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Biomedical subjects

J M Stewart

Publications and source records attributed to J M Stewart.

At least 55 records · Page 3Linked to original sources
PubMed1999

Attention is needed to the high prevalence of vitamin D deficiency in our older population.

The aim of this study was to assess the prevalence of vitamin D deficiency in females residing in one large, aged-care facility in Auckland. Thirty-nine residents, most of whom were able to go outdoors without assistance, were tested for midwinter 25-hydroxyvitamin D, and, of these, 36 were tested again in midsummer. The prevalence of frank hypovitaminosis (<10 microg/L) was found to be 49% in midwinter and 33% in midsummer. The vitamin D status of such at-risk individuals could be normalised either by 15-30 minutes of daily sun exposure or, alternatively, a programme of supplementation.

Aged↗
PubMed1999

Declining CD4+ T-lymphocyte counts are associated with increased risk of enteric parasitosis and chronic diarrhea: results of a 3-year longitudinal study.

From January 1991 through September 1994, we observed people who were infected with HIV to assess the impact of enteric parasite-associated diarrhea. Respondents answered comprehensive questionnaires covering clinical and epidemiologic information and provided stool specimens monthly, which were examined unstained as well as stained with trichrome, chromotrope 2R, and with Kinyoun carbol-fuchsin, and with indirect immunofluorescence for Cryptosporidium. In all, 602 participants, who were interviewed, provided stool specimens at 3254 monthly visits. Parasites were associated with 50 of 354 (14.1%) acute diarrheal episodes (lasting < or = 28 days) and with 97 of 279 (34.8%) chronic episodes (lasting > 28 days). A parasite was associated with 31 of 222 (14.0%) episodes that occurred when CD4+ counts were > or = 200 cells/microl and with 150 of 566 (26.5%) episodes that occurred when CD4+ counts were < 200 cells/microl. The most commonly identified parasite was C. parvum, which was associated with 18 of 354 (5.1%) acute episodes and 36 (12.9%) of the 279 chronic episodes of diarrhea. In this patient population, enteric protozoan parasites were commonly associated with illness, particularly as immunosuppression worsened, and were more likely to be associated with chronic rather than acute diarrhea.

AIDS-Related Opportunistic Infections↗
PubMed1999

An nmr conformational analysis of a synthetic peptide Cn2(1-15)NH2-S-S-acetyl-Cn2(52-66)NH2 from the New World Centruroides noxius 2 (Cn2) scorpion toxin: comparison of the structure with those of the Centruroides scorpion toxins.

The solution structure of a synthetic peptide, Cn2(1-15)NH2-S-S-acetyl-Cn2(52-66)NH2 from toxin 2 (Cn2) of the New World scorpion Centruroides noxius was determined using nmr and molecular dynamics calculations. The peptide has no significant secondary structure such as an alpha-helix or a beta-sheet, yet it has a fixed conformation for the first chain. The backbone secondary structure involving residues 6-12 in this peptide shows an excellent overlap with the structures of natural neurotoxins from Centruroides sculpturatus Ewing. Residues 6-9 form a distorted type I beta-turn and residues 10-12 form a gamma-turn. As residues 7-10 in the Centruroides toxins correspond to one of the regions of highest sequence variability, it may account for the species specificity and/or selectivity of toxic action. The conformation of this region evidently plays an important role in receptor recognition and in binding to the neutralizing monoclonal antibody BCF2 raised against the intact toxin.

Amino Acid Sequence↗
PubMed1999

Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue.

OBJECTIVES: To describe the orthostatic tachycardia syndrome (OTS) in adolescents, similarities to and differences from chronic fatigue syndrome (CFS), and patterns of orthostatic intolerance during head-up tilt (HUT). STUDY DESIGN: Using electrocardiography and arterial tonometry, we investigated the heart rate and blood pressure responses during HUT in 20 adolescents with OTS compared with 25 adolescents with CFS, 13 healthy control subjects, and 20 patients with simple faint. RESULTS: Of the control subjects, 4 of 13 experienced typical vasovagal faints with an abrupt fall in blood pressure and heart rate, and 14 of 20 patients with simple faint experienced similar HUT responses. All patients with CFS (25/25) experienced severe orthostatic symptoms with syncope in 2 of 25, early orthostatic tachycardia during HUT in 16 of 23 (13/16 hypotensive), and delayed orthostatic tachycardia in 7 of 23 (6/7 hypotensive). Acrocyanosis and edema occurred in 18 of 25. Early orthostatic tachycardia occurred in 10 of 20 patients with OTS. Of these, 9 of 10 were hypotensive, but hypotension was delayed in 4 of 9. Delayed tachycardia occurred in 10 of 20 (all hypotensive). Acrocyanosis and edema occurred in most patients with CFS, fewer patients with OTS, and in one patient with simple faint. Orthostatic symptoms were similar but more severe in patients with CFS compared with patients with OTS. CONCLUSIONS: Symptoms and patterns of orthostatic heart rate and blood pressure change in OTS overlap strongly with those of CFS. Orthostatic intolerance in OTS may represent an attenuated form of chronic fatigue pathophysiology.

Adolescent↗
PubMed1999

Bradykinin antagonists: present progress and future prospects.

Bradykinin (BK) antagonist peptides have been powerful tools for delineating roles of kinins in both normal and pathological physiology and offer promise of drug development for a variety of inflammatory conditions and cancers. At the present time, potent peptide antagonists are available that are either specific for BK B1 or B2 receptors, or are effective on both receptor classes. Non-peptide BK B2 antagonists are now being announced and are under investigation in several companies. The best peptide B1-B2 peptide antagonist is stable against all kininases, is orally available, and has a very long lifetime in vivo. Certain dimers of this antagonist, as well as several smaller molecules, are active against several cancers, both in vitro and in vivo.

Amino Acid Sequence↗
PubMed1999

Cyclic and linear bradykinin analogues: implications for B2 antagonist design.

Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism, and a D-directed side chain is crucial for antagonism. For residue-1 an L-orientation is important, and Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue-5, led to improved pA2.

Animals↗
PubMed1999

Mapping of an epitope recognized by a neutralizing monoclonal antibody specific to toxin Cn2 from the scorpion Centruroides noxius, using discontinuous synthetic peptides.

The Na+-channel-affecting toxin Cn2 represents the major and one of the most toxic components of the venom of the Mexican scorpion Centruroides noxius Hoffmann. A monoclonal antibody BCF2 raised against Cn2 has been shown previously to be able to neutralize the toxic effect of Cn2 and of the whole venom of C. noxius. In the present study the epitope was mapped to a surface region comprising the N- and C-terminal segments of Cn2, using continuous and discontinuous synthetic peptides, designed on the basis of the sequence and a three-dimensional model of Cn2. The study of peptides of varying length resulted in the identification of segments 5-14 and 56-65 containing residues essential for recognition by BCF2. The peptide (abbreviated SP7) with the highest affinity to BCF2 (IC50 = 5.1 microM) was a synthetic heterodimer comprising the amino acid sequence from position 3-15 (amidated) of Cn2, bridged by disulfide to peptide from position 54-66, acetylated and amidated. Similar affinity was found with peptide SP1 [heterodimer comprising residues 1-14 (amidated) of Cn2, bridged with synthetic peptide 52-66 (acetylated)]. SP1 and SP7 were used to induce anti-peptide antibodies in mouse and rabbit. Both peptides were highly immunogenic. The sera obtained were able to recognize Cn2 and to neutralize Cn2 in vitro. The most efficient protection (8.3 microgram Cn2 neutralized per mL of serum) was induced by rabbit anti-SP1 serum.

Amino Acid Sequence↗
PubMed1999

Orthostatic intolerance in adolescent chronic fatigue syndrome.

OBJECTIVES: To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children. STUDY DESIGN: We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age. RESULTS: A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings. CONCLUSIONS: We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.

Adolescent↗
PubMed1998

Fatty acid binding to rat liver fatty acid-binding protein is modulated by early glycolytic intermediates.

Fatty acid binding to rat liver fatty acid binding protein in the presence of glycolytic metabolites and at different pH (optimal 7.2) and ionic strength was studied. Binding decreased logarithmically with ionic strength. Glucose and glucose-6-phosphate increased fatty acid binding significantly with K0.5 within physiological ranges while glucose-1-phosphate and phosphate ion caused no effect.

Animals↗
PubMed1998

Update on adjuvant treatment of colorectal cancer.

Developments in the adjuvant therapy of colorectal cancer have been reported recently. Important questions regarding the most appropriate regimen, the optimal duration of treatment, the preferred route of administration, and which subgroups are most likely to benefit are addressed. A number of studies in rectal cancer considered the timing of chemoradiation, mode of administration of chemotherapy, and the role of intraoperative radiotherapy. Quality of life issues also are being addressed. Several new agents and novel therapies have produced interesting and, it is hoped, clinically useful results. The prognostic significance of a number of molecular markers also is the subject of ongoing research.

Chemotherapy, Adjuvant↗
PubMed1998

Exercise reduces epicardial coronary artery wall stiffness: roles of cGMP and cAMP.

OBJECTIVE: Exercise enhances the dilation of the epicardial coronary arteries by vasodilator drugs and blood flow. Our goal was to determine whether coronary artery elastic properties were affected by brief exercise training. METHODS: Arterial pressure and left circumflex coronary artery diameter were measured in dogs. Venous bolus injections of acetylcholine 5 microg x kg(-1) (ACH) and nitroglycerin 25 microg x kg(-1) (NTG) or infusions of adenosine 0.5 microM/kg/min (ADO) were given. Fifteen-second coronary artery occlusions were performed. Dogs exercised 2 h x d(-1) for 7 d at 10.9 km x h(-1). Experiments were repeated. Pressure and coronary radius data were used to calculate vessel wall stress and incremental wall modulus, Einc. RESULTS: Baseline Einc and radius were not changed by exercise. Before exercise Einc increased similarly from baseline for all vasodilators. After exercise, the increase in Einc with ADO was unchanged. However, the increase was attenuated during ACH, abolished with occlusion, and reversed with NTG despite enhanced dilation. CONCLUSION: Data suggest that functional remodeling of epicardial arteries begins soon after starting exercise training, before changes in resting vessel diameter, is mediated by cGMP, and contributes to increased vascular dilation. Brief exercise training enhances the vasodilating capability and elastic properties of large coronary arteries.

Acetylcholine↗
PubMed1998

The effects of nebulised isotonic saline and terbutaline on breathlessness in severe chronic obstructive pulmonary disease (COPD).

BACKGROUND: There is anecdotal evidence that nebulised saline relieves breathlessness at rest in patients with severe chronic obstructive pulmonary disease (COPD). It is unclear whether nebulised beta agonists are any more effective than nebulised saline in relieving breathlessness at rest in these individuals. AIM: To compare the effects of nebulised saline and nebulised terbutaline on breathlessness at rest in patients with severe COPD. METHODS: We studied 18 patients with severe COPD with a mean age of 71.1 years, forced expiratory volume in 1 second (FEV1) of 0.58 L and vital capacity (VC) of 1.59 L, in a randomised, double-blind, crossover trial. The subjects received three doses of nebulised saline on one study day, and three doses of nebulised terbutaline (cumulative dose 10 mg) on the other. Breathlessness was measured using Likert and Visual Analogue Scales (VAS). RESULTS: Both treatments led to a significant improvement in breathlessness on VAS and Likert scales but there was no significant difference in breathlessness scores for saline compared with terbutaline. There was a small but significant increase in FEV1 with terbutaline of 74 mL, but no change with saline. CONCLUSIONS: A saline aerosol has no effect on lung function but reduces breathlessness at rest in subjects with severe COPD. Nebulised saline may be considered as an adjunct to the use of nebulised bronchodilators for the treatment of breathlessness in patients with COPD.

Adrenergic beta-Agonists↗
PubMed1998

NMR and CD conformational studies of bradykinin and its agonists and antagonists: application to receptor binding.

Most physiological processes are regulated by peptides that perform their functions by interacting with specific receptors on cells. Specific conformations of the peptides are required for correct interactions to take place, and a knowledge of the biologically important conformation is vital for the understanding of biological function. Over the last few years extensive studies using nuclear magnetic resonance and circular dichroism have been carried out on bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) and its antagonists with the objective of developing new drugs to combat severe pathologies associated with its production. In the present review, these techniques for the determination of peptide conformation are reviewed and applied to the study of bradykinin and its antagonists. Modeling of these conformational data in the presence of the B2 receptor or an antibody allows the biologically active conformations to be deduced and these are presented in this review.

Amino Acid Substitution↗
PubMed1998

Comparisons of the effects of temperature on the liver fatty acid binding proteins from hibernator and nonhibernator mammals.

Hibernating mammals rely heavily on lipid metabolism to supply energy during hibernation. We wondered if the fatty acid binding protein from a hibernator responded to temperature differently than that from a nonhibernator. We found that the Kd for oleate of the liver fatty acid binding protein (1.5 microM) isolated from ground squirrel (Spermophilus richardsonii) was temperature insensitive over 5-37 degrees C, while the rat liver fatty acid binding protein was affected with the Kd at 37 degrees C being about half (0.8 microM) that found at lower temperatures. This same trend was observed when comparing the specificity of various fatty acids of differing chain length and degree of unsaturation for the two proteins at 5 and 37 degrees C. At the lower temperature, ground squirrel protein bound long-chain unsaturated fatty acids, particularly linoleate and linolenate, at least as well as at the higher temperature and matched requirements for these fatty acids in the diet. The most common long-chain fatty acid, palmitate, was a more effective ligand for ground squirrel liver fatty acid binding protein at 5 degrees C than at 37 degrees C, with the opposite occurring in the eutherm. Rat protein was clearly not adapted to function optimally at temperatures lower than the animal's body temperature.

Animals↗
PubMed1998

Cytokine and matrix metalloproteinase expression in pigmented villonodular synovitis may mediate bone and cartilage destruction.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is characterized by hypervascular proliferative synovium containing multinucleated giant cells, macrophages, and hemosiderin. The destruction of articular cartilage and erosion of periarticular bone is thought to be mediated by matrix metalloproteinases (MMPs). Expression of MMPs in some tumors appears to be stimulated through local production of cytokines, and several specific cytokines (TNF alpha, IL-1, and IL-6) play an important role in the stimulation of osteoclastic bone resorption. The role of cytokine secretion and regulation of MMP production in PVNS has not been investigated. DESIGN: In the present study, ten specimens from eight patients (ages 19 to 80) were evaluated histologically according to a modified Mirra classification and immunohistochemically (IHC) for the expression of MMP-9 (92 kDa gelatinase B), tumor necrosis factor alpha (TNF alpha), interleukin 1-beta (IL-1 beta), and interleukin 6 (IL-6). Localization of IL-6 and TNF alpha production was confirmed by in situ hybridization (ISH) for mRNA. RESULTS: All specimens, regardless of location (six knees, one ankle, one subtalar joint), showed diffuse and intense immunoreactivity for cytokines in the giant cells and synovial cells, and less intense and diffuse staining in the activated macrophages. Staining in the fibroblastic elements was minimal. In situ hybridization for TNF alpha and IL-6 mRNA mirrored the immunohistochemistry results, although the IL-6 staining was weaker than that for TNF alpha. Immunoreactivity for MMP-9 was diffuse and strong in giant cells, diffuse and moderate in synovial cells, and focal and moderate to strong in macrophages. In contrast, normal synovium demonstrated focal, moderate immunoreactivity for IL-1 beta, IL-6, TNF alpha and MMP-9 localized in the synovial lining cells. CONCLUSION: These findings suggest that periarticular bone resorption and cartilage destruction which characterize PVNS may be related to the expression of inflammatory cytokines, which in turn stimulate MMP production.

Adult↗
PubMed1997

A comparative NMR and molecular dynamics study of the conformations of bradykinin B1 and B2, B2, and B1-specific receptor antagonists B-9430, B-9436, and B-9858.

Extensive proton magnetic resonance experiments were carried out on three bradykinin peptide antagonists B-9430, B-9436, and B-9858 in aqueous solutions as well as in sodium dodecylsulphate micelles (B-9430 and B-9436) and CD3OH/H2O (60%/40%) mixtures for B-9858. All three peptides showed no observable secondary structure in aqueous solution. However, in their respective structure-inducing solvents, B-9430 (B1 and B2 receptor antagonist) and B-9436 (a B2 receptor antagonist) exhibit a type II beta-turn involving residues 2-5, and B-9430 also exhibits a type II' beta-turn involving residues 6-9 (in sodium dodecylsulfate micellar solutions), whereas B-9858, a B1-specific receptor antagonist, exhibits only a type II beta-turn involving residues 2-5 (in CD3OH/H2O solutions). Simulated annealing calculations on B-9858 confirm the experimental conclusions based on the nmr data. In addition, simulated annealing of the (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic residue), which is present in two of the three decapeptides studied, show that the one-chair conformation of the six-membered ring predominates, in agreement with the experimental data. The activities of these peptides are compared with their secondary structures and the specific receptor activity appears to depend on the presence of specific amino acid residues, such as N-(2-indanyl) glycine (Nig) and D[alpha-(2-indanyl) glycine] (D-Igl) as well as on elements of secondary structure.

Amino Acid Sequence↗
PubMed1997

Bradykinin antagonists in human systems: correlation between receptor binding, calcium signalling in isolated cells, and functional activity in isolated ileum.

The determination of the relationship between ligand affinity and bioactivity is important for the understanding of receptor function in biological systems and for drug development. Several physiological and pathophysiological functions of bradykinin (BK) are mediated via the B2 receptor. In this study, we have examined the relationship between B2 receptor (soluble and membrane-bound) binding of BK peptidic antagonists, inhibition of calcium signalling at a cellular level, and in vitro inhibition of ileum contraction. Only human systems were employed in the experiments. Good correlations between the studied activities of BK antagonists were observed for a variety of different peptidic structures. The correlation coefficients (r) were in the range of 0.905 to 0.955. In addition, we analyzed the effect of the C-terminal Arg9 removal from BK and its analogs on B2 receptor binding. The ratios of binding constants (Ki(+Arg)/Ki(-Arg)) for the Arg9 containing compounds and the corresponding des-Arg9 analogs varied from about 10 to 250,000. These ratios strongly depend on the chemical structures of the compounds. The highest ratios were observed for two natural agonist pairs, BK/des-Arg9-BK and Lys0-BK/des-Arg9-Lys0-BK.

Bradykinin↗