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Biomedical subjects

A Hoffman

Publications and source records attributed to A Hoffman.

At least 19 recordsLinked to original sources
PubMed1997

Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart failure: role of angiotensin II.

BACKGROUND: Congestive heart failure (CHF) is associated with a decrease in renal perfusion. Because endothelium-derived NO is important in the regulation of renal blood flow (RBF), we tested the hypothesis that an impairment in the NO system may contribute to the decrease in RBF in rats with experimental CHF. METHODS AND RESULTS: Studies were performed in rats with experimental high-output CHF induced by aortocaval (AV) fistula and sham-operated controls. In controls, incremental doses of acetylcholine (ACh, 1 to 100 microg x kg(-1) x min(-1)) increased RBF and caused a dose-related decrease in renal vascular resistance (RVR). However, the increase in RBF and decrease in RVR were markedly attenuated in rats with CHF. Likewise, the effects of ACh on urinary sodium and cGMP excretion were also diminished in CHF rats, as was the renal vasodilatory effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). These attenuated responses to endothelium-dependent and -independent renal vasodilators in CHF rats occurred despite a normal baseline and stimulated NO2+NO3 excretion and normal expression of renal endothelial NO synthase (eNOS), as determined by eNOS mRNA levels and immunoreactive protein. Infusion of the NO precursor L-arginine did not affect baseline RBF or the response to ACh in rats with CHF. However, administration of the nonpeptide angiotensin II receptor antagonist A81988 before ACh completely restored the renal vasodilatory response to ACh in CHF rats. CONCLUSIONS: This study demonstrates that despite a significant attenuation in the NO-related renal vasodilatory responses, the integrity of the renal NO system is preserved in rats with chronic AV fistula. This impairment in NO-mediated renal vasodilation in experimental CHF appears to be related to increased activity of the renin-angiotensin system and may contribute further to the decrease in renal perfusion seen in CHF.

Acetylcholine↗
PubMed1997

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.

Animals↗
PubMed1997

Correlations among bone mineral density, broadband ultrasound attenuation, mechanical indentation testing, and bone orientation in bovine femoral neck samples.

Broadband ultrasound attenuation (BUA) of the calcaneus has been found to correlate with bone mineral density (BMD) of the femoral neck. The purpose of this study was to determine if a correlation exists among femoral neck BUA, femoral neck BMD, and incremental indent depth, a qualitative indicator of local mechanical bone strength, in bovine samples, and if this correlation is dependent upon orientation. For 12 of the bovine samples obtained, BUA was measured at the femoral neck and was followed by a BMD determination of the same area. A 19 mm diameter bicortical core containing the center of the area of interest was removed, transversely cut into 7 mm, thick disks, and tested for hardness by indent depth. For these tests, BMD was well correlated with BUA (R2 = 0.85, P < 0.001). An inversely proportional relationship with a modest correlation was found between indent depth and BMD (R2 = 0.59, P = 0.026), and indent depth and BUA (R2 = 0.57, P = 0.031). In a second set of tests involving 15 different bovine samples, a bicortical core was removed from the femoral neck. A trabecular bone cube measuring 1.5 cm on a side was removed from the center of the core. BUA and BMD measurements were made along the anterior-posterior (AP), medial-lateral (ML), and cephalic-caudal (CC) aspects of the cube. The cubes were randomly separated into three groups, cut in half perpendicular to the axis of interest, and tested for hardness by indent depth. In these tests, no significant difference was found in BMD among the three orientations of the cubes scanned (P = 0.77). In contrast, the BUA along the ML orientation of the cube was significantly greater than that along the AP orientation (P < 0.05). No significant difference was found in the incremental indent depth measurements among cube orientations (P = 0.41). In the test involving only trabecular bone, a much higher correlation between BMD and incremental indent depth was found regardless of cube orientation (R2 = 0.64, P < 0.001). The data indicate that BUA, but not BMD, is affected by trabecular orientation, and that BMD is negatively correlated with incremental indent depth.

Animals↗
PubMed1997

Effect of bovine bone constituents on broadband ultrasound attenuation measurements.

Broadband ultrasound attenuation (BUA) has been found to correlate positively with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. However, because there is a significant amount of unexplained variation in this correlation, it has been suggested that BUA might also provide information about bone structure. The purpose of this study was to determine the contribution of bone mineral and organic matrix to BUA and BMD measurements. The influence of sample length on both BUA and BMD was also investigated by normalizing these measurements to length. BUA (Walker Souix, 575+) and BMD (Lunar DPX) values were obtained on bicortical cores removed from 12 bovine femoral necks. BMD and BUA measurements were repeated on the samples after: (1) mechanical removal of the cortices; (2) defatting using a 2:1 chloroform:methanol solution; and (3) decalcifying using formic acid. The data demonstrate that the cortical component of the bone contributes significantly to BMD. We found that 41.7% of the normalized BMD reflect cortical bone. Defatting the samples did not affect BUA. Decalcifying the trabecular bone while maintaining an intact collagenous structure significantly reduces BUA by 89% and BMD by 96% compared to the whole core samples. Normalizing BMD and BUA to sample length, in cases where large variation is present, does influence the correlation between the variables. We conclude that BUA is influenced mainly by the presence of bone mineral, whereas the presence of the organic matrix contributes very little to BUA.

Absorptiometry, Photon↗
PubMed1997

Modeling of drug release from erodible tablets.

A general mathematical model was developed to describe drug release from erodible tablets undergoing surface erosion. The model (which is based on the Hopfenberg equation) takes into account the three dimensions of a tablet dosage form. The model enables the characterization of the release kinetics by one or two erosion rate constants depending on the hydrodynamic conditions of the system. The model can be used to compare the release rates of the drug within different batches produced under different conditions. The model was utilized to evaluate some factors affecting the release rate from erodible tablets consisting of hydroxypropyl methylcellulose and amoxicillin. The release data of amoxicillin measured from the whole tablet followed the equation developed. Amoxicillin release data measured from the planar surface of the tablet appeared to follow zero-order kinetics as predicted by theory for drug release from an erodible device maintaining constant surface area with time.

Amoxicillin↗
PubMed1997

Managed care and the cystic fibrosis patient.

Since the first published report of mortality in cystic fibrosis in 1969, the median survival among cystic fibrosis patients has risen from 14 to 31 years. The reasons for this improved survival are complex and include earlier diagnosis; improved control of pulmonary infection; aggressive nutritional intervention; and enhanced monitoring of patients in peer-reviewed, accredited centers for cystic fibrosis care, teaching, and research. Emphasis on the importance of research on changing and improved treatment has been effectively communicated to patients and families. As a result, a group of highly educated medical consumers has been created. During the last decade, another focus of rapid change has appeared, that of cost containment in the medical profession, creating the field of managed care. Practicing medical professionals perceive the need for reduction in excessive spending in medicine and have taken a variety of approaches to balance better the value and cost of medical care while maintaining superb quality. Physicians and consumers continue to have concerns about the potential negative impact of managed care on a relatively rare, specialized, and chronic illness such as cystic fibrosis if managed care concepts are applied without proper understanding of the disease. A great concern is that managed care in cystic fibrosis may cause reversal of trends in improved quality and length of survival. The increased length of survival places an increasing demand on the already stressed system of health care financing. Understanding the changing area of managed care is therefore of paramount importance to clinicians involved in cystic fibrosis care. The Cystic Fibrosis Foundation has presented symposia on managed care at each of the last three annual meetings, including the North American Cystic Fibrosis Meeting, October 1996. The following issues were addressed by speakers and panel discussants, with portions excerpted for this review: trends in managed care, measures and guidelines useful in managed care, Medicaid managed care and cystic fibrosis, and practical aspects of using pathways in caring for patients with cystic fibrosis.

Critical Pathways↗
PubMed1997

Pharmacokinetic considerations of new insulin formulations and routes of administration.

There is a continuing search for improved insulin formulations in order to imitate as closely as possible the physiological pattern of insulin secretion, and thereby to minimise the complications of diabetes mellitus. The major advances achieved to date are in the area of human insulin analogue synthesis resulting from the introduction of recombinant DNA techniques, and in improved delivery systems that utilise noninvasive or minimally invasive modes of administration. To accommodate postprandial hyperglycaemia, monomeric insulin formulations have been developed, of which insulin lispro (the Lys-Pro analogue) is already approved for clinical use. These formulations have a rapid rate of absorption and, therefore, have to be administered at meal time (unlike the previous short-acting formulations). Their residence time is also about 2-fold shorter than regular human insulin; this minimises the risk of the excessive hypoglycaemic effect that characterises regular human insulin formulations. Certain proinsulin formulations with hepatoselective activity have been developed but were found to be poorly tolerated. The newer proinsulin molecules do not show hepato-selective properties. In order to generate basal insulin levels, peakless long-acting formulations have been developed, including: a soluble formulation (which upon subcutaneous administration, produces a 'depot-like' sustained release mechanism), albumin-bound insulin and cobalt-insulin hexamer formulations. To improve patient compliance the 'pen' device was developed for subcutaneous injections. Programmable infusion pumps were developed to avoid repetitive subcutaneous injections. Great efforts have been made in searching for noninvasive modes of insulin administration that will avoid the need for parenteral administration. These include: oral, colonic, rectal, nasal, ocular, buccal, pulmonary, uterine and transdermal routes of administration. Various enhancers have been tested to increase the bioavailability of each route. At present these alternative routes do not provide clinically relevant substitutes for the subcutaneous mode of administration. In conclusion, although the newer formulations provide certain advantages, there is still much to be done to further facilitate and improve insulin therapy.

Amino Acid Sequence↗
PubMed1997

The anticonvulsant effect of deprenyl on pentylenetetrazol-induced seizures in Lewis rats.

There is recent evidence that deprenyl may have anticonvulsant action in a rat kindling model of epilepsy as well as in a maximal electroshock model. We therefore investigated the effect of deprenyl on the brain sensitivity threshold to pentylenetetrazol (PTZ)-induced maximal seizures in Lewis rats, in a model that provides pharmacodynamic information free of pharmacokinetic interference. The novel finding of this investigation was the anticonvulsant effect of deprenyl following repetitive administration whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures. The data suggests that the mechanism of this effect is not associated with the dopaminergic activity of deprenyl since pretreatment with both bromocriptine (a dopamine D2 agonist) and haloperidol (dopamine antagonist) did not affect the seizure threshold, whereas levodopa caused a proconvulsant effect. It was also concluded that the mechanism is not related to changes in acetylcholine levels since prolonged pretreatment with deprenyl did not attenuate the brain sensitivity to pilocarpine-induced seizures. The fact that long term administration of deprenyl was needed to produce its anticonvulsant effect may indicate that the anticonvulsant effect of deprenyl may be due to changes in levels of certain endogenous compounds or down or up-regulation of relevant receptor/effector units.

Animals↗
PubMed1996

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure.

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (-30%) and medulla (-23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.

Animals↗
PubMed1996

Possible role for endothelins in penile erection.

The effects of endothelins (endothelin-1 and endothelin-3) on penile erection were studied in vivo in the pithed rat. Penile erectile responses were evaluated by measurements of intracorporal pressure via a needle inserted into one corpus cavernosum. Injection of endothelins (0.1-10 micrograms/kg i.v.) was followed by a rapid rise in corporal pressure. The responses to endothelin-1 and endothelin-3 were equivalent at the lower doses, but at 10 micrograms/kg the response to endothelin-3 was greater than that to endothelin-1. NG-Nitro-L-arginine-methyl ester (20 mg/kg) but not indomethacin (10 mg/kg) antagonized the rise in corporal pressure caused by submaximal doses of endothelins. Electrical nerve stimulation-induced increase in corporal pressure was reduced after 5 micrograms/kg endothelin-1 but not after the same dose of endothelin-3. The results indicate that in corporal vasculature endothelin-3 has a predominantly vasodilator effect, while endothelin-1 has a vasodilator effect at lower doses and a vasoconstrictor effect at higher doses. The vasodilator action of endothelins is probably mediated by activation of endothelin ETB receptors and local release of nitric oxide. Thus, endothelins may participate in initiation and/or maintenance of penile erection.

Animals↗
PubMed1996

Crystal structure of a human TATA box-binding protein/TATA element complex.

The TATA box-binding protein (TBP) is required by all three eukaryotic RNA polymerases for correct initiation of transcription of ribosomal, messenger, small nuclear, and transfer RNAs. The cocrystal structure of the C-terminal/core region of human TBP complexed with the TATA element of the adenovirus major late promoter has been determined at 1.9 angstroms resolution. Structural and functional analyses of the protein-DNA complex are presented, with a detailed comparison to our 1.9-angstroms resolution structure of Arabidopsis thaliana TBP2 bound to the same TATA box.

Amino Acid Sequence↗
PubMed1996

Alterations in the promoter-specific imprinting of the insulin-like growth factor-II gene in Wilms' tumor.

The human IGF2 gene, which encodes a mitogenic peptide required for normal fetal development, is overexpressed in many types of tumors. IGF2 is transcribed from four promoters (P1-P4), and in most tissues, the gene is imprinted. In this study, we have analyzed IGF2 promoter usage and determined the allelic expression from each promoter in 19 ApaI- and 22 AluI-heterozygous Wilms' tumors. Loss of IGF2 imprinting (LOI) was observed in 8 ApaI-informative tumors. In these tumors, each parental allele was expressed in equal abundance, indicating that there was complete relaxation of IGF2 imprinting. In each LOI tumor, expression from promoter P1 as well as from the normally imprinted promoters P2-P4 was biallelic. In the 11 ApaI-informative tumors which maintained IGF2 imprinting (maintenance of imprinting), transcription from promoters P2-P4 was always monoallelic, while transcripts from P1 were derived from either one or both alleles. The lack of consistency of IGF2 imprinting of promoter P1 in maintenance of imprinting tumors was also observed in normal fetal tissues of 6 12 weeks gestation, suggesting a similarity in IGF2 regulation between Wilms' tumors and embryonic tissue development. These data suggest that the increased expression of IGF2 in Wilms' tumor may be caused either by biallelic gene expression in LOI tumors from promoters P2-P4 and/or by a reversion to an earlier stage of development which is characterized by increased synthesis of this fetal growth factor.

Alleles↗
PubMed1996

Clinical significance of hepatitis C viral RNA status and its correlation to antibodies to structural HCV antigens in anti-HCV reactive patients with normal liver tests.

Extensive serological testing and HCV RNA determination by RT-PCR was performed in serum, PBMCs, and liver tissue in thirteen anti-HCV reactive patients with persistently normal liver tests. Absolute concordance in the status of HCV RNA between serum, PBMCs, and liver was noted. Five patients were HCV RNA positive but only three had mild histological changes. Eight patients were HCV RNA negative in all three sites and had virtually normal liver histology. Patterns of reactivity in RIBA 2.0 strip immunoblot assay did not differentiate viremic from nonviremic patients. ELISA testing using multiple individual HCV recombinant antigens from the structural and non-structural regions of HCV demonstrated mean antibody titers to the structural antigens, in particular HCV E2 antibodies, to be significantly lower in HCV RNA negative patients. The status of HCV RNA in the serum appears to infer the status of HCV RNA in the liver and PBMCs in patients with persistently normal liver tests. Patients with persistently normal liver tests and undetectable HCV RNA have probably spontaneously cleared HCV infection.

Adult↗
PubMed1996

Probing self assembly in biological mixed colloids by SANS, deuteration, and molecular manipulation.

Small-angle neutron scattering was used to obtain information on the form and molecular arrangement of particles in mixed colloids of bile salts with phosphatidylcholine, and bile salts with monoolein. Both types of systems showed the same general characteristics. The particle form was highly dependent on total lipid concentration. At the highest concentrations the particles were globular mixed micelles with an overall size of 50A. As the concentration was reduced the mixed micelles elongated, becoming rodlike with diameter about 50A. The rods had a radial core-shell structure in which the phosphatidylcholine or monoolein fatty tails were arranged radially to form the core with the headgroups pointing outward to form the shell. The bile salts were at the interface between the shell and core with the hydrophilic parts facing outward as part of the shell. The lengths of the rods increased and became more polydispersed with dilution. At sufficiently low concentrations the mixed micelles transformed into single bilayer vesicles. These results give insight on the physiological function of bile and on the rules governing the self assembly of bile particles in the hepatic duct and the small intestine.

Bile Acids and Salts↗