Unexpected results in long-term medically treated ruptured intracranial aneurysm including data on 14 patients followed more than 30 years each

This is the longest reported follow-up of patients with ruptured intracranial aneurysms treated entirely medically with hypotension. Patients with ruptured brain aneurysms, untreated except for plain bedrest, are at a well-recognized risk of recurrent hemorrhage. Some surgically treated patients also remain at risk of recurrent hemorrhage in follow-up. This is a review of results in patients whose active but entirely medical (hypotensive) treatment was started in the first 10 years of a 40-year study. It suggests a way of reducing risks in both of the above 2 groups. 53 consecutive patients with proven ruptured brain aneurysm(s) were treated as early as possible with medical-hypotensive therapy alone by the author and followed, personally, until death or, if they survived, for at least 30 years each (or until lost to follow-up). The patients included many considered to have been poor operative risks with some having been designated inoperable by the referring neurosurgeons. As part of the long-term follow-up, magnetic resonance angiography (MRA) has been begun. Long-term follow-up was defined as the time beginning after 9 weeks from (admission) hemorrhage. 9 patients had died during the earlier stages of hemorrhage (and treatment) i.e., before the 9 weeks period had elapsed; their data was presented previously. This yielded 44 patients for long-term follow-up. Only 2 patients (both had multiple aneurysms) on this regimen have died of either proven hemorrhage (1 patient) or presumed hemorrhage (1 patient). Most patients survived and maintained an excellent condition. Medical-hypotensive therapy of ruptured intracranial aneurysms has produced much better long-term results than expected. This is significant for (1) patients requiring medical treatment alone and (2) surgically treated patients who may benefit from additional long-term protection.     

Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation

Insulin-like growth factor-I (IGF-I) induces neuronal differentiation in vitro. In the present study, we examined the signaling pathway underlying IGF-I-mediated neurite outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I induced concentration- and time-dependent tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and extracellular signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR phosphorylation was observed within 1 min, maximal phosphorylation of ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorylation were maintained for at least 24 h. Also, the concentration dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation paralleled that of IGF-I-mediated neurite outgrowth. We further examined the role of mitogen-activated protein kinase activation in IGF-I-stimulated neuronal differentiation using the mitogen-activated protein kinase/ERK kinase inhibitor PD98059. Whereas PD98059 had no effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ERK tyrosine phosphorylation and ERK phosphorylation of the substrate Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated neurite outgrowth. Finally, consistent with its ability to block neuronal differentiation, PD98059 inhibited IGF-I-dependent changes of GAP-43 and c-myc gene expression. Together these results suggest that activation of ERKs is essential for IGF-I-stimulated neuronal differentiation.     

Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea

BACKGROUND: Subhypnotic doses of propofol possess direct antiemetic properties. The authors sought to determine the plasma concentration of propofol needed to effectively manage postoperative nausea and vomiting. METHODS: Patients aged 18-70 yr who were classified as American Society of Anesthesiologists physical status 1 or 2 and had surgery during general anesthesia were approached for the study. Only patients who had nausea (verbal rating score > 5 on a 0- to 10-point scale), retching, or vomiting in the postanesthetic care unit participated. Propofol was administered to these patients to achieve target plasma concentrations of 100, 200, 400, and 800 ng/ml using a computer-assisted continuous infusion device. Target concentrations were increased every 15 min until patients described at least a 50% reduction in symptoms on the verbal rating score. An arterial blood sample was obtained at each step. The measured plasma propofol concentrations were used to analyze data. Blood pressure, heart and respiratory rates, arterial blood saturation, sedation score, and overall satisfaction with treatment were recorded. RESULTS: Of the 89 patients who consented to the study, 15 patients met entry criteria and were enrolled. Five of these patients also had retching or vomiting when they entered the study. Fourteen patients responded successfully to treatment. One patient did not achieve the required response at plasma concentrations of 830 ng/ml. Hence the success rate for the treatment of postoperative nausea and vomiting was 93%. Among patients who responded, the median plasma concentration associated with an antiemetic response was 343 ng/ml. There was no difference in sedation scores from baseline and no episodes of desaturation. Hemodynamic parameters were stable during the study. CONCLUSIONS: Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce increased sedation. Simulations indicate that to achieve antiemetic plasma propofol concentrations of 343 ng/ml, a bolus dose of 10 mg followed by an infusion of approximately 10 microg x kg(-1) x min(-1) are necessary.     

Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, including inflammatory epithelial cells. NO has been detected in the exhaled air of normal human subjects, and its concentration is raised in asthmatic patients. To study whether exhaled NO arises from the respiratory tract, we administered a NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), by inhalation (490 mg) in a double-blind randomized manner in nine normal and six asthmatic subjects. Because exhaled NO may arise from an inducible isoform of NO synthase that may be inhibited by glucocorticosteroids, we also studied the effects of oral prednisolone (30 mg orally for 3 d) in seven normal and six asthmatic subjects in a separate double-blind crossover study with matched placebo. After nebulized L-NMMA, there was a significant fall in peak exhaled NO compared with saline control values, with a mean fall of 43.6 +/- 5.6% in normal subjects (p < 0.01) and of 39.7 +/- 6.5% (p < 0.01) in asthmatic subjects, which persisted for 4 h. There were no effects of L-NMMA inhalation on heart rate, blood pressure, or FEV1 in either normal or asthmatic patients. Administration of oral prednisolone (30 mg) resulted in a fall in exhaled NO concentrations in asthmatic subjects by 21.6 +/- 5.0% at 48 h (p < 0.01) but no significant change in normal subjects. These data suggest that NOS inhibitors may be safely given in normal and asthmatic patients and that the increased exhaled NO seen in asthmatic patients is likely to be caused by induction of inducible NOS.     

The catalytic domain of protein kinase C chimeras modulates the affinity and targeting of phorbol ester-induced translocation

Emerging evidence suggests important differences among protein kinase C (PKC) isozymes in terms of their regulation and biological functions. PKC is regulated by multiple interdependent mechanisms, including enzymatic activation, translocation of the enzyme in response to activation, phosphorylation, and proteolysis. As part of our ongoing studies to define the factors contributing to the specificity of PKC isozymes, we prepared chimeras between the catalytic and regulatory domains of PKCalpha, -delta, and -epsilon. These chimeras, which preserve the overall structure of the native PKC enzymes, were stably expressed in NIH 3T3 fibroblasts. Their intracellular distribution was similar to that of the endogenous enzymes, and they responded with translocation upon treatment with phorbol 12-myristate 13-acetate (PMA). We found that the potency of PMA for translocation of the PKCalpha/x chimeras from the soluble fraction was influenced by the catalytic domain. The ED50 for translocation of PKCalpha/alpha was 26 nM, in marked contrast to the ED50 of 0.9 nM in the case of the PKCalpha/epsilon chimera. In addition to this increase in potency, the site of translocation was also changed; the PKCalpha/epsilon chimera translocated mainly into the cytoskeletal fraction. PKCx/epsilon chimeras displayed twin isoforms with different mobilities on Western blots. PMA treatment increased the proportion of the higher mobility isoform. The two PKCx/epsilon isoforms differed in their localization; moreover, their localization pattern depended on the regulatory domain. Our results emphasize the complex contributions of the regulatory and catalytic domains to the overall behavior of PKC.     

Lack of protection against avian cholera by vaccination with recombinant P6-like protein from Pasteurella multocida

The gene encoding the P6-like protein of Pasteurella multocida was cloned in the baculovirus expression system. Baculovirus-expressed recombinant protein was used to parenterally immunize 6-wk-old Nicholas broad-breasted white turkeys. Turkeys developed significant antibody titers to the recombinant protein as measured by enzyme-linked immunosorbent assay. Two weeks after the last immunizing injection, vaccinated turkeys were placed in contact with turkeys infected with P. multocida strain P1059, as were nonvaccinated control birds. No differences occurred in percent mortality between the two groups. We conclude that parenterally administered recombinant P6-like protein does not protect turkeys from avian cholera.     

Isolation of the PufX protein from Rhodobacter capsulatus and Rhodobacter sphaeroides: evidence for its interaction with the alpha-polypeptide of the core light-harvesting complex

Using mutant strains of Rhodobacter capsulatus and Rhodobacter sphaeroides in which the pufX gene had been deleted, it was possible to identify by HPLC membrane protein components present in pufX+ cells but absent in pufX- cells. In parallel preparations, membrane proteins soluble in chloroform/methanol containing ammonium acetate were first extracted from lyophilized membrane fractions of the pufX+ cells and separated from pigments and larger protein material by gel-filtration chromatography. Protein-containing fractions were examined by HPLC, and several peaks were collected from pufX+ material that were not present in pufX- material. From N-terminal amino acid sequencing, the PufX protein of Rb. capsulatus was identified, and from positive interaction with a PufX protein antibody, the Rb. sphaeroides PufX protein was identified. Although overall yields were very small, sufficient quantities of these proteins were isolated to evaluate their effect on the reconstitution of the core light-havesting antenna (LH1) and its subunit complex. From the behavior of the PufX protein and the alpha-polypeptide of LH1 on HPLC, qualitative evidence was obtained that the two proteins have a high affinity for each other. In reconstitution assays with bacteriochlorophyll (Bchl) and the LH1 alpha- and beta-polypeptides of Rb. capsulatus, the PufX protein of Rb. capsulatus was inhibitory to LH1 formation at low concentration. A similar inhibition was exhibited by Rb. sphaeroides PufX protein for reconstitution of LH1 with Bchl and the LH1 alpha- and beta-polypeptides of Rb. sphaeroides. In both cases, the ratios of concentrations of the PufX protein to the alpha-polypeptide causing 50% inhibition were approximately 0.5. Formation of the heterologous (alpha beta) subunit-type complex formed with Bchl and the alpha- and beta-polypeptides of LH1 of Rb. capsulatus was also inhibited by low concentrations of the Rb. capsulatus PufX protein (approximately 50% inhibition at PufX:alpha-polypeptide ratios = 0.5). However, neither PufX protein inhibited formation of a homologous (beta beta) subunit-type complex, which indicates that the PufX proteins do not interact with the beta-polypeptides.     

Effects of establishment of community psychiatry in Aalborg]

The aim of the present study was to illustrate the effects of community-based psychiatry. The catchment area was divided into three homogeneous districts, East, North and West. Teams were established on 1.9. 1990, 1.10.91 and 1.5.1992, respectively. Social, diagnostic and treatment related data were gathered from two cross-sectional investigations (I: February 1992 and II: February 1993) and from in-patients and out-patients files. In cross-section I a majority of long-term ward patients and hospital-based employment offers was found in the district where the community district team had not yet been established. In the district where the first community district team was established most primary target patients were treated. In cross-section II the hospital-based psychiatric service were more homogeneously distributed between the districts. The establishment of community-based psychiatric teams resulted in new referrals, and increasing numbers of patients becoming attached to the psychiatric teams, but crowding and use of compulsory measures in hospital also increased.