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Biomedical subjects

D Baran

Publications and source records attributed to D Baran.

At least 19 recordsLinked to original sources
PubMed2001

Deposition of nacystelyn from a dry powder inhaler in healthy volunteers and cystic fibrosis patients.

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with 99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 +/- 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 +/- 7.0% for adults and 16.5 +/- 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.

Absorption↗
PubMed2001

Osteoporosis. Efficacy and safety of a bisphosphonate dosed once weekly.

Trabecular and cortical bone is continuously being remodeled at microscopic loci called basic multicellular units (BMU). Estrogen deficiency in menopause contributes to an increase in osteoclastic resorption and/or a decrease in osteoblastic formation, which leads to microscopic bone loss at the BMUs. Drug treatments for osteoporosis are intended to inhibit bone resorption, reduce the rate of bone turnover, and increase bone mass. The bisphosphonate alendronate was recently approved for once-a-week dosing for the prevention and treatment of postmenopausal osteoporosis. A 70-mg, once-a-week dose of alendronate has been shown to be therapeutically equivalent to the standard daily 10-mg dose. Tolerability and safety of weekly dosing appear to be similar to daily dosing.

Alendronate↗
PubMed2000

Overall and peripheral inhomogeneity of ventilation in patients with stable cystic fibrosis.

We studied distribution of ventilation in patients with cystic fibrosis (CF) who had not had an exacerbation for some time. Patients performed either the vital capacity nitrogen (N(2)) single-breath washout test (VC test) or a modified single-breath washout consisting of 1 L inspired from functional residual capacity (FRC test) of 90% oxygen (O(2)), 5% helium (He), and 5% sulfur hexafluoride (SF(6)). We computed the slopes of phase III of N(2) concentration from the VC test (S(N2) (VC)) and the phase III slopes of the He (S(He)): The SF(6) (S(SF6)), and curves from the FRC test. S(N2) (VC) may be regarded as an index of overall ventilation and the difference (S(SF6) - S(He)) as an index of peripheral ventilation. Three groups were studied: CF, 28 CF patients (8-36 years of age); normal controls (NC), 33 normal nonsmokers (9-55 years of age); and a smoking group (SG), 42 non-CF smoking patients (39-79 years of age). Compared to the NC group, S(N2) (VC) is increased in the CF group, reflecting an overall ventilation impairment. There is no difference in S(N2) (VC) between the CF group and the SG group, suggesting that S(N2), though sensitive, is nonspecific. Compared to both NC and SG groups, (S(SF6) - S(He)) is decreased in the CF group, being on the average negative. This may imply that there is a peripheral impairment in the distribution of ventilation that originates in terminal and respiratory bronchioles. Negative (S(SF6) - S(He)) is statistically associated with the youngest CF patients, suggesting that terminal and respiratory bronchiolar involvement is linked to early stages of the disease. In older CF patients, (S(SF6) - S(He)) is more often positive, suggesting that even more distal airways, such as alveolar ducts, become involved in peripheral inhomogeneity of ventilation.

Adolescent↗
PubMed2000

Cell adhesion molecule expression in murine lupus-like nephritis induced by lipopolysaccharide.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM) are thought to play important roles in leukocyte recruitment to the kidney. We therefore chose to study mesangial cell adhesion molecule expression in vitro, and the role of these molecules in experimental lupus-like nephritis. METHODS AND RESULTS: When cultured murine mesangial cells were stimulated with interferon-gamma (IFgamma) and tumor necrosis factor-alpha (TNFalpha), mRNA levels for ICAM-1 and VCAM markedly increased. These molecules were detected at the cell surface by flow cytometry. Since lipopolysaccharide (LPS) stimulates TNFalpha and IFgamma production in vivo, we treated mice with Streptococcus minnesota LPS in order to study renal adhesion molecule expression. LPS treatment induced mesangial proliferative glomerulonephritis characterized by leukocyte infiltration, and increases in total glomerular cellularity, volume and matrix area. mRNA levels for ICAM-1 and VCAM were increased in the kidneys of LPS-treated versus control mice. ICAM-1 and VCAM molecules were constitutively expressed in renal vascular endothelium. At 3 and 5 weeks, this vascular staining intensified, and some ICAM-1 and VCAM expression was induced in the glomerular mesangium. ICAM-1 and VCAM induction occurred early and correlated in time with leukocyte infiltration. CONCLUSION: Interactions between cell adhesion molecules expressed by intrinsic glomerular cells and infiltrating leukocytes play a role in the initiation of LPS-induced lupus-like nephritis. These observations are potentially relevant to the understanding and treatment of certain types of human glomerulonephritis.

Animals↗
PubMed2000

Quantitative ultrasound: an indicator of osteoporosis in perimenopausal women.

The key to effective treatment of osteoporosis is early detection; however, the disease in perimenopausal women is frequently undiagnosed. To assess the utility of quantitative ultrasound (QUS) at the calcaneus in perimenopausal women, broadband ultrasound attenuation (BUA); speed of sound (SOS); quantitative ultra-sound index (QUI), an algorithm of BUA and SOS; and bone mineral density by dual X-ray absorptiometry (DXA) of the posteroanteiror spine, femoral neck, and total hip were measured in 420 women (ages 45-55 yr). Thirty (7.1%) of the women were found to be osteoporotic by DXA. All QUS measurements were predictors of osteoporosis. QUS values did not differ between postmenopausal women on estrogen replacement therapy (ERT) and those not on ERT. There were no differences among BUA, SOS, and QUI in the area under the receiver operating characteristic curves for predicting osteoporotic vs nonosteoporotic cases. At a QUI of 89, ultrasound had an 80% sensitivity for the diagnosis of osteoporosis, but only a 74% specificity. The use of QUS in perimenopausal women will facilitate the identification of women with osteoporosis. However, the high false-positive rate (26%) limits the utility of QUS as the sole diagnostic technique on which to base therapeutic decisions. Nevertheless, low QUS measurements may provide a means for targeting those women who would benefit most from more extensive evaluation (e. g., DXA).

Bone Density↗
PubMed2000

Effects of beta-blockers on neurohormonal activation in patients with congestive heart failure.

The effect of beta-adrenoceptor antagonists (beta-blockers) on neurohormonal activation in patients with congestive heart failure has been the subject of study in numerous small clinical trials. Short term therapy with beta-blockers is associated with a variable acute neurohormonal response which may be determined by the pharmacology of the agent under study and the baseline characteristics of the patient population. Long term therapy with beta-blockers devoid of intrinsic sympathomimetic activity (partial agonist activity) is associated with evidence of decreased plasma markers of activation of the sympathetic nervous system, the renin-angiotensin system, and endothelin-1. Beta1-selective and nonselective beta-blockers appear to be associated with evidence of decreased neurohormonal activation, with differential effects on beta-adrenoceptor density. Agents with partial agonist activity appear to differ from pure antagonists, with some studies reporting evidence of increased neurohormonal activation. The mechanisms by which beta-blockers reduce neurohormonal activation and the clinical relevance of changes in adrenergic function to their use in the treatment of heart failure require further investigation.

Adrenergic beta-Antagonists↗
PubMed1999

Recovery from prolonged metabolic acidosis due to accidental ethylene glycol poisoning.

In this report, we describe a case of accidental ethylene glycol poisoning in a 90-year-old woman. Despite a delay in diagnosis and treatment of over 24 hours, this patient recovered completely from profound and lengthy metabolic acidosis. She is therefore the oldest known survivor of severe ethylene glycol intoxication. We review 79 additional cases of ethylene glycol intoxication reported in the literature since 1976 and comment on diagnostic, therapeutic and prognostic features of this form of poisoning.

Acidosis↗
PubMed1998

An oligonucleotide decoy for transcription factor E2F inhibits mesangial cell proliferation in vitro.

The transcription factor E2F controls expression of several genes involved in cell proliferation including c-myc, c-myb, proliferating cell nuclear antigen (PCNA), and cdk2 kinase. Having established that both PCNA and cdk2 kinase are induced in rat mesangial cells (MC) by serum stimulation, we attempted to inhibit MC proliferation in vitro by transfecting these cells with cationic liposomes containing a synthetic double-stranded oligodeoxynucleotide (ODN) with high affinity for E2F. Using a gel mobility shift assay, we detected increased specific binding of E2F in MC following serum stimulation. This binding was completely inhibited by preincubation of MC nuclear extracts with the double-stranded ODN with high affinity for E2F but not by preincubation with a missense ODN containing two point mutations. MC were also transfected with a luciferase reporter gene construct containing three E2F binding sites. Luciferase activity was enhanced by serum stimulation of MC, and this effect was specifically abolished by cotransfection of MC with E2F decoy ODN. Furthermore, RT-PCR analysis revealed that serum-induced upregulation of PCNA and cdk2 kinase gene expression was inhibited by E2F decoy ODN transfection but not by transfection of missense ODN. These changes in gene expression were paralleled by a reduction in PCNA and cdk2 kinase protein expression in E2F decoy ODN transfected cells. MC number increased following serum stimulation. This effect was blunted by transfection with E2F decoy ODN but not by transfection of missense ODN. These data suggest that the transcription factor E2F plays a crucial role in the regulation of MC proliferation and that this factor can be successfully targeted to inhibit MC cell cycle progression.

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

Interrelating of ventricular pressure and intracellular calcium in intact hearts.

Although the mechanistic link between variations in intracellular calcium and its effects on myofilament regulatory proteins and subsequent impact on cardiac muscle force production have been known for some time, characterization of cardiac contractile properties are predominantly confined to phenomenological descriptions of the relationship between either muscle length and force or ventricular pressure and volume. However, as recognition of the limitations of these theories grow, investigators have begun to look toward more fundamental theories of cardiac contraction to explain whole heart function. The goal of the present study was first to explore, on a theoretical level, the degree of complexity required in a biochemical model necessary to adequately explain both equilibrium and twitch contraction behavior of cardiac muscle. Central to this analysis was a critical examination of the evidence for and against the importance of a calcium-free, force-generating state. Next, we determined whether such theories can actually account for the interrelationships between the experimentally measured time courses of pressure generation and the calcium transient measured from intact ventricles during both normal twitches as well as during complex contraction sequences. The results of this analysis provide strong support for a four-state model, including the calcium-free, force-generating state. These results will help guide the continuing quest for a mechanistic theory of ventricular function.

Aequorin↗
PubMed1997

D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature.

Therapeutic use of D-penicillamine has been associated with a range of adverse effects. We present a patient with scleroderma, treated with D-penicillamine for 5 years, who developed severe renal failure due to rapidly progressive glomerulonephritis with both crescents and subepithelial immune deposits on renal biopsy. Serological findings included perinuclear antineutrophil cytoplasmic antibodies and antihistone antibodies. She was treated with cyclophosphamide, prednisone, discontinuation of D-penicillamine, and hemodialysis. Therapy resulted in partial recovery of renal function. The clinical course of our patient is in keeping with D-penicillamine-induced chronic membranous nephropathy, followed by rapidly progressive crescentic glomerulonephritis. We discuss the effects of D-penicillamine in our patient, and review the literature on immune-mediated renal disease associated with the use of this drug.

Aged↗
PubMed1997

Activity of the osteocalcin promoter in skeletal sites of transgenic mice and during osteoblast differentiation in bone marrow-derived stromal cell cultures: effects of age and sex.

The bone-specific osteocalcin gene is a well established marker of osteoblast activity. We have studied osteocalcin transcription in transgenic mice carrying rat osteocalcin promoter-chloramphenicol acetyltransferase (CAT) reporter constructs. Transgenic lines carrying each of the 1.7-, 1.1-, 0.72-, or 0.35-kilobase promoter constructs expressed the reporter gene in a tissue-specific manner. However, each of these constructs was sensitive to site of integration effects, reflected by a high frequency of nonexpressing transgenic lines. High expression of the 1.7-kilobase promoter in osseous tissues was accompanied by low ectopic expression in the brain. Analysis of CAT expression in femurs, calvariae, and lumbar vertebrae of this line indicated considerable variability in promoter activity among individual transgenic animals. Analysis of the variance in CAT activity demonstrated a linkage between promoter activities in these distant skeletal sites. Promoter activity was inversely correlated with age, and females exhibited severalfold higher activity than age-matched males. Bone marrow stromal cells from these animals, cultured under conditions that support osteoblast differentiation, exhibited the expected postproliferative onset of osteocalcin promoter activity, as assessed by CAT assay. The ex vivo CAT activity was not dependent on the sex or the age of the donor transgenic mouse. Taken together, our results are consistent with the hypothesis that a common, probably humoral, factor(s) regulates osteocalcin transcription in distant skeletal sites. We suggest that the abundance of this factor(s) is different between males and females and among individual mice at a given time point, and that ex vivo culturing of osteoblasts reduces the variation in osteocalcin promoter activity by eliminating the physiological contribution of this factor.

Aging↗
PubMed1996

Structural change of the acinus during growth assessed by single-breath tracer gas washouts.

In the present investigation we wanted to study the functional and structural development of the acinus, using a vital capacity (VC) single-breath tracer gas washout test, modified so that the subject inspired helium (He) and sulfurhexafluoride (SF6) in oxygen. We used as indices of ventilation the slopes of N2 (SN2), He (SHe), and SF6 (SSF6) as well as (SSF6-SHe), which may be considered an index of acinar mixing linked to acinar structure. We studied two populations: Population I-49 children and adolescents (8-18 years of age); and Population II-18 non-smoking adults (22-48 years of age). Age and vital capacity (VC) were correlated in Population I, but not in Population II. In both populations there was a significant decrease of SN2, SSF6, and SHe as a function of VC. Growth and VC changes were determinants of these decreases in Population I, while only changes in VC were significant determinants in Population II. For each gas, the regression lines of slope versus VC for Populations I and II were not significantly different; we therefore suggest that the decrease in slope in Population I is mainly due to an increase in lung volume during growth. (SSF6-SHe) was not correlated with VC in Population I and was negatively correlated with VC in Population II (P < 0.01). This discrepancy implies that a child will have a smaller (SSF6-SHe) than an adult at comparable VC. Since the magnitude of (SSF6-SHe) values are related to acinar branching asymmetry, our results suggest that asymmetry of the acinus increases with lung growth and maturation.

Adolescent↗
PubMed1995

Correlation of bone mineral density and femoral neck hardness in bovine and human samples.

Bone mineral density (BMD) is a predictor of fracture risk. The purpose of this study was to determine whether a correlation exists between femoral neck BMD and an indicator of mechanical bone strength in human and bovine samples. Human proximal femurs were obtained from seven men and two women undergoing total hip arthroplasty (THA), mean age 60.3 years. Preoperative BMD measurements of the femoral neck were obtained (Lunar DPX). A 3 cm2 area of interest on each excised femoral neck corresponding to the preoperative BMD measurement site was carefully marked and BMD was remeasured postoperatively. Ten excised bovine femoral necks were also measured for BMD. A bicortical core, each cortex 2.8 cm2 in area, containing the center of the area of interest was removed from the human and bovine femoral necks, cut into multiple 7-mm thick, multiple cross-sectional discs, and measured for hardness by indent depth (Rockwell International Hardness Tester, Wilson Mechanical Instruments, New York, NY). In vivo human femoral neck BMD measurements correlated with in vitro BMD measurements (r = 0.99). BMD measurements of human femoral necks were significantly lower than BMD measurements of bovine femoral necks (P < 0.05). Inverse relationships were found between in vivo and in vitro human BMD measurements and indent depth (r = -0.58 and -0.59, respectively). Bovine BMD measurements and indent depth were also inversely related (r = -0.64).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Effects of vitamin D3 and cyclosporin A on HgCl2-induced autoimmunity in brown Norway rats.

BACKGROUND: Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway (BN) rats. This syndrome is the consequence of T cell-dependent polyclonal B cell activation and autoantibody production. We have previously shown that HgCl2-induced autoimmune perturbations can be prevented in BN rats by the administration of cyclosporin A (CsA). The most potent vitamin D3 metabolite 1,25(OH)2 D3 (Vit D3) shares certain immunomodulatory properties with CsA. We therefore chose to compare the effects of Vit D3 to those of CsA in BN rats treated with HgCl2 in order to establish whether Vit D3 either alone or in combination with CsA can attenuate an autoimmune syndrome in vivo. METHODS: BN rats were treated with HgCl2 according to a standard protocol. Subgroups of rats were also given CsA alone, Vit D3 or synthetic analogues of Vit D3 alone, or combinations of both agents. Different doses and routes of administration were compared. The following markers of disease activity were evaluated: mortality, peak proteinuria, serum IgE concentrations, and renal immunoglobulin deposition. RESULTS: Disease activity was markedly attenuated in all rats treated with CsA alone. Vit D3 and certain of its synthetic analogues administered alone also tempered the autoimmune process, but to a lesser extent than did CsA. The effect of CsA alone was so potent, that no additive or synergistic effects could be demonstrated when CsA was administered in combination with Vit D3. CONCLUSIONS: Despite similar described immunomodulatory effects in vitro, CsA is clearly more effective than Vit D3 in preventing HgCl2 autoimmune disease in BN rats. This suggests that there is a difference in the cellular targets of these two agents in vivo, and/or a difference in the potency with which HgCl2-triggered immune activation is suppressed.

Animals↗