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Biomedical subjects

D M Smith

Publications and source records attributed to D M Smith.

At least 37 records · Page 2Linked to original sources
PubMed2004

Relative accuracy of algorithm-based prescription of nasal CPAP in OSA.

BACKGROUND: Patients with OSA on nasal continuous positive airway pressure (CPAP) have considerable night-to-night variation in their pressure requirements, suggesting that a one-night titration might not be very precise. This study investigates the likely error incurred using a one-night titration, and explores whether an algorithm-based approach to determine the pressure is as accurate. METHODS: Thirty patients with OSA used an autotitrating CPAP device for 28 nights and the average was regarded as the 'reference' pressure for that patient. Using estimates of precision and bias, this 'reference' pressure was compared with (1) an algorithm-derived pressure (based on neck circumference and OSA severity), (2) a one-night titration (using four alternative nights), and (3) a fixed pressure of 10 cmH2O. RESULTS: The mean 'reference' pressure for the group was 9.83 (SD 2.12) cmH2O. There was little bias from any of the alternatives. However, the precision varied between 1.65 and 2.45 cmH2O for the four one-night titrations, was 2.00 for the algorithm, and was 2.12 using a fixed pressure of 10 cmH2O. CONCLUSIONS: Considerable night-to-night variation means that a one-night titration is not very precise and is subject to random variation. A one-night titration has a similar inaccuracy to that resulting from using an algorithm, based on OSA severity and neck circumference. Setting all patients with OSA at 10 cmH2O is little worse.

Algorithms↗
PubMed2004

A novel, simplified approach to starting nasal CPAP therapy in OSA.

BACKGROUND: Due to ever increasing referral rates, we have had to move the nasal CPAP induction program for patients with obstructive sleep apnoea (OSA) out of the sleep laboratories and into an outpatient setting. We report the effects this has had on patient outcomes. METHODS: The last 75 patients with OSA who had an overnight CPAP titration in the sleep laboratory (group 1) were compared with the first 75 coming to an afternoon clinic and set up on CPAP in groups, and who had their CPAP pressure determined from an algorithm (group 2). They were assessed at 1 and 11 months using the Epworth Sleepiness Score, compliance with CPAP (h/night), whether still using CPAP, and the number of clinic appointments required in the first 11 months. RESULTS: The two groups were similar at baseline. There were no differences in any of the outcome measures. ESS values fell from 14.6 to 5.0 and from 14.0 to 5.1 at 11 months in groups 1 and 2, respectively: compliance, 5.2 versus 5.1 h/night; clinic appointments, 1.75 versus 1.96; discontinuation rates at 1 month, 8% and 7%, and at 11 months, 25% and 21%. CONCLUSIONS: Using these simple outcome measures, we have shown that using an outpatient-based approach, and CPAP pressure based on an algorithm, have not reduced the efficacy of our CPAP induction program for patients with OSA.

Algorithms↗
PubMed2003

CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS.

Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: we report the effects of the antagonist fragments of human AM and CGRP (AM22-52 and CGRP8-37) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. AM22-52 (10 microM) antagonised AM at all CL/RAMP2 complexes (apparent pA2 values: 7.34+/-0.14 (hCL/hRAMP2), 7.28+/-0.06 (Rat 2), 7.00+/-0.05 (L6), 6.25+/-0.17 (rCL/hRAMP2)). CGRP8-37 (10 microM) resembled AM22-52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent pA2 values: 7.04+/-0.13 (hCL/hRAMP2), 6.72+/-0.06 (Rat2), 7.03+/-0.12 (L6)). On CL/RAMP3 receptors, 10 microM CGRP8-37 was an effective antagonist at all combinations (apparent pA2 values: 6.96+/-0.08 (hCL/hRAMP3), 6.18+/-0.18 (rCL/rRAMP3), 6.48+/-0.20 (rCL/hRAMP3)). However, 10 microM AM22-52 only antagonised AM at the hCL/hRAMP3 receptor (apparent pA2 6.73+/-0.14). BIBN4096BS (10 microM) did not antagonise AM at any of the receptors. Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/RAMP3 receptor was AM approximately betaCGRP>alphaCGRP. rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. This study shows that on CL/RAMP complexes, AM22-52 has significant selectivity for the CL/RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP8-37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.

Adrenomedullin↗
PubMed2003

Effect of heat on phycoerythrin fluorescence: Influence of thermal exposure on the fluorescence emission of R-phycoerythrin.

The goal of this work was to measure and model the effect of thermal exposure on the fluorescence emission of R-phycoerythrin (R-PE). The long-term objective of our work is to assess the feasibility of encapsulating R-PE for use as the critical component of a time-temperature integrator (TTI) for ascertaining the degree of inactivation of food pathogens such as Salmonella. In this article we present a study to measure and model the thermally induced fluorescence emission decay of R-PE in several isothermal experiments. We used the isothermal data to determine the kinetic parameters, based on a general n(th) order reaction, and evaluated the utility of the resulting model by using it to predict R-PE fluorescence emission decay for several nonisothermal experiments based on published USDA safe harbor guidelines for cooked beef products. The transient experiments were conducted over the same temperature range used in the isothermal study. Very good agreement was obtained between theory and experiment at temperatures of 62.8 degrees C and above, although the model slightly underpredicted the extent of fluorescence emission decay at 60 degrees C. Our results indicate that R-PE fluorescence emission decay kinetics is well behaved and that the protein is a strong candidate for use as a time-temperature integrator.

Biosensing Techniques↗
PubMed2003

gamma-MSH increases intracellular cAMP accumulation and GnRH release in vitro and LH release in vivo.

The roles of the melanocortin 3 receptor (MC3-R) and its agonist, gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis are poorly understood. Here we show gamma(2)-MSH stimulated intracellular cAMP accumulation and gonadotrophin-releasing hormone (GnRH) secretion in the immortalised GnRH cell line GT(1)-7. The MC3/4-R antagonist Agrp blocked these actions. Reverse transcriptase polymerase chain reaction demonstrated GT(1)-7 cells express MC3-R mRNA. gamma(2)-MSH also stimulated GnRH release from hypothalamic explants. In vivo, gamma(2)-MSH administration into the medial preoptic area significantly increased plasma luteinising hormone. MC3-R and gamma(2)-MSH may modulate the HPG axis.

Animals↗
PubMed2003

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence.

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Adaptive responses in human glioma cells assessed by clonogenic survival and DNA strand break analysis.

PURPOSE: Human gliomas are known to be radioresistant and the aim was to determine if this resistance in part could be due to an adaptive response. MATERIALS AND METHODS: Human U-87MG glioma cells were used. Three different radiation regimens that could be related to clinical treatments were tested for their ability to cause an adaptive response. Cell survival and DNA double-strand breakage were the measured endpoints. RESULTS: All three regimens caused an adaptive response in terms of cell survival when given priming doses of radiation. The DNA double-strand break endpoint also showed fewer breaks when the adaptive response occurred. CONCLUSIONS: Using irradiation regimens that closely resembled clinical applications, in vitro data are presented that show an adaptive response in human glioma cells. This effect in part could be responsible for the radioresistance of human gliomas.

Adaptation, Physiological↗
PubMed2002

Effects of intracerebroventricular injection of glucagon like peptide-1 and its related peptides on serotonin metabolism and on levels of amino acids in the rat hypothalamus.

High concentrations of glucagon-like peptide-1 (7-36) amide (GLP-1) and its specific receptor (GLP-1R) have been found in the rat hypothalamus. In this study the actions of GLP-1 and its related peptides, exendin-4 (GLP-1R agonist), exendin (9-39) (GLP-1R antagonist) and GLP-1 (9-36) amide (the major GLP-1 metabolite) on levels of serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA) and amino acids (Glu, Asp, Gln, Gly, Tyr, Trp, GABA) in the hypothalamus were investigated. Intracerebroventricular (ICV) injection of GLP-1 (4 nmol) produced a significant reduction in levels of 5-HT (54%) and all measured amino acids (34 to 56%) compared with saline injected controls, whereas exendin (9-39) (4 nmol) was ineffective. ICV injection of exendin-4 produced a significant reduction in the levels of 5-HT, 5-HIAA, Trp, Glu, and Tyr. ICV injection of GLP-1(9-36) amide showed a statistically significant increase in the level of 5-HT, 5-HIAA and all the amino acids tested in this study. Prior administration of exendin (9-39) or GLP-1 (9-36) amide blocked the effects of GLP-1 on the levels of 5-HT and the amino acids. These data are consistent with exendin-4 being a GLP-1R agonist and exendin (9-39) being a specific GLP-1R antagonist. GLP-1 (9-36) amide, a primary metabolite of GLP-1, appears to act as an endogenous antagonist at the GLP-1R.

Animals↗
PubMed2002

Adrenomedullin: receptor and signal transduction.

Adrenomedullin is a vascular tissue peptide and a member of the calcitonin family of peptides, which includes calcitonin, calcitonin-gene-related peptide (CGRP) and amylin. Its many biological actions are mediated via CGRP type 1 (CGRP(1)) receptors and by specific adrenomedullin receptors. Although the pharmacology of these receptors is distinct, they are both represented in molecular terms by the type II family G-protein-coupled receptor, calcitonin-receptor-like receptor (CRLR). The specificity here is defined by co-expression of receptor-activity-modifying proteins (RAMPs). CGRP(1) receptors are represented by CRLR and RAMP1, and specific adrenomedullin receptors by CRLR and RAMP2 or 3. Here we discuss how CRLR/RAMP2 relates to adrenomedullin binding, pharmacology and pathophysiology, and how chemical cross-linking of receptor-ligand complexes in tissue relates to that in CRLR/RAMP2-expressing cells. CRLR, like other type II family G-protein-coupled receptors, signals via G(s) and adenylate cyclase activation. We demonstrated that adrenomedullin signalling in cell lines expressing specific adrenomedullin receptors followed this expected pattern.

Adrenomedullin↗
PubMed2002

Interaction of calcitonin-gene-related peptide with its receptors.

The receptor for calcitonin-gene-related peptide (CGRP) is a heterodimer formed by calcitonin-receptor-like receptor (CRLR), a type II (family B) G-protein-coupled receptor, and receptor-activity-modifying protein 1 (RAMP1), a single-membrane-pass protein. It is likely that the first seven or so amino acids of CGRP (which form a disulphide-bonded loop) interact with the transmembrane domain of CRLR to cause receptor activation. The rest of the CGRP molecule falls into three domains. Residues 28-37 and 8-18 are normally required for high-affinity binding, while residues 19-27 form a hinge region. The 28-37 region is almost certainly in direct contact with the receptor; 8-18 may make additional receptor contacts or may stabilize an appropriate conformation of 28-37. It is likely that these regions of CGRP interact both with CRLR and with the extracellular domain of RAMP1.

Animals↗
PubMed2002

Effects of melanocortin receptor ligands on thyrotropin-releasing hormone release: evidence for the differential roles of melanocortin 3 and 4 receptors.

The hypothalamic melanocortin system is important in the central regulation of food intake and body weight. We have previously demonstrated that intracerebroventricular administration of alpha-melanocyte stimulating hormone (alpha-MSH), a nonselective MC3 and MC4 receptor agonist, stimulated plasma thyroid-stimulating hormone, and agouti-related protein (AgRP), an MC3 and MC4 receptor antagonist, suppressed it. In this study, we investigated the effects of MC3 and MC4 receptor (MC3-R and MC4-R) selective agonists and antagonists on the release of thyrotropin-releasing hormone (TRH) from hypothalamic explants in vitro. alpha-MSH stimulated TRH release from the rat hypothalamic explants (alpha-MSH 100 nm 230 +/- 22.9% basal, P < 0.005). In contrast, gamma 2-MSH, a selective MC3-R agonist, suppressed TRH release (gamma 2-MSH 10 microns 76.2 +/- 7.4% basal, P < 0.05). AgRP (83-132), a nonselective MC3/4-R antagonist, induced no change in TRH release whilst JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH 11-22), a selective MC4-R antagonist, suppressed it (JKC-363 10 nm 57.2 +/- 11.5% basal, P < 0.05). Both AgRP (83-132) and JKC-363 blocked alpha-MSH stimulated TRH release but only AgRP (83-132) blocked the inhibitory effect of gamma 2-MSH on TRH release. These data suggest differential roles for the MC3 and MC4 receptors in TRH release; MC3-R agonism inhibiting and MC4-R agonism stimulating TRH release.

Agouti-Related Protein↗
PubMed2002

Moniliformin in barley inoculated with Fusarium avenaceum.

To assess production of the mycotoxin moniliformin, inoculation trials with four barley cultivars and local isolates of Fusarium avenaceum were performed at two different experimental farms in southern Manitoba, Canada, during 1997-99. In the 1997 study, moniliformin was detected in 11 of 16 barley rows at levels between 0.19 and 1.62 mg g(-1), and F. avenaceum infection ranged from 10 to 57% in rows where the toxin was detected. In the 1998 study, moniliformin was detected in only three of 16 barley rows, with levels between 0.06 and 0.43 micro g g(-1), and F. avenaceum infection between 16 and 39%. In the 1999 study, moniliformin was detected in 11 of 16 barley rows with levels between 0.09 and 0.42 micro g g(-1), and F. avenaceum infection between 37 and 76%. In the 1997 trial, moniliformin was found in a single water-inoculated control row at 0.15 micro g g(-1). The data suggest that in years of high rainfall and F. avenaceum infection, moniliformin is likely to be found in Manitoba barley.

Cyclobutanes↗
PubMed2002

Can mandibular advancement devices be a satisfactory substitute for short term use in patients on nasal continuous positive airway pressure?

BACKGROUND: Mandibular advancement devices (MADs) can successfully control both snoring and obstructive sleep apnoea (OSA). Many patients on nasal continuous positive airway pressure (NCPAP) for OSA would like a more portable alternative, even if only temporarily. This study assesses what proportion of patients with OSA already on NCPAP can successfully use a MAD for short periods (up to 1 month) as a temporary alternative to NCPAP. METHODS: Fifty patients with OSA, already on NCPAP for at least 3 months, were recruited by invitation. They were provided with a simple fixed MAD estimated to provide 75% of maximum mandibular protrusion. Sleep studies using a portable home recorder were performed on and after three nights without NCPAP to provide control data. Following acclimatisation to the MAD, sleep studies were also planned after 3, 7, and 28 days while using the MAD. If their overnight >4% SaO(2) dips per hour deteriorated to >20 or the Epworth sleepiness score (ESS) rose to >9 (or increased by >4 over baseline) on nights 3 or 7, they were then deemed to have failed the trial and were withdrawn. RESULTS: Of the 50 patients entered, one had inadequate teeth for a MAD and 31 gave up trying to use the device during the acclimatisation period because of side effects. Of the 18 prepared to use the device, two patients failed at night 3, five at night 7, and two at night 28. Thus, nine patients remained controlled by our criteria at night 28. On average, sleep study indices while using the MAD were poor compared with the night on NCPAP. CONCLUSIONS: Simple MADs are poorly tolerated by patients with OSA already on NCPAP. OSA was adequately controlled by our criteria in 32% of those recruited for the equivalent of a weekend, in 22% for 1 week, and in 18% for up to 1 month. Better tolerated devices would be likely to improve on these figures.

Heart Rate↗
PubMed2002

Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic resonance imaging study.

BACKGROUND: It is not clear how far brain abnormalities in early-onset schizophrenia result from progressive neurodevelopmental or neurodegenerative processes. Aims To investigate the hypothesis that structural brain abnormalities in adolescent-onset schizophrenia are progressive in the early phase of the illness. METHOD: A magnetic resonance imaging case-control study of 16 adolescents with schizophrenia (mean age 16.6 years, s.d.=1.9 years) with a mean time of 2.7 years (s.d.=1.7 years) between measurements and 16 matched controls (average age 16.0 years, s.d.=2.0 years) with a mean time of 1.7 years (s.d.=0.5 years) between measurements. RESULTS: There was no evidence of progressive structural brain changes during late adolescence. Significant ventricular enlargement (greater in males) and left-sided temporal lobe changes were evident from the outset of the illness. CONCLUSIONS: Neurodevelopmental brain abnormalities are non-progressive during late adolescence.

Adolescent↗
PubMed2002

Time-dependent effects of maternal continuous propranolol on fetal lung development in rats.

Previous studies have demonstrated a role for the beta-adrenergic system in the maturation of the fetal alveolar epithelium. Chronic blockade of beta-adrenergic binding sites has been shown to adversely effect physiologic and biochemical indices of fetal lung maturation. In the present study timed-pregnant female Sprague-Dawley rats were treated with a continuous 0.5 mg/hr dose of propranolol HCl, or saline, via an osmotic pump. The treatment periods were days 18-21, or 20-23 of gestation. Fetal body weights were obtained, and the morphology of the fetal lungs studied by light and electron microscopy. Cytoplasmic volume densities of lamellar inclusion bodies and glycogen within developing type II alveolar epithelial cells were also determined. In addition, total phospholipids (as phosphorus) and glycogen content were determined biochemically. The fetuses from females treated from day 20-23 demonstrated no differences between saline-treated and propranolol-treated groups, in either fetal weight or the morphologic appearance of the developing lung. In contrast, the fetuses from mothers treated from day 18-21 with propranolol were significantly smaller, and their lungs appeared less mature than saline-treated counterparts. The glycogen content of developing type II alveolar epithelial cells was significantly more abundant (as judged by stereologic and biochemical analyses) in the propranolol-treated fetuses. In addition, total phospholipids were decreased in the propranolol-treated 21-day fetuses. The results of the present study suggest that the development of the alveolar epithelium is sensitive to continuous beta-adrenergic blockade by propranolol during a critical time late in gestation.

Adrenergic beta-Antagonists↗
PubMed2002

R-phycoerythrin as a time-temperature integrator to verify the thermal processing adequacy of beef patties.

The objective of this study was to relate R-phycoerythrin (PE) fluorescence decay to the inactivation of Salmonella in beef patties cooked using adequate and inadequate thermal processes as defined by the U.S. Department of Agriculture (USDA) safe harbor requirements and lethality standards. Ground beef containing 4.8 or 19.1% fat was inoculated with an eight-strain cocktail of Salmonella and formed into 113-g patties. Capillary tubes containing PE in borate buffer at pH 9.0 were attached to a thermocouple and inserted horizontally into the patties. Patties (n = 43) were cooked on a grill maintained at 177 degrees C for 6 to 13 min and reached internal temperatures ranging from 57 to 77 degrees C. Patties were analyzed for Salmonella survivors and for fluorescence decay of PE. The thermal lethality of each process was calculated at a reference temperature of 65 degrees C. Twenty-four of the 43 high-fat patties met the USDA safe harbor regulations, with thermal lethalities of >66 s, whereas only 20 of these patties met the proposed 5-log10 lethality standard. Three of the 20 low-fat patties that met USDA regulations did not meet the proposed lethality standard. A normalized PE fluorescence value of about 0.3 (confidence interval = 99%) indicated that patties had been processed sufficiently to reduce Salmonella by 5 log10 cycles. PE has the potential for use as a marker to verify processing adequacy in food-processing plants and in other settings in which the use of the target pathogen is inappropriate.

Animals↗
PubMed2001

The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) blocks vasodilatation in inflamed rat skin: involvement of adrenomedullin in addition to CGRP.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent microvascular vasodilator in rat skin and effects are antagonised by CGRP(8-37). In this study, CGRP(8-37) significantly (P<0.05) inhibited the time-dependent (3-5 h) increase in skin blood flow measured in the anaesthetised rat, after intradermal administration of the inflammatory cytokine interleukin-1beta (3 pmol/site), indicating the involvement of CGRP1 receptors. The CGRP-related peptide adrenomedullin (ADM) is also a potent vasodilator in rat skin, with effects antagonised by CGRP(8-37). We show that ADM mRNA expression is increased in rat skin after treatment with IL-1beta and that the IL-1beta-induced blood flow is blocked by a selective ADM antibody (P<0.05). Thus ADM is expressed locally in the inflamed cutaneous microvasculature where it can, in addition to, or as an alternative to CGRP, contribute to IL-1beta-induced vasoactive effects.

Adrenomedullin↗