Containing the costs of Medicare.
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British Columbia↗
Biomedical subjects
H E Smith
Publications and source records attributed to H E Smith.
Acute medical beds could be cut.
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Humans↗
Preparation of 17 alpha-iodoethynylandrosta- and 17 alpha-(2-iodoethenyl)androsta-4,6-dien-17 beta-ol-3-ones as active site-directed photoaffinity ligands for androgen-binding proteins.
Unsaturated analogues of androst-4-en-17 beta-ol-3-one, each with a 17 alpha-iodoethynyl or 17 alpha-(2-iodoethenyl) substituent, were prepared, and their relative binding affinities (RBAs) for androgen-binding protein (ABP) were compared with those of 5 alpha-androstan-17 beta-ol-3-one, androst-4-en-17 beta-ol-3-one, androsta-4,6-dien-17 beta-ol-3-one, and androsta-1,4,6-trien-17 beta-ol-3-one. These binding studies indicate that the iodine[125I] analogues of 17 alpha-iodoethynyl and 17 alpha-[(E)-2-iodoethenyl] derivatives of androsta-4,6-dien-17 beta-ol-3-one and androsta-1,4,6-trien-17 beta-ol-3-one will have RBAs at least twice as great as that of 5 alpha-androstan-17 beta-ol-3-one. They can be prepared from 17 alpha-ethynylandrosta-4-en-17 beta-ol-3-one, the final synthetic step using N-[125I]iodosuccinimide, and are potential radioiodinated, active site-directed photoaffinity ligands for ABP and testosterone-binding globulin.
Affinity Labels↗
Virulence of Streptococcus suis type 2 strains in newborn germfree pigs depends on phenotype.
To determine whether the virulence of Streptococcus suis type 2 is associated with the phenotype of the strain, we infected newborn germfree pigs with 10 strains of S. suis type 2 categorized by three phenotypes. In an earlier study, the phenotypes were distinguished by the presence or absence of the muramidase-released protein (MRP) and an extracellular factor (EF) and were designated MRP+ EF+, MRP+ EF- and MRP- EF-. Pigs were first inoculated with Bordetella bronchiseptica to predispose them to infection and were then intranasally inoculated with the streptococci. Strains of the MRP+ EF+ phenotype induced fever and increased the number of polymorphonuclear leukocytes in blood. Specific clinical signs of disease such as nervous disorders and lameness were also observed. At necropsy bacteriologic and pathologic examination disclosed meningoencephalitis, polyserositis, and polyarthritis. Strains of the MRP+ EF- phenotype induced only nonspecific clinical signs of disease such as recumbency, lack of appetite, and fever; only slight pathologic changes were detected in the serosae. The four strains of the MRP- EF- phenotype induced no signs of disease. These findings indicate that the 110-kDa EF and, to a lesser degree, the 136-kDa MRP may be associated with the virulence of the bacterium. The results demonstrated that S. suis type 2 strains producing both MRP and EF are pathogenic for pigs.
Animals↗
Cloning and nucleotide sequence of the gene encoding the 136-kilodalton surface protein (muramidase-released protein) of Streptococcus suis type 2.
We cloned and sequenced the gene encoding the muramidase-released protein (MRP) of a pathogenic Streptococcus suis type 2 strain to determine whether its amino acid sequence resembles that of proteins with known functions and to determine its function in virulence. The complete nucleotide sequence composing the gene and the regions flanking it was determined. The deduced amino acid sequence revealed the presence of a signal peptide at the N terminus and a cell envelope anchor at the C terminus, both of which resembled similar regions in several other surface proteins from gram-positive bacteria. The processed form of MRP has a length of 1,209 amino acids and a calculated molecular weight of 131,094. A highly repetitive region preceded the envelope anchor. The repeated units were preceded by a proline-rich stretch of amino acids (26 of 86). No overall homologies were observed between the amino acid sequence of MRP and protein sequences in the EMBL data bank. A particular region within the amino acid sequence, however, showed some similarity with the fibronectin-binding protein of Staphylococcus aureus. Binding of MRP to human fibronectin, however, could not be confirmed.
Amino Acid Sequence↗
Detection of multiple retroviral infections in cattle and cross-reactivity of bovine immunodeficiency-like virus and human immunodeficiency virus type 1 proteins using bovine and human sera in a western blot assay.
Bovine antibovine immunodeficiency-like virus (BIV) antibodies were detected by Western blot analysis (WBA) using a chemiluminescence protocol. Bovine sera with anti-BIV activity, obtained from cows in two dairy herds, had antibodies directed against a variety of BIV-specific antigens indicating chronic infections. These sera were also tested for serological reactivity against bovine leukemia virus (BLV) and bovine syncytial virus (BSV). Cows most commonly had anti-BSV antibodies (12 of 39). Evidence for infection with BSV and BIV or BSV and BLV occurred with almost equal frequency (5 of 39 and 4 of 39, respectively) while only one instance of BIV and BLV coseropositivity was detected. The high prevalence of BSV seropositivity is consistent with a relatively infectious virus, which, as is known, may be transferred congenitally. Similar rates of coseropositivity of BIV or BLV with BSV in this population suggest that BIV is no more infectious than BLV and probably requires prolonged close contact for transmission. Seven of nine cows with anti-BIV antibodies detected primarily human immunodeficiency virus type 1 (HIV-1) p51 and p63 antigens by WBA using an alkaline phosphatase detection system, suggesting that HIV-1 proteins have potential usefulness in screening cattle for BIV seropositivity. Six human sera that showed strong reactivity against multiple HIV-1 proteins and the serum from one of three patients considered to be an "indeterminate" HIV-1 reactor, cross-reacted primarily with BIV p26. This is the first report of human sera with antibody to BIV-specific proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Lifestyle limitation in asthma.
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Asthma↗
Medical audit: the differing perspectives of managers and clinicians.
The objectives of this study were to gauge the attitudes and perceptions of managers and clinicians to medical audit, and to identify differences which might be barriers to the effective implementation of audit. A questionnaire survey of consultants and health service managers in one health district was conducted prior to the introduction of medical audit. Replies were received from 113/144 (78%) clinicians and 53/70 (76%) managers. Managers and clinicians concurred about the potential benefits of audit but had divergent opinions regarding its disadvantages. Seventy-one per cent of clinicians thought that audit would interfere with clinical work and 41% that audit would consume resources that could be better used on patient care. Only one in eight managers shared these views. Clinicians were divided on the threats to clinical autonomy and were three times more likely than managers to agree that audit would enable managers to influence medical practice. Most clinicians considered that audit would require one session a week, while 49% of responding managers thought audit could be performed within existing timetables. Although managers and clinicians are broadly in favour of the introduction of audit, they differ in their assessment of the time required and the opportunity costs. Appreciation of these differing perspectives should facilitate the effective introduction of audit.
Attitude↗
Prolonged recombinant activated factor VII (rFVIIa) treatment for severe bleeding in a factor-IX-deficient patient with an inhibitor.
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Child↗
Cytolysins of Actinobacillus pleuropneumoniae serotype 9.
Cytolysin I (ClyI) and cytolysin II (ClyII), which are present in the culture supernatant of Actinobacillus pleuropneumoniae serotype 9, are thought to play an important role in the pathogenesis of pig pleuropneumonia. The purpose of this study was to clone and characterize the genetic determinants of these cytolysins. Cloning was accomplished by the screening of DNA libraries for the presence of cytolytic activity and for the presence of DNA sequences homologous to leukotoxin DNA of Pasteurella haemolytica. Both genetic determinants were found to be members of the RTX cytotoxin family. The ClyII determinant was characterized in more detail. It appeared that ClyII more closely resembled the leukotoxin of P. haemolytica than the alpha-hemolysin of Escherichia coli. The ClyII amino acid sequence was identical to a hemolysin gene sequence of A. pleuropneumoniae serotype 5; this finding indicates that the latter gene also codes for ClyII and not for ClyI, as has previously been suggested. The genetic organization of the ClyII determinant differed from the genetic organization of other RTX determinants. Genes responsible for secretion of ClyII were not contiguous with the toxin gene. Instead, secretion genes were present elsewhere in the genome. These secretion genes, however, belong to the ClyI operon. This indicates that the secretion genes of the ClyI operon are responsible for secretion of ClyI and ClyII.
Actinobacillus pleuropneumoniae↗
Identification of two proteins associated with virulence of Streptococcus suis type 2.
The protein profiles of various cell fractions of 180 strains of Streptococcus suis type 2, which were isolated from diseased pigs, from healthy pigs when they were slaughtered, and from human patients, were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The isolates from diseased pigs contained two proteins that were absent in most of the isolates from healthy pigs. One of these proteins was a 136-kDa protein that was previously identified as the muramidase-released protein (MRP). This protein was predominantly detected in protoplast supernatants and culture supernatants. The second protein was a 110-kDa protein that was detected only in culture supernatants and therefore was provisionally called extracellular factor (EF). Three phenotypes of S. suis type 2 strains were recognized. Isolates from organs of diseased pigs mainly belonged to the MRP+ EF+ phenotype (77%), while isolates from tonsils of healthy pigs mainly had the MRP- EF- phenotype (86%). Most of the isolates from human patients contained MRP (89%); 74% had the MRP+ EF- phenotype. These findings confirm the results of previous investigations which demonstrated that S. suis type 2 strains differ in virulence. Monoclonal antibodies raised against the 110-kDa EF recognized proteins with higher molecular weights in culture supernatants of all of the strains with the MRP+ EF- phenotype. However, none of the strains with the MRP+ EF+ phenotype produced these high-molecular-weight proteins. Our results demonstrate that MRP and EF are associated with virulence. This suggests that one or both of these proteins are virulence factors that play a role in the pathogenesis of S. suis type 2 infections in pigs and human patients.
Animals↗
High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides.
Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.
Animals↗
Sequence of the dermonecrotic toxin of Pasteurella multocida ssp. multocida.
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Amino Acid Sequence↗
The incidence of liability claims in ophthalmology as compared with other specialties.
Ophthalmologists continue to share in the professional liability claims that plague the medical profession. Data have been extrapolated from the April 1987 publication of the United States General Accounting Office (GAO) entitled, "Medical Malpractice Characteristics of Claims Closed in 1984." This document presents information pertaining to the comparative incidence of professional liability claims of ophthalmologists with other specialties.
Humans↗
Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.
Animals↗
Role of IME1 expression in regulation of meiosis in Saccharomyces cerevisiae.
Two signals are required for meiosis and spore formation in the yeast Saccharomyces cerevisiae: starvation and the MAT products a1 and alpha 2, which determine the a/alpha cell type. These signals lead to increased expression of the IME1 (inducer of meiosis) gene, which is required for sporulation and sporulation-specific gene expression. We report here the sequence of the IME1 gene and the consequences of IME1 expression from the GAL1 promoter. The deduced IME1 product is a 360-amino-acid protein with a tyrosine-rich C-terminal region. Expression of PGAL1-IME1 in vegetative a/alpha cells led to moderate accumulation of four early sporulation-specific transcripts (IME2, SPO11, SPO13, and HOP1); the transcripts accumulated 3- to 10-fold more after starvation. Two sporulation-specific transcripts normally expressed later (SPS1 and SPS2) did not accumulate until PGAL1-IME1 strains were starved, and the intact IME1 gene was not activated by PGAL1-IME1 expression. In a or alpha cells, which lack alpha 2 or a1, expression of PGAL1-IME1 led to the same pattern of IME2 and SPO13 expression as in a/alpha cells, as measured with ime2::lacZ and spo13::lacZ fusions. Thus, in wild-type strains, the increased expression of IME1 in starved a/alpha cells can account entirely for cell type control, but only partially for nutritional control, of early sporulation-specific gene expression. PGAL1-IME1 expression did not cause growing cells to sporulate but permitted efficient sporulation of amino acid-limited cells, which otherwise sporulated poorly. We suggest that IME1 acts primarily as a positive regulator of early sporulation-specific genes and that growth arrest is an independent prerequisite for execution of the sporulation program.
Amino Acid Sequence↗
Positive control of sporulation-specific genes by the IME1 and IME2 products in Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, meiosis and spore formation require the induction of sporulation-specific genes. Two genes are thought to activate the sporulation program: IME1 and IME2 (inducer of meiosis). Both genes are induced upon entry into meiosis, and IME1 is required for IME2 expression. We report here that IME1 is essential for expression of four sporulation-specific genes. In contrast, IME2 is not absolutely essential for expression of the sporulation-specific genes, but contributes to their rapid induction. Expression of IME2 from a heterologous promoter permits the expression of these sporulation-specific genes, meiotic recombination, and spore formation in the absence of IME1. We propose that the IME1 and IME2 products can each activate sporulation-specific genes independently. In addition, the IME1 product stimulates sporulation-specific gene expression indirectly through activation of IME2 expression.
Blotting, Northern↗
Sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
Sterically hindered 5,11-dicarbo analogues of clozapine were prepared as potential chiral antipsychotic agents, with the possibility that for a particular analogue the antipsychotic activity of clozapine may reside in one enantiomer of the analogue whereas other unwanted biological effects of clozapine may be caused by the other enantiomer. Variable-temperature proton nuclear magnetic resonance studies showed that although 5-methylene-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene exists at room temperature as configurational enantiomers, the activation energy for thermal racemization is 19 kcal mol-1 at 105 degrees C, and it is doubtful that the enantiomers of this analogue can be isolated under usual laboratory conditions. The (Z)-5-ethylidene and 5-isopropylidene analogues have activation energies greater than 23 kcal mol-1 at 160 degrees C, and thus there is a possibility that the analogues can be obtained as their respective enantiomers. 5-Methyl-10-(4-methylpiperazino)-5H-dibenzo[a,d]cycloheptene incorporates a chiral center which is not thermally racemized, but it exists at room temperature as two diasteromers with an activation energy for inversion of the 5H-dibenzo[a,d]cycloheptene ring of 21 kcal mol-1. When the 5,11-dicarbo analogues were tested in vitro for biological activity and their activities were compared to that of clozapine, the affinities for muscarinic and dopamine D-1 and D-2 sites were reduced but were still substantial. Thus the respective biological activities of the racemates indicate that the biological activities of the thermally stable enantiomers may be of importance in finding a clozapine derivative with fewer side effects than those shown by clozapine itself. Because of the susceptibility of the enamines to acid-catalyzed hydrolysis, resolution into respective enantiomers is not anticipated.
Animals↗