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Z Vajo

Publications and source records attributed to Z Vajo.

At least 19 recordsLinked to original sources
PubMed2001

Recombinant DNA technology in the treatment of diabetes: insulin analogs.

After more than half a century of treating diabetics with animal insulins, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogs were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analog, lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. Two new insulin analogs, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States, and several other analogs are being intensively tested. Thus, it appears that a rapid acceleration of basic and clinical research in this arena will be seen, which will have direct significance to both patients and their physicians. The introduction of new short-acting analogs and the development of the first truly long-acting analogs and the development of analogs with increased stability, less variability, and perhaps selective action, will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control. Data on the currently available and tested analogs, as well as data on those currently being developed, are reviewed.

Amino Acid Sequence↗
PubMed2001

Estrogen improves impaired musculocutaneous vascular adrenergic reactivity in pharmacologically ovariectomized rats: a potential peripheral mechanism for hot flashes?

Hot flashes are among the most common complaints of perimenopausal women. Despite the high prevalence of the phenomenon, the background to the development of hot flashes is still not completely understood, through a hypothesized central mechanism, involving norepinephrine and luteinizing hormone-releasing hormone (LH-RH) secretion is widely accepted. We studied the influence of sex steroid deficiency and hormone replacement therapy on the biomechanical properties of musculocutaneous arterioles, to see whether a peripheral mechanism also exists in the development of hot flashes. Fifty adult, nulliparous, non-pregnant female Sprague-Dawley rats received pharmacological ovariectomy, and estradiol, medroxyprogesterone, or both hormones. After 12 weeks the saphenous artery was isolated by microdissection. Norepinephrine-induced tone (active tangential strain) was measured as a function of intraluminal pressure in an organ bath. The norepinephrine-induced arterial tone was significantly different between the control group and the ovariectomized animals in the range of 80-150 mmHg intraluminal pressure (p < 0.05). Also, significant differences were found between the ovariectomized group and the animals receiving estradiol monotherapy (p < 0.01 between 80 and 170 mmHg, and p < 0.05 between 180 and 200 mmHg intraluminal pressure). Neither medroxyprogesterone monotherapy nor combined hormone replacement therapy induced significant changes in the norepinephrine-induced vascular tone. The absence of sex steroids leads to decreased reactivity to norepinephrine in small musculocutaneous arteries, while chronic estradiol replacement therapy restores the impaired responsiveness of the vessels. Our data raise the possibility that in addition to the central mechanism, a previously unknown peripheral background mechanism for perimenopausal hot flashes may exist.

Animals↗
PubMed2000

Insulin and analogue effects on protein degradation in different cell types. Dissociation between binding and activity.

In adult animals, the major effect of insulin on protein turnover is inhibition of protein degradation. Cellular protein degradation is under the control of multiple systems, including lysosomes, proteasomes, calpains, and giant protease. Insulin has been shown to alter proteasome activity in vitro and in vivo. We examined the inhibition of protein degradation by insulin and insulin analogues (Lys(B28),Pro(B29)-insulin (LysPro), Asp(B10)-insulin (B10), and Glu(B4),Gln(B16),Phe(B17)-insulin (EQF)) in H4, HepG2, and L6 cells. These effects were compared with receptor binding. Protein degradation was examined by release of trichloroacetic acid-soluble radioactivity from cells previously labeled with [(3)H]leucine. Short- and intermediate-lived proteins were examined. H4 cells bound insulin with an EC(50) of 4.6 x 10(-9) m. LysPro was similar. The affinity of B10 was increased 2-fold; that of EQF decreased 15-fold. Protein degradation inhibition in H4 cells was highly sensitive to insulin (EC(50) = 4.2 x 10(-11) and 1.6 x 10(-10) m, short- and intermediate-lived protein degradation, respectively) and analogues. Despite similar binding, LysPro was 11- to 18-fold more potent than insulin at inhibiting protein degradation. Conversely, although EQF showed lower binding to H4 cells than insulin, its action was similar. The relative binding potencies of analogues in HepG2 cells were similar to those in H4 cells. Examination of protein degradation showed insulin, LysPro, and B10 were equivalent while EQF was less potent. L6 cells showed no difference in the binding of the analogues compared with insulin, but their effect on protein degradation was similar to that seen in HepG2 cells except B10 inhibited intermediate-lived protein degradation better than insulin. These studies illustrate the complexities of cellular protein degradation and the effects of insulin. The effect of insulin and analogues on protein degradation vary significantly in different cell types and with different experimental conditions. The differences seen in the action of the analogues cannot be attributed to binding differences. Post-receptor mechanisms, including intracellular processing and degradation, must be considered.

Animals↗
PubMed2000

For debate: defective mitochondria, free radicals, cell death, aging-reality or myth-ochondria?

As both experimental evidence and theoretical considerations may suggest that free radicals and mitochondria might be associated as key factors in aging, these organelles have been implicated in various versions of the free radical theory of aging. However, except for a few cases, no evidence for a death process specifically activated in respiratory defective cells could be found in patients with a mitochondrial disorder, including those harboring high levels of mutant mtDNA associated with profound respiratory chain deficiencies. This and more recent evidence suggest that damages produced by free-radicals endogenously generated in the mitochondria result in a distinctive biochemical profile, only occur under exceptional conditions and that a dysfunction of the respiratory chain does not cause opening of the permeability transition pore and is not sufficient per se to trigger massive entrance of cells into death processes, neither apoptosis nor necrosis. Therefore, defective mitochondria and their particular genome, should not be considered as a major and primary source of free radicals either leading cells into a death cascade or resulting in an accelerated aging process.

Aging↗
PubMed2000

Postmenopausal hormone replacement therapy and cardiovascular mortality in Central-Eastern Europe.

BACKGROUND: The leading cause of death among elderly women is cardiovascular (CV) disease in the United States and in Western Europe as well. The protective effect of postmenopausal hormone replacement therapy (HRT) on coronary heart disease has been verified in epidemiologic studies. There are no data available on the rate of HRT use in Eastern Europe. Our goals were to study the rates of HRT in Eastern Europe, to compare them to those of the United States and Western Europe, as well as to compare their CV mortality rates. METHODS: The use of HRT in Eastern Europe was calculated from sales records obtained from all pharmaceutical companies that ship HRT preparations to the given area. Data on HRT in Western countries were taken from the literature. Mortality rates were obtained from the World Health Organization. RESULTS: The rate (mean +/- SD) of HRT in Eastern Europe was 2.88 +/- 2.67%, whereas 12.67 +/- 9.97% in Western Europe and the United States, p < .05. The cardiovascular mortality rate per 100,000 women older than 45 years in Eastern Europe was higher (1766 +/- 158.3) than in the Western countries (1155 +/- 164.1, p < .001). CONCLUSIONS: The rate of HRT is markedly lower. whereas CV mortality rates are notably higher in Eastern Europe than in the United States or Western Europe. Because HRT seems to be underutilized in Eastern Europe, to increase its use might be an important tool to improve CV mortality rates. However, due to the risks associated with HRT, other measures to prevent coronary heart disease, such as smoking cessation programs, and other efforts should also be considered in Eastern Europe.

Aged↗
PubMed2000

Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.

OBJECTIVE: To determine whether hormone replacement therapy can reverse established renal microvascular damage in type 2 diabetes and hypertension. DESIGN: Prospective, single centre clinical trial. SETTING: Outpatient clinics. PARTICIPANTS: Sixteen diabetic and hypertensive postmenopausal women (age 47-57 years) METHODS: Administration of a cyclic combination of oestradiol and norgestrel orally for 3.5 monthly cycles. RESULTS: Comparing the baseline values, mean (SD) 24-hour urine protein excretion was reduced from 0.452 g (0039) to 0.370 g (0.047) (P < 0.01) and creatinine clearance was increased from 1.68 mL/sec (0.11) to 1.77 mL/sec (0.08) (P < 0.05). Fasting plasma glucose also improved from 6.92 mmol/L (0.47) to 6.51 mmol/L (0.28) (P < 0.05), as did serum total cholesterol from 7.26 mmol/L (0.28) to 6.65 mmol/L (0.14) (P < 0.05). Blood pressure did not change significantly. Univariate linear regression analysis showed no significant correlation between the individual changes in blood pressure, fasting plasma glucose or serum cholesterol and the individual changes in proteinuria or creatinine clearance. CONCLUSIONS: This study shows that hormone replacement therapy may reduce proteinuria, and even improve creatinine clearance, in diabetic and hypertensive postmenopausal women. These effects are additive to nephroprotective therapy, and the mechanisms appear unrelated to conventional risk factors for vascular complications, such as high blood pressure, elevated plasma glucose or serum cholesterol.

Blood Glucose↗
PubMed2000

Alterations of venous drug reactivity in humans: acquired and genetic factors.

Until recently, studies dealing with veins have almost always been the neglected part of vascular research. Recent data show an increasing rate of venous disease, and increasing evidence supports a role for veins in systemic diseases. The authors discuss and comment on findings of recent studies on venous drug reactivity. Alterations in venous reactivity to alpha- and beta-adrenergic, NO-dependent, and other drugs have been shown in many genetically determined and acquired conditions, such as hypertension, smoking, and aging. In some of them, the changes of venous responsiveness are most likely secondary to another process, while in others the they seem to play a primary role in the development of systemic disease states. Studying the drug reactivity of the venous system more extensively provides useful information for clinicians and researchers and will no doubt help to further knowledge of the normal and pathologic processes of the vasculature.

Animals↗
PubMed2000

The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans.

Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.

Acanthosis Nigricans↗
PubMed2000

Genetically engineered insulin analogs: diabetes in the new millenium.

Tight glucose control is essential to minimize complications in diabetic patients. However, the pharmacokinetic characteristics of the currently available rapid-, intermediate-, and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. Until recently, improvements in insulin formulations were seriously limited as advances were only achieved in insulin purity, species, and characteristics of the retarding agent. The availability of molecular genetic techniques opened new windows to create insulin analogs by changing the structure of the native protein and to improve the therapeutic properties. The first clinically available insulin analog, Lispro, confirmed the hopes by showing that improved glycemic control can be achieved without an increase in hypoglycemic events. This requires, however, optimal basal insulin replacement, either by multiple daily injections of neutral protein Hagedorn (NPH) insulin or by insulin pump. Evidence suggests that short-acting insulin analogs would be better matched by a true basal insulin than by the erratically absorbed and rather short-acting NPH insulin. Therefore, future availability of long-acting analogs raises the hope to realize the true potential benefits of the currently available short-acting analog, Lispro, and of those still awaiting approval. The introduction of new short-acting and the first truly long-acting analogs, the development of analogs with increased stability, less variability and perhaps selective action will help to develop more individualized treatment strategies targeted to specific patient characteristics and to achieve further improvements in glycemic control.

Amino Acid Sequence↗
PubMed1999

Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging.

Mutations in the Caenorhabditis elegans gene clk-1 have a major effect on slowing development and increasing life span. The Saccharomyces cerevisiae homolog COQ7 encodes a mitochondrial protein involved in ubiquinone biosynthesis and, hence, is required for respiration and gluconeogenesis. In this study, RT-PCR and 5' RACE were used to isolate both human and mouse clk-1/COQ7 homologs. Human CLK-1 was mapped to Chr 16(p12-13.1) by Radiation Hybrid (RH) and fluorescence in situ hybridization (FISH) methods. The number and location of human CLK1 introns were determined, and the location of introns II and IV are the same as in C. elegans. Northern blot analysis showed that three different isoforms of CLK-1 mRNA are present in several tissues and that the isoforms differ in the amount of expression. The functional equivalence of human CLK-1 to the yeast COQ7 homolog was tested by introducing either a single or multicopy plasmid containing human CLK-1 cDNA into yeast coq7 deletion strains and assaying for growth on a nonfermentable carbon source. The human CLK-1 gene was able to functionally complement yeast coq7 deletion mutants. The protein similarities and the conservation of function of the CLK-1/clk-1/COQ7 gene products suggest a potential link between the production of ubiquinone and aging.

Aging↗
PubMed1999

Paradoxically enhanced bradykinin-induced venodilation in young, healthy, short-term smokers.

Bradykinin is a nonapeptide, whose mechanism of vasodilation is mediated chiefly through the release of endothelium-derived relaxing factor (EDRF). Diminished vasodilatory response to EDRF has been demonstrated in many pathologic states such as hypertension, atherosclerosis, diabetes, and long-term, heavy smoking. We studied whether the diminished EDRF-mediated vasodilatory response seen in chronic diseases can be demonstrated in young, clinically healthy smokers. We used the dorsal hand-vein compliance technique, an in vivo technique used to measure response to local infusions of vasoactive substances. Full dose-response curves to bradykinin (dosing range, 0.5-500 ng/min) were generated in 11 young, healthy smokers and 11 young, healthy nonsmokers by using hand veins preconstricted with phenylephrine (dosing range, 20-6,800 ng/min). In addition, after a washout period, a single maximal dose of a non-endothelium-dependent vasodilator, isoproterenol (300 ng/min) was infused. Our results demonstrated that smokers had a greater maximal venodilation to bradykinin than did nonsmokers (106 +/- 40% vs. 69 +/- 49%; p < 0.05). The log of the dose that produced half-maximal response to bradykinin was smaller in smokers: -0.10 +/- 0.93 (0.79 ng/min) versus 0.75 +/- 0.84 (5.6 ng/min); p < 0.05. There was no difference in the maximal dilatory response to isoproterenol: 80 +/- 45% (smokers) versus 89 +/- 50% (nonsmokers), nor was there a difference in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein (2.7 +/-0.7 vs. 2.7 +/- 0.9 ng/min) between the two groups. We conclude that young, otherwise healthy smokers have a paradoxic hyperactive response to the endothelium-dependent vasodilator, bradykinin, but maintain a similar response to the nonendothelium-dependent vasodilator, isoproterenol as compared with nonsmokers. Their reactivity to the alpha1-adrenergic agonist phenylephrine was found to be intact. It is possible that a hyperactive response to EDRF in young smokers contributes to endothelium damage seen in chronic disease. To our knowledge, this is the first report on increased reactivity to bradykinin in short-term smokers.

Adult↗
PubMed1998

Supraclavicular abscess caused by Salmonella enteritidis in patient without gastrointestinal symptoms.

Soft tissue infections are among the rare manifestations of extra intestinal salmonellosis and occur more frequently in immunocompromised patients. Herein we report a case of a 51-year-old white male with type II. diabetes mellitus, diagnosed with supraclavicular abscess caused by Salmonella enteritidis. The patient denied any gastrointestinal symptoms, and stool cultures were negative. After incision, drainage, and administration of intravenous ampicillin (4 x 1.5 g/day for two weeks) the patient recovered completely. To our knowledge, this is the first reported case of cervical soft tissue abscess caused by Salmonella enteritidis without preceding gastrointestinal symptoms. We feel that the presence of diabetes was a risk factor for developing the infection.

Abscess↗
PubMed1998

Decreased beta2 adrenergic mediated venodilatation in Native Americans.

BACKGROUND: A considerable body of research has been accumulated regarding the pathogenesis and treatment of hypertension in Whites (Caucasians) and in Blacks. This research has led to more effective therapies geared specifically towards these ethnic groups. Unfortunately, very little information is available regarding the pathogenesis of hypertension and the effect of antihypertensive treatment in Native Americans (North-American Indians). Ethnic variability in the response to adrenergic mediated stimulation has been previously described, and reduced compliance of the venous system has been suggested among the possible mechanisms responsible for essential hypertension. The aim of this study was to compare venous responsiveness between Native Americans and Whites to vasoactive substances. METHODS: The alpha1-adrenergic agonist, phenylephrine and the beta2-adrenergic agonist isoproterenol were studied in 10 Native American and White volunteers. The dorsal hand vein technique was used, which is a simple, relatively non-invasive method to study the response to vasoactive substances, in vivo. RESULTS: The maximal venodilatory response to isoproterenol in the Native American group was 53.2+/-27.5%; while in the White group it was 103.4+/-66.0% (p<0.05). The maximal venoconstriction for phenylephrine in the Native American subject group was similar to that of the White group (85.4+/-24.0% vs. 89.4+/-10.9%) (p = n.s.). CONCLUSIONS: Based on our findings, we can anticipate that Native Americans may respond differently to antihypertensive therapy. However, further investigation needs to be done with an eye towards the development of drug therapy and treatment strategies tailored to this specific population.

Adrenergic alpha-Agonists↗
PubMed1997

Bradykinin-induced venodilation is not different in blacks.

AIMS: The aim of this study was to determine whether young, normotensive blacks who have been recently demonstrated to have a venodilator response to isoprenaline decreased compared with whites, also have an decreased vasodilatory response to bradykinin. METHODS: Eleven black and 11 white subjects were studied. Full dose-response curves to bradykinin (dosing range 0.5-500 ng min-1) were generated in hand veins preconstricted with phenylephrine (dosing range 20-6800 ng min-1). RESULTS: The groups had a similar maximal response to bradykinin (57.6 +/- 32.2% vs 67.8 +/- 49.3%, P = NS 95% confidence interval for the difference (CI): -47.3, 26.8). Also, the log of the dose that produced half maximal response to bradykinin was similar for the two groups (0.89 +/- 0.58 vs 0.78 +/- 0.61 ng min-1, P = NS, 95% CI: -0.42, 0.64). There was no difference between the two groups in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein. CONCLUSION: Diminished vasodilatory response to endothelium-derived relaxing factor (EDRF) does not seem to be associated with the increased prevalence of hypertension in blacks.

Adult↗
PubMed1996

Impaired beta 2-adrenergic agonist-induced venodilation in Indians of Asian origin.

OBJECTIVES: Vascular responsiveness to infusions of vasoactive substances varies between ethnic groups. Indians of Asian origin are a rapidly growing ethnic group in the United States but have not been extensively studied. We sought to determine whether there was any difference in venous responsiveness to a local infusion of vasoactive substances between Indians of Asian origin and white subjects. METHODS: We used the dorsal hand vein compliance technique to construct full dose-response curves to the beta 2-agonist isoproterenol (2 to 270 ng/min) in hand veins preconstricted with phenylephrine in 11 young white subjects and in 11 young Asian Indian subjects. In addition, six subjects in each group were randomly selected to have full dose-response curves to nitroglycerin (0.006 to 1485 ng/min) generated. RESULTS: The maximal response (E(max)) to isoproterenol was smaller in Asian Indians (33.9% +/- 41.1% in Asian Indians versus 107.0% +/- 60.1% in white subjects; p < 0.01). There was no difference in the log of the dose that produced half-maximal venodilation [log(ED50)] between the two groups (1.10 +/- 0.57 in Asian Indians versus 1.15 +/- 0.50 in white subjects). However, nitroglycerin infusion produced similar responses for both the E(max) and the log(ED50) between the two groups. CONCLUSION: These results indicate that differences may exist in beta-adrenergic responsiveness among white subjects and Indians of Asian origin. Therapy for diseases that use beta-adrenergic responses, such as hypertension, must take into account these differential vascular responses because they may affect their efficacy in Asian Indians.

Adrenergic beta-Agonists↗
PubMed1996

Prostacyclin and thromboxane production of rat and cat arterial tissue is altered independently by several vasoactive substances.

The modulation of the production of prostacyclin and thromboxane from cat and cat aortic tissue slices by different vasoactive agents has been studied in order to reveal whether the release of these main two vasoactive prostanoids goes in parallel or may be controlled independently. Norepinephrine, isoproterenol, phentolamine, propranolol, angiotensin II, vasopressin, bradykinin, thrombin, verapamil, gallopamil, dopamine or methionin enkephalin were added to the incubation medium and 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) and TxB2 (the stable metabolite of thromboxane) were determined in the supernatant by radioimmunoassay. The ratio of the release of prostacyclin and thromboxane was computed. Norepinephrine increased both prostacyclin and thromboxane release. Isoproterenol increased the ratio of prostacyclin and thromboxane released in cat aortic tissue slices. Phentolamine and propranolol had no effects. Angiotensin II induced a slight but statistically insignificant increase in the ratio of the two prostanoids released. Vasopressin increased thromboxane release only. Bradykinin stimulated the prostacyclin while thrombin stimulated the thromboxane release. Verapamil decreased both prostacyclin and thromboxane production. Gallopamil decreased prostacyclin release and increased thromboxane release from vessel wall slices in a certain concentration range causing a characteristic dose dependent minimum in the ratio of prostacyclin and thromboxane release. Dopamine separately increased prostacyclin release while enkephalin had no significant effect. The data obtained show that in vascular tissue some unidentified yet cytophysiological mechanisms might exist which specifically control the activities of the prostacyclin synthase and thromboxane synthase enzymes.

6-Ketoprostaglandin F1 alpha↗