Search PubMed⌕ Search

Biomedical subjects

C A Smith

Publications and source records attributed to C A Smith.

At least 181 records · Page 10Linked to original sources
PubMed1997

Neural-mechanical coupling of breathing in REM sleep.

During rapid-eye-movement (REM) sleep the ventilatory response to airway occlusion is reduced. Possible mechanisms are reduced chemosensitivity, mechanical impairment of the chest wall secondary to the atonia of REM sleep, or phasic REM events that interrupt or fractionate ongoing diaphragm electromyogram (EMG) activity. To differentiate between these possibilities, we studied three chronically instrumented dogs before, during, and after 15-20 s of airway occlusion during non-REM (NREM) and phasic REM sleep. We found that 1) for a given inspiratory time the integrated diaphragm EMG (Di) was similar or reduced in REM sleep relative to NREM sleep; 2) for a given Di in response to airway occlusion and the hyperpnea following occlusion, the mechanical output (flow or pressure) was similar or reduced during REM sleep relative to NREM sleep; 3) for comparable durations of airway occlusion the Di and integrated inspiratory tracheal pressure tended to be smaller and more variable in REM than in NREM sleep, and 4) significant fractionations (caused visible changes in tracheal pressure) of the diaphragm EMG during airway occlusion in REM sleep occurred in approximately 40% of breathing efforts. Thus reduced and/or erratic mechanical output during and after airway occlusion in REM sleep in terms of flow rate, tidal volume, and/or pressure generation is attributable largely to reduced neural activity of the diaphragm, which in turn is likely attributable to REM effects, causing reduced chemosensitivity at the level of the peripheral chemoreceptors or, more likely, at the central integrator. Chest wall distortion secondary to the atonia of REM sleep may contribute to the reduced mechanical output following airway occlusion when ventilatory drive is highest.

Air Pressure↗
PubMed1997

Morphologic, immunohistochemical, and ultrastructural characterization of a distinctive renal lesion in dogs putatively associated with Borrelia burgdorferi infection: 49 cases (1987-1992).

A distinctive renal lesion consisting of glomerulonephritis, diffuse tubular necrosis with regeneration, and interstitial inflammation was found in 49 biopsy/necropsy cases obtained from 1987 to 1992. This lesion is manifested clinically as a rapidly progressive glomerular disease that was uniformly fatal. Immune-mediated membranoproliferative glomerulonephritis predominated (43/49, 88%). Membranous glomerulonephritis (5/49, 10%) and amyloidosis (1/49, 2%) were also noted. Subendothelial deposits, IgG, IgM, and C3 were present along glomerular basement membranes. IgA was absent. The exact cause of the tubular necrosis is unknown. Affected dogs were significantly younger (5.6 +/- 2.6 years) than dogs with other forms of glomerulonephritis (7.1 +/- 3.6 years) and amyloidosis (7.8 +/- 3.5 years) both in the studied population for the same period and in the reported canine population. Labrador and Golden retrievers were 6.4 and 4.9 times more likely, respectively, to develop this lesion. This is the first report of a breed predilection for spontaneous canine glomerulonephritis. Previous reports have associated this lesion with Borrelia burgdorferi exposure. All dogs in this study were from Lyme disease-endemic areas. Of 18 dogs serologically tested, all were positive for exposure. Silver stain examination of kidneys revealed rare spirochetes, suggesting that the presence of spirochetes in the kidney is apparently unrelated to lesion development. The role of vaccination in development of the renal lesion is undetermined. The association of this histologically and clinically unique lesion, Lyme nephritis, with Borrelia burgdorferi infection is significant because it is the only fatal form of canine Lyme borreliosis.

Age Factors↗
PubMed1997

Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer.

1. Genetic variation at the glutathione S-transferase M1 locus (GSTM1) has been associated with a number of apparently unrelated cancers, including lung cancer. Emphysema is a common lung disease often found concomitant with lung cancer. Both emphysema and lung cancer may result from chemical and oxidative damage caused by reactive species present in cigarette smoke or released from neutrophils recruited following cigarette smoke induced injury. GSTM1 may protect against such damage through detoxification of cigarette smoke components. Polymorphism of this gene may thus influence susceptibility not just to lung cancer, but to other forms of lung disease. 2. Resection specimens from a group of 168 lung cancer patients were assessed for the presence of macroscopic centriacinar and panacinar emphysema. DNA was extracted from archival material and genotyped for the GSTM1 polymorphism using the polymerase chain reaction. A control group of 384 anonymous blood donations was used to determine the frequency of the GSTM1 gene deletion in a random control population. Reverse transcription on lung tissue was performed to investigate mRNA expression of GSTM1 and GSTM4. 3. In 57 lung cancer cases with no emphysema there was no association with homozygous deletion of the GSTM1 gene (51% null in cancer and 53% null in control groups). However in 111 patients with emphysema and lung cancer there was an increase in the frequency of deletion (65%, P = 0.032) giving an odds ratio of 1.36(0.32-2.40). In 43 cases there was evidence of both centriacinar and panacinar emphysema. The frequency of GSTM1 deletion was 70% (Odds ratio 2.11, 0.97-3.25). Both GSTM1 and GSTM4 mRNAs were expressed in lung tissue. 4 These findings suggest that GSTM1 has a general but rather small protective effect against toxicological injury in the lung which is not specific to cancer. This is of relevance in considering the health effects of exposure to a wide range of reactive chemicals in the environment.

Base Sequence↗
PubMed1997

Racial attitudes of preschoolers: age, race of examiner, and child-care setting.

Racial attitudes of 60 preschool children (28 boys, 32 girls) from either a monoracial Euro-American child-care program (n = 16), a monoracial African-American program (n = 12), or a multiracial program (25 Euro-Americans, 7 African-Americans) were assessed using the Preschool Racial Attitudes Measure II. Despite the over-all neutral attitudes reflected by these children, evidence of a Euro-American bias among older children was found. If replicated with a large randomly selected sample recognizing and understanding early racial attitudes may be a key factor in fostering positive racial identity and preventing the formation of prejudice.

Black or African American↗
PubMed1997

Suspected malignant hyperthermia in a 13-month-old: today's "typical" episode--a case report.

A case of suspected malignant hyperthermia in a 13-month-old female, to whom succinylcholine was not administered, is presented. The patient presented for a repair of the right radial nerve under general anesthesia. Induction was accomplished with halothane, nitrous oxide, and oxygen. Tracheal intubation was facilitated with intravenous vecuronium. Controlled ventilation was initiated, and anesthesia was maintained with isoflurane, nitrous oxide, oxygen, morphine sulfate, and vecuronium. At the conclusion of the surgical procedure, an abrupt increase in ETCO2, an elevation in body temperature, and a mixed acidosis was observed. Resolution of symptoms followed the administration of dantrolene sodium. The patient underwent an uneventful postoperative recovery and was discharged home. It was felt that the patient was too young to undergo a muscle biopsy for a caffeine-halothane stimulation test.

Age Factors↗
PubMed1997

Reduced incidence of peritonitis by utilizing "flush before fill" in APD.

Studies first theorized and then proved that "flush before fill" decreased the incidence of peritonitis in continuous ambulatory peritoneal dialysis (CAPD). The purpose of this study was to examine the relationship between the incidence of peritonitis and the use of cyclers with the "flush-before-fill" option. We followed our automated PD (APD) population from 1 August 1994 to 30 September 1996. The patients were divided into two groups. Group I utilized cyclers with the "flush-before-fill" option and experienced 8 incidences of peritonitis in 225 patient-months of use, for a peritonitis rate of 1:28. Group II utilized cyclers without the "flush-before-fill" option and experienced 22 incidences of peritonitis in 225 patient-months of use, for a peritonitis rate of 1:10.2. Gram-positive organisms were responsible for 3/8, or 37.5%, of incidences of peritonitis for Group I and 13/22, or 59%, of peritonitis incidence for Group II. The results of the study indicate a reduction in both the incidence of peritonitis and the incidence of peritonitis caused by gram-positive organisms for APD when utilizing cyclers with the "flush-before-fill" option.

Adult↗
PubMed1996

Transcriptional regulation of gamma-glutamylcysteine synthetase-heavy subunit by oxidants in human alveolar epithelial cells.

We studied the regulation of glutathione (GSH) synthesis and characterised the 5'-promoter region of the gamma-glutamylcysteine synthetase-heavy subunit (gammaGCS-HS) gene in human alveolar type II cells (A549) following exposure to menadione (MQ) and hydrogen peroxide (H2O2). Both MQ (100 microM) and H2O2 (100 microM) exposure increased intracellular GSH levels associated with increased gammaGCS activity. This was concomitant with enhanced expression of gammaGCS-HS mRNA. Transfection of deletion constructs of the gammaGCS-HS promoter (-1050 to +82 bp) in a chloramphenicol acetyl transferase (CAT) reporter system revealed that an human antioxidant response element (hARE), present within the proximal region of the promoter (-1050 to -818 bp), is not required for oxidant-mediated gene induction. We conclude that oxidant stress-induced gammaGCS-HS mRNA expression is associated with AP-1 or AP-1 like responsive elements (-817 to +45 bp).

Cells, Cultured↗
PubMed1996

Induction of gamma-glutamylcysteine synthetase by cigarette smoke is associated with AP-1 in human alveolar epithelial cells.

Increased levels of glutathione (GSH) occur in the epithelial lining fluid (ELF) of chronic cigarette smokers. Therefore we investigated the effect of cigarette smoke condensate solution (CSC) on GSH synthesis and the regulation of gamma-glutamylcysteine synthetase (gammaGCS) in human type II alveolar epithelial cells (A549). CSC exposure increased GSH levels, gammaGCS activity and gammaGCS heavy subunit (HS) mRNA, as well as increasing DNA binding of the activator protein-1 (AP-1) and the human antioxidant response element (hARE). Transfection of deletion constructs of the gammaGCS-HS promoter in a chloramphenicol acetyl transferase (CAT) reporter system revealed that an hARE, present within promoter, is not required for the CSC mediated induction. We conclude that CSC induction of gammaGCS-HS expression is associated with AP-1/AP-1-like responsive elements.

Antioxidants↗
PubMed1996

Reverse signaling via CD30 ligand.

CD30 ligand (CD30L), a member of the TNF family, is a type II membrane protein with a C-terminal extracellular domain that is homologous with the extracellular domains of other TNF family members. Also, like most TNF family members, the N-terminal cytoplasmic domain of CD30L is conserved across species, but not between family members, suggesting a possible biological function. Motivated by this observation, we investigated the potential for CD30L, when activated by cross-linking, to directly transduce a signal to the ligand-bearing cell. Cross-linking of CD30L by a mAb or by CD30-Fc fusion protein induced the production of IL-8 by freshly isolated neutrophils. Further, both cross-linking mechanisms produced a rapid oxidative burst. Indirect effects through CD30 were ruled out, since CD30L, but not CD30, is expressed on neutrophils. Expression of CD30L can be induced in peripheral blood T cells by cross-linking the CD3 component of the TCR. Peripheral blood T cells exposed to suboptimal concentrations of anti-CD3 increased metabolic activity, proliferated, and produced IL-6 in response to cross-linking of CD30L. These results indicate that cross-linked CD30L can transduce a signal to the ligand-bearing cell. This "reverse signaling" via CD30L taken together with previously published data concerning other ligands in the TNF family strongly suggest that, as a rule, TNF family members and their cognate receptors signal bidirectionally, blurring the distinction between ligand and receptor.

Antibodies, Monoclonal↗
PubMed1996

Characterization of the human cytochrome P4502D6 promoter. A potential role for antagonistic interactions between members of the nuclear receptor family.

The functional mapping of the human cytochrome P4502D6 (CYP2D6) promoter in HepG2 cells revealed the presence of both positive and negative regulatory elements. One of these regulatory elements overlapped a sequence that is highly conserved in most members of the CYP2 family. This element, which consists of a degenerate AGGTCA direct repeat spaced by 1 base pair (DR1) and is known to be a target for members of the steroid receptor superfamily, was found to bind in vitro translated hepatocyte nuclear factor 4 (HNF4) in gel retardation analysis. Using HepG2 nuclear extracts, three protein-DNA complexes were formed on the DR1 element, one of which was confirmed to be dependent on the binding of HNF4. The other DR1 complexes were shown to be due to the interaction of the orphan receptor chicken ovalbumin upstream promoter transcription factor I (COUP-TFI). Experiments in COS-7 cells showed that HNF4 could activate the CYP2D6 promoter 30-fold. Surprisingly, mutation of the DR1 element produced a relatively minor 23% decrease in activity in HepG2 cells. Additionally, COUP-TFI was shown to inhibit HNF4 stimulation of the CYP2D6 promoter in COS-7 cells, suggesting that COUP-TFI could attenuate the effect of HNF4 in HepG2 cells. However, when HNF4 levels were increased in HepG2 cells by co-transfection, it resulted in the enhancement of CYP2D6 promoter activity, indicating that HNF4 could overcome the repressive effect of COUP-TFI. Therefore, the contribution of the DR1 element in controlling the transcription of the CYP2D6 gene depends on the balance between positively and negatively acting transcription factors.

Animals↗
PubMed1996

Viral peptide specific induction of MHC class II expression by murine T cell clones.

We report that I-Ab-restricted T cell clones, elicited by influenza infection of C57BL/10 mice and specific for the hemagglutinin peptide HA1 186-205, express class II. They respond to peptide stimulation by IL release (IL-3 or IFN-gamma) without a requirement for APC but do not proliferate. Moreover, surface expression of class II requires de novo synthesis in the presence of the stimulatory peptide and is inhibited by coculture with TCR-specific Ab, or brefeldin A or cycloheximide. Clonotypic specificity of peptide induction was confirmed by failure of other allele specific peptides to enhance class II expression. Addition of the viral peptide to T cells induced homotypic adhesion, which provides a physical basis for stabilization of class II-peptide complexes at the cell surface. Extinction of class II expression was evident in the corresponding T cell hybridomas, which might account for the failure to report class II expression by murine T cells. Control studies indicated that class II was not passively acquired from APC by demonstrating 1) failure of processed Ag to induce class II expression, 2) allo-class II (Ak) was not acquired by coculture with peptide and semisyngeneic (H-2 b/k) APC, 3) absence of class II expression by a NP peptide-specific Th2 clone under identical culture conditions, and most significantly, 4) reverse-transcriptase PCR amplification and surface expression of class II using highly purified preparations of FACS-selected CD4+ class II- cells cocultured with the stimulatory peptide.

Alleles↗
PubMed1996

Cowpox virus genome encodes a second soluble homologue of cellular TNF receptors, distinct from CrmB, that binds TNF but not LT alpha.

We show the cowpox genome (Brighton Red strain) contains a single copy gene, crmC, expressed at late times during viral infection, encoding a soluble, secreted protein whose sequence marks it as a new member of the TNF receptor family. The cysteine-rich protein contains 186 amino acids, the N-terminal 21 of which constitute a signal peptide, and two potential N-linked glycosylation sites. The approximately 25-kDa recombinant protein binds TNF specifically and completely inhibits TNF-mediated cytolysis. The strongest sequence homologues are the ligand-binding regions of the type II cellular TNF receptor (TNFRII) and CrmB, a distinct pox virus gene also encoding a soluble TNF binding protein. Unlike TNFRII and CrmB, CrmC does not bind lymphotoxin (LT alpha, TNF beta) and lacks the conserved (but nonhomologous) approximately 150-residue C-terminal domain of CrmB proteins. The presumed function of CrmC is viral inhibition of host-elicited TNF.

Amino Acid Sequence↗
PubMed1996

Anion binding by transferrins: importance of second-shell effects revealed by the crystal structure of oxalate-substituted diferric lactoferrin.

Proteins of the transferrin family bind, with high affinity, two Fe3+ ions and two CO3(2)- ions but can also bind other metal ions and other anions. In order to find out how the protein structure and its two binding sites adapt to the binding of larger anions, we have determined the crystal structure of oxalate-substituted diferric lactoferrin at 2.4 A resolution. The final model has a crystallographic R-factor of 0.196 for all data in the range 8.0-2.4 A. Substitution of oxalate for carbonate does not produce any significant change in the polypeptide folding or domain closure. Both binding sites are perturbed, however, and the effects are different in each. In the C-lobe site the oxalate ion is bound to iron in symmetric 1,2-bidentate fashion whereas in the N-lobe the anion coordination is markedly asymmetric. The difference arises because in each site substitution of the larger anion causes displacement of the arginine that forms one wall of the anion binding site; the movement is different in each case, however, because of different interactions with "second shell" amino acid residues in the binding cleft. These observations provide an explanation for the site inequivalences that accompany the substitution of non-native anions and cations.

Anions↗
PubMed1996

X-ray structure of the magnesium(II).ADP.vanadate complex of the Dictyostelium discoideum myosin motor domain to 1.9 A resolution.

The structure of the vanadate-trapped ADP complex of a truncated head of Dictyostelium myosin II consisting of residues Asp 2-Asn 762 has been determined by molecular replacement at 1.9 A resolution and refined to a crystallographic R-factor of 19.4%. The crystals belong to the orthorhombic space group C2221 where a = 84.50 A, b = 145.4 A, and c = 152.8 A. The conformation of the protein is similar to that of MgADP.AlF4.SlDc [Fisher, A.J., et al. (1995) Biochemistry 34, 8960-8972]. The nucleotide binding site contains a complex between MgADP and vanadate where MgADP exhibits a very similar conformation to that seen in previous complexes. The vanadate ion adopts a trigonal bipyramidal coordination. The three equatorial oxygen ligands are fairly short, average 1.7 A, relative to a single bond distance of approximately 1.8 A and are coordinated to the magnesium ion, N zeta of Lys 185, and five other protein ligands. The apical coordination to the vanadate ion is filled by a terminal oxygen on the beta-phosphate of ADP and a water molecule at bond distances of 2.1 and 2.3 A, respectively. The long length of the apical bonds suggests that the bond order is considerably less than unity. This structure confirms the earlier suggestion that vanadate is a model for the transition state of ATP hydrolysis and thus provides insight into those factors that are responsible for catalysis. In particular, it shows that the protein ligands and water structure surrounding the gamma-phosphate pocket are oriented to stabilize a water molecule in an appropriate position for in-line nucleophilic attack on the gamma-phosphorus of ATP. This structure reveals also an orientation of the COOH-terminal region beyond Thr 688 which is very different from that observed in either MgADP.BeFx.SlDc or chicken skeletal myosin subfragment 1. This is consistent with the COOH-terminal region of the molecule playing an important role in the transduction of chemical energy of hydrolysis of ATP into mechanical movement.

Adenosine Diphosphate↗