in S mu and S alpha 1 gene or phenotype frequencies between RA and control groups nor within the RA population between DR4 positive and negative subjects. The Gm allotype G1m(x), coded for by genes at the gamma-1 locus, was found in 29/92 (32%) of DR4 positive and 5/52 (10%) of DR4 negative subjects with RA, as compared with 25/115 (22%) cf controls. The A2m allotype A2m(2), coded for by the alpha 2 locus, was found in 11/92 (12%) of DR4 positive subjects with RA, zero of 52 DR4 negative subjects, and 5/115 (4%) of controls. These results exclude a major effect of genes within the heavy chain constant region linked to mu or alpha 1 loci on susceptibility to RA, but suggest that further study of variants closely linked to the alpha 2 locus is indicated.