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Conformational differences between surface-bound and fluid-phase complement-component-C3 fragments. Epitope mapping by cDNA expression. In previous studies a subset of complement-component-C3 (C3) epitopes, C3(D), expressed in denatured and surface-bound C3 and C3 fragments, has been described. These epitopes were detected by antibodies raised against denatured C3. In the present study we used a cDNA expression strategy to localize epitopes recognized by monoclonal and polyclonal anti-C3(D) antibodies. First, DNAse I digestion of C3 cDNA was used to generate 200-300 bp fragments. These cDNA fragments were expressed as beta-galactosidase-C3 fusion proteins using the lambda gt11 vector. The fusion proteins were tested by Western-blot analysis for reactivity with monoclonal and polyclonal anti-C3 antibodies, and the location of the epitopes were determined by sequencing the cDNA fragments. Affinity-purified polyclonal anti-C3(D) antibodies specific for denatured C3 reacted strongly with the C3 fusion fragments corresponding to segments of the 40 kDa subunit of C3c (residues 1477-1510) and the C3d fragment (residues 1117-1155 and 1234-1294) of C3. Adsorption of the polyclonal antibodies with a mixture of EAC3b and EAC3bi (degradation fragments of C3 bound to sheep erythrocytes) abolished binding to fusion proteins spanning the C3d region, but not the 40 kDa fragment of C3c. No effect was seen with the corresponding soluble C3 fragments. The monoclonal anti-C3(D) antibodies (mAbs) 7D326.1 and 7D331.1, specific for EAC3b and EAC3bi, bound to a fusion protein corresponding to amino acid residues 1312-1404, whereas mAb 7D9.2, specific for EAC3d, reacted with a fusion protein spanning amino acid residues 1082-1118. mAbs 4SD11.1 and 4SD18.1, which did not bind to any physiological C3 fragment, detected a fusion protein covering residues 1477-1510. In summary, the segments of C3 represented by amino acid residues 1082-1118, 1117-1155, 1234-1294 and 1312-1404 accommodate C3(D) epitopes that are expressed by erythrocyte-bound C3 fragments, but not by the corresponding fluid-phase fragment, whereas the segments spanning residues 973-1026 and 1477-1510 contain C3(D) epitopes that are exposed exclusively in denatured C3 and therefore hidden in physiological fragments of the protein.
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[Electrophysiological study of the functional connections of the hypothalamus with the forebrain in the tortoise Emys orbicularis]. During stimulation of the posterior hypothalamus, the evoked potentials with short latent periods, high amplitude and poor exhaustion by rhythmic stimulation were recorded in the hippocampal cortex. In the piriform cortex, the evoked potentials exhibited longer latent periods and complex configuration. Less readily the evoked potentials appeared in the neocortex, their latency being very large. During stimulation of the anterior hypothalamus, maximum activity was also localized in the hippocampal cortex. The data obtained indicate close connection between hypothalamic structures and the hippocampal cortex. The latter is presumably the main projectional area for the ascending afferentation from the hypothalamus.
| 17 |
Self-diffusion of water in multicellular spheroids measured by magnetic resonance microimaging. Nuclear magnetic resonance microimaging measurements of the self-diffusion coefficient of water in large (greater than 2 mm) EMT-6 multicellular spheroids were performed in order to elucidate diffusion mechanisms in tumors. Pulsed gradient spin echo-imaging methods were developed for measuring diffusion in an intravoxel multicompartment system. The self-diffusion coefficient (at 22 degrees C) for water in the medium (Dm) consisted of only a single diffusion compartment [Dm = 1.99 +/- 0.03 (SE) x 10(-5) cm2/s]. Similarly, the spheroid necrotic center showed a single water diffusion compartment with a self-diffusion coefficient (Dc) significantly lower than that of the medium (Dc = 1.54 +/- 0.05 x 10(-5) cm2/s). The spheroid viable rim region showed two distinct compartments of approximately equal volume, one with a large diffusion coefficient (1.70 +/- 0.12 x 10(-5) cm2/s) and a second with a significantly smaller diffusion coefficient (0.25 +/- 0.01 x 10(-5) cm2/s). We propose that these two experimentally distinguishable compartments correspond to the extra- and intracellular regions, respectively, of the viable rim of the spheroid. Although the diffusion coefficients were significantly different in the medium, the necrotic center, and the viable rim, the activation energy for diffusion was the same in the three regions (0.20 eV). Studies of perfused spheroids at 37 degrees C show the same dependence of the diffusion coefficients on the diffusion filter as observed for unperfused spheroids at 22 degrees C. These results demonstrate the ability of nuclear magnetic resonance microimaging to investigate diffusion at the cellular level, which will lead to a better understanding of microenvironmental regulation in tumors.
| 21 |
Site-directed mutagenesis in human tissue-plasminogen activator. Distinguishing sites in the amino-terminal region required for full fibrinolytic activity and rapid clearance from the circulation. Recombinant variants of tissue plasminogen activator (t-PA) containing either substitutions or deletions of amino acids within the fibronectin finger-like domain (residues 6-50) were found to exhibit widely varying in vivo clearance profiles in rats and fibrinolytic activity in 125I-fibrin clot lysis assays. Clearance was not significantly affected by changes in the densely charged region of amino acid residues 7-10. Deletions or substitutions of amino acids in the region 14-32 decreased both fibrinolytic activity and the clearance of the enzyme. Modifications within the predicted omega loop of residues 37-41 affected clearance only to a small degree, whereas amino acid alterations in the region of residues 42-49 resulted in as much as a 6-fold decrease in the rate of clearance with only relatively minor decreases in the fibrinolytic activity of the variants. The cumulative results distinguish discrete sections of the NH2-terminal region of the enzyme as determinants of in vivo clearance and fibrinolytic activity of t-PA. In addition, the fibrinolytic activity of a variant containing the substitutions Gln42----Asn, His44----Glu, and Asn117----Gln, when compared with wild-type t-PA in an in vivo rabbit venous clot lysis model, was found to have similar lytic efficacy at approximately one-fourth the dose. We conclude that decreases in the in vivo clearance of t-PA can result in more potent thrombolytic agents in vivo, even though the in vitro fibrinolytic activity of the enzyme may be somewhat impaired.
| 20 |
Enhanced alpha-adrenergic vasoconstriction by n-3 fatty acids in conscious dogs. The effect of dietary fish oil supplementation on cardiac function and the pressor response to selective agonists of postjunctional alpha 1- and alpha 2-adrenoceptors was investigated in chronically instrumented dogs (n = 12). Following ganglionic, cholinergic, and beta-adrenergic blockade, dose responses to phenylephrine (0.3-1.2 micrograms/kg iv), a selective alpha 1-adrenoceptor agonist, and azepexole (B-HT 933, 5-20 micrograms/kg iv), a selective alpha 2-adrenoreceptor agonist, were obtained in conscious dogs. Fish oil capsules containing eicosapentaenoic acid (1.12 g) and docosahexaenoic acid (480 mg) were administered orally twice daily for 1 wk, and dose-response curves were repeated. Dose-response curves were again obtained 1 wk after fish oil was discontinued. Fish oil supplementation resulted in significantly (P less than 0.05) increased arterial pressure at rest, and after autonomic nervous system blockade there was an increase in peripheral vascular resistance. Cardiac output was reduced in fish oil-treated dogs during autonomic nervous system blockade. The pressor response to selective alpha 1- and alpha 2-adrenoceptor stimulation was increased secondary to elevated peripheral vascular resistance. Hemodynamics and exaggerated vascular reactivity returned to control 1 wk after dietary fish oil was discontinued. The results of this study demonstrate that dietary fish oil supplementation produces an increase in arterial pressure via peripheral vasoconstriction and that the vascular response to alpha-adrenergic stimulation is exaggerated.
| 19 |
Effect of a triclosan/copolymer/fluoride dentifrice on plaque formation and gingivitis: a 7-month clinical study. A total of 108 adult male and female subjects completed a 7-month, double-blind clinical study designed to compare the effect of a dentifrice containing 0.3% triclosan and 2% of a copolymer of methoxyethylene and maleic acid on plaque formation and gingivitis, as compared to a placebo dentifrice. The subjects were stratified into two balanced groups according to baseline plaque and baseline gingivitis scores. They then received an oral prophylaxis and were assigned to the use of either a placebo dentifrice or the triclosan/copolymer dentifrice for the next 7 months. After this time, the dentifrice containing triclosan/copolymer provided a 58.96% statistically significant (99% level of confidence) reduction in plaque [corrected], as compared to the placebo dentifrice. Further, after 7-months' use, the dentifrice containing triclosan/copolymer also provided a 30.17% statistically significant (99% level of confidence) reduction in gingivitis as compared to the placebo dentifrice. The results after 7 months also indicated that the dentifrice containing triclosan/copolymer provided a 97.74% statistically significant (99% level of confidence) reduction in the supragingival plaque deposits on those tooth surfaces with the greatest amount of plaque formation, when compared to the placebo dentifrice. The dentifrice containing triclosan/copolymer also provided 87.56% less sites with the most severe amount of gingival disease, as compared to the placebo dentifrice. This decrease in diseased gingival sites was statistically significant at the 99% level of confidence. It was concluded that the twice daily use of a dentifrice containing 0.3% triclosan and 2% of a copolymer reduces supragingival plaque deposit formation and gingivitis to a highly significant degree, without any extrinsic stains observed.
| 22 |
Quantitative effect of roxithromycin and rifampicin on mucoid cultures from directly plated sputum of cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa. A previous study has shown that non-anti-Pseudomonas aeruginosa antibiotics can modify the mucoid character, a major virulence factor in cystic fibrosis P. aeruginosa. The purpose of the present study was to investigate further this phenomenon using a quantitative approach on fresh sputum. A total of 0.1 to 0.5 ml of sputum were homogenized, decimally diluted, plated on three series of Difco Pseudomonas isolation agar containing no antibiotics, roxithromycin (16.0 microgram/ml) or Rifampicin (16.0 microgram/ml) and incubated at 35 degrees C. In each of the three series, the cfus of PA by ml of sputum were evaluated after 24h, and the entire culture of plates with confluent growth was harvested after 96h and weighed on an analytical scale according to the correlation observed between the mucosity and the density of the culture. To date, 36 sputa from twenty-nine cystic fibrosis patients known to be chronically colonized by mucoid P. aeruginosa have been submitted to the protocol; the mean weight of control, roxithromycin and rifampicin cultures was respectively 3.12 +/- 1.62, 1.90 +/- 1.67 (p less than or equal to 0.0005) and 1.83 +/- 1.24 g (p less than or equal to 0.005) in parallel with mean cfu/ml of 2.24 +/- 6.45 x 10(8) (p less than 0.03) and 1.65 +/- 4.42 x 10(8) (p greater than 0.05); a more constant reduction (greater than or equal to 20%) of mucosity (expressed as the ratio of weight of antibiotic culture/control culture x 100) was observed with rifampicin (29 vs. 23/36 sputa), whereas a more drastic reduction (greater than or equal to 80%) was observed with roxithromycin (12 vs. 4).(ABSTRACT TRUNCATED AT 250 WORDS)
| 24 |
Reconstruction of postburn breast deformities. Postburn breast deformity is a sequela of severe scar contraction of the burned chest. During the past 3 years, 24 female patients with such deformities required reconstruction, the surgery was performed in our department. These patients, the types of the deformities and the techniques used for reconstruction have been reviewed. For mild deformities (10 patients) reconstructions with skin grafts and local skin flaps were found to be satisfactory. For deformities which affected the mammary development (14 patients), mammary prostheses directly or under the soft tissue obtained by skin expansion or musculocutaneous flaps were used. In three of our patients, reduction mammaplasty or mastopexy was needed to symmetrize the breasts.
| 13 |
Evaluation of human dynamic contraction by phonomyography. Phonomyogram (PMG, or acoustic myogram) is known to increase with force in isometric contractions. We investigated this relationship for dynamic contractions against different inertias. PMG and surface electromyogram (EMG) from biceps brachii and brachioradialis muscles were simultaneously recorded with the angular acceleration of elbow flexions. These were self-initiated movements (30 degrees) toward a fixed target and performed against two different inertias. PMG and EMG were integrated from the onset of the signal to the end of the acceleration phase. Phono- and electromechanical delays were also measured. For integrated EMG (iEMG), there was a linear relationship between integrated PMG (iPMG) and force, the slope of which did not depend on inertia. There was also a linear relationship between iPMG or iEMG and angular acceleration, with a higher slope for the highest inertia condition. There was also a family of linear relationships between iPMG or iEMG and angular acceleration, and their slopes depended on inertia. Measurements of the phono- and electromechanical delays showed that onset of PMG followed that of EMG but preceded onset of acceleration. It is suggested that PMG expresses tension of the underlying muscle contractile elements. Given the simplicity of the PMG method, we conclude that PMG allows convenient evaluation of muscle tension during human dynamic contraction.
| 13 |
[Treatment of Parkinson's syndrome with L-dopa and L-carbidopa (author's transl)]. In a clinical investigation on the treatment of Parkinson's syndrome it is shown that a combination of L-dopa with decarboxylase inhibitor (L-carbidopa) shows advantages compared to treatment with L-dopa alone. To achieve the same therapeutic effect a quarter of the dose is sufficient; the good tolerance, even in relation to the digestive and cardiovascular apparatus, permits the use of relatively larger daily doses. The favorable action appears more quickly. The effect of the treatment can be potentiated by pyridoxine. The only disadvantage is the fairly frequent occurrence of hyperkinesia, especially of oral automatism. But treatment does not need to be broken off because of this.
| 13 |
Fractionation of chromatin by differential solubility in dilute salt. Chromatin prepared from the livers of rats was fractionated on the basis of solubility in dilute NaCl. Neither of the fractions obtained was enriched in newly synthesized DNA. The salt-soluble fraction had a higher protein content (usually up to 50%) relative to the DNA, and contained 72% or more of the rapidly synthesized RNA. This RNA was found to be complexed with the salt-soluble deoxyribonucleoprotein, not merely co-solubilized with it. Also, polylysine-binding studies showed that about 70% or more of the nucleic acid phosphates were accessible as compared to about 40% in the unfractionated chromatin. These properties suggested that the soluble fraction was enriched in activity transcribed chromatin. In contrast molecular hybridization studies showed that the complexity of the DNA and its homology with cDNA transcribed from rat-liver polysomal mRNA were the same as those of DNA from unfractionated chromatin, or from the salt-insoluble fraction. This suggests that the criteria commonly accepted as distinguishing between euchromatin and heterochromatin in vitro are not invariably valid.
| 15 |
Experimental cataract production by high frequency ultrasound. In vivo animal experiments were performed to study the cataractogenic effects of high-frequency, high-intensity ultrasound. A series of anesthetized rabbits was insonified with quantified exposures of ultrasound using a 9.8 MHz focused ultrasonic beam. Ophthalmoscopic and slit lamp examinations revealed small haze cataracts as the first stage of lenticular damage. Larger exposures produced totally opaque cataracts. These first appeared as fine white threads surrounded by haze cataracts. The intensity-exposure time conjugates required to produce haze cataracts were determined over times ranging from 35 msec to 5 sec. At short times (under 100 msec) a relatively constant amount of energy was needed for cataract production. At longer times, the requried energy progressively increased. This observation, together with the physical appearance of these cataracts, suggests that those lesions are the result of thermal phenomena.
| 14 |
Age-dependent changes in alpha-adrenoceptor-mediated contractility of isolated human resistance arteries. Human subcutaneous resistance arteries (122-298 microns), isolated from 139 patients undergoing surgery, were mounted in an isometric myograph. With the use of multiple regression analysis, five different modes of activation were examined for possible associations with age and mean arterial blood pressure of the patients: the contractile responses to 10 microM norepinephrine (mixed alpha 1-agonist/alpha 2-agonist), perivascular nerve stimulation, 10 microM phenylephrine (alpha 1-agonist), 100 microM B-HT 933 (alpha 2-agonist), and depolarization by potassium chloride. Blood pressure increased significantly with age. Blood pressure independently was not correlated to any mode of activation. With increasing patient age, however, responses to norepinephrine, phenylephrine, and perivascular nerve stimulation decreased, whereas the response to B-HT 933 increased; responses to potassium chloride were unaltered. Also corrected for changes in blood pressure, age independently was negatively correlated to the response to norepinephrine and phenylephrine, whereas a positive, though nonsignificant (P value = 0.12), correlation was observed between age independently and the response to B-HT 933. These data suggest that the ability of isolated human resistance arteries to evoke contractions medicated by postjunctional alpha 1-, but not alpha 2-adrenoceptors, decreases with age.
| 20 |
Characterization of transcription initiation and termination signals of the proteinase genes of Lactococcus lactis Wg2 and enhancement of proteolysis in L. lactis. The transcription initiation signals of the prtP and prtM genes specifying the proteolytic activity of Lactococcus lactis subsp. cremoris Wg2 were mapped by primer extension. The strength of these promoters was analyzed with promoter-screening vector pGKV410, and they appeared to be weaker than previously isolated promoters of strain Wg2. In addition, a putative transcription terminator downstream of the prtP gene was characterized by using the terminator-screening vector pGKV259. The putative terminator decreased the transcription activity of lactococcal promoter P59 by approximately 70% in both Bacillus subtilis and L. lactis. Deletion of a part of the stem-loop structure of the terminator decreased the negative effect on transcription, indicating that the structure could indeed function as a terminator of transcription. The proteolytic activity of the lactococcal host was enhanced by placing the originally oppositely oriented prt genes in tandem and replacing the relatively weak promoters upstream of the prt genes with the stronger promoter, P32, from the chromosome of L. lactis Wg2.
| 18 |
A hemopoietic specific gene encoding a small GTP binding protein is overexpressed during T cell activation. We have isolated, from a human B cell line cDNA library, a cDNA (Gx) encoding a small G protein identical to rac 2, a member of the ras superfamily. Gx/rac 2 gene is expressed as a unique mRNA of 1,7 Kb in peripheral blood lymphocytes, in purified B and T cells, in thymus as well as in several B and T cell lines. It is not expressed in many other tissues analysed including liver, brain, lung, heart and kidney. Upon in vitro stimulation with phytohemagglutinin A, peripheral blood lymphocytes show a clear increase of the Gx/rac 2 mRNA after 6 hours; a 30-50 fold accumulation is reached at 24 hours and persists thereafter. Purified T lymphocytes exhibit a similar increase in Gx/rac 2 mRNA expression upon mitogenic stimulation. Therefore, the expression of the Gx/rac 2 gene appears to be restricted to cells of the hemopoietic lineage and to be strongly stimulated during T cell activation. Gx/rac 2 protein must fulfill a specific role in activated T cells that could provide a new model for studying the function of small G proteins.
| 15 |
[Isolation of sarcolemma acetylcholinesterase fractions by gel-filtration through Sepharose 2B]. Gel-filtration of 0,6 M NaCl and 0,6 M NaCl--0,1% Triton X-100 extracts of freshly isolated sarcolemma through Sepharose 2B (1,5 X 72 cm) has revealed one symmetric peak of acetylcholinesterase activity containing phospholipid and cholesterol, moving faster than fibrinogen and tyreoglobulin. The acetylcholinesterase fraction is substantially separated from other extract proteins. Gel-filtration of extracts from long-store, treated by ultrasound or high concentration of detergent sarcolemma has revealed some peaks of acetylcholinesterase activity, which may be suggested to be degraded forms of the complex high molecular weight structure. All species of acetylcholinesterase are converted by treatment with trypsin to a form moving upon gel-filtration with enzyme-marker catalase. The microsome extracts contain only the form moving with catalase.
| 17 |
Activation of hepatic microsomal glutathione S-transferase of rats by a glutathione depletor, diethylmaleate. The effect of glutathione depletor diethylmaleate on rat hepatic glutathione S-transferase and glutathione peroxidase was studied in vivo and in vitro. When diethylmaleate (600 mg/kg) was given i.p. to rats, liver glutathione was depleted within 2 h and recovered to the control level 5 h after diethylmaleate treatment. Both glutathione S-transferase and peroxidase activities in microsomes, not in cytosol, were markedly increased during glutathione depletion and only glutathione S-transferase activity remained at high levels after recovery of the glutathione content. The increase in microsomal glutathione S-transferase and peroxidase activities with concomitant exhaustion of glutathione was also observed by perfusion of the isolated liver with diethylmaleate (10 mM). When liver microsomes were incubated with diethylmaleate in vitro at 37 degrees C, glutathione S-transferase, but not peroxidase, activity was increased; the increase was not reversed by dithiothreitol. These results indicate that diethylmaleate activates microsomal glutathione S-transferase by direct reaction to the enzyme during glutathione depletion and suggest that glutathione S-transferase activity and glutathione peroxidase activity in the microsomal enzyme may be differently regulated.
| 20 |
Differential inhibition of HIV-1 cell binding and HIV-1-induced syncytium formation by low molecular weight sulphated polysaccharides. Dextran sulphate (MW 5000 and 8000) and a polysulphated glycosaminoglycan (MW 10,000), at concentrations that provided complete protection in a homologous infection assay, failed to block syncytium formation and the resulting cytopathic effect when MT-2 cells were mixed with H9/HIV-1 cells. These substances also had no antiviral activity when added to cells, after virus challenge, at a time when binding and entry were complete. However, a high molecular weight (500,000) dextran sulphate blocked HIV-1 infection at both stages. Thus, the gp120-CD4 interactions mediating HIV-1 binding and HIV-1-induced syncytium formation are differentially affected by this class of polyanionic substances. Furthermore, size may be a determining factor in their potential application as anti-HIV treatment.
| 16 |
Clinico-pathological analysis of foal diseases from 237 autopsy cases. To elucidate the current status of foal diseases in Japan, clinico-pathological analysis was conducted on 237 foal autopsy cases. As a result, bacterial infection was identified as an important cause of foal death. Most of the bacteria isolated from these cases were ubiquitous, opportunistic, environmental organisms, known to be non-pathogenic to mature animals. Most of cases with bacterial infection were diagnosed as having hypogammaglobulinemia, i.e., failure of passive transfer. In addition, the mean weight of thymuses in foals affected by bacterial infection tended to be lower than that of foals without infection. These findings suggest that the common cause of foal diseases were mainly due to the opportunistic bacterial infections associated with the weakened immune function, serving as precursor to or promotor of infection.
| 15 |
Genital human papillomavirus infection among women from major ethnic groups in Singapore. The close epidemiological relationships between specific genital human papillomavirus (HPV) types and neoplasia of the cervix uteri have been extensively documented worldwide, including Singapore. Cervical cancer incidence rates in Singapore show variations between the major ethnic groups. To ascertain the corresponding HPV infection rates among the various races in Singapore, we analysed the cervical smears of 225 women by filter in situ DNA hybridization, and compared the data with a previous similar study. Fourteen (6.2%) individuals were HPV-positive, with HPV 16 and HPV 31 being the commonest types. No significant difference between HPV positivity rates in Chinese (5.0%) and in Malays (6.7%) was found, even though Chinese have a higher cervical cancer incidence than Malays. Furthermore, the cervical HPV carriage rate among women with normal cytology was 5.9%. In the light of reports of high genital HPV prevalence rates detected by DNA amplification, these data support the notion that HPV infection is commonly latent and requires the cooperation of other factors for cervical carcinogenesis.
| 16 |
Brief exposure to the G-protein activator NaF/AlCl3 induces prolonged enhancement of synaptic transmission in area CAl of rat hippocampal slices. Rat hippocampal slices were exposed briefly (12-15 min) to AlF4- (10 mmol/l NaF, 10 mumol/l AlCl3). The effect on synaptic transmission in area CAl was measured using extracellular electrodes placed in the stratum pyramidale and stratum radiatum. During fluoride exposure, both spike and EPSP amplitude fell to very low levels. Upon washout, spike amplitude recovered beyond control values, and in half of the preparations a prolonged enhancement of spike amplitude (greater than 2 h) occurred. Similar modulation of EPSP slope indicated that these charges were primarily synaptic. If Al3+ was omitted from the F(-)-containing saline, enhancement of spike amplitude, when observed, was brief (20-30 min) and no enhancement of EPSP slope was seen. Omission of Ca2+ from the AlF(4-)-containing saline also abolished any long-lasting enhancement of synaptic transmission, though population spike amplitude in most slices showed a brief (20-30 min) stimulatory response. In preparations in which LTP had previously been saturated, synaptic transmission was not enhanced by exposure to AlF4-. It is concluded that NaF/ACl3 exposure induces an LTP-like process by G-protein activation, which involves recruitment of processes involved in LTP, possibly including an enhancement of Ca(2+)-influx.
| 16 |
Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Using immunohistochemistry and a panel of monoclonal antibodies, we have compared T-lymphocyte, eosinophil, macrophage, and neutrophil infiltration in bronchial biopsies from 10 intrinsic (nonallergic) asthmatics (IA) and seven extrinsic (allergic) asthmatic (EA), with similar degrees of disease severity. The results were compared with 12 normal healthy nonatopic controls (NC). All subjects were nonsmokers and were not taking oral or inhaled corticosteroids. An intense mononuclear cell infiltrate was identified in IA with an increase in the number of CD45+ cells (total leukocytes), CD3+ and CD4+ lymphocytes, and CD68+ macrophages (p < 0.03, p < 0.01, p < 0.03, and p < 0.03, respectively), compared with NC. Increases were also found in CD4+ (p < 0.05) and CD68+ (p < 0.05) cell numbers between IA and EA. IL-2 receptor-bearing cells (CD25+) and the number of total (MBP+) and actively secreting (EG2+) eosinophils, were also increased in IA compared with NC (p < 0.01, p < 0.01, and p < 0.01, respectively). Similar increases in EG2+ eosinophils and CD25+ (IL-2 receptor-positive) cells were observed in EA (p < 0.01 and p < 0.02, respectively). No differences were detected in the three groups for the number of elastase-positive cells (neutrophils). EG2+ numbers in IA correlated with the Aas asthma symptoms score (r = 0.65, p < 0.05), whereas EG2+ cell numbers in all asthmatics (IA + EA) correlated with airway methacholine responsiveness (r = -0.55, p < 0.03) and with the Aas asthma symptom score (r = 0.54, p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
| 14 |
[Otoplasty: results of a modified form of Mustardé's method]. In order to investigate the results obtained after surgical treatment of prominent ears with a modified method basically derived from the technique of Mustardé 340 patients had been interrogated and 150 had been examined postoperatively. In 91.4% of the cases the patients themselves and in 84.7% the surgeon was satisfied by the postoperative result. Recurrence was observed in 17% and was due partly to the intermittent use of a resorbable suture material. In some cases recurrence consisted in a slight asymmetry, that was not really disturbing and did not need a further correction. A fundamental advantage of our surgical method is the fact that the cartilage has not to be destroyed, so that ugly and unnatural rims are avoided as well as some further postoperative complications (othematoma, perichondritis, pain and sensibility to the cold). Revision surgery even by another technique is always possible because the cartilage is left intact.
| 16 |
Effect of subarachnoid haemorrhage on micro-circulation in hypothalamus and brain stem of dogs. In order to investigate the relationship between cerebral vasospasm and microvasculature in the hypothalamus and brain stem, colloidal carbon was infused into the vertebral artery at various time intervals after experimental subarachnoid haemorrhage in dogs. Experiments which demonstrated vasospasm on angiogram were always accompanied by ischaemic changes in serial sections taken from the anterior hypothalamus to the brain stem. However, when it was demonstrated by angiography that the vasospasm had disappeared, the micro-circulation was restored to normal. Electron microscopy of the hypothalamus 48 hours and one week after subarachnoid haemorrhage, demonstrated swelling of the endothelial cells, enlargement of the perivascular glia and increase in number of the pinocytic vesicles in the cytoplasm, thus showing vasogenic oedema in this area. It is assumed that in addition to the vasogenic substance in extravasated blood, changes in irritability of cerebral vessels through the vasomotor pathways in the hypothalamus and brain stem might play an important role in the production of cerebral vasospasm.
| 22 |
Effects of NO2-modification of Tyr83 on the reactivity of spinach plastocyanin with cytochrome f. We have investigated the electron transfer (ET) reactions between turnip cytochrome f, and the native and NO2-Tyr83-modified forms of spinach plastocyanin (PCu) at 10.0 degrees C and ionic strength 0.200 M(NaCl), in both directions as a function of pH. The PCu(II)/cytochrome f(II) rate constants in the pH-range 4-6.8 reflect active and remote binding site protonation. At higher pH, NO2-Tyr83 and positively charged residues on cytochrome f are deprotonated, and both native and NO2-modified PCu exhibit a composite rate constant variation in this pH range. When framed by ET theory this pattern is fully understandable in terms of variations in reduction potentials and electrostatic interactions, caused by the protonation equilibria. The rate constant ratio knitro/knative is, however, only 1.04 for the PCu(II)/cytochrome f(II) reactions in spite of a 18 mV higher reduction potential for NO2-Tyr83-modified PCu. This is much lower than the value of 1.42 expected from ET theory solely on the basis of such a reduction potential effect. A similar effect is seen for PCu(I)/cytochrome f(III) for which the low-pH knitro/knative ratio is 0.51. Notable but smaller effects are also observed for the small reaction partners [Fe(CN)6]3-/4- and [Co(phen)3]3+/2+. The effect of NO2-modification in addition to the reduction potential effect can be resolved into a small reorganization energy increase around the copper atom and a smaller electronic transmission coefficient for ET through the Cu/Cys84/Tyr83 sequence. The former effect dominates in the reactions with the small reaction partners, while the electronic effects contribute significantly for PCu/cytochrome f, supporting the concept that the PCu/cytochrome f ET is at the remote PCu binding site.
| 20 |
Expression of bovine herpesvirus 1 glycoprotein gIV by recombinant baculovirus and analysis of its immunogenic properties. The gene encoding the gIV glycoprotein of bovine herpesvirus 1 has been inserted into the genome of Autographa californica baculovirus in lieu of the coding region of the A. californica baculovirus polyhedrin gene. Recombinant protein was identified by its reactivity with gIV-specific monoclonal antibodies and expressed at high levels (about 85 micrograms per 2.5 x 10(6) cells) in Spodoptera frugiperda (SF9) cells. The recombinant glycoprotein had an apparent molecular mass of 63 kDa, indicating that it was incompletely glycosylated. However, it was transported to and expressed on the cell surface of infected SF9 cells. Furthermore, reactivity with polyclonal and monoclonal antibodies specific for gIV suggested that most epitopes were functionally unaltered on the recombinant gIV. Immunization of cattle with recombinant gIV in crude, partially purified, or pure form resulted in the induction of neutralizing antibodies to BHV-1, which were reactive with authentic gIV. However, the neutralizing antibody titers were lower than those elicited by an equivalent amount of affinity-purified authentic gIV, which appeared to be mainly due to reduced recognition of one of the neutralizing antigenic domains of gIV, designated domain I. The potential use of this recombinant gIV glycoprotein as a vaccine to bovine herpesvirus 1 infection in cattle is discussed.
| 20 |
Support systems and mental illness in the elderly. Clinical experience indicates an especially important role for support systems in a bio-psychosocial approach to understanding the development of mental illness in elderly persons and the provision of appropriate services for them. Family, work, and community supports are reviewed. The authors believe optimistically that the present traditional supports are not worse than those of the past and that new models exist for future use. In addition, the anticipated increased numbers of elderly make it important that clinicians be well informed and plan multifaceted responses and that community mental health centers, as service and support systems actually in place in many underserved areas, take advantage of multiple available funding streams to increase substantially their assistance for the elderly.
| 18 |
Minority student success and failure with the National Intern and Resident Matching Program. Doubts have been raised concerning the success of minority students in obtaining the more desirable teaching hospital internships in the United States. Earlier reports by others indicated that minority graduates may be anywhere from 41 percent to 70 percent successful in obtaining their first, second, or third choice of internship through the National Intern and Resident Matching Program. Ninety percent of those in the sample reported here were successful. At least one minority applicant was a successful intern candidate in 79 out of the 103 institutions where internships had been most sought after by this group. Possible reasons for these different findings are not adequately explained because of a lack of comparable data on minority and nonminority pools; further sample studies are required to establish the actual facts.
| 16 |
Factors related to preventive health behavior: implications for social work intervention. As acute and infectious diseases become controlled, further improvement in the health status of a population increasingly depends on prevention. Social workers are frequently involved in activities designed to influence individuals and groups to use preventive services or engage in health-maintaining practices. Understanding the determinants of preventive health behavior should contribute to the effectiveness of these social work activities. Therefore, this article reviews numerous empirical studies of preventive health behavior and attempts to integrate them into a theoretical framework. A series of factors that may serve as barriers or supports to preventive health behavior are identified, and their implications for social work intervention are discussed.
| 17 |
Effects of oxygen saturation on the CO2 transport properties of Lampetra red cells. We investigated the effects of haemoglobin oxygenation on the carbon dioxide transport properties of lamprey (Lampetra fluviatilis) erythrocytes. The non-bicarbonate buffering capacity of deoxygenated lamprey erythrocytes was -43 mmol.L-1.pH unit-1. The carbon dioxide content of oxygenated erythrocytes was 7-8 mM lower than that of deoxygenated erythrocytes over a range of carbon dioxide tensions. This was the result of a pronounced Haldane effect (proton uptake by haemoglobin upon deoxygenation): at extracellular pH 7.5, the intracellular pH of oxygenated erythrocytes was 7.67, and increased to 7.91 when the haemoglobin-oxygen saturation decreased to 7%. No specific oxylabile binding of bicarbonate or carbon dioxide to haemoglobin occurred under the conditions of the present study. Owing to the high red cell pH and its large increase upon deoxygenation, carbon dioxide can be effectively transported in lamprey blood, although plasma bicarbonate is not available for carbon dioxide excretion because of the lack of rapid anion exchange across the red cell membrane.
| 17 |
Effect of melatonin implants on secretion of luteinizing hormone in intact and castrated rams. Rams were treated with melatonin implants in 2 experiments designed to examine the control of reproductive seasonality. In Exp. 1, rams (n = 12) were allocated to 3 treatment groups: 2 groups were treated with 2 melatonin implants per ram for 4 months from 11 November (N) and 9 December (D) and the remaining group was untreated (C). The seasonal increase in luteinizing hormone (LH) pulse frequency and testes size was advanced in Groups N and D. A second seasonal cycle in LH secretion and testes size occurred in Groups N and D after melatonin implants became exhausted. In Exp. 2, rams (n = 20) were allocated to 4 treatment groups: 10 rams were castrated on 6 October and 1 group of entire rams (EM) and one group of castrated rams (CM) were treated with 2 melatonin implants per ram each month from 3 November until 8 January. The other group of entire rams (EC) and castrated rams (CC) was untreated. An increase in LH pulse frequency occurred after castration. Melatonin treatment increased LH pulse frequency in entire rams and reduced LH pulse frequency in castrated rams. The results demonstrated that the advanced reproductive development as a result of treatment with melatonin implants was due to an effect of melatonin on the hypothalamic pulse generator to increase LH pulse frequency. The ability of melatonin to influence LH pulse frequency in entire and castrated rams indicated that an effect of melatonin on the hypothalamic pulse generator is independent of testicular steroids.
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Enantiospecificity of kappa receptors: comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics. Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (-) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(-) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X-ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail-flick tests following subcutaneous administration, and binding affinity for kappa and mu receptors, were found to reside predominantly in the (-) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers. For compounds with some affinity also for mu receptors (Ki less than 1,000 nM), the kappa/mu selectivity was maintained within each enantiomeric pair, in contrast to results found for other kappa agonists.
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[Liver damage caused by ranitidine]. The case history is presented of a woman who developed serious liver injury while using ranitidine (Zantac). Complete clinical recovery and normalization of liver function tests were seen after discontinuation of the drug. Since 1983 five other similar cases have been reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs. No viral cause was found in these cases and three of the six patients used no other medication that may cause liver injury, so that a causal relationship with the use of ranitidine may be assumed. The clinical symptoms of the cases and the available literature suggest metabolic idiosyncrasy as the mechanism, most likely through an immunoallergic reaction.
| 14 |
Experimental study of vaccines against Salmonella typhimurium infection. Serological and protective activities of vaccines from S. typhimurium and S. minnesota were studied. It has been demonstrated that active protection against infection in experimental salmonellosis in mice can only be obtained by immunization of the animals using vaccines from complete antigenic complexes isolated from S-strains. It has been found that expressed anti-infection immunity (unlike anti-endotoxic immunity) is induced to the same extent by either high-molecular components (2,000,000 daltons and more), showing great serological activity, or components with relatively low molecular weight (15,000--20,000 daltons) and minimum serological activity. Vaccines from Ra- and Re-strains of S. minnesota do not induce resistance to S. typhimurium infection in mice in either active protection tests or passive protection tests.
| 20 |
Techniques for pharmacological and toxicological studies with isolated hepatocyte suspensions. Since its introduction in 1969, the high-yield preparation of isolated hepatocytes has become a frequently used tool for the study of hepatic uptake, excretion, metabolism and toxicity of drugs and other xenobiotics. Basic preparative methods are now firmly established involving perfusion of the liver with a balanced-saline solution containing collagenase. Satisfactory procedures are available for determining cell yields, for expressing cellular activities and for establishing optimal incubation conditions. Gross cellular damage can be detected by means of trypan blue or by measuring enzyme leakage, and damaged cells can be removed from the preparation. Specialized techniques are available for preparing hepatocyte couplets and suspensions enriched with periportal or perivenous hepatocytes. The isolated hepatocyte preparation is particularly convenient for the study of the kinetics of hepatic drug uptake and excretion because the cells can be rapidly separated from the incubation medium. Isolated liver cells have also proved valuable for investigating drug metabolism since they show many of the features of the intact liver. However, they also show important differences such as losses of membrane specialization, some degree of cell polarity and the capacity to form bile. The many consequences of the hepatic toxicity of xenobiotics including lipid peroxidation, free radical formation, glutathione depletion, and covalent binding to macromolecules are also readily studied with the isolated liver cell preparation. A particular advantage is the ease with which morphological changes as a result of drug exposure can be observed in isolated hepatocytes. However, it must be remembered that the isolation procedure inevitably introduces changes that may make the cells more susceptible than the normal liver to damage by xenobiotic agents. Despite its limitations, the isolated hepatocyte preparation is now firmly established in the armamentarium of the investigator examining the interaction of the liver with xenobiotics.
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Two cases of inherited triple deficiency in a large kindred with thrombotic diathesis and deficiencies of antithrombin III, heparin cofactor II, protein C and protein S. Thirty-three subjects, belonging to a large family with functional antithrombin III (ATIII) deficiency (type IIa) and recurrent thromboembolism, were investigated for ATIII, heparin cofactor II (HCII), protein C (PC) and protein S (PS). We report the exceptional finding of two cases of triple deficiency: ATIII combined with HCII and PC in the first case aged 15 and ATIII combined with HCII and PS in the second case aged 27. Interestingly, both are asymptomatic thus far. Twenty-five other deficient members were found, among which seven are affected with a double deficiency. Totally, the results of our study show 38 deficiencies of four distinct antithrombotic protein: ATIII (n = 9), HCII (n = 9), PC (n = 7) or PS (n = 13). Two types of HCII deficiency were observed and type I PC deficiency was found. Functional PS deficiency was characterized by reduced levels of cofactor activity for activated PC. Our report demonstrates that combined deficiencies should be sought in a family already known to be deficient in one antithrombotic protein.
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Rates of Obsessive Compulsive Disorder in first degree relatives of patients with trichotillomania: a research note. To explore a possible relationship between trichotillomania, (TTM) (compulsive hair pulling) and Obsessive Compulsive Disorder (OCD), 65 out of 69 (94%) first degree relatives of 16 female probands with severe chronic TTM were compared with two control groups for OCD and for TTM. Three (19%) of the 16 TTM probands had at least one first degree relative with a lifetime history of OCD, and there was an age corrected rate of 6.4% of first degree relatives with OCD. No relative in control group (A) met criteria for OCD. There was a trend (Fishers exact p = .07, two tailed) for a higher rate (age corrected) of OCD in TTM families; these pilot data are consistent with the concept of a spectrum of obsessive compulsive disorders which includes TTM and other pathological grooming behaviours.
| 17 |
Local anesthesia for mediastinoscopy: experience with 450 consecutive cases. Mediastinoscopy has been widely applied in the evaluation of patients with suspected bronchogenic carcinoma over the past decade. Though there remain those who feel that such findings should not play a significant role in determining resectability, we have found a number of patients who have been saved from exploratory thoracotomy in obviously incurable situations. We have had a relatively high degree of success in the diagnosis of benign diseases. Wtih no mortality and a morbidity of 1.1%, we feel that mediastinoscopy under local anesthesia is applicable in many clinical circumstances in which the requirement for general anesthesia would preclude such evaluation. Though it is not necessary that local anesthesia be exclusively applied, we feel that our experience with over 450 cases in the last six years has demonstrated safety and efficacy in universal application of local anesthesia for cervical mediastinal exploration.
| 19 |
[Peroral terbutaline in the treatment of patients with severe irreversible obstructive pulmonary disease]. This investigation assesses the effect of oral terbutaline in doses of 7.5 mg twice daily as compared with placebo in patients with moderate to severe chronic airflow limitation (CAL) without reversibility. Seventeen patients completed this double-blind randomised cross-over trial. Diaries with reports of dyspnoea during activities of daily living and peak-flow measurements, were obtained. Measurement of pulmonary function, walking distance and various scorings of function after treatment for three and five weeks were assessed. The investigation demonstrates that in patients with CAL treatment with terbutaline tablets may lead to improvement of several subjective effect variables although no real improvement in the majority of objective effect variables is observed. In patients with irreversible obstructive reduction of pulmonary function, in whom no other form of treatment can be considered, oral treatment with beta-2-agonists may be attempted. If no effect is obtained, the treatment should be withdrawn after one to two months.
| 16 |
Functional changes implicating dopaminergic systems following perinatal treatments. A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviors in the laboratory. Rat dams were administered either metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams was studied with behavioral tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-hydroxydopamine (6-OHDA) (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound, or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adults. The behavioral battery the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviors, and a parameter under which diverse behaviors were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spatial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphetamine-induced activity. It was shown that prenatal metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine-induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded according to the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine-induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85% depletion compared to control values) caused notable impairments. One tentative conclusion from the pattern of behavioral changes, generally in the absence of any measurable neurochemical changes, observed after these treatments is that the functional development of dopaminergic systems had, to a greater or lesser degree, been altered.
| 21 |
[Effects of taurine and dipeptide Tyr-Tyr on ventricular defibrillation]. Results of the study of taurine and dipeptide Tyr-Tyr effect on the threshold values of functional lesions of the myocardium and heart defibrillation are reported. The experiments were carried out on 27 narcotized mongrel dogs weighing 12-30 kg. Defibrillation was performed using Lifepak-7 defibrillator (USA). Lesion threshold (LT), defibrillation threshold (DT) and electrotherapeutic index (ETI) as a LT:DT ratio were determined. In 14 experiments (control group) these parameters were evaluated during 3 h. In group 1 (6 experiments) taurine (100 mg/kg) was infused intravenously by the end of the 1st hour, in group 2--Tyr-Tyr (25 mg/kg). It was shown that infusion of taurine did not have a noticeable effect of the LT, DT and ETI values. Infusion of Tyr-Tyr resulted in an increase in LT and DT. The possibility to use dipeptide Tyr-Tyr in the complex of measures aimed at ceasing ventricular fibrillation is discussed.
| 12 |
Cytochemical and cytoenzymatic investigations in the management of leukemias. The value of certain cytochemical and cytoenzymatic investigations in the management of leukemias is discussed in different types of acute or chronic leukemias. Among the data resulting from cytochemical methods those related to cellular biochemical components such as DNA, RNA, glycogen and lipids are particularly noteworthy. The results of cytoenzymatic investigations have stressed the necessity of knowing the activity of certain enzymes such as peroxidases, alkaline and acid phosphatases, beta-glucuronidase, succinate dehydrogenase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase a.o. The prospective value of enzymes such as dehydrofolate reductase, DNA and RNA polymerases, DNA and RNA-ases a.o. in the management of leukemias is also mentioned.
| 18 |
Myristylated polyomavirus VP2: role in the life cycle of the virus. The double-stranded genome of the small DNA tumor virus, polyomavirus, is enclosed in a capsid composed of a major protein, VP1, which associates as pentameric capsomeres into an icosahedral structure, and two minor proteins, VP2 and VP3, whose functions and positions within the structure are unknown. The N-terminal glycine of the VP2 coat protein has been shown to be cotranslationally acylated with myristic acid. To study the function of this modification and the role of VP2 in the life cycle of polyomavirus, the N-terminal glycine, critical to the myristylation consensus sequence, has been altered to a glutamic acid or a valine residue by site-directed oligonucleotide mutagenesis. The glycine----glutamic acid mutant DNA has been further studied. When transfected into cells permissive for the polyomavirus full lytic life cycle, this mutant DNA replicated at levels comparable to those of wild-type viral DNA, and small amounts of nonrevertant (mutant) virus could be harvested from the cultures. The virus particles viewed by electron microscopy appeared slightly distorted, but the ratio of full to empty particles was similar to that produced in a wild-type viral infection. Mutant virus was capable of reinfecting permissive cells but with a considerably reduced efficiency.
| 17 |
[Late postoperative apnea in a premature newborn infant]. We report the case of a premature newborn child (36 weeks) who was operated on a teratoma of the sacrum when he was 12 days old and weighed 2,950 g. The patient presented a late postoperative apnea 17 hours after anesthesia. The anesthetic technique consisted of lumbar epidural blockade with 0.33% bupivacaine at a dose of 2.25 ml and superficial inhalation anesthesia with 0.5% isoflurane. Relaxing muscular agents used in this case were succinylcholine (3 mg) for orotracheal intubation and pancuronium bromide (0.3 mg) for maintaining the anesthetic level. The immediate postoperative phase was uneventful but 17 hours after surgery the patient presented apnea, bradycardia (40 beats/min), and marked cyanosis requiring assisted ventilation with bag and mask during 3 min and initial cardiac massage. Recovery of heart rate was immediate and recovery of ventilation was progressive. The patient was treated with caffeine during one week and no relapses occurred. Pneumocardiographic recordings obtained later on revealed sporadic short lasting episodes of apnea (shorter than 15 s) sometimes associated with bradycardia (40 beats/min lower than baseline). There were no apparent intercurrent or precipitating factors for this apnea. We believe that the present clinical picture corresponds to a late postoperative apnea of unknown origin which required reanimation measures and that until present, there are no reported complications of the anesthetic technique that can explain this episode.
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[Kinetics of the compensation of respiratory acidosis induced by experimental chronic hypercapnia in man (author's transl)]. Four groups of male volunteers have been exposed in a tight climatical chamber to PICO2 of 14, 21, 28 and 32 torr; exposure periods varied from two to 30 days, between two reference periods in normal air. The results deal with the evolution of arterial blood acid-base equilibrium and that of renal response in relation to PICO2. In all exposures, the carbon dioxide alveolar overload increases by several torr during the first 24 hours on account of attenuation of the initial hyperventilation. Kinetics of the respiratory acidosis compensation differs according to hypercapnia which is moderate (PICO2 of 14 and 21 torr) or relatively severe (PICO2 of 28 and 32 torr). The decrease in arterial pH lessens as early as the 24th hour at PICO2 28 and 32 torr, and only after two days at PICO2 14 and 21 torr. The renal response is characterized by a significant increase in aciduria during the first 24 hours at PICO2 28 and 32 torr; the changes are smaller and start latter at PICO2 14 torr.
| 16 |
DNA adduct formation in mice treated with ochratoxin A. Several authors have reported the occurrence of renal and hepatic tumours in mice and rats exposed to ochratoxin A in long-term studies. The compound was not mutagenic, however, in various microbial and mammalian gene mutation assays, either with or without metabolic activation. Contradictory results were obtained for induction of unscheduled DNA synthesis and sister chromatid exchange. We showed previously that ochratoxin A causes DNA damage, manifested as single-strand breaks in mouse spleen cells and in vivo. These findings, which suggest that ochratoxin A is weakly genotoxic to mammalian cells, prompted us to search for DNA adducts using a modified 32P-postlabelling method, the sensitivity of which was improved by treatment with nuclease P1. DNA was isolated from liver, kidney and spleen excised from mice 24, 48 and 72 h after oral treatment with ochratoxin A at 0.6, 1.2 and 2.5 mg/kg body weight. Several adducts were found in the DNA of the three organs, the levels varying greatly. After administration of 2.5 mg/kg body weight, 40 adducts per 10(9) nucleotides were found in kidney DNA and 7 adducts per 10(9) nucleotides in liver after 72 h. The levels of most of the adducts increased from 24 to 72 h, but those of others diminished after 24 or 48 h. Adducts were found in spleen only at 24 and 48 h. These results confirm the genotoxicity of ochratoxin A.
| 16 |
Unexplained fever and chronic fatigue: abnormal circadian temperature pattern. Standard clinical and biological investigations can be used to determine the origin of persistent and moderate fever in a large number of otherwise asymptomatic patients. However, in a small proportion of cases, isolated fever and fatigue persist despite the absence of detectable organic malfunction. This study was conducted to investigate the circadian thermic pattern in patients with apparently unexplainable fever and chronic fatigue and in those with fever of recognized origin. We recorded central temperature continuously for 24 hours in patients with moderate fever of both unexplained and recognized origin, and in a control group of healthy volunteers. A Fourier series was used for harmonic analysis. Thermic patterns specific to the three groups were identified by statistical and factorial analysis. The patients with fever of unknown origin and chronic fatigue were clearly characterized in terms of the phase, amplitude of the first (fundamental) harmonic and minimum circadian temperature. The abnormal central temperature pattern in these patients may prove to be an important step in the management of febrile patients.
| 17 |
Moderate head injury: an overview. This review summarizes currently available epidemiologic, clinical, pathologic, and outcome data in patients with moderate head injury (MHI, GCS 9-12). This important subset comprises about 20% of head injuries in the United States. Affected patients usually are young, and most injuries are due to vehicular accidents. Current evidence (mortality rate and outcome) from various studies suggests an apparent dichotomy within the MHI category (9-10 vs 11-12). The former is more in keeping with the favorable subgroup of severe head injuries, and the latter is more appropriate to the mild head injury group. Should there be a reclassification based on this dichotomy? This is obviously important for clinical management and prognostication in these patients. The experimental evidence for a pathologic and biochemical substrate of MHI is reviewed. It is becoming increasing evident that biochemical mediators of secondary neuronal injury in MHI are at least as important as those attributed to severe head injury, but MHI may be more amenable to therapy. It may be prudent, therefore, to direct further effort to this subgroup of patients. Although additional study is required, the pattern of recovery in MHI as determined by extant neurobehavioral studies is analyzed.
| 14 |
Portal and biliary phases of enterohepatic circulation of corrinoids in humans. The assimilation of labeled cobalamin and the transport of corrinoids in portal blood, peripheral venous blood, and bile were studied in eight cholecystectomized patients, after ingestion of a dose of cyano[57Co]cobalamin (0.5 microCi). The radioactivity appeared in the portal vein after a delay of 1.5-2 hours and in the peripheral vein 1 hour later. In bile, it reached a maximum at 24-72 hours; the excreted cobalamin corresponded to 1.42% +/- 0.92% of the dose ingested. The output of total corrinoids was 1.85 nmol/day. The high-performance liquid chromatography analysis of bile showed the presence of methylcobalamin, 5'-deoxyadenosylcobalamin, hydroxocobalamin, and an unknown corrinoid. This corrinoid bound to R binder but not to the intrinsic factor, and it had the same retention time as cobinamide. The R binder was the single cobalamin-binding protein found in bile. It was completely saturated in some periods of bile secretion. The corrinoids corresponding to such a period were eluted in Sephacryl S 300 gel filtration (Pharmacia Fine Chemicals, Uppsala, Sweden) in two peaks corresponding to saturated R binder and to free cobalamin. The mean level of total corrinoid was significantly higher in the portal vein (593 +/- 238 pmol/L) than in the peripheral vein (376 +/- 114 pmol/L) (P less than 0.01). This "cobalamin analogue" fraction was hypothetical because it was calculated from the difference between total corrinoid concentration and the so called "true cobalamin" concentration. This difference corresponded to the cobalamin analogue fraction. These data show that bile removes not only cobalamin but also cobalamin analogues and that R binder is the single carrier protein involved in their excretion.
| 15 |
Restoration of sensitivity to sulfonylurea after strict glycaemic control with insulin in non-obese type 2 diabetic subjects. Ten non-obese type 2 diabetic patients with secondary failure to sulfonylureas received an intensive insulin therapy (four doses schedule) for 90 days. The glycaemic control was poor at entry (HbA1c = 11.7 +/- 1.2%) and ameliorated significantly after insulin (HbA1c = 7.1 +/- 0.7%, p less than 0.01). The reintroduction of the sulfonylurea after insulin withdrawal resulted in a persistent satisfactory long-term control (300 days) in all, but two diabetics responded no more after about 3 and 4 months of clinical remission (good control on sulfonylurea). Both basal and stimulated (iv glucagon and mixed meal) beta-cell secretory activity increased significantly at 3 months and declined thereafter without falling below baseline values. Three months of strict metabolic control seem to restore the sensitivity to sulfonylurea by enhancing beta-cell secretory activity in non-obese type 2 diabetic patients.
| 19 |
Quantitation of model digestive mixtures by 13C NMR. 13C nuclear magnetic resonance (NMR) spectra were obtained at 50.3 and 100.5 MHz for methanolic and aqueous mixtures of sodium taurocholate, 1-monocapryloyl-rac-glycerol, and caprylic acid. Distortionless Enhancement by Polarization Transfer (DEPT) was used to improve spectral sensitivity and resolution, and to generate calibration curves for quantitative determinations of each lipid in methanol. Alternatively, the heights for nonoverlapping peaks in a 13C NMR spectrum acquired with inverse-gated decoupling provide reliable quantitative estimates for each component of the mixture, particularly when the data are obtained in methanol. These experiments also demonstrate the feasibility of detailed NMR structural investigations in model systems for glyceride digestion.
| 19 |
Hematologic findings in cases of mammary cancer metastatic to bone marrow. The hematologic findings in 22 cases of mammary cancer metastatic to bone marrow are presented. Cancer of the breast was the most frequent neoplasm metastatic in bone marrow in this study of 2,878 bone-marrow examinations. All 22 patients who had carcinoma of the breast metastatic to bone marrow had clinical, radiographic, or hematologic evidence of widespread metastatic disease. Peripheral blood was abnormal in 58% of the cases, and in most of these cases two or more abnormalities were present. Bone-marrow biopsies were superior to particle sections and aspirates in identifying tumor, but correlations among all modalities were necessary for proper interpretation. Although the morphologic features of tumor cells in sections and smears were quite characteristic for carcinoma of the breast, pitfalls in interpretation were numerous and should be recognized. The mean survival time of these patients was only 6.9 months after identification of bone-marrow metastases. The significant response to chemotherapy obtained with some individuals, however, should encourage aggressive therapy of this disorder.
| 15 |
A hemolytic plaque assay for the detection of direct and indirect antibody-forming cells to keyhole limpet hemocyanin. A procedure is described for the in vitro enumeration of individual lymphoid cells producing antibody against Keyhole Limpet Hemocyanin (KLH) by a modification of the hemolytic plaque technique. Optimal conditions for the coupling of KLH to sheep erythrocytes by chromic chloride are described. Plaque-forming cells are detected in a liquid monolayer slide chamber assay system. The kinetics of the in vivo primary and secondary PFC responses of both rabbit popliteal lymph node cells and mouse spleen cells are described. Both direct (IgM) and indirect (IgG) plaque-forming cells can be enumerated. The method can also be used to detect an in vitro anamnestic response in dispersed rabbit lymph node cell suspensions. The method is simple, extremely sensitive and the results correlate with those previously obtained in which newly synthesized antibody was detected in similar systems using the coprecipitation assay.
| 15 |
Helical Bacillus subtilis macrofibers: morphogenesis of a bacterial multicellular macroorganism. Helical bacterial macroorganisms have been produced by the selection of appropriate Bacillus subtilis mutants and the establishment of specific growth conditions. Threadlike fibers ranging in length to approximately 1 cm are produced in fluid culture by the parallel association of many division-suppressed filaments in helical arrangement. A more open ball-like structure of complicated woven architecture may also be produced. Macrostructure morphology is regulated by genetic, physiological, and nutritional factors. The pitch angle of surface filaments in helical macrofibers varies as a function of macrofiber diameter, indicating a flexible response of individual cell surfaces to the forces responsible for helical morphology. Three classes of mutants have been obtained that are concerned with helix directionality: (i) mutants that form only left-handed helix macrofibers, (ii) mutants that form only right-handed helix macrofibers, and (iii) conditional mutants able to form either left- or right-handed helix macrofibers depending upon nutritional environment. Aggregate structures containing both left- and right-handed macrofibers have been obtained by coculturing appropriate mutants. In addition to providing information on the organization of the bacterial cell surface, this new system offers unique and unusual opportunities to study cell-cell interactions, primitive morphogenesis, and the properties of a multicellular bacterial form.
| 20 |
Presentation, clinical course, and outcome of childhood stroke. We reviewed the presentations, clinical courses, and outcomes of 42 children with unilateral hemispheric stroke. Infants with strokes identified within the first few days of life usually presented with seizures. These infants had few abnormal neurologic findings as neonates, but hemiparesis became evident as gross motor development proceeded. Infants with strokes identified later in the first year of life usually presented with pathologic early hand preference without a history of an ictus. During subsequent development, the motor deficits in these children became more evident, producing an apparent progression of the neurologic abnormalities. Strokes identified in older children typically presented as sudden hemiparesis, often associated with seizures. The hemiparesis in these children was most severe at the onset, followed by some improvement in strength in all patients. Functional outcome was variable. At last follow-up, all children were ambulatory, some with clinically apparent hemiparesis. Eight of the 42 children (19%) developed recurrent seizures with an onset ranging from 4 months to more than 10 years (median: 26 months) after the stroke.
| 13 |
Possible roles of arachidonic acid and its metabolites in induction of tissue plasminogen activator (t-PA) production in human fibroblast, IMR-90 cells by proteose peptone. Proteose peptone (p.peptone) had an ability to induce tissue plasminogen activator (t-PA) production by human embryonic lung fibroblast, IMR-90 cells. We previously demonstrated that the induction was closely related to the activation of phospholipase A2 in the cells stimulated by p.peptone. In this report, we describe the involvement of arachidonate metabolism in the induction. The induction was inhibited in a dose-dependent manner by 5,8,11,14-eicosatetraenoic acid (ETYA), an inhibitor of both cycloxygenase and lypoxygenase, and also by nordihydroguaiaretic acid (NDGA), which in low concentrations selectively inhibits lipoxygenase. However, indomethacin, a specific inhibitor of cycloxygenase, had no effect on the induction. 5-hydroxyeicosatetraenoic acid (5-HETE), which is an arachidonate metabolite derived from lipoxygenase pathway, had an inductive effect, but prostaglandin E1 (PGE1), which is a metabolite from cycloxygenase pathway, had no effect on t-PA production by the cells. These results suggest that arachidonate metabolism is involved in the induction of t-PA production in IMR-90 cells by p.peptone, and that arachidonate metabolite(s) from lipoxygenase pathway is responsible for the induction.
| 20 |
Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. 1. Intracellular recordings were made from CA1 pyramidal cells in the rat hippocampal slice to study the cholinergic modulation of GABAergic inhibition. The cholinergic receptor agonist, carbamylcholine (carbachol), depressed evoked excitatory postsynaptic potentials (EPSPs) and evoked inhibitory postsynaptic potentials (IPSPs), but enhanced small spontaneously occurring membrane potential fluctuations that resembled IPSPs. Both atropine (1 microM) and picrotoxin (25-60 microM) abolished the small fluctuations. 2. Recording from cells with potassium or caesium chloride (KCl or CsCl)-filled microelectrodes enhanced and inverted spontaneous Cl(-)-dependent GABAA-mediated IPSPs. These events appeared to result from the spontaneous firing of GABAergic interneurons since they could be inhibited by picrotoxin or bicuculline and nearly eliminated by tetrodotoxin. 3. Muscarinic acetylcholine (ACh) receptor activation significantly increased the frequency of spontaneous-activity-dependent IPSPs from 1.7 +/- 0.4 s (mean +/- S.E.M.) in control saline to 7.0 +/- 1.1 s in carbachol (10-50 microM)-containing saline, although evoked IPSPs were inhibited. All effects of carbachol were completely reversed by atropine. 4. The increase in frequency of spontaneous IPSPs observed in carbachol was not secondary to changes in the postsynaptic cell and was not blocked by high doses of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM) and 2-amino-5-phosphonovaleric acid (APV, 10-20 microM), which abolished evoked excitatory transmission. Amplitude histograms showed an increase in mean size as well as of frequency of spontaneous IPSCs in carbachol. 5. Stimulation of cholinergic afferents in stratum oriens in the presence of the acetylcholinesterase inhibitor eserine (1 microM) also increased spontaneous IPSP frequency, and the time course of this response was similar to that of the muscarinic slow EPSP. Postsynaptic factors or the activation of glutamatergic excitatory pathways could not account for this effect. 6. Evoked monosynaptic IPSCs in CNQX and APV were diminished by carbachol. 7. We conclude that GABAergic inhibitory interneurons possess muscarinic receptors, that activation of these receptors increases the excitability of the interneurons and that synaptically released ACh increases interneuronal activity. Cholinergic reduction of the monosynaptic IPSC may point to additional complexity in cholinergic regulation of the GABA system.
| 15 |
Apolipoprotein synthesis in newborn piglet intestinal explants. To determine the effects of hormones and epidermal growth factor (EGF) on the small intestinal synthesis of apolipoproteins B-48, A-I, and A-IV in the neonatal mammal, apolipoprotein synthesis by proximal jejunal explants from 2-d-old female piglets was studied in tissue culture. Initial comparison studies with various media showed optimal total protein and apo A-I synthesis with Williams' medium E without fetal bovine serum. Sets of explants were prepared containing EGF and various hormones in the medium. After 35S-methionine radiolabeling, explants were homogenized, and specific apolipoprotein synthesis was quantitated by immunoprecipitation as the percentage of total protein synthesis. Apo B-48 synthesis was not affected by any additives except the combination of EGF and hydrocortisone, which slightly decreased synthesis. Apo A-I synthesis was significantly increased by EGF. This EGF-induced increase in apo A-I synthesis was blunted by concomitant treatment with hydrocortisone. In contrast, the combination of insulin and hydrocortisone induced a significant increase in apo A-I synthesis. Although EGF and insulin modestly increased apo A-IV synthesis, the combination of insulin and hydrocortisone treatment up-regulated apo A-IV synthesis by 2.6-fold. Thyroid hormone lacked effect on synthesis of any of the apolipoproteins. EGF, glucocorticoids, and insulin may play regulatory roles in the developmental expression of apolipoprotein synthesis in the neonatal small intestine.
| 16 |
Assessing pathogenicity potential of waterfowl-origin type A influenza viruses in chickens. Intravenous pathogenicity index (IVPI) tests on 29 wild duck-origin type A influenza viruses, two turkey-origin type A influenza viruses, and one chicken-origin type A influenza virus resulted in indices ranging from 0.0 to 0.49. Most of the wild duck-origin viruses and the two turkey-origin viruses had indices of 0.0, indicating they are not pathogenic. Six of the duck-origin viruses had indices ranging from 0.25 to 0.49, and the IVPI for A/chicken/Alabama/75 (H4N8) was 0.49, indicating they had low pathogenic potential. An IVPI of 1.25 up to the maximum score of 3.0 is necessary for a type A influenza virus to be classified as highly pathogenic. Gross lesions observed in chickens dying following intravenous viral challenge included kidney swelling with more prominent lobular patterns, but visceral urate deposits were not present. The usefulness of the IVPI test in evaluating the pathogenicity potential of nonpathogenic and low-pathogenic strains of avian influenza virus may be limited.
| 16 |
Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Herpes zoster occurred in nine patients with methotrexate-treated rheumatoid arthritis. We compared these patients to a large group of methotrexate-treated rheumatoid arthritis patients in order to uncover potential factors explaining the occurrence of herpes zoster. Data from 187 patients taking methotrexate were reviewed and compared with data from another nine patients who developed herpes zoster while taking the drug for rheumatoid arthritis, all from the same university-based arthritis clinic. Literature pertinent to infection in rheumatoid arthritis patients treated with methotrexate is reviewed. Herpes zoster occurred in 14.5 cases per 1,000 patient-years in our methotrexate-treated rheumatoid arthritis patients, as compared with the general population incidence of 1.3 to 4.8 cases per 1,000 patient-years. The infection was unrelated to duration of methotrexate usage, prednisone treatment, or the co-existence of diabetes mellitus, but appeared to occur in patients with high titers of rheumatoid factor and an overall longer duration of rheumatoid arthritis. There were no cases of systemic dissemination or recurrence of herpes zoster despite 27.4 years cumulative follow-up on continued methotrexate therapy. Herpes zoster may occur more frequently in patients with rheumatoid arthritis treated with low-dose methotrexate than in the general population. Herpes zoster in rheumatoid arthritis patients treated with methotrexate appears to be self-limited, benign, and statistically related to methotrexate use in the presence of longer-term rheumatoid disease.
| 18 |
Digitalis in experimental acute myocardial infarction. Differential effects on contractile performance of ischemic, border and nonischemic ventricular zones in the dog. The effects of digoxin priming dose of 0.04 mg/kg body weight followed by infusion of 0.02 mg/kg per min) on local tension and length characteristics of the nonischemic, border and ischemic left ventricular zones were studied in 30 dogs using Walton-Brodie strain gauge arches and mercury-in-Silastic segment length gauges. Total tension in the nonischemic zone increased to 130.9 plus or minus 5.3 percent (P smaller than 0.001) of the control level in association with parallel changes in preejection and ejection tension and rate of rise of tension when infusion of digoxin was instituted 15 to 30 minutes after ligation. Consistent increases in tension variables were noticed when infusion of digitalis was initiated 45 to 60 minutes or 2 to 3 hours after ligation. Segment length remained unchanged. In the border zone, total tension decreased to 68.9 plus or minus 5.9 percent (P smaller than 0.01) after infusion of digitalis. When infusion of digitalis was instituted 45 to 60 minutes or 2 to 3 hours after occlusion, similar increases in total tension and other tension variables were seen. Segment length again showed no significant changes. There was an increase in total tension in 5 of the 12 ischemic zones studied when digitalis was infused 15 to 30 minutes after coronary arterial ligation, whereas a consistent (3 to 5 percent) decrease in tension was observed when infusion of digitalis was instituted 45 to 60 minutes and 2 to 3 hours after coronary occlusion. There was no increase in segment length. In summary, digitalis uniformly increased contraction of the nonischemic and border zones after coronary arterial ligation, but the effects on contraction and aneurysmal bulging in the ischemic zone were minimal.
| 17 |
Characterizations of acylagmatine amidohydrolase and carboxypeptidase from Fusarium anguioides. Previously an enzyme, named acylagmatine amidohydrolase, hydrolyzing bleomycin B2 to bleomycinic acid and agmatine was found in the mycelia of Fusarium anguioides Sherbakoff. In this work the enzyme was purified further, but not completely. The crude enzyme preparation hydrolyzed various acylagmatines and also peptidyl arginine, but the latter activity could be separated from acylagmatine amidohydrolase activity by gel filtration on Sephadex G-100. The enzyme was inhibited by PCMB and its molecular weight was estimated as 65,000 by gel filtration. It showed substrate specificity with respect to the alkyl-chain length of the amine moiety. The other hydrolase fraction with activity toward Bz-Gly-Arg was found to be of a sort of carboxypeptidase, which preferentially hydrolyzed peptides with arginine or lysine at the carboxyl terminus, including bradykinin, but liberated neutral amino acids as well from the terminus when the penultimate residue of the substrates was phenylalanine. With Bz-Gly-Arg as substrate Fusarium carboxypeptidase was sensitive to chelating agents but not to diisopropyfluorophosphate, and its molecular weight was estimated to be 145,000.
| 19 |
Costs and benefits of preemployment drug screening. This study provides a cost-benefit analysis of preemployment drug screening and evaluates the sensitivity of this analysis to variation in its underlying assumptions. Cost-benefit analysis, based on a cohort analytic study previously reported. Employees of the US Postal Service in Boston, Mass. Estimates of costs and benefit are based on a cohort of 2533 postal workers in Boston and on average costs for the Postal Service in Boston and nationwide. Drug screening would have saved the Postal Service $162 per applicant hired. However, these results were sensitive to the assumptions in the model. If the prevalence of drug use in the population screened were 1% rather than 12%, the program would lose money. Similarly, if the cost per urine sample screened were $95 rather than the $49 assumed, then the program would lose money, even if the prevalence of drug positives was as high as 9%. Because of the sensitivity of this analysis to changes in its underlying assumptions, any company considering preemployment drug screening should carefully weigh the costs and benefits in its own industry.
| 12 |
Pharmacological modulation of inhaled sodium metabisulphite-induced airway microvascular leakage and bronchoconstriction in the guinea-pig. 1. We have investigated the effects of chlorpheniramine, atropine and capsaicin pretreatment on inhaled sodium metabisulphite (MBS)-induced airway microvascular leakage and bronchoconstriction in anaesthetized guinea-pigs in order to clarify the mechanisms involved in these responses. The effects of frusemide and nedocromil sodium were also examined. 2. Lung resistance (RL) was measured for 6 min after inhalation of MBS (20, 40, 80 and 200 mM; 30 breaths), followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. MBS caused an increase in RL and leakage of dye at all airway levels in a dose-dependent manner. 3. Chlorpheniramine (10 mg kg-1, i.v.), atropine (1 mg kg-1, i.v.), their combination or inhaled nedocromil sodium (10 mg ml-1, 7 min) had no effect against the airway microvascular leakage induced by 80 mM MBS (30 breaths). Capsaicin pretreatment (50 mg kg-1, s.c.) caused a significant decrease in the leakage of dye in the main bronchi and inhaled frusemide (10 mg ml-1, 7 min) also in the main bronchi and proximal intrapulmonary airway. 4. Chlorpheniramine, atropine, their combination, capsaicin pretreatment and frusemide, but not nedocromil sodium, inhibited significantly the peak RL induced by 80 mM MBS (30 breaths) by approximately 50%. 5. We conclude that a cholinergic reflex and neuropeptides released from sensory nerve endings may participate in the mechanisms of MBS-induced airway responses. Frusemide but not nedocromil sodium may have an inhibitor effect on these neural mechanisms. The inhibitory effect of nedocromil sodium against lower doses of MBS is not excluded.
| 13 |
The presence of interferon and type A immunoglobulins in the nasopharyngeal secretions of volunteers immunized with an inactivated influenza vaccine. The presence of interferon and type A immunoglobulins (IgA) was followed up in the nasopharyngeal washings collected from volunteers immunized intranasally with an inactivated influenza vaccine [strain A/Rom 1/73 (H3N2)]. Interferon was detected 24 hours after vaccine administration, its incidence being similar to that in the course of acute infection. Intranasal administration of inactivated influenza vaccine stimulated the production of secretory IgA in 3 of 10 samples collected 12 days after vaccination. At the same time, IgA were found in 4 samples collected before vaccination, and inhibited in certain cases the stimulation of interferon synthesis. The practical importance of the route of influenza vaccine administration is discussed.
| 18 |
Insertion of a disulfide-containing neurotoxin into E. coli alkaline phosphatase: the hybrid retains both biological activities. We have inserted a disulfide-containing snake neurotoxin into the N-terminal end of Escherichia coli alkaline phosphatase, between residues +6 and +7 of the mature enzyme. For this purpose, we have designed a cloning and expression vector which allows insertion of foreign DNA between the corresponding codons, and visual selection of the desired recombinant clones upon recovery of phosphatase activity. The hybrid protein is exported to the bacterial periplasm, the alkaline phosphatase signal peptide is correctly processed, and both domains are functionally conformed. The phosphatase domain displays catalytic activity, and the inserted toxin is able to bind to its biological target, the nicotinic acetylcholine receptor. The hybrid molecule is remarkably stable and resistant to proteolysis. Crude periplasmic extract containing the hybrid can be used as a tracer-containing reagent in competitive enzymo-immuno and enzymo-receptor assays. We propose to use the system described in this paper for fast preparation of properly folded disulfide-containing enzymatic probes.
| 17 |
Anastomotic intimal hyperplasia: mechanical injury or flow induced. All anastomotic intimal thickening may not be the same, and the underlying mechanism(s) regulating the different types may vary. We investigated the localization of experimental anastomotic intimal thickening in relation to known biomechanical and hemodynamic factors. Bilateral iliofemoral saphenous vein and polytetrafluoroethylene grafts were implanted in 13 mongrel dogs. The distal end-to-side anastomotic geometry was standardized, and the flow parameters were measured. After 8 weeks, seven of 10 animals (group I) with patent grafts were killed and the anastomoses fixed by perfusion. Histologic sections from each anastomosis were studied with light microscopy, and regions of intimal thickening were identified and quantitated with use of oculomicrometry. To characterize the anastomotic flow patterns, transparent silicone models were constructed from castings of the distal anastomosis of three animals (group II), and flow was visualized with use of helium-neon laser-illuminated particles under conditions simulating the in vivo pulsatile flow parameters. Histologic sections revealed two separate and distinct regions of anastomotic intimal thickening. The first, suture line intimal thickening, was greater in polytetrafluoroethylene anastomoses (0.35 +/- 0.23 microns) than in vein anastomoses (0.15 +/- 0.03 microns, p less than 0.05). The second distinct type of intimal thickening developed on the arterial floor and was the same in polytetrafluoroethylene (0.11 +/- 0.11 microns) and vein anastomoses (0.12 +/- 0.03 microns). Model flow visualization studies revealed a flow stagnation point along the arterial floor resulting in a region of low and oscillating shear where the second type of intimal thickening developed. High shear and short particle residence time were observed along the hood of the graft, an area devoid of intimal thickening.(ABSTRACT TRUNCATED AT 250 WORDS)
| 16 |
Exploration of the early insulin response by two small successive loads of I.V. glucose in normal and obese subjects. Two 5 g glucose loads at 1-h interval were given to healthy controls and obese subjects with slightly altered or normal OGTT in order to explore the capacity of restoration of the "rapid insulin response" to i.v. glucose. In the normal subjects, the two successive loads gave rise to identical responses as far as maximum increase (delta max), average increase at 2-5 min (delta 2-5 min), area of increase 0-15 min (delta 0-15 min) for both glucose and IRI, were concerned. Obese subjects could be divided on the basis of their insulin response to the first load into normal responders (group I) and high-responders (group II). In group I obese subjects, the responses to the second load were identical to those to the first. In group II obese subjects delta max, delta 2-5 min and delta 0-15 min of the insulin response to the second load were reduced as compared to the first.
| 12 |
Disorders of leukocyte chemotaxis. The rapid accumulation of inflammatory cells at sites of microbial invasion or neoplastic transformation is a central event in immunologically-mediated host defense. The availability of methodology to accurately quantify leukocyte migration in vitro has allowed the disclosure of previously unrecognized clinical disorders, namely leukocyte dysmotility syndromes. Although this area of clinical investigation is in its infancy, one can identify several processes associated with abnormal leukocyte accumulation. Abnormalities of immune recognition, chemotactic factor production, cellular motility or inhibitors of chemotaxis have been identified in different human diseases. In the upcoming years, pharmacological intervention directed at correcting specific causes of leukocyte dysmotility may well enhance our ability to treat certain infectious, inflammatory, and neoplastic diseases.
| 21 |
Changes in the intestinal lactase activity in the small intestine of two breeds of swine from birth to 6 weeks of age. Total and specific lactase activities in the small intestine of Chester White and Hampshire pigs were measured at 1, 8, 15, 22, 29, and 43 days of age. The small intestine was divided into 10 segments of equal length, the proximal 10 cm of each segment was scraped, and the scrapings were homogenized for use in the lactase determinations. Significant breed, age, and segment differences were observed for both specific and total activities. In both breeds, the total lactase activity at 1 day of age was lower than that at any other age. After reaching maximal levels at 15 days of age, the total activity declined with the loss of activity occurring primarily in the ileum. At 1 and 8 days of age, the total lactase activities for the two breeds were similar, but the Chester White pigs had higher activities at all other ages. The pattern of changes in specific activity with age was similar for both breeds. The mean specific activity was highest at 1 and 8 days of age and then fell progressively to minimal levels at 43 days of age. Chester Whites had higher specific activities than Hampshires during the first 4 weeks of life, but at 6 weeks of age there was little difference between the breeds. The peak lactase activity, expressed as total or specific activity, occurred in the proximal one-third of the small intestine of both breeds, and the distal one-third of the gut had relatively low activities as the animals matured.
| 14 |
Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Male Dunkin Hartley guinea pigs, actively sensitized to ovalbumin (OA) and pretreated with mepyramine (1 mg/kg i.p.), were challenged with OA as an aerosol. Histological analysis of the lung for eosinophils (EOs) showed significant accumulations in the submucosa of the airways (8 h: 1.477.3 +/- 43 EOs/mm2 airway, n = 3, p less than 0.01), after antigen challenge compared to saline control (478.6 +/- 104 EOs/mm2 airway, n = 4). Pretreatment with both mepyramine and cimetidine (10 mg/kg i.p.) did not affect this response. Aerosolization of OA to unsensitized guinea pigs resulted in no significant accumulation of EOs (360.2 +/- 49 EOs/mm2 airway, n = 4) when compared with the saline-challenged sensitized control group. Pretreatment with the leukotriene (LT)D4 receptor antagonist MK-571 (1 mg/kg p.o.) significantly inhibited the OA-induced EO migration (95 +/- 5% inhibition, n = 5, p less than 0.01) compared to vehicle in the presence of mepyramine and cimetidine, while indomethacin (3 mg/kg p.o., n = 4) had no effect. Aerosolization of synthetic LTC4 (0.3-30 micrograms/ml) resulted in a dose-dependent migration of EOs into the submucosal layer over 8 h, reaching significance at the 10-micrograms/ml dose, with comparable results obtained with LTD4. Pretreatment of animals with MK-571 (1 mg/kg p.o.) before LTC4 and LTD4 aerosol results in inhibition of the response in both cases, suggesting that this effect may be mediated through the LTD4 receptor. We conclude that peptide LTs produce eosinophilia in the airways of the guinea pig.
| 14 |
Site-specific initiation of a DNA fragment: nucleotide sequence of the bacteriophage G4 negative-strand initiation site. The synthesis of the bacteriophage G4 negative strand is an example of the de novo initiation of a polynucleotide chain. This initiation is performed by the Escherichia coli replication protein dna G which selects a unique site on 5400-base positive-strand template. In this paper we present the nucleotide sequence of the G4 negative-strand initiation site. This is the template element recognized by the dna G priming protein. In conjunction with the sequence of the nascent negative strand, obtained by Bouché, Rowen, and Kornberg [Bouché, J.-P., Rowen, L. & Kornberg, A. (1978) J. Biol. Chem. 253, 765-769], the present data provide a description of a dna G-dependent origin of replication in which one knows the place at which polymerization starts at the nucleotide level.
| 11 |
Intracerebroventricular injection of platelet-activating factor induces secretion of adrenocorticotropin, beta-endorphin and corticosterone in conscious rats: a possible link between the immune and nervous systems. To investigate whether platelet-activating factor (PAF) exerts an indirect action on immune cells by altering the secretion of hypothalamic-pituitary-adrenal (HPA) axis products, the effects of intracerebroventricular (i.c.v.) PAF on adrenocorticotropic hormone (ACTH), beta-endorphin and corticosterone blood levels were examined in adult male rats. Hormones were radioimmunoassayed on blood samples from conscious or ether-anesthetized rats after i.c.v. injection of PAF or vehicle into the left lateral ventricle. PAF induced significant increases in these stress-related hormones under both, basal and ether-induced stress conditions. The analysis of the time course response to PAF of hormone release into the blood of unrestrained rats revealed that: i.c.v. injection of 5.4 nmol PAF resulted in rapid increases in ACTH and beta-endorphin, at the latest within 15 min after the onset of injection. The maximal response of both hormones was reached within 45 min after the onset of injection and was followed by an elevation of plasma corticosterone. Hormone release is related to the PAF dose infused, the lowest effective PAF concentration was 1 nmol. The stimulatory effect of PAF on ACTH and beta-endorphin secretion was strongly decreased in rats previously treated with purified anti-rat corticotropin-releasing factor (CRF) antibody. These results, associated with the in vitro demonstration that PAF increases CRF release from incubated rat median eminence, strongly support the hypothesis that the stimulatory action of PAF on the secretion of HPA axis products is mediated at least partly, by stimulating hypothalamic CRF release.(ABSTRACT TRUNCATED AT 250 WORDS)
| 15 |
Studies on the mechanism of action of guinea pig lymphotoxin. II. Increase of calcium uptake rate in LT-damaged target cells. In the previous paper it was suggested that the primary action of guinea pig lymphotoxin (LT) involved creation of ionic imbalances within the target L cells. The nature of these ionic disturbances is explored in this paper. The exogenous addition of CaCl2, but not KCl or NaCl, inhibited the cytotoxic action of LT. Cellular uptake rates of 45Ca++, but not 86Rb+, increased in LT-damaged L cells. The factor responsible for increasing the 45Ca++ uptake rate cochromatographed on a hydroxyapatite column with the cytotoxic activity of LT. Ouabain prevented the LT-mediated lysis and, concomitantly, depressed the LT-induced increase of 45Ca++ uptake rate. The LT-damaged L cells excluded trypan blue to the same extent as the normal cells. The addition of LT to and LT-resistant L cell mutant affected neither the 45Ca++ uptake rate nor the viability. From these observations, damage to the calcium transport system in the L cell plasma membrane is proposed as a mechanism of LT action.
| 12 |
Influence of vitamin E on platelet function in humans. alpha-tocopherol, a natural antioxidant, has been found to inhibit platelet aggregation and release when tested in an in vitro system. This effect of vitamin E was thought to be due to a slight reduction of platelet cyclooxygenase activity and inhibition of lipid peroxide formation. Aggregation of platelets derived from individuals on a dietary supplementation of alpha-tocopherol ranging from 400 to 1200 IU/day showed no significant reduction. The discrepancy between the effectiveness of alpha-tocopherol in vitro and ex vivo is probably related to the levels of alpha-tocopherol attainable in platelets and plasma. Investigation of the effect of alpha-tocopherol on platelet adhesion showed a major inhibitory activity at doses of vitamin E as low as 200 IU/day. Measurements were performed in a laminar flow chamber at both high and low shear rates. Reduced platelet adherence to collagen, fibrinogen, and fibronectin could be documented. alpha-tocopherol-enriched platelets that adhered to adhesive surfaces failed to show the usual long thin pseudopodia but exhibited short, rounded, blunt projections. The reason for this shape change is still unclear, but we speculate that it may be causing the vitamin E-induced reduction of platelet adhesiveness. We believe that dietary supplementation with this vitamin could play a role in the treatment of thromboembolic disease, especially when given in conjunction with an inhibitor of platelet aggregation.
| 17 |
Occult microlithiasis in 'idiopathic' acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gallstone pancreatitis is usually related to small stones, which may not be detected by conventional cholecystographic techniques. In the current study, it was hypothesized that some patients with acute pancreatitis of unknown cause could harbor occult microstones in the gallbladder. Therefore, evidence was sought prospectively of missed gallstones by biliary drainage and microscopic examination of centrifuged duodenal bile in 51 patients recovering from an attack of acute pancreatitis, including 24 patients with relapsing episodes. Clusters of cholesterol monohydrate crystals, calcium bilirubinate granules, and/or CaCO3 microspheroliths were found in 67% of the patients. Biliary drainage showed no abnormal findings in 12 patients convalescing from a bout of known alcoholic pancreatitis. Examination of gallbladder bile at cholecystectomy and/or serial ultrasonography of the gallbladder for up to 12 months showed that 73% of the patients with unexplained pancreatitis had biliary sludge or microlithiasis; the prior finding of biliary crystal/solid markers predicted their existence with both a sensitivity and a specificity of 86% and a predictive value of 94%. The probability of harboring occult gallstones was also associated with age (P = 0.004), prior recurrent pancreatitis (P = 0.024), and altered liver function tests results during an index episode (P = 0.003). In 13 patients with cholesterol monohydrate crystals in bile, ursodeoxycholic acid (10 mg.kg-1.day-1) eliminated gallbladder microlithiasis within 3-6 months, and subsequent maintenance treatment with a daily dose of 300 mg prevented both gallstone recurrence and further attacks of pancreatitis over a mean follow-up period of 44 months. Cholecystectomy also prevented gallstone-associated relapses in 17 of 18 patients followed up for a mean postoperative period of 36 months. This study provides firm evidence showing that in most patients with idiopathic acute pancreatitis, the disease is related to microscopic gallstones, as evidenced by the follow-up development of macroscopic stones or sludge and by the prevention of relapses with either cholecystectomy or a cholelitholytic bile acid. Occult gallstones should be strongly suspected when acute pancreatitis of unknown cause occurs in a relapsing manner and in aged patients and when it is associated with altered liver function test results. Biliary microscopy and/or follow-up ultrasonography of the gallbladder provide a simple means of uncovering them to institute appropriate therapy and prevent further attacks.
| 20 |
Contraction time and voluntary discharge properties of individual short toe extensor motor units in man. 1. The contraction time and the voluntary discharge properties of forty-five short toe extensor motor units were studied in man. 2. The contraction time of the individual motor unit was studied by using selective electrical nerve stimulation or by averaging the increase in force related to its electromyographic potential in tonic voluntary contraction. 3. Both methods showed a range of contraction times from 40 to 90 ms. 4. The discharge properties of the individual motor unit were studied with e.m.g. techniques, permitting the identification of its potentials during maximum voluntary effort. 5. A motor unit which could be driven continously and had a minimum rate of about 10/s and a maximum rate of about 30/s had a contraction time between 60 and 90 ms. 6. A motor unit which could not be driven continously and had a minimum rate of about 20/s and a maximum rate above 40/s had a contraction time between 40 and 55 ms. 7. A motor unit with intermediate voluntary discharge properties had an intermediate contraction time. 8. It is concluded that each motor unit fires at its fusion frequency in voluntary contraction and that the voluntary discharge frequency range of a motor unit can be used as an indication of its contraction time.
| 11 |
The neurobiology of neurotensin: focus on neurotensin-dopamine interactions. Neurotensin (NT) is a tridecapeptide which fulfills many of the requisite criteria for a role as a central nervous system (CNS) neurotransmitter. It is closely associated with CNS dopamine neurons and has been shown to interact with dopamine at physiological, anatomical and behavioral levels. Neurotensin is colocalized with dopaminergic neurons in the hypothalamus and midbrain. In addition, it blocks behaviors associated with activation of the dopaminergic pathways. Centrally administered NT has been shown to mimic many of the actions of antipsychotic drugs. In addition, the concentration of NT in cerebrospinal fluid is decreased in patients with schizophrenia. Administration of clinically effective antipsychotic drugs increases concentrations of NT in the caudate nucleus and nucleus accumbens. NT has been shown to play a role in signal transduction by mostly mobilizing calcium stores following inositol phosphate formation. This has been linked to subsequent events in protein phosphorylation. Lipophilic NT receptor agonists may represent a novel approach to the development of a new class of antipsychotic drugs.
| 14 |
[Proctocolectomy and mechanical ileo-anal anastomosis without mucosectomy]. The present study compared the outcome in a small series of patients (7 cases) who underwent total proctocolectomy without mucosal proctectomy and stapled ileal pouch-anal anastomosis, constructed at the apex of the anal transitional zone, with our previous experience (17 cases) in which the ileal pouch was anastomosed at the dentate line after mucosectomy. Though not statistically significant, our limited experience showed excellent clinical results with better continence and discriminating ability between gas and faeces in the former group. The resting anal pressure profile showed no chances in the postoperative period. The operation time was significantly reduced compared with our previous approach which was a time-consuming procedure. Furthermore, a reduced risk of complications (pelvic sepsis, haemorrhage) was observed.
| 17 |
Reduced arachidonate metabolism in ATP-depleted myocardial cells occurs early in cell injury. Exposure of cultured neonatal rat myocardial cells to metabolic inhibitors results in cellular ATP depletion. If prolonged, arachidonic acid is released from membrane phospholipid and irreversible cell injury may ensue. The present study was undertaken to identify the major products of arachidonic acid formed when myocardial cells are depleted of ATP by the metabolic inhibitors 2-deoxy-D-glucose (2-DG) and oligomycin (OG). Under basal conditions, myocardial cells metabolize [3H]arachidonic acid to 6-keto-[3H]prostaglandin (PG)F1 alpha, [3H]PGE2, [3H]PGF2 alpha, 12-[3H]hydroxy-6,8,11,14-eicosatetraenoic acid (12-[3H]HETE) and 11-[3H]HETE, indicating that these cells contain both cyclooxygenase and lipoxygenase pathways. After exposure of myocardial cells to 10 mM 2-DG and 0.1 micrograms/ml OG for 4 h, the basal release of 6-keto-PGF1 alpha and PGE2 is reduced by 3.4-fold and 2-fold, respectively. Supernatants obtained from cells prelabeled with [3H]arachidonic acid and treated with 2-DG and OG for 4 or 12 h did not contain detectable [3H]prostaglandins or [3H]HETEs, but only [3H]arachidonic acid when compared with untreated cells. After 4 and 12 h of treatment with 2-DG and OG, there was a 3.4- and 4.4-fold net release of endogenous arachidonic acid from treated compared with untreated cells. When stimulated with bradykinin, melittin (a phospholipase activator), or arachidonic acid, the synthesis of 6-keto-PGF1 alpha increased to a similar extent in both 2-DG- and OG-treated and -untreated cells. Hence, ATP-depleted myocardial cells do not convert arachidonic acid to oxygenated metabolites under basal conditions. The reduced arachidonic acid metabolism during ATP depletion is not due to direct inactivation of cyclooxygenase or membrane phospholipase. This impairment in arachidonic acid metabolism may represent an early event in myocardial cell injury.
| 19 |
Sucking efficiency of early orthopaedic plate and teats in infants with cleft lip and palate. Intraoral negative pressure during bottle feeding with two kinds of teats (a regular Nuk and a cleft Nuk) was measured in 7 infants with cleft lip and palate, 8 infants with cleft palate, 2 infants with cleft lip, 4 infants with operated cleft lip and palate and 7 normal infants. Infants with cleft lip and palate or cleft palate were unable to generate negative pressure before cleft lip and palate closure. The presence or absence of an early orthopaedic plate did not make any difference. In infants with unoperated cleft lip and with operated cleft lip and palate, peak negative pressure during feeding differed little from that of normal infants.
| 13 |
Pharmacokinetics of amikacin and chloramphenicol in the aqueous humor of rabbits. Composite data describing ocular pharmacokinetics are unreliable because of intersubject variation. To address this problem, an animal model was developed in which multiple aqueous samples from single subjects were obtained. Following direct anterior chamber or intravenous administration of amikacin or chloramphenicol, pharmacokinetic analysis of drug concentrations in the serum and anterior chamber was performed by using a nonlinear least-squares regression program. The number of anterior chamber paracenteses performed did not alter the beta elimination rates or percent penetration into the anterior chamber. The aqueous humor and peripheral-compartment terminal slopes were identical. These data indicate that complete ocular concentration-time curves can be obtained without altering antibiotic pharmacokinetics. Following direct injection into the anterior chamber, the elimination rates for both antibiotics followed a one-compartment model, whereas those following intravenous administration best fit an open, first-order, two-compartment model. Following intravenous administration, the anterior chamber elimination rate constants for both drugs were equal to that of the serum and significantly longer than that following direct injection. The elimination rates of both drugs following direct injection were similar. Systemic administration resulted in drug levels in aqueous humor that persisted longer than those following direct injection. Chloramphenicol, a lipophilic compound, gave higher mean concentrations in aqueous humor than did amikacin. Our model provides a new approach which rigorously examines ocular pharmacokinetics and provides data which suggest that for selected compounds the parenteral route of administration is preferable.
| 18 |
Effects of retinoids on iodine metabolism, thyroid peroxidase gene expression, and deoxyribonucleic acid synthesis in porcine thyroid cells in culture. Effects of retinoids on DNA synthesis, iodine metabolism, and thyroid peroxidase messenger RNA levels were studied in cultured porcine thyroid cells. Retinol (10(-8)-10(-5) M) alone did not affect DNA synthesis but potentiated that induced by epidermal growth factor or insulin-like growth factor-I without changes in the number or affinity of receptors for the growth factors, suggesting that retinol stimulates postreceptor events responsible for DNA synthesis. Retinol was an inhibitor of TSH-stimulated iodine metabolism. Iodide uptake and release of organified iodine stimulated by TSH or forskolin were inhibited dose dependently by treatment with retinol. The inhibition was detected at 10(-8) M and was approximately 50% at 10(-6) M. The potency of retinoic acid was comparable to that of retinol. The inhibitory effect of retinol was detected after treatments of thyroid cells for 24 h, and the maximal effect occurred after 48 h incubation. The cAMP accumulation in cultures treated with TSH plus retinol was lower than that of control cultures treated with TSH alone. However, iodide uptake stimulated by 8-bromo-cAMP was also inhibited by retinoids. Retinol reduced TSH- or 8-bromo-cAMP-stimulated gene expression of thyroid peroxidase. Thus, the data suggest that retinoids inhibit TSH-stimulated iodine metabolism by reducing cAMP accumulation and also by acting on the steps subsequent to cAMP production.
| 16 |
Susceptibility of recent clinical isolates to temafloxacin (A-63004) and other antimicrobial agents. In vitro susceptibility of 1008 strains of recent clinical isolates was determined against the new aryl fluoroquinolone temafloxacin (T-167, A-63004) ciprofloxacin, norfloxacin, ampicillin, piperacillin, cephalothin, cefoxitin, ceftazidime, gentamicin, amikacin, oxacillin and vancomycin. The minimum inhibitory concentrations (MICs) of temafloxacin in micrograms/ml required for > or = 90% isolates were 0.13-0.5 for enterobacter, 0.03-0.25 for Escherichia coli, 0.12-0.5 for Klebsiella, 0.5-1.0 for Proteus mirabilis, 0.12-0.5 for Morganella morganii, 0.03-0.12 for Salmonella, 0.25-1.0 for Serratia marcescens, 0.03-0.12 for Shigella, 0.06-4.0 for Pseudomonas aeruginosa, 0.06-0.12 for Aeromonas hydrophila, 0.12-0.5 for Staphylococcus aureus, 0.12-1.0 for coagulase negative staphylococci and 4.0-8.0 for enterococci. The antibacterial activity of temafloxacin was comparable or superior to other drugs tested against most organisms. However, Xanthomonas malthophilia was relatively more susceptible to ciprofloxacin and norfloxacin, and temafloxacin had significantly high antibacterial activity against enterococci as compared to other fluoroquinolones.
| 26 |
Mechanisms of action of the intragastric balloon in obesity: effects on hunger and satiety. We evaluated the effect of a 500-ml intragastric balloon (Ballobes) on some aspects of eating-related behaviour and weight loss on nine massively obese patients. An 800-kcal mixed meal test was performed some days before, 2-3 days and 2 months after the implant of the balloon. A hypocaloric program was started after the second meal test. At hourly intervals, before and after the meal, patients were asked to rate the desire to eat, hunger, satiety and prospective consumption of food. After 2 months, weight loss was 12.0 +/- 5.1 kg. A significant decrease in the balloon diameters was observed, but none completely deflated. During the meal test performed 2-3 days after the implant, subjects rated themselves as significantly less hungry, fuller and desiring to eat less food. These patterns, however, returned to the baseline levels at the meal test performed after 2 months. No relationship was found between weight loss and reduction in the balloon diameters, nor between the latter and the changes in temporal profiles of eating ratings. The effect of a 500-ml balloon on meal-related hunger and satiety therefore seems to disappear with time.
| 12 |
P3 from auditory stimuli in healthy elderly subjects: hearing threshold and tone stimulus frequency. The P3 event-related potential (ERP) was elicited by auditory stimuli under two conditions: (1) 250 Hz standard, 500 Hz target; and, (2) 1000 Hz standard, 2000 Hz target. A group with normal hearing (n = 10), defined as subjects with less than a 16 dB loss at each tone frequency was compared to a group with hearing impairment (n = 8), defined as subjects with a loss of 16 dB or more at each tone frequency. The hearing impaired group showed significant P3 latency prolongations compared to those with normal hearing under the 2000 Hz, but not the 500 Hz target, even though subject age was used as a covariate. Under both conditions, hearing impaired subjects showed reduced P3 amplitudes compared to those with normal hearing. These findings are discussed in relation to the sensitivity of ERP assessment procedures in older adults.
| 16 |
Coincidence of blockade of synaptosomal 5-hydroxytryptamine uptake and decrease in tryptophan hydroxylase activity: effects of fenfluramine. A single injection of fenfluramine hydrochloride resulted in a short-term increase in striate synaptosomal conversion of tryptophan to serotonin (5-HT) in rat brain. In contrast, D- and L-amphetamine sulfate resulted in a short-term decrease of this index of 5-HT biosynthesis. None of the amphetamines studied altered the kinetics of synaptosomal uptake of L-[3-14C]-tryptophan measured in the same striate preparation. Within 4 hours after fenfluramine administration, 3H-5-HT uptake into synaptosomes was markedly decreased; it returned to control levels in 10 to 14 days. Intrasynaptosomal tryptophan hydroxylase activity dropped markedly within 4 hours of drug administration and remained depressed for 10 to 14 days, its return to control levels coinciding with that of 3H-5-HT uptake. Only 5-HT cell body enzyme prepared from the lateral midbrain (B9) demonstrated a reduction in activity comparable to that seen in the synaptosomes; very small decreases occurred in cell body enzyme prepared from whole midbrain (B7, B8, B9) or medial midbrain (B7, B8). Lateral midbrain tryptophan hydroxylase activity returned to control levels by 8 days. In vitro, fenfluramine (100 muM) affected none of these indices of central 5-HT synthesis except 3H-5-HT uptake, which it reduced, and synaptosomal 3H-5-HT release, which it facilitated. The effects of fenfluramine on 5-HT biosynthesis persisted longer than those of D-amphetamine, which lasted less than 24 hours. However, the fenfluramine effects were much shorter than those reported for p-chloroamphetamine, which persist for up to 3 months. These three amphetamines apparently affect the lateral midbrain raphe nuclei selectively.
| 16 |
The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels. The effects of MK-801 [( +]-5-methyl-10,11-dihydro-5H-di-benzo[a, d]cyclohepten-5,10-imine) on peripheral and central nicotinic receptors were studied using electrophysiological and biochemical techniques. MK-801 depressed the peak amplitude and accelerated the decay of end-plate currents. The drug (1-10 microM) decreased the frequency of activation of acetylcholine (ACh)-induced single-channel currents in addition to shortening the mean open and burst times of channels activated by either ACh or (+)anatoxin-a (AnTX). MK-801 (10-40 microM) depressed the single potentials and trains of ACh and AnTX-induced potentials in chronically denervated rat soleus muscles. MK-801 blocked the twitch responses (20-100 microM) of both frog sartorius and rat diaphragm muscles evoked by stimulation of their respective nerves. Also this drug (less than 1 microM) decreased the frequency of channels activated by AnTX or ACh in outside-out patch membranes of rat retinal ganglion cells with minimal changes in the channel open time. MK-801 (10-25 microM) depressed (-)nicotine-evoked gamma-amino[2,3-3H]butyric acid release from rat hippocampal synaptosomes; however, it failed to affect the binding of [3H](-)nicotine to brain membranes and also failed to interfere with the binding of [125I]alpha-bungarotoxin to either frog muscle or Torpedo membranes. On the other hand, MK-801 inhibited the binding of [3H]perhydrohistrionicotoxin to Torpedo membranes and such an effect was more pronounced in the presence of carbamylcholine. Neither AnTX nor any other nicotinic agonist increased the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor ion channel complex. The actions of MK-801 were evident at concentrations comparable with those needed to block N-methyl-D-aspartate receptors. These results demonstrate the existence of at least three different types of nicotinic AChR, all of which were blocked noncompetitively by MK-801.
| 17 |
Differences in the altered energy metabolism of hemorrhagic shock and hypoxemia. The effect of hemorrhagic shock, hypoxemia, and anoxia on the levels of adenine and pyridine nucleotides of liver and kidney was assessed. ATP levels in liver and kidney of animals in shock or animals subjected to 7 min of anoxia decreased by 85 and 73%, respectively. Under hypoxic conditions (arterial PO2 AT 18 MMHg), the decrease was only 62 and 48% in liver and kidney, respectively. Tissue NAD levels decreased and NADH levels increased during shock but were found to be essentially unaltered during experimental hypoxemia. Thus, shock produced greater alterations in adenine and pyridine nucleotides than did hypoxemia alone, indicating that stagnant hypoxemia due to shock is more deleterious to energy metabolism than is severe hypoxemia with an otherwise normal circulation. The results also suggest that if an anterial PO2 OF 18 MMHg represents the initial stages of tissue hypoxia, then tissue ATP levels are a more sensitive indicator of this than NAD levels.
| 18 |
Identification of a novel gene expressed in activated natural killer cells and T cells. We have isolated a cDNA clone from a human activated NK cell-derived cDNA library that identifies a transcript (NK4) that is selectively expressed in lymphocytes. The expression of this transcript is increased after activation of T cells by mitogens or activation of NK cells by IL-2 (lymphokine-activated killer cells). The transcript levels demonstrated by Northern blot analysis increase by 12 h after activation, remain high for at least 48 h, and require protein synthesis for expression. Southern blot analysis of B lymphoblastoid lines derived from 18 unrelated individuals reveal variable banding patterns suggestive of polymorphism within the NK4 gene. No homology was found between the sequence of the coding region of this transcript and any sequences in the GenBank data base. Sequence homology to the U1 small nuclear RNA was found within the 3' untranslated region immediately upstream of the site of polyadenylation, suggesting a possible role for U1 in the polyadenylation process. Sequence analysis indicates the transcript would encode a protein having a mass of 27 kDa. The presence of a signal sequence and lack of a transmembrane region suggests that the protein is secreted. In addition, the protein contains an RGD sequence that may be involved in cellular adhesion. This transcript appears to encode a novel product common to the activation pathways of both NK cells and T cells.
| 14 |
[The electrocardiogram during bilharziosis caused by Schistosoma mansoni]. The electrocardiographic abnormalities associated with bilharziasis are not well-known. This study, carried out in Guadeloupe, involved 220 cases of both sexes with bilharziasis, and 157 control subjects. The changes on the electrocardiogram were: an ST elevation of 0.1 to 0.5 mV associated with a large T wave in the intermediate and left precordial leads (16.8%), flattening of the T wave (13%) in V1 to V3 and beyond, a negative T wave (10.8% in the right precordial leads V1, V2, V3, and left ventricular hypertrophy (10%). The abnormalities which were found were identical to those described in the "normal" black person, and led us to discuss whether there was really a characteristic ECG for the black races. Additionally we were able to conclude that these abnormalities were unrelated to anaemia or to therapy against bilharziasis, and that there was no abnormal sex distribution. Moreover this study has revealed that the population of Guadeloupe who have no parasitic infection have ECG abnormalities (4.8%) more commonly than the white races, and has led us to suspect the possibilities of as yet underfined abnormalities which cannot be regarded as "normal".
| 18 |
[Clinical studies on morphological changes in the prostate in patients with benign prostatic hypertrophy after antiandrogen therapy--by means of transrectal ultrasonotomography]. Transrectal ultrasonotomography is useful in following patients with benign prostatic hypertrophy, because prostatic shape and weight are precisely assumed. We studied the effect of chlormadinone acetate (CMA) on benign prostatic hypertrophy. CMA (50 mg/day) was administered to 30 patients with benign prostatic hypertrophy. Weight reduction over 10% of the gland was noticed in 24 cases (80%). Mictional conditions were improved in 70% subjectively and in 71.4% objectively. However, the number of nocturia decreased in only 18.9%. Reduction rate of the weight was unrelated with the weight of prostate before administration of CMA. Duration of administration of CMA and the reduction rate were estimated. There was no definite difference in reduction rate for the first 15 months, but there was a slightly high reduction rate after administration of CMA for more than 24 months. In 3 cases, the shape and weight of prostate were studied after discontinuation of CMA. The size of prostate showed a tendency to increase gradually.
| 12 |
The effect of EMHP on post-cardiac arrest survival of rats. 1-Ethyl-2-methyl-3-hydroxy-pyrid-4-one (EMHP), a low molecular weight iron chelator that is soluble in hydrocarbon solvents and presumably in lipids, was studied for in vitro inhibition of radical-mediated peroxidation of DNA. We also investigated the acute toxicity of EMHP by administering 40, 100, and 300 mg/kg intravenously to Wistar rats, and we then examined the in vivo effect of the 40 mg/kg dose following a 10-min cardiac arrest and resuscitation in rats. EMHP prevented iron-dependent radical-mediated DNA breaks of the supercoiled plasmid Bluescribe by the Fenton reagent (400 microM iron, 30 microM H2O2) when present at EMHP/Fe ratios of 16:1 and 32:1. The 300-mg/kg dose was lethal in 3 of 5 normal rats, and the 100-mg/kg dose was associated with excessive mortality post-resuscitation. The 40-mg/kg dose was well tolerated post-resuscitation, but it did not improve either 3-day survival or neurologic outcome.
| 16 |
Histochemical study of the muscle spindles in parkinsonism, motor neuron disease and myasthenia. An examination of the pathological fusimotor endings by the acetylcholinesterase technic. Pathological changes of the fusimotor endings in parkinsonism, motor neuron disease and myasthenia were examined by the acetylcholinesterase technic on serial sections. In parkinsonism, the diffuse endings, which are thought to be supplied by the static gamma nerve fibers, showed remarkable enlargement, while en plaque and en grappe endings were atrophic. In motor neuron disease, en plaque and en grappe endings, which are thought to be innervated by the beta nerve fibers and dynamic gamma nerve fibers respectively, revealed marked atrophy. However the diffuse endings were normal. In myasthenia gravis and myasthenic syndrome (Eaton-Lambert syndrome), en plaque and en grappe endings were atrophic, though only the diffuse endings were spared. The significance of these changes in the fusimotor endings is discussed.
| 13 |
Dopamine-1 receptors in rat proximal convoluted tubule: regulation by intrarenal dopamine. Dopamine (DA) is synthesized in the renal proximal convoluted tubule (PCT) and may act as a paracrine substance at tubular DA-1 receptors to decrease sodium transport. Although DA-1 receptors have been identified in rabbit renal PCT by use of nonselective dopaminergic radioligands, DA-1 receptors have not been localized in specific nephron segments with the use of selective DA-1 radioligands. In these studies we used a novel DA-1 dopaminergic ligand 125I-SCH-23982, which has been shown to have a high affinity for brain and renal DA-1 receptors, to identify DA-1 receptors in the rat renal PCT and distal convoluted tubule (DCT). DA-1 receptors in the microdissected PCT and DCT were studied by a quantitative autoradiographic technique and by measuring adenylate cyclase (AC) activity. No specific 125I-SCH-23982 binding could be measured in the DCT indicating the absence of DA-1 receptors in this segment. Binding of 125I-SCH-23982 to PCT was saturable with time and radioligand concentration and was stereoselective. Saturation isotherm analysis in control rats yielded a dissociation constant (Kd) of 7.5 +/- 0.14 nM (n = 4) and a maximum receptor density (Bmax) of 0.69 +/- 0.04 pmol/mg protein (n = 4). The rank-order potency for agonist and antagonist displacement of 125I-SCH-23982 binding was consistent for DA-1 receptors: SCH-23390 greater than fenoldopam = SKF 38393 greater than SCH-23388. The stimulatory effect of the DA-1 agonist fenoldopam (10 microM) on AC activity was blocked by the DA-1 antagonist SCH-23390 (10 microM) but not by the beta-adrenergic antagonist (-)-propranolol (10 microM), indicating specificity. The DA-beta-hydroxylase blocker, SKF 102698, increased renal DA concentrations threefold, reduced the PCT DA-1 receptor Bmax by 33%, and abolished the stimulatory effect of 10 microM fenoldopam on AC activity in the PCT but had no effect on Kd. It is concluded that DA-1 receptors are present in rat PCT but not DCT and can be regulated by renal DA.
| 19 |
The potential of cyclosporin A as an anti-tumour agent. Cyclosporin A (CsA) has become established as the agent of choice for the prevention of organ allograft rejection and has shown considerable promise in the clinical management of certain autoimmune disorders. The impact of CsA as an immunotherapeutic agent of major importance is attributable to its powerful, selective inhibitory action on T-lymphocyte activation and proliferation. Moreover, CsA lacks the myelotoxic and other major side effects associated with cytotoxic immunosuppressive agents, such as cyclophosphamide or azathioprine. It is now clear that CsA has a potential therapeutic role in the treatment of malignancies, especially T-cell cancers. Recent studies suggest that there may be several areas of application for CsA, either as a direct antiproliferative agent or in combination with other drugs, including inhibitors of polyamine biosynthesis or cytotoxic anti-tumour agents, including vincristine and adriamycin. In addition, CsA and non-immunosuppressive analogues have been shown to restore multi-drug sensitivity in cancer cells with acquired drug resistance. A further application of CsA may be to prevent the induction of human immune responses to therapeutic mouse monoclonal antibodies directed against tumour antigens, thereby enhancing the efficiency and safety of this form of cancer immunotherapy. Due to our incomplete understanding of the antiproliferative properties of CsA, further exploration of its potential as an anti-tumour agent must be accompanied by detailed studies aimed at elucidating its action on subcellular molecular events in both normal and malignant cells.
| 20 |
Trace element movement and oxidative stress in skeletal muscle atrophied by immobilization. The movements of trace elements and the level of oxidative stress in the soleus, a typical slow red muscle which, atrophied by immobilization, were investigated in designated intervals. Male Wistar rats (14 wk old) whose one ankle joints were immobilized in the extended position were killed after 4, 8, and 12 days. Fe, Zn, Mn, and Cu concentrations and the levels of thiobarbituric acid-reactive substance (TBARS) and glutathione were measured. The rate of atrophy increased rapidly until the 8th day and slowly after that. In whole muscle, Fe concentration kept increasing, and Zn and Mn increased temporarily. Their subcellular distributions also changed; especially, the Fe level of the microsomal fraction kept increasing and reached threefold at 12 days. Increased TBARS and glutathione disulfide and decreased total glutathione indicated the increased oxidative stress in atrophy, which might result from an increased Fe level, especially that of the microsomal fraction. Vitamin E injection lessened the rate of atrophy, which showed that oxidative stress accelerated muscle atrophy. This might be mediated by increased intracellular Ca. Also metallothionein was induced in muscle atrophy.
| 15 |
Prospective randomized study of once-daily versus thrice-daily netilmicin regimens in patients with intraabdominal infections. One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netilmicin administered once daily (n = 98) versus thrice daily (n = 99) in combination with tinidazole administered once daily. Randomization was achieved for the infection site, clinical severity score, daily and total netilmicin dose, and duration of treatment. The mean maximum peak and trough levels of netilmicin in serum were 21.1 and 1.3 mg/l respectively for once daily treated patients, and 10.0 and 2.3 mg/l for thrice daily treated patients (p less than 0.05 for both parameters). The clinical response did not differ between patients treated once daily and those treated thrice daily. Overall rates for clinical cure, improvement and failure of therapy were 77%, 17% and 6% respectively. No significant differences were found between once daily and thrice daily regimens in the occurrence of auditory, vestibular and renal toxicity, overall rates being 5%, 1% and 10% respectively. Impairment of renal function was significantly related to higher maximum netilmicin serum trough levels during therapy, a higher clinical severity score and advanced age. It is concluded that netilmicin given once daily is as effective and safe as the multiple dose regimen. However, monitoring of aminoglycoside serum through levels is still advisable, especially in the old and severely ill patient.
| 17 |
Increases of neuron-specific enolase, S-100 protein, creatine kinase and creatine kinase BB isoenzyme in CSF following intraventricular catheter implantation. In 15 patients without acute brain injury the concentrations of Neuron-specific Enolase (NSE), S-100 Protein (S-100), Creatine Kinase (CK), and Creatine Kinase BB isoenzyme (CK-BB) in ventricular cerebrospinal fluid (CSF) were measured immediately after lateral ventricle cannulation for diagnostic or treatment purposes. From patients who were treated with a shunt another CSF sample was obtained one week after shunt implantation by puncture of the antechamber of the valve. The CSF concentrations of NSE, S-100, CK and CK-BB after cannulation were found to be of the same order as found in patients with severe head injury, stroke or subarachnoid haemorrhage. One week after shunt implantation the concentrations of S-100, CK and CK-BB had returned to normal levels in almost all patients, while the NSE concentrations remained elevated. These findings indicate that the sampling procedure may result in contamination of CSF with NSE, S-100, CK and CK-BB and they should be taken into account in the prognostic evaluation of enzyme concentrations after brain injury.
| 19 |
Evaluation of a chemiluminometric immunoassay for detection of Chlamydia trachomatis in the urine of male and female patients. A chemiluminometric immunoassay (Magic Lite Chlamydia) for detection of Chlamydia trachomatis antigens in first-void urine samples was compared with cell culture using urogenital swabs from 221 men and 242 women. The rate of isolation of Chlamydia trachomatis was 23.5% in men, nearly 80% of whom had symptoms of urethritis, and 8.3% in women, in whom both cervix and urethra samples were tested. In urine sediments from men and women respectively the chemiluminometric assay showed a sensitivity of 80.8% and 70%, a specificity of 97% and 95%, a positive predictive value of 89.4% and 58.3%, and a negative predictive value of 94.3% and 97.2%. Discrepancies between results obtained with the chemiluminometric assay and cell culture were resolved using two polymerase chain reaction techniques to test urogenital samples. The detection of Chlamydia trachomatis in urine samples with the chemiluminometric assay was confirmed to be superior for screening symptomatic men with urogenital infections than women as a lower prevalence population.
| 20 |
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