Nutrition and survival in cystic fibrosis.
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Adult↗
Biomedical subjects
S C Bell
Publications and source records attributed to S C Bell.
Resting energy expenditure and oxygen cost of breathing in patients with cystic fibrosis.
BACKGROUND: Resting energy expenditure (REE) is often increased and may contribute towards energy imbalance in patients with cystic fibrosis. Several mechanisms may lead to increased REE including the gene defect, the effect of chronic infection, and abnormal pulmonary mechanics. Increased oxygen cost of breathing (OCB) has been demonstrated in patients with chronic obstructive pulmonary disease (COPD), but has not been the subject of extensive study in cystic fibrosis. METHODS: Ten clinically stable patients with cystic fibrosis and 10 healthy control subjects were studied. OCB was estimated using the dead space hyperventilation method. Mixed expired gas fractions were measured by online gas analysers and ventilation by a pneumotachograph. After measurement of resting ventilation and gas exchange, minute ventilation (VE) was stimulated by 6-10 1/min by the addition of a dead space and OCB calculated from the slope of the differences in oxygen uptake (VO2) and VE. REE and the non-respiratory component of REE were calculated from gas exchange data. To assess the repeatability of OCB all subjects had a further study performed one week later. RESULTS: The patients had lower weight, fat free mass (FFM), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and transfer factor for carbon monoxide (TLCO) than controls. Resting respiratory rate, VE, and oxygen uptake per kilogram of FFM (VO2/kg FFM) were higher in patients (20 (7), 10.4 (1.4) 1/min and 5.5 (0.8) ml/kg FFM/min) than in controls (13 (4), 7.0 (1.2), and 4.2 (0.5), respectively.) The error standard deviation for replicated measures of OCB was 0.5 ml O2/l VE in controls and 0.8 ml O2/l VE in patients with coefficients of variation of 24% in controls and 28% in patients. The mean OCB in patients was 2.9 (1.4) ml O2/l VE and 2.1 (0.7) ml O2/l VE in controls. OCB, expressed as ml/min (VO2resp) was 28.5 (11.7) in patients and 14.0 (3.6) in controls. REE was higher in patients (125.9 (14.0)% predicted) than in controls (99.0 (9.4)%). The estimated non-respiratory component of REE was 112.1 (14.9)% for patients and 93.0 (10.0)% for controls. CONCLUSIONS: In clinically stable patients with cystic fibrosis the OCB at rest is increased but is not the sole explanation for increased metabolic rate. This contrasts with the finding in COPD where the increase in REE is largely explained by increased OCB. This study also showed poor repeatability and OCB measurements similar to earlier studies, which indicates that the technique is not suitable for longitudinal studies.
Adult↗
Evidence for opioid modulation and generation of prostaglandins in sulphur dioxide (SO)2-induced bronchoconstriction.
BACKGROUND: Inhalation of sulphur dioxide (SO2) provokes bronchoconstriction in asthmatic subjects. Cholinergic mechanisms contribute, but other mechanisms remain undefined. The effect of morphine, an opioid agonist, on the cholinergic component of SO2-induced bronchoconstriction was investigated, and the effect of indomethacin, a cyclooxygenase inhibitor, on SO2-induced bronchoconstriction and tachyphylaxis was studied. METHODS: In the first study 16 asthmatic subjects inhaled either ipratropium bromide or placebo 60 minutes before an SO2 challenge on days 1 and 2. On day 3 an SO2 challenge was performed immediately after intravenous morphine. In the second study 15 asthmatic subjects took either placebo or indomethacin for three days before each study day when two SO2 challenges were performed 30 minutes apart. The response was measured as the cumulative dose causing a 35% fall in specific airways conductance (sGaw; PDsGaw35). RESULTS: Ipratropium bromide significantly inhibited SO2 responsiveness, reducing PDsGaw35 by 0.89 (95% CI 0.46 to 1.31) doubling doses. This effect persisted after correction for bronchodilatation induced by ipratropium bromide. The effect of ipratropium bromide and morphine on SO2 responsiveness also correlated (r2 = 0.71). In the second study SO2 tachyphylaxis developed with PDsGaw35 on repeated testing, being reduced by 0.62 (95% CI 0.17 to 1.07) doubling doses. Indomethacin attenuated baseline SO2 responsiveness, increasing PDsGaw35 by 0.5 (95% CI 0.06 to 0.93) doubling doses. CONCLUSIONS: These results suggest that opioids modulate the cholinergic component of SO2 responsiveness and that cyclooxygenase products contribute to the immediate response to SO2.
Adult↗
Expression of mRNA encoding decidualization-associated protein, a variant of acute-phase alpha 2 macroglobulin, by rat uterine tissues during pregnancy and pseudopregnancy.
The patterns of expression of mRNA encoding decidualization-associated protein (DAP) in the rat uterus from early, mid-, and late stages of pregnancy were examined by in situ hybridization to provide an insight into the function of DAP during pregnancy. Parallel studies were performed on rat uteri during the oestrous cycle and oil-induced deciduomata. DAP transcripts were absent in virgin uteri and during the day of implantation (day 5), low in early gestation tissues (days 8, 9) and high during midgestation (days 10-14). Expression of mRNA encoding DAP was first detected on day 8 of pregnancy in decidual cells of the lateral decidual glycogen wing areas. On day 9, mRNA encoding DAP was found in the same area as on day 8 as well as in the outer layer of cells in the antimesometrial decidua adjacent to the myometrium termed the fibrinoid capsula. On days 11 and 12, expression appeared in the decidual cells of the mesometrial decidua, and was particularly strong around the ectoplacental cone and blood vessels that were invaded by the trophoblast. By day 13 and throughout the remainder of pregnancy, expression occurred in the mesometrial decidua and metrial gland. No signal was observed in granulated metrial gland cells. mRNA encoding DAP was also found in the smooth circular muscle coat adjacent to the mesometrial decidua. A similar pattern and cellular localization of expression of mRNA encoding DAP expression was detected during the development of the deciduomata, artificially induced in the absence of a conceptus. The spatial and temporal patterns of expression correlated with a possible role for DAP in mediating fetal-maternal interactions and the establishment of the placental structure.
Animals↗
Can tumor necrosis factor-alpha (TNF-alpha) be reliably measured in blood?
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Humans↗
Smooth muscle myosin II and alpha smooth muscle actin expression in the baboon (Papio anubis) uterus is associated with glandular secretory activity and stromal cell transformation.
The objective of this study was to investigate the localization and hormonal regulation of smooth muscle myosin II (SMM II) and alpha smooth muscle actin (alpha SMA) in the baboon uterus, since cytoskeletal proteins are involved in secretory function and morphological transformation. Uterine tissue was obtained from baboons 1) during the menstrual cycle, 2) following steroid treatment of ovariectomized baboons, 3) during pregnancy (Days 14-60 postovulation [PO]), and 4) during simulated pregnancy (Days 18-32 PO). Tissues were processed for immunocytochemical localization of SMM II or alpha SMA with specific polyclonal or monoclonal antibodies, respectively. SMM II stained all smooth muscle cells of blood vessels and myometrium regardless of treatment. Glandular epithelial staining was present only in endometrium obtained during the luteal phase or following estrogen and progesterone treatment. Staining intensity was greater in the basalis than in the functionalis. The number of glands staining positive for SMM II on Days 18-32 of pregnancy and simulated pregnancy was variable. Glandular stain was absent after Day 32 PO. These immunocytochemical data were confirmed by immunoblot analysis of glandular cytosolic extracts. Stromal staining for SMM II was present under the luminal epithelium during simulated pregnancy (Days 18-32), on Day 25 of steroid treatment in the simulated-pregnant controls, and in nonimplantation sites during pregnancy. In contrast, alpha SMA staining was low or absent in all uterine cell types in ovariectomized baboons. Under estrogen-dominated conditions (follicular phase and estrogen treatment), alpha SMA staining was present in smooth muscle cells, and this staining persisted throughout the remaining treatment periods. Glandular epithelial staining for alpha SMA was absent in all treatment groups. However, alpha SMA staining in stromal fibroblasts underneath the luminal epithelium was evident as early as Day 14 of pregnancy and Day 18 of simulated pregnancy. The number of stromal fibroblasts that stained positive increased in the surface region of the functionalis between Days 18 and 32 PO, and the staining extended throughout the upper functionalis region. There was a decrease in the number of positively stained stromal fibroblasts, particularly at the implantation site, between Days 32 and 40 of pregnancy. By Days 50-60 of pregnancy, this staining was almost absent. The induction of alpha SMA in stromal fibroblasts in the functionalis region in pregnant baboons was confirmed by immunoblot analysis of stromal cell cytosol extracts. We conclude that the progesterone-induced glandular expression of SMM II may be involved in uterine secretory function and that alpha SMA expression in stromal fibroblasts during pregnancy and after long-term steroid treatment is associated with the decidualization process.
Actins↗
Small-molecule immunostimulants. Synthesis and activity of 7,8-disubstituted guanosines and structurally related compounds.
A series of 7,8-disubstituted guanosine derivatives was designed and prepared as potential B-cell-selective activators of the humoral immune response. These compounds were evaluated for their ability to act as B-cell mitogens and to augment the antibody response of B cells to sheep red blood cell (SRBC) challenge (adjuvanticity). In addition, they were tested for their ability to stimulate the natural killer (NK) cell response in murine in vitro cell assays. Certain of the compounds demonstrated in vivo activity when administered either intravenously, subcutaneously, or orally. Analogues with a medium-length alkyl chain (2-4 carbons, 5-7) on the 7-position of 7-alkyl-8-oxoguanosines were found to be particularly potent. Compounds bearing hydroxyalkyl, aminoalkyl, or substituted aminoalkyl substituents on this 7-position were weakly active. However, benzyl groups, including those substituted with heteroatoms (e.g., p-nitrobenzyl, 14), were active. Oxo, thioxo, and seleno groups on C-8 of the guanosine ring all imparted strong activity, whereas other larger substituents did not (e.g., N = CN). Stereochemical inversion of the 2'-hydroxyl on the ribose ring in this series, giving arabinose analogue 70, lessened activity. However, removal of the 2'-hydroxyl, either with (64) or without (73) removal of the 3'-hydroxyl, resulted in excellent activity and improved solubility; 64 also displayed good oral in vivo activity as well. A series of ketals involving the 2',3'-hydroxyls were prepared; certain of the nonpolar ketals (e.g., 48) were remarkably active, pointing to an ancillary hydrophobic binding region that can augment activity. 5'-Phosphate derivative 57 was fairly active, and acyclovir analogue 90 displayed good NK-selective activity: other N-9 sugar mimetics were also active (97-104), although this activity did not carry over into the human B-cell assay. A total of 80 compounds were prepared and evaluated for their immunostimulating activity. Within this group, compounds could be divided into those that were active in all three assays, those that displayed some measure of selectivity for the adjuvanticity assay, and those that preferentially activated NK responses. Because of its overall biological profile and ease of synthesis, 7-allyl-8-oxoguanosine (6; loxoribine, RWJ-21757) was chosen for further development. It is among the most potent compounds evaluated in the three biological assays.
Adjuvants, Immunologic↗
Formation of the chorio-decidual interface of human fetal membranes. Is it analogous to anchoring villi development in the placenta?
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Alkaline Phosphatase↗
Morphometric characteristics of the decidua, cytotrophoblast, and connective tissue of the prelabor ruptured fetal membranes.
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Connective Tissue↗
Absence of antinuclear antibodies in dogs infected with Ehrlichia canis.
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Animals↗
On tumor necrosis factor alpha in CF.
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Adult↗
Distribution of fibrillin-containing microfibrils and elastin in human fetal membranes: a novel molecular basis for membrane elasticity.
OBJECTIVES: The aim of this study was to determine the distribution of the elastic fiber components, elastin and the extensible fibrillin-containing microfibrils, in human fetal membranes, to understand the possible molecular basis of the membrane elasticity. STUDY DESIGN: Multiple fetal membrane specimens were obtained immediately after 10 normal vaginal deliveries at term. The distribution of elastin and fibrillin-containing microfibrils was studied by histochemical, immunohistochemical, immunofluorescence, and electron microscopic techniques. RESULTS: We failed to detect elastin in the fetal membranes with any of the applied techniques. However, fibrillin-containing microfibrils formed abundant longitudinal bundles that were primarily found in the fibroblast and reticular layers. The orientation of these bundles was parallel to direction of membrane stretch. They also formed bundles that extended from the amniotic, chorionic, and decidual basement membranes to the adjacent tissues. The fibrillin-containing microfibrils were also identified in the compact layer and in intercellular spaces of the trophoblasts but not in the spongy layer. CONCLUSIONS: We suggest that, in the absence of elastin, the structural organization and the extensibility of the fibrillin-containing microfibrils may represent a novel molecular basis for the elastic properties of the fetal membranes and contribute to their strength.
Actin Cytoskeleton↗
Immune responses to canine distemper virus in joint diseases of dogs.
Measurement of immune complexes, antibodies against canine distemper virus (CDV) and anti-CDV antibodies in immune complexes were made in sera and SF from 'normal' dogs and from dogs with joint diseases. These data were compared with cytological analyses of SF samples. In dogs with canine rheumatoid-like arthritis (CRA) there were correlations between circulating anti-CDV antibody levels and circulating immune complex levels (P < 0.001) and between SF anti-CDV antibody levels and SF immune complex levels (P < 0.01). Furthermore, the SF PMN count in dogs with CRA correlated with both the SF anti-CDV antibody levels (P < 0.001) and the SF immune complex anti-CDV antibody levels (P < 0.001). The results demonstrated a relationship between CDV and ongoing synovial inflammation in dogs with CRA.
Animals↗
Structural characteristics of term human fetal membranes: a novel zone of extreme morphological alteration within the rupture site.
OBJECTIVE: To determine the structural characteristics of the rupture site of term fetal membranes (amniochorion and decidua) that rupture spontaneously after the onset of labour. DESIGN: Fourteen term fetal membranes were examined immediately after delivery at the light microscope level. Multiple samples were taken along the whole rupture site and long an axis between this site and placental edge. Morphometric analysis of the thickness of the constituent layers of the fetal membranes was performed. SETTING: Leicester Royal Infirmary Maternity Hospital. RESULTS: A restricted zone of extreme altered morphology, characterised by marked swelling and disruption of the connective tissue, thinning of the trophoblast layer and thinning or absence of decidua, was identified in the rupture site of all patients. Morphometric analysis of the thickness of membrane layers showed that these changes and the ratio between the thickness of the connective tissue layers and that of the trophoblast and decidua (termed fetal membrane morphometric index) were significant between the zone of extreme altered morphology and the rest of the membranes. CONCLUSIONS: The morphological features of the zone of extreme altered morphology suggests that it represents an area of structural weakness of the membranes. Since this zone did not include the whole length of the rupture site, it is likely that it was present before membrane rupture and was generated during pregnancy. We hypothesise that the zone of extreme altered morphology represents the site of initial rupture after which the tear is transmitted through the membranes to produce the rupture site. It is possible that if these changes become more extreme, then prelabour membrane rupture may occur. Further characterisation of this zone may help to understand the mechanism of its genesis and its role in predisposing the fetal membranes to rupture.
Amnion↗
Epithelial localization of insulin-like growth factor binding protein 1 in the uterus of the rat during pregnancy, deciduoma-bearing pseudopregnancy and hormone treatment.
A monospecific antibody was used to determine the immunocytochemical localization of insulin-like growth factor binding protein 1 (IGFBP-1) in the rat uterus. Immunoreactive IGFBP-1 was first detected from day 5 of pregnancy in the luminal and glandular epithelium. However, immunoreactivity was most intense from day 6 in the glandular epithelium, where it was associated with apically located granules. Immunoreactive glands were located only in non-decidualized endometrium, which was limited at the implant site to a thin basal layer by growth of the antimesometrial decidua from day 7. However, glands and associated immunoreactive IGFBP-1 were prominent in the inter-implant sites until day 9, although they were detected throughout pregnancy. Similar reactivity was detected in the glands of the basal endometrium in deciduomata-bearing animals, but these decreased in number from day 7 of pseudopregnancy. No immunoreactivity was detected during the oestrous cycle but could be induced in ovariectomized animals by sequential oestradiol and oestradiol plus progesterone treatment. The observations were consistent with IGFBP-1 representing a secretory product of the glandular epithelium and could either play a role in development of the trophoblastic component of the conceptus during the pre-placental period of anti-mesometrial implantation or in the endometrium acting as an inhibitor of local IGF-I action and in either case by transporting IGF-I from the stromal to the glandular luminal environment.
Animals↗
Differential expression of the integrin subunits in human fetal membranes.
The distribution of the alpha 1, alpha 3-alpha 6, beta 1, beta 3 and beta 4 integrin subunits in fetal membranes at term was examined using an indirect immunofluorescence technique and confocal laser scanning microscopy. In the amniotic epithelium, beta 4 integrin (alpha 6 beta 4) exhibited distinct basal localization, whereas beta 1 integrins (alpha 3 beta 1, alpha 5 beta 1) were localized basolaterally. This finding suggests that integrins, especially alpha 6 beta 4 which is a structural component of the hemidesmosomes, may function as basement membrane receptors. Integrins localized laterally may play a role in cell-cell interactions. beta 1 (alpha 1 beta 1, alpha 5 beta 1) integrins are probably involved in cell-matrix interactions in the connective tissue layers which are rich in collagens and fibronectin. Cytotrophoblasts, located predominantly towards the chorionic basement membrane, mainly expressed alpha 6 beta 4, while those located predominantly in the vicinity of decidua expressed alpha 5 beta 1, alpha 3 beta 1 and alpha 1 beta 1. Decidual cells expressed alpha 3 beta 1 and alpha 1 beta 1, whereas alpha 1, alpha 5, alpha 6, beta 1 and beta 4 were expressed in blood vessels. This pattern of integrin expression reflects the reported difference in composition of the extracellular matrix at these locations and obviates an important role for alpha 5 beta 1 at the chorio-decidual interface. The differential integrin expression at the cell-basement membrane interfaces demonstrated in this study (at amniotic epithelium, cytotrophoblasts, decidual cells and blood vessels) indicated a differential recognition of basement membranes by these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Amnion↗
Prevalence of canine distemper antibodies in the pagetic population.
Recent molecular evidence has implicated canine distemper virus (CDV) as a possible aetiologic agent in Paget's disease. However, previous serological studies have shown no differences in levels of anti-CDV antibodies between Paget's patients and controls. In this study, the technique of enzyme linked immunosorbent assay was used to measure anti-CDV antibodies in a group of Paget's patients from the North West of England. Some patients were undergoing treatment with 3-amino-hydroxypropylidene (APD), and the pre-treatment levels of antibody were compared with those following treatment. With several patients, it was also possible to compare the antibody levels with results from in situ hybridisation studies. No significant difference was found between the levels of anti-CDV antibodies in patients and controls. However, several patients and some of the controls did have markedly elevated levels of anti-CDV antibody. Antibody levels remained fairly constant following treatment with APD, except for two patients who showed marked changes. The patients positive for CDV by in situ hybridisation had significantly lower levels of anti-CDV antibodies when compared with those that were negative by in situ hybridisation. These results suggest that if CDV does cause Paget's disease, anti-CDV antibodies play little or no part in the disease pathogenesis. High levels of anti-CDV antibodies in both Paget's patients and controls suggest that a canine virus can infect humans. The fact that those patients that had CDV transcripts detectable in their bone cells had low levels of anti-CDV antibodies might suggest failure to clear the virus during an initial infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inhaled FMLP increases microvascular permeability in the rabbit trachea.
This study was designed to determine the effect of inhaled N-formyl-methionyl-leucyl-phenylalanine (FMLP) on microvascular permeability in the rabbit trachea and to determine if the effect could be modified by cholinergic antagonism, neutral endopeptidase (NEP) inhibition, opioid receptor antagonism, or an opioid agonist. New Zealand White rabbits were anesthetized and pretreated intravenously with one of the following: saline, dimethyl sulfoxide (DMSO) (both controls), thiorphan, phosphoramidon (both NEP inhibitors), thiorphan and naloxone, morphine, or atropine. All rabbits were then given intravenous Evans blue before inhalation of nebulized DMSO (control) or FMLP. Extravascular tracheal Evans blue concentration was subsequently determined spectrophotometrically. FMLP caused a highly significant increase in microvascular permeability (92.6 +/- 7.1 micrograms/g of trachea, control 20.4' +/- 3.4). The effect of FMLP was significantly modified by cholinergic blockade (61.1 +/- 6.9) and by NEP inhibition (thiorphan 38.8 +/- 5.6, phosphoramidon 52.6 +/- 4.2). This effect of NEP inhibition could be reversed by concurrent treatment with the opioid receptor antagonist naloxone (95.9 +/- 34.6). Morphine had no significant effect. We concluded that FMLP increases microvascular permeability, which may in part explain the effect of FMLP on airway resistance in the rabbit. Inhibiting NEP decreases the response possibly through an effect on endogenous opioids. The response appears to be partially vagally mediated.
Administration, Inhalation↗