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Biomedical subjects

D Hunter

Publications and source records attributed to D Hunter.

At least 73 records · Page 4Linked to original sources
PubMed1999

A novel, biodegradable polymer conduit delivers neurotrophins and promotes nerve regeneration.

OBJECTIVE/HYPOTHESIS: A wide variety of substances have been shown to promote neuritic extension after nerve injury. An obstacle to achieving the maximal benefit from these substances has been the difficulty in effectively delivering the substances over a protracted time course that promotes maximal, directed growth. In this study the delivery of a growth-promoting substance through a biodegradable conduit, using materials originally designed for drug delivery applications, was hypothesized to promote more robust neural regeneration than through conduits lacking the substance. The objectives of this study were to create a growth factor-loaded biodegradable nerve guidance conduit, and to assess in vivo nerve regeneration through the conduit compared with that through conduits lacking the substance. MATERIALS/METHODS: Inosine, a purine analogue thought to promote axonal extension following neural injury, was loaded into cylindrical polymer foams composed of a polylactide-co-glycolide copolymer. First, in vitro extravasation of inosine was measured over a several week period using spectrophotometry. Second, the foams were fashioned into single-channel cylindrical nerve guidance conduits via a novel, low-pressure injection molding technique. The conduits were then used to bridge 7-mm defects in the rat sciatic nerve (n = 8). Control conduits lacking inosine were implanted into another set of animals as controls (n = 12). RESULTS: In vitro spectrophotometric measurements indicated appreciable leaching of inosine from the loaded foams over a period of at least 9 weeks. In the in vivo model, after 10 weeks, a higher percentage cross sectional area composed of neural tissue existed through the inosine-loaded conduits compared with controls (mean 44%, SD 7.5% vs. 36%, SD 8.6%, respectively). A difference was also found in mean fiber diameter between the two groups, with the inosine-loaded tubes showing a statistically significantly larger diameter than controls (P < .05). CONCLUSIONS: A nerve regeneration conduit was successfully created that delivers growth promoting substances over a protracted time course. In an in vivo model, the presence of inosine, a purine analogue, yielded neural regeneration whose histological features suggest possible superior long-term motor function.

Absorbable Implants↗
PubMed1998

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alphabeta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Animals↗
PubMed1998

Klippel-Trenaunay syndrome.

Patients with Klippel-Trenaunay (KT) syndrome have a complex constellation of anomalies that includes cutaneous capillary malformation (usually on an affected limb), abnormal development of the deep and superficial veins, and limb asymmetry, usually enlargement. Mixed vascular malformations may be present and include capillary, venous, arterial, and lymphatic systems. The records of 79 patients referred for vascular anomalies were reviewed and 49 were found to have the three "cardinal" anomalies of KT syndrome. Twenty-six females and 23 males had 46 affected legs (27 right legs), 23 affected arms (15 right), 21 affected trunks, and 10 affected heads. Thirty-six had only one affected quadrant, 8 had two, and 5 had three or more. Although 40 patients had increased limb girth, measurable length discrepancy was noted in only 17 individuals. Patients were evaluated using a noninvasive imaging strategy including color duplex ultrasonography, MRI, lymphoscintigraphy, and plain radiographs. Treatment included compression, pulsed-dye laser treatment, reduction of arteriovenous malformations, and orthopedic procedures for overgrowth. All KT cases in this series occurred sporadically. We speculate that KT syndromes may be due to a somatic mutation for a factor critical to vasculogenesis and angiogenesis in embryonic development.

Adolescent↗
PubMed1998

A calcium-dependent tyrosine kinase splice variant in human monocytes. Activation by a two-stage process involving adherence and a subsequent intracellular signal.

Freshly isolated human monocytes do not express p125(FAK) but upon adherence to substrata activate the highly related calcium-dependent tyrosine kinase (CADTK), also known as Pyk2, CAKbeta, RAFTK, and FAK2. The monocyte CADTK was 5 kDa smaller than protein from epithelial cells; isolation and sequencing of the monocyte CADTK cDNA revealed a predicted 42-amino acid deletion between the two proline-rich domains of the enzyme. The nucleic acid sequence suggests that the deletion is caused by alternative RNA splicing. This species was also found in T and B lymphocytes and appears to be the predominant form of cytoskeletal associated tyrosine kinase in non-neoplastic, circulating, hematopoietic cells. CADTK was not activated when monocytes maintained in suspension were treated with agents that produce an intracellular calcium (thapsigargin) or protein kinase C (phorbol 12-myristate 13-acetate) signal including a chemokine, RANTES, that binds to the HIV co-receptor, CCK5. In contrast, monocyte adherence to tissue culture plastic-stimulated CADTK tyrosine phosphorylation, a process that was enhanced by thapsigargin, phorbol 12-myristate 13-acetate, and RANTES but that was completely blocked by preincubation with cytochalasin D. When compared with plastic, adherence to fibronectin- or collagen-coated surfaces produced only minimal CADTK activation but permitted significant stimulation by added thapsigargin. These data suggest that in a cell type that lacks p125(FAK), CADTK plays an early role in post-adherence signaling. Its activation involves two stages, cytoskeletal engagement, which is permissive, and co-stimulatory signals (calcium or protein kinase C) generated by extensive cell surface engagement, agonists, or inflammatory chemokines.

Alternative Splicing↗
PubMed1998

Regulation of a calcium-dependent tyrosine kinase in vascular smooth muscle cells by angiotensin II and platelet-derived growth factor. Dependence on calcium and the actin cytoskeleton.

A novel, p125FAK homologue, CADTK, has been detected in neural, epithelial, or hematopoietic cells but not in fibroblasts. We now demonstrate CADTK expression in a mesenchymal cell, rat aortic smooth muscle cells (RSMC). Angiotensin II (Ang II) or platelet-derived growth factor (PDGF-BB and PDGF-AA) markedly stimulated CADTK tyrosine phosphorylation in RSMC but did not affect p125FAK phosphorylation. The PDGF-depedent CADTK tyrosine phosphorylation was slower and more prolonged than that of Ang II, correlating well with the differential effects of these agonists on cytosolic calcium ([Ca2+]i) signaling. An intracellular calcium chelator inhibited both the rapid and sustained activation of CADTK by Ang II and PDGF. Extracellular calcium chelation inhibited the PDGF-stimulated increase in CADTK tyrosine phosphorylation as well as the sustained (but not the early) activation by Ang II. In contrast, p125FAK tyrosine phosphorylation was maximal in quiescent, adherent RSMC and was not affected by incubation with EGTA. Depletion of protein kinase C activity partially inhibited both the Ang II- and PDGF-induced CADTK tyrosine phosphorylation. Additional results confirm a relation between CADTK and the cytoskeleton. First, the tyrosine phosphorylation of paxilin correlated with activation of CADTK; this increase was inhibited by EGTA. Second, cytochalasin D blocked the PDGF- or Ang II-stimulated tyrosine phosphorylation of CADTK, suggesting a role for the cytoskeleton in agonist-dependent CADTK activation. Third, immunofluorescence analysis of CADTK localization demonstrated actin-like cytoskeleton staining extending into focal contacts. These results suggest that in mesenchymal cells, CADTK is localized to and activated by an actin cytoskeleton-dependent mechanism; a mechanism that is regulated in a calcium and protein kinase C-dependent manner independently of p125FAK.

Angiotensin II↗
PubMed1998

A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer.

BACKGROUND: Animal studies suggest that monounsaturated and polyunsaturated fat may have opposite effects on the risk of breast cancer. METHODS: We performed a population-based prospective cohort study, including 61,471 women aged 40 to 76 years from 2 counties in central Sweden who did not have any previous diagnosis of cancer; 674 cases of invasive breast cancer occurred during an average follow-up of 4.2 years. All subjects answered a validated 67-item food frequency questionnaire at baseline. Cox proportional hazards models were used to obtain adjusted rate ratio (RR) estimates with 95% confidence intervals (CIs). RESULTS: After mutual adjustment of different types of fat, an inverse association with monounsaturated fat and a positive association with polyunsaturated fat were found. The RR for each 10-g increment in daily intake of monounsaturated fat was 0.45 (95% CI, 0.22-0.95), whereas the RR for a 5-g increment of polyunsaturated fat was 1.69 (95% CI, 1.02-2.78); the increments correspond to approximately 2 SDs of intake in the population. Comparing the highest quartile of intake with the lowest, we found an RR of 0.8 (95% CI, 0.5-1.2) for monounsaturated fat and 1.2 (95% CI, 0.9-1.6) for polyunsaturated fat. Saturated fat was not associated with the risk of breast cancer. CONCLUSIONS: Our results indicate that various types of fat may have specific opposite effects on the risk of breast cancer that closely resemble the corresponding effects in experimental animals. Research investigations and health policy considerations should take into account the emerging evidence that monounsaturated fat might be protective for risk of breast cancer.

Adult↗
PubMed1998

An alternative for women initially declining genetic amniocentesis: individual Down syndrome odds on the basis of maternal age and multiple ultrasonographic markers.

OBJECTIVE: Our purpose was to develop a method of calculating the individual odds of Down syndrome on the basis of a combination of maternal age and multiple ultrasonographic parameters that can be used to counsel women at high risk who initially decline amniocentesis. STUDY DESIGN: Maternal age and ultrasonographic biometry data were collected prospectively on 3254 normal and 30 Down syndrome singleton fetuses between 15 and 24 weeks' gestation. Humerus length data were expressed as multiples of the normal median. Log transformation of the humerus length data permitted their expression in gaussian frequency distributions and the calculation of likelihood ratios for Down syndrome on the basis of humerus length. We also developed likelihood ratios on the basis of the degree of nuchal skinfold thickening and the presence or absence of hyperechoic fetal bowel and hypoplastic fifth digit. RESULTS: The ultrasonographic parameters and maternal age did not significantly correlate with each other and were significant independent predictors of Down syndrome. We therefore calculated the individual odds of Down syndrome by using the product of the age-related risk and the likelihood ratios associated with nuchal thickening, humerus length shortening, and the presence or absence of hyperechoic fetal bowel or fifth digit hypoplasia, respectively. At a Down syndrome risk level of >1:50, a 60.0% detection rate with 4.5% false-positive rate was observed with a screen-positive rate of 5.5%, positive predictive value of 1:10, and odds ratio (95% confidence interval) of 28.4 (12.8 to 64.0). CONCLUSION: This is the first report of individual odds calculation based on multiple midtrimester biometry parameters and maternal age. The screening efficiency is similar to that reported with triple-analyte serum screening. These data are useful for counseling women who are at increased Down syndrome risk and initially decline amniocentesis.

Adult↗
PubMed1998

Effect of additional questions about fat on the validity of fat estimates from a food frequency questionnaire. Study Group of MRS SWEA.

OBJECTIVE: We studied whether the validity of fat estimates from food frequency questionnaires (FFQ) can be increased by using in nutrient calculation an additional qualitative information about the type of fat and reduced consumption of visible fat and skin. DESIGN: A random sample of women answered an 88-item self-administered FFQ and performed 4 x 1-week weighed dietary records (DR). SETTING: Uppsala County in central Sweden. SUBJECTS: One hundred and eighty-four women aged 30-77 y, with FFQ and complete DR; 73 women with subcutaneous adipose tissue (AT) samples. METHODS: Fat intake from the FFQ was calculated with/without use of qualitative information and compared to DR and fat composition of AT. MAIN OUTCOME MEASURES: Estimates of long-time intake of total fat, saturated, monounsaturated, polyunsaturated fat and ten specific fatty acids based on FFQ, DR and composition of AT. RESULTS: Mean absolute fat intake estimates based on FFQ (without vs with use of additional fat information) were 21.2 vs 20.2 g/d for saturated, 17.1 vs 16.0 g/d for monounsaturated and 7.3 vs 7.3 g/d for polyunsaturated fat. The Pearson correlation coefficient between the FFQ and AT for polyunsaturated fat was 0.65 vs 0.67. Corresponding correlation between the FFQ and DR was 0.40 vs 0.41; adjustment for energy intake increased this correlation from 0.40 to 0.52. CONCLUSIONS: The increase in the validity of fat estimates due to use of qualitative information about fat was negligible; energy adjustment had greater impact than asking additional questions.

Adipose Tissue↗
PubMed1998

Scanning laser Doppler flowmetry and intraluminal recirculating gas tonometry in the assessment of gastric and jejunal perfusion during oesophageal resection.

BACKGROUND: The ability of the new techniques of scanning laser Doppler flowmetry and recirculating gas tonometry to measure changes in gastric serosal and mucosal blood flow respectively during oesophageal resection was assessed. METHODS: Changes in regional and total gastric blood flow were assessed in 16 patients undergoing oesophagectomy at three stages of the procedure. Laser Doppler images were analysed and perfusion expressed as mean perfusion units. Tonometric measurements of gastric and jejunal intramucosal pH (pHi) were made synchronously. RESULTS: There were significant falls in gastric perfusion measured with scanning laser Doppler flowmetry in all subjects between each measurement. Mean perfusion of the stomach fell 41 per cent after mobilization. There was a gradient of reduced perfusion between the antrum (mean fall 25 per cent) and the area used for the anastomosis in the fundus (mean fall 55 per cent). Before mobilization mean gastric and jejunal pHi were 7.37 and 7.46 respectively. These fell to 7.18 and 7.37 respectively after mobilization and to 7.29 and 7.38 after anastomosis. CONCLUSION: These new techniques could be employed at operation, appear to overcome the limitations of single-point laser Doppler flowmetry and saline tonometry, and have measured significant changes in gastric perfusion. They may have widespread clinical application.

Adult↗
PubMed1998

[Real-time MRI with radial k-radial scanning technique for control of angiographic interventions].

PURPOSE: To test the feasibility of real-time MR controlled guidance of field-inhomogeneity catheters in vitro and in vivo as a first step to MR-guided angiographic interventions. METHODS: Applying a combination of radial scanning with the sliding window reconstruction technique, a frame rate of 23 low resolution images per second was achieved. Field inhomogeneity catheters were steered through a flow phantom and into the renal arteries of a pig. RESULTS: It was possible to visualize flow or, respectively, vessels and to depict catheter movements. This enabled real-time MR-guidance of the catheter into the renal arteries of the flow phantom and into those of the pig. CONCLUSIONS: The new technique yields a sufficiently high temporal resolution for MR-guidance of catheters through vessels.

Angiography↗
PubMed1998

Isolated iliac artery stenosis as a cause of kidney graft dysfunction post-transplant.

We report the case of a kidney transplant recipient who, 1 yr post-transplant, presented with a serum creatinine level elevation secondary to iliac artery stenosis proximal to the graft anastomosis site. Stenosis of the transplant renal artery was initially suspected because of new onset of hypertension in addition to the rising creatinine level. Physical examination, however, revealed a diminished femoral pulse and a significantly lower ankle-brachial index on the right (versus left) lower extremity; these findings suggested a stenosis of the right iliac artery. Angiography confirmed a short stenotic lesion of the external iliac artery just proximal to the graft anastomosis site. The lesion--given its focal nature, its location, and the absence of disease elsewhere in the peripheral vascular system--was most consistent with a vascular clamp injury. The stenosis was managed by placement of an intravascular stent at the time of angiography. This resulted in normalization of the vascular examination findings, return to baseline of the serum creatinine level, and resolution of hypertension. This case demonstrates the value of physical examination in diagnosing this uncommon cause of an increased serum creatinine level post-transplant and the effectiveness of intravascular stents for its management.

Arterial Occlusive Diseases↗
PubMed1997

An intracellular calcium signal activates p70 but not p90 ribosomal S6 kinase in liver epithelial cells.

In the rat liver epithelial cell lines GN4 and WB, angiotensin II (Ang II) activates the Gq class of regulatory G-proteins, increasing intracellular calcium, protein kinase C activity, and protein tyrosine phosphorylation. We compared the ability of Ang II and other compounds that increase intracellular calcium (i.e. the calcium ionophore A23187 and thapsigargin) or protein kinase C activity (the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) to activate p70 ribosomal S6 kinase (p70(S6K)) and p90 ribosomal S6 kinase (p90(RSK)). In GN4 cells, increasing intracellular calcium stimulated p70(S6K) activity in a rapamycin- and wortmannin- sensitive manner, but did not affect p90(RSK) activity. In contrast, 12-O-tetradecanoylphorbol-13-acetate strongly activated p90(RSK) but only weakly stimulated p70(S6K). The ability of calcium to activate p70(S6K) was confirmed by blocking the A23187-dependent activation through chelation of extracellular calcium with EGTA; the effect of thapsigargin was inhibited by the cell permeant chelator bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM). Similarly, BAPTA-AM prevented the activation of p70(S6K) by Ang II, suggesting that this signal was largely calcium-dependent. In contrast, the Ang II-dependent activation of mitogen-activated protein kinase and p90(RSK) was not inhibited but was enhanced by BAPTA-AM. These results show that in GN4 cells, Ang II selectively activates p70(S6K) through effects on calcium, p90(RSK) through effects on protein kinase C. The activation of p70(S6K) by calcium stimuli or Ang II was independent of calmodulin but correlated well with the activation of the recently identified, nonreceptor calcium-dependent tyrosine kinase (CADTK)/PYK-2. Both calcium- and Ang II-dependent activation of p70(S6K) were attenuated by the tyrosine kinase inhibitor genistein, and activation of p70(S6K) was higher in GN4 than WB cells, correlating with the increased expression and activation of CADTK/PYK-2 in GN4 cells. In summary, these results demonstrate that intracellular calcium selectively activates p70(S6K) in GN4 cells, consistent with increased CADTK/PYK-2 signaling in these cells.

Amino Acid Sequence↗
PubMed1997

Design considerations for small, special-system developmental databases

Small developmental databases, devoted to special systems and run by a normal research laboratory, differ qualitatively as well as quantitatively from larger databases described elsewhere in this volume. Resource limits set different optimum balances between computing elegance and ease of construction, while flexibility of design and semantics often assume greatest importance because specialist research databases are most useful when understanding of the biology is partial and still evolving. In this article we discuss the main considerations when building a small database-scope, access, data input, storage, searching and semantics-and illustrate them with examples of real working databases.Copyright 1997 Academic Press Limited Copyright 1997Academic Press Limited

Journal Article↗
PubMed1997

Nitric oxide production during exercise in chronic heart failure.

In chronic heart failure (CHF), the ventilatory response is increased compared with normal. This response is, in part, caused by reduced perfusion to ventilated lung. Nitric oxide (NO) is a potent vasodilator and may have an important role in pulmonary vasodilatation during exercise. NO is present in exhaled air. The amount of NO in exhaled air, when breathing NO-free compressed air, is known to increase in normal subjects during exercise. In this study, we quantified NO output in exhaled air in patients with CHF during exercise. Six patients with CHF (New York Heart Association Class II and III; two with dilated cardiomyopathy, three with ischemic heart disease, and one with hypertensive heart disease) and six normal subjects were studied with a symptom-limited incremental exercise test on a cycle ergometer. Oxygen uptake (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were measured breath by breath with a mass spectrometer, flow meter, and computer. The NO concentration was continuously measured in mixed expired air by chemiluminescence. Peak exercise work rate was lower in patients with CHF than in normal subjects (71.3 +/- 41.6 W vs 257.0 +/- 49.7 W; p < 0.01). Patients with CHF showed a higher VE/VCO2 level at peak exercise than normal subjects (CHF, 47.0 +/- 10.7; normal subjects, 35.6 +/- 5.2; p < 0.01). NO concentration of exhaled air at rest was lower in CHF patients than in normal subjects (4.0 +/- 2.2 ppb vs 10.5 +/- 6.2 ppb, respectively; p < 0.05). NO output from the respiratory tract (VNO) was significantly lower in patients with CHF compared with normal subjects at rest (45.3 +/- 24.3 nl/min, 117.5 +/- 60.1 nl/min, respectively, p < 0.05), and although it increased during exercise, it did not increase in patients with CHF as much as in normal subjects (75.3 +/- 43.4 nl/min vs 512.9 +/- 253.6 nl/min, respectively; p < 0.01). The increase above rest (exercise/rest) was smaller in patients with CHF than in normal subjects (2.10 +/- 1.92 vs 4.81 +/- 2.67, p < 0.05). These data support the concept that the smaller increase in NO production (VNO) during exercise may be responsible for a blunted vasodilation in patients with CHF, resulting in a smaller reduction in dead space/tidal volume and VE/VCO2 at the lactic acidosis threshold than normal. This finding may play a role in the abnormally high ventilatory response to exercise in patients with CHF.

Adult↗
PubMed1997

Ethical and social issues in the use of biomarkers in epidemiological research.

The use of biomarkers in epidemiological research may raise ethical and social issues. These issues stem from the belief that research participants have 'rights' to appropriate information before, during and after studies so that they can make informed decisions. Ethical issues can arise during protocol development, obtaining participation, and in the interpretation and notification of text and study results. Additionally, there are ethical considerations concerning the use of biological specimens collected and stored for one purpose and subsequently used for other research purposes. A major ethical issue is the maintenance of participants' privacy and the confidentiality of their test and study results. Ethics committees need to be well-informed about the scope, limitations and expectations of biomarker research in order to be able to respond to social and scientific developments in the use of biomarkers.

Biomarkers↗