Search PubMed⌕ Search

Biomedical subjects

G Fink

Publications and source records attributed to G Fink.

At least 55 records · Page 3Linked to original sources
PubMed1998

Ethene-Norbornene Copolymerization with Homogeneous Metallocene and Half-Sandwich Catalysts: Kinetics and Relationships between Catalyst Structure and Polymer Structure. 4. Development of Molecular Weights.

The molecular weights of ethene-norbornene copolymers, produced with various metallocene- and amidocyclopentadienyl-methylaluminoxane (MAO) catalysts, have been determined by high-temperature gel-permeation chromatography: with one exception, increasing molecular weights were found with an increasing norbornene content in the copolymer. This observation is due to the fact that the beta-hydride elimination process is not possible in the case of norbornene, because of special steric conditions of the cis-2,3-exo inserted norbornene; other possible termination reactions are discussed, considering the specialties of the norbornene. The effect of the catalyst structure on the molecular weights is discussed in terms of steric and electronic factors of the different ligands: sterically less hindered ligands produce ethene-norbornene copolymers with relatively low molecular weights; ligands with a larger extension and electron-pushing effect such as the fluorenyl ligand, induced the formation of high molecular weights. Additional alkyl groups at the indenyl or fluorenyl ligand increased the molecular weights additionally.

Journal Article↗
PubMed1998

Rhodopsin-family receptors associate with small G proteins to activate phospholipase D.

G-protein-coupled receptors of the rhodopsin family transduce many important neural and endocrine signals. These receptors activate heterotrimeric G proteins and in many cases also cause activation of phospholipase D, an enzyme that can be controlled by the small G proteins ARF and RhoA. Here we show that the activation of phospholipase D that is induced by many, but not all, Ca2+-mobilizing G-protein-coupled receptors is sensitive to inhibitors of ARF and of RhoA. Receptors of this type were co-immunoprecipitated with ARF or RhoA on exposure to agonists, and the effects of GTP analogues on ligand binding to the receptor changed to a profile that is characteristic of small G proteins. These receptors contain the amino-acid sequence AsnProXXTyr in their seventh transmembrane domain, whereas receptors capable of activating phospholipase D without involving ARF contain the sequence AspProXXTyr. Mutation of this latter sequence to AsnProXXTyr in the gonadotropin-releasing hormone receptor conferred sensitivity to an inhibitor of ARF, and the reciprocal mutation in the 5-HT2A receptor for 5-hydroxy-tryptamine reduced its sensitivity to the inhibitor. Receptors carrying the AsnProXXTyr motif thus seem to form functional complexes with ARF and RhoA.

ADP-Ribosylation Factors↗
PubMed1998

Significance of prominent atrial-wave and diastasis deflection in radionuclide diastolic volume curve during exercise in detection of coronary artery disease.

BACKGROUND: Exercise testing with multigated acquisition technetium radionuclide cineangiography (MUGA) is a useful modality that can discriminate systolic and diastolic performance in patients with ischemic heart disease. However, some patients may have abnormal left ventricular filling dynamics with normal regional and global systolic function. HYPOTHESIS: The purpose of the study was to assess exercise-induced diastolic dysfunction as expressed by a prominent atrial (A) wave or diastasis deflection at the left ventricular volume curve, in patients with different degrees of ischemic heart disease. METHODS: In all, 32 men and 7 women aged 35-70 years (mean 54 +/- 8.6 years) underwent MUGA at rest and during exercise for analysis of the radionuclide volume curve. Within 6 weeks, thallium-201 scintigraphy and coronary angiography were performed and the patients were categorized into three groups: (1) disease-free (n = 10), (2) single-vessel disease (> 50% stenosis) (n = 19), and (3) double-vessel disease or more (n = 10). A waves or diastasis deflections were compared among the groups. RESULTS: Significant differences (p < 0.01) were noted in A-wave deflection relative to peak diastolic volume curve during exercise (Aexe/T) between Group 1 and Groups 2 and 3. Group 1 manifested only a mild rise in A-wave deflection from rest (20.20 +/- 8.49%) to exercise (25.85 +/- 8.49%), whereas Groups 2 and 3 exhibited a significant increase from 25.89 +/- 9.55% and 28.40 +/- 12.6%, respectively, to 60.21 +/- 22.5% and 63.0 +/- 22.86%, respectively. Group 2 had a significantly (p < 0.05) higher maximal heart rate than Group 3. CONCLUSIONS: The addition of prominent A-wave or diastasis deflection to a normal systolic response during exercise testing with multigated radionuclide cineangiography might be a sensitive marker of coronary artery disease. The A wave represents diastolic dysfunction of the left ventricle, considered an early event in the ischemic cascade.

Adult↗
PubMed1998

TNF but not IL-1 decreases pancreatic acinar cell survival without affecting exocrine function: a study in the perfused human pancreas.

Substantial quantities of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are produced within the pancreatic parenchyma during acute pancreatitis. Recent evidence suggests that IL-1 beta and TNF-alpha propagate acute pancreatitis and intensify the resulting pancreatic acinar cell death. This study examines the direct effect of IL-1 beta and TNF-alpha on pancreatic acinar cells. Human pancreata (n = 6), harvested during organ procurement, were perfused ex vivo through the splenic artery using a sterile, oxygenated colloid solution. Each pancreas was perfused with either recombinant human IL-1 beta or TNF-alpha for 2 h and subsequently with the cholecystokinin analogue caerulein (positive control). Venous effluent was collected continuously and amylase and lipase were determined at 15-min intervals. Pancreatic histology was graded at baseline and following cytokine and caerulein perfusion. To examine the long-term effects of these cytokines on acinar cell viability, additional in vitro studies utilized the AR42J acinar cell line which was exposed to either IL-1 beta or TNF-alpha with survival determined daily by MTT assay. Perfusion of the human pancreas with either IL-1 beta or TNF-alpha did not alter amylase, lipase, or histology. Caerulein did induce pancreatitis as measured by increased amylase, lipase, and pancreatic histology. Survival of pancreatic acinar cells decreased when they were incubated with TNF-alpha but not IL-1 beta. Although present in large amounts within the pancreas during acute pancreatitis, IL-1 beta and TNF-alpha have no direct effect on acinar cell viability or exocrine function acutely nor do they induce pancreatitis. When present for more than 24 h, however, TNF-alpha but not IL-1 beta has a dramatic effect on acinar cell survival.

Acute Disease↗
PubMed1998

Pulmonary function threshold for distinguishing ventilatory- and nonventilatory-limited patients with airflow obstruction.

Patients with chronic obstructive pulmonary disease (COPD) may demonstrate great variability between results on the pulmonary function test (PFT) compared to those on the cardiopulmonary exercise test (CPXT). The purpose of this study was to correlate PFT and CPXT indices and to identify PFT threshold values for predicting exercise capacity in patients with airflow limitation. Fifty-seven patients (48 men and 9 women) of mean age 66.4 +/- 4.8 years with COPD and 40 age-matched control patients underwent PFT and CPXT. Based on the CPXT results, the patients were divided into ventilatory-limited (VL) and nonventilatory-limited (NVL), and the findings were correlated with the PFT indices. Linear regression analysis was used to determine the relationship between dyspnea index (VEmax/MVV) and forced expiratory volume in one second (FEV1). The cutoff value for VL was FEV1 < 38% and for NVL FEV1 > 68%. The prominent limiting symptom (61%) in the VL group was dyspnea sensation, with leg discomfort presenting in only 14%; corresponding rates in the NVL group were 38% and 31%. We conclude that the FEV1 is a reliable index for distinguishing VL from NVL COPD patients during CPXT at two extremes: below 38% of the predicted value (VL) and above 68% of the predicted value (NVL).

Aged↗
PubMed1998

Sex steroid control of mood, mental state and memory.

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.

Affect↗
PubMed1998

Assessment of functional results after percutaneous transluminal coronary angioplasty by cardiopulmonary exercise test.

Twenty-nine patients with documented coronary artery disease underwent cardiopulmonary exercise tests before and following a percutaneous transluminal coronary angioplasty (PTCA). The patients medication regimen and exercise protocols remained the same in both cases. Following PTCA, significant improvement (p < 0.001-0.0001) was noted in oxygen consumption (1,526.8 +/- 470.0 vs. 1,686.2 +/- 390 ml/min), oxygen pulse (12.40 +/- 2.73 vs. 13.44 +/- 2.9 ml/beat), oxygen pulse score (7.62 +/- 1.29 vs. 8.85 +/- 1.26 points) and in the ventilatory anaerobic threshold (993.1 +/- 177.6 vs. 1,089.8 +/- 150.9 ml/min) but not (p > 0.05) in maximal heart rate (128.7 +/- 16.9 vs. 132.0 +/- 17.2 beats/min). Thus, a cardiopulmonary exercise test is an effective method to assess functional results following PTCA.

Adult↗
PubMed1997

The density of 5-hydoxytryptamine2A receptors in forebrain is increased at pro-oestrus in intact female rats.

We have shown previously that in ovariectomised rats, oestradiol-17beta, in its positive-feedback mode for luteinizing hormone (LH) release, induces a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) receptors in the forebrain. Here we investigated whether there are any changes in 5-HT2A receptor density in relation to the spontaneous surge of oestradiol-17beta in female COB Wistar rats between dioestrus and pro-oestrus. Using [3H]RP62203-binding and autoradiography, we found that 5-HT2A binding sites were significantly increased at 1630-1800 h on pro-oestrus compared with 0900-1130 h on dioestrus in frontal and cingulate cortex, olfactory tubercle and nucleus accumbens. The densities of 5-HT2A binding sites in male rats were similar to dioestrous female values in cortex, and to pro-oestrous female values in nucleus accumbens. The changes in the density of 5-HT2A binding sites in the forebrain of female rats may be relevant to oestrogen effects on mood and mental state.

Animals↗
PubMed1997

Pancreatic ascites as a powerful inducer of inflammatory cytokines. The role of known vs unknown factors.

OBJECTIVES: To determine if pancreatic ascites will induce interleukin 1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF-alpha) production outside the pancreas and examine the possible components responsible. DESIGN: Severe pancreatitis was induced in rats (n = 30) by pancreatic duct infusion with 4% glycodeoxycholic acid; pancreatic ascites was collected 18 hours later. In vitro studies used quiescent murine splenic or pulmonary macrophages (10(5)/mL) which were exposed to media alone (control), trypsin, chymotrypsin, cathepsin-B, 20% ascites (vol/vol), 50% ascites, or endotoxin (lipopolysaccharide, 10 micrograms/mL, positive control) for 4 hours. Subsequently, pancreatic ascites was cultured for bacteria and assayed for endotoxin and cytokines (interleukin 1, interleukin 6, interleukin 8, TNF-alpha, or interferon gamma). The experiments were then repeated using 20% and 50% ascites that was sterile and cytokine-free (SCF ascites). In vivo studies used 100% (n = 8) or 50% (n = 12) SCF ascites or normal rat serum (control, n = 12) for a 10-second pulmonary lavage (100 microL) in adult mice, with lungs collected at 6 hours for cytokine gene analysis. SETTING: Surgical basic science research laboratory. MAIN OUTCOME MEASURES: Interleukin 1 beta and TNF-alpha gene induction was assessed by quantitative competitive reverse-transcription polymerase chain reaction and cytokine protein production was determined by enzyme-linked immunosorbent assay. RESULTS: Macrophages responded to untested and SCF ascites in a dose-dependent fashion, with a multifold increase in both IL-1 beta and TNF-alpha messenger RNA (mRNA) and protein, which was often more potent than lipopolysaccharide. Expression of IL-1 beta and TNF-alpha mRNA could not be induced by trypsin, chymotrypsin, or cathepsin-B. All animals undergoing lavage with 100% SCF ascites died within 2 hours, while those undergoing lavage with 50% SCF ascites showed a multifold increase in pulmonary IL-1 beta and TNF-alpha mRNA. CONCLUSIONS: Pancreatic ascites contains factors that are capable of inducing IL-1 beta and TNF-alpha production in vitro and in vivo. This effect cannot be reproduced by activated digestive enzymes and is propagated despite the absence of known inducers of cytokines such as bacteria, endotoxin, or other inflammatory cytokines.

Animals↗
PubMed1997

Acute pancreatitis-induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism.

Interleukin-1 beta (IL-1) is a proinflammatory cytokine which is produced within the pancreas during acute pancreatitis reaching levels which are toxic to many cell types. Since antagonism of this cytokine provides dramatic survival benefits during lethal pancreatitis, we hypothesized that IL-1 had direct secretagogue and cytolytic effects within the pancreas. The effect of IL-1 on pancreatic exocrine function and tissue viability was assessed in vivo by blockade of IL-1 with varying doses of IL-1 receptor antagonist (IL-1ra) prior to the induction of either moderate (caerulein-induced) or severe (choline deficient diet-induced) necrotizing pancreatitis. Subsequent in vitro studies were conducted to determine the direct effect of IL-1 on dispersed rat acini prepared through collagenase digestion. Amylase release was measured after a 30-min incubation with varying doses of recombinant IL-1 beta. Viability was determined in the presence of IL-1 via trypan blue exclusion at multiple time points. Blockade of the IL-1 receptor decreased pancreatic amylase release and tissue necrosis in both models of pancreatitis in a dose-dependent fashion (1.0 mg/kg, P = NS; 10 mg/kg, P < 0.05; 100 mg/kg, P < 0.05). Despite these in vivo findings, the addition of IL-1 to acini in vitro had no effect on exocrine function and failed to decrease acini viability (both, P = NS). Pancreatic amylase release and tissue necrosis are significantly attenuated during experimental pancreatitis by IL-1 antagonism. These changes do not appear to be due to the direct action of IL-1 on pancreatic acini and are likely due to more complex interactions between acini and cytokine-producing leukocytes.

Acute Disease↗
PubMed1997

Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain.

The aim of the present study was to determine the effect of estradiol-17 beta (E2), in its positive feedback mode for gonadotropin release, on the serotonin transporter (SERT) in female rat brain. Levels of SERT mRNA were determined by in situ hybridization and SERT-binding sites were measured by quantitative [3H]paroxetine receptor autoradiography. The injection of estradiol benzoate (EB) in acutely ovariectomized rats increased significantly (approximately 50%) the numbers of cells that expressed SERT mRNA in the dorsal raphe nucleus and the density of SERT-binding sites in lateral septum (90%), basolateral amygdala (20%), ventral nucleus of thalamus (250%) and ventromedial hypothalamic nucleus (250%). SERT-binding sites in EB-treated rats were significantly lower in periaqueductal central grey (15%). These findings indicate that effects on SERT gene expression may be involved in the E2-induction of the gonadotropin surge. Together with our previous findings, they also suggest that the sex differences in depression and the apparent psychotropic effect of E2 may be due to the action of E2 on the serotonin transporter as well as 5-HT2A receptors.

Animals↗
PubMed1997

Endopeptidase EC 3.4.24.15 presence in the rat median eminence and hypophysial portal blood and its modulation of the luteinizing hormone surge.

The endopeptidase EC 3.4.24.15 (EP24.15) is a zinc metalloendopeptidase that is widely distributed in a variety of tissues, including the testes, pituitary and the central nervous system. Among its numerous roles in metabolizing and processing biologically-active peptides, the enzyme degrades gonadotropin-releasing hormone (GnRH) by cleaving the central Tyr5-Gly6 bond. The aim of the present studies was to determine whether EP24.15 can modulate the concentrations of GnRH within the hypothalamo-hypophysial portal blood and thereby play a physiological role in reproduction. Our data suggest the presence of immunoreactive EP24.15 in the perivascular space of the median eminence and that this enzyme is secreted into portal blood. We have also shown a physiological role for this enzyme in that an inhibition of its activity with a specific inhibitor augmented the steroid-induced LH increase in ovariectomized rats. The present results suggest that secretory and post-secretory mechanisms are important in shaping the GnRH signal from the central nervous system; GnRH metabolism by EP24.15 may be one such mechanism.

Animals↗
PubMed1997

Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis.

BACKGROUND & AIMS: During severe pancreatitis, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are produced in large quantities. The aim of this study was to determine whether either one plays a more dominant role and if their detrimental effects are additive. METHODS: Necrotizing pancreatitis was induced in transgenic (-/-) knockout mice deficient in either IL-1 type 1 receptors, TNF type 1 receptors, or both IL-1 and TNF type 1 receptors. Wild-type mice served as controls. Mortality was assessed for 10 days. Additional animals were killed on days 0, 1, 2, 3, and 4 for determination of pancreatitis severity. RESULTS: All three knockout groups showed decreased amylase and lipase, histological score, serum IL-6, and mortality compared with wild-type groups. Animals devoid of receptors for both cytokines showed improved survival and decreased IL-6 levels compared with those devoid of either IL-1 or TNF receptors individually, yet they failed to show a further decrease in pancreatitis severity. CONCLUSIONS: Preventing the activity of IL-1beta or TNF-alpha has a nearly identical beneficial effect on the severity and mortality of acute pancreatitis. Preventing the activity of both cytokines concurrently has no additional effect on pancreatitis severity but further attenuates the systemic stress response and is associated with an additional but modest decrease in mortality.

Amylases↗
PubMed1997

Severity and mortality of experimental pancreatitis are dependent on interleukin-1 converting enzyme (ICE).

Interleukin-1 beta (IL-1 beta) is produced in large amounts during acute pancreatitis and is believed to play a role in disease progression. Because secretion of IL-1 beta is dependent on intracellular processing of pro-IL-1 beta by IL-1 converting enzyme (ICE), we aimed to determine the efficacy of a novel ICE inactivator (VE-13045) in inhibiting secretion of active IL-1 beta in vivo and if the loss of ICE activity would affect the severity and mortality of experimental pancreatitis. Severe hemorrhagic pancreatitis was induced in adult rats by infusion of bile acid into the pancreatic duct. Animals were randomized to receive VE-13045 or vehicle before induction of pancreatitis. To confirm our findings and to ensure that the results were not model dependent, a second series of experiments was conducted using mice possessing a homozygous knockout of the ICE gene in which lethal pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was assessed for both experiments by standard surrogate markers, blind histologic grading, and serum IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels. Pancreatic IL-1 beta mRNA induction was assessed by differential RT-PCR. Acute pancreatitis was associated with a 120-fold increase in IL-1 beta mRNA, which was not affected by ICE inhibition or gene deletion. Cytokine processing and secretion were affected, as evidenced by decreased serum levels of IL-1 beta and TNF-alpha (p < 0.001) in all animals with an inactive ICE enzyme. This lack of cytokine production increased survival from 32% to 78% following bile salt pancreatitis (p < 0.01) and from 24% to 80% following diet-induced pancreatitis (p < 0.005). Both ICE-defective groups demonstrated decreased pancreatic necrosis, edema, inflammation, wet weight (all p < 0.05), and amylase and lipase (p < 0.01). In vivo blockade or genetic deletion of ICE inhibits pancreatitis-induced secretion of proinflammatory cytokines without altering IL-1 mRNA production and is associated with decreased pancreatitis severity and dramatic survival benefits.

Animals↗
PubMed1997

[Therapeutic and toxic theophylline levels in asthma attacks--is there a need for additional theophylline?].

Although first-line therapy for bronchial asthma has changed over the past decade to anti-inflammatory medication such as inhaled corticosteroids and cromolyn with possible addition of beta-agonists, theophylline is still useful and therefore widely used. However, several studies have raised serious questions regarding its efficacy in acute asthmatic exacerbations. These studies, the narrow therapeutic range of the drug, the frequency of side effects and interactions with common drugs, and individual variation in clearance and metabolism, have prompted its reevaluation in the management of asthma. Therapeutic serum levels of theophylline are between 10 to 20 mcg/ml. Most adults achieve these concentrations with daily slow-release oral theophylline preparations, 200-400 mg (approximately 10 mg/Kg) twice a day. However, when such a patient presents to the emergency room (ER) in an asthmatic attack, immediate intravenous theophylline is often given, regardless of maintenance treatment. Since the rationale for this common therapeutic approach has been challenged, the current study was undertaken. Serum theophylline levels were measured in 23 consecutive asthmatics presenting to the ER in an acute attack. 15 (68%) had therapeutic levels (above 10 mcg/ml) and 2 had toxic levels (above 20 mcg/ml), prior to receiving the standard intravenous theophylline dose given for an attack. These data indicate that most patients with bronchial asthma on oral maintenance theophylline do not require additional intravenous theophylline when in an attack. It probably will not benefit them and may even induce serious theophylline toxicity.

Adult↗
PubMed1997

Small molecule inhibition of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity.

The morbidity and mortality associated with acute pancreatitis are primarily a result of pancreatic parenchymal necrosis and the development of marked pulmonary dysfunction. Recent evidence suggests that both of these conditions are propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, which are produced in large quantities within these organs. Because the generation of these cytokines occurs in a predictable manner early in the development of acute pancreatitis, we aimed to determine whether cytokine gene processing could be inhibited in vivo and what effects this would have on pancreatitis severity. Mild [caerulein, 50 micrograms/kg/hour intraperitoneally (IP) x 4; n = 40] or severe (choline-deficient diet; n = 40) necrotizing pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel small molecule (CNI-1493; 10 mg/kg IP) known to inhibit macrophage production of TNF and IL-1 in vitro by inhibiting translation of TNF mRNA into protein. Control animals received IP vehicle. All animals with acute pancreatitis showed dramatic up-regulation of the IL-1 beta and TNF-alpha genes. Those animals receiving CNI-1493 demonstrated attenuated production of both species of mRNA in pancreatic as well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as serum amylase and lipase, as well as pancreatic necrosis, were decreased in animals treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF production precludes induction of the proinflammatory cytokine cascade that normally occurs during acute pancreatitis. This lack of cytokine gene processing in the pancreas and lungs results in dramatic reductions in tissue damage and pancreatitis severity, which is not model dependent. This is the first time that a small molecule has been shown to influence this disease.

Amylases↗