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  • Articles  (444)
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  • 1
    facet.materialart.
    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Health Technology Assessment; VOL: 3; DOC03 /20070308/
    Publication Date: 2007-08-24
    Description: Background In Western countries hormone replacement therapy (HT) is widely used in the treatment of climacteric women who are affected with hot flashes and night sweats. Besides, long-term HT was frequently used to manage the higher risks for osteoporosis and heart attack in postmenopause. Estrogens alone or combined with progestin feature most frequently in HT. Objectives This HTA report addresses the questions on medical efficacy and cost-effectiveness of HT as a treatment of hot flashes and night sweats as well as in the primary prevention of osteoporosis and cardiovascular disease in postmenopause in general healthy women. Methods The literature search for articles published after 1998 was conducted in March 2004 in standard medical and economic databases. The analysis included randomised controlled trials, systematic reviews, meta-analysis and economic evaluations considering relevant clinical endpoints in English or German language. The quality of the studies was assessed using checklists corresponding to the study type. Results HT is highly effective in treating hot flashes in climacteric women. The question of economical efficiency cannot be answered due to the scarce database. As the positive effects (lower risk for fractures and endometrial cancer) do not outweigh the negative effects (higher risk for breast cancer and general cardiovascular risk) estrogen-progestin combination HT cannot be recommended for primary prevention of osteoporosis and cardiovascular disease in postmenopausal women. Discussion The observation period of most of the studies regarding therapy of hot flashes and night sweats were too short to evaluate possible risks of long-term HT. The economic publications assessing HT for this indication varied vastly in terms of applied methods and were not carried out with respect to the German health care system. Conclusions HT can be recommended in the short-term treatment of hot flashes and night sweats in climacteric women. To explore the economic effects of HT for this indication for Germany, studies constructed with respect to the German health care system are desirable.
    Description: Hintergrund Viele Frauen in westlichen Ländern sind von klimakterischen Beschwerden wie Hitzewallungen und nächtlichen Schweißausbrüchen betroffen, die häufig mit einer Hormontherapie (HT) behandelt werden. Darüber hinaus wurde das erhöhte Osteoporose- und Herzinfarktrisiko nach der Menopause (Postmenopause) häufig langfristig mit HT behandelt. Die wichtigste Rolle in der HT spielen bis heute die Estrogene, einzeln oder kombiniert mit Gestagenen. Fragestellung Ziel dieses Health Technology Assessment (HTA)-Berichts ist es, bei allgemein gesunden Frauen medizinische Effektivität und ökonomische Effizienz der HT zur Therapie von Hitzewallungen und nächtlichen Schweißausbrüchen sowie zur Primärprävention von Osteoporose und Herz-Kreislauferkrankungen in der Postmenopause anhand publizierter Studien zu bewerten. Methodik In den Datenbanken von MEDLINE, EMBASE, Int. Health Technology Assessment, der Cochrane Library u. a. wurden für den Zeitraum 1999 bis 23. März 2004 nur englisch- und deutschsprachige randomisierte Studien, systematische Übersichtsarbeiten und ökonomische Evaluationen zu patientinnennahen Endpunkten berücksichtigt und bei Erfüllung qualitativer Mindestanforderungen bewertet. Ergebnisse Zur Therapie von Hitzewallungen und nächtlichen Schweißausbrüchen im Klimakterium erwies sich die HT als effektiv. Die Frage der ökonomischen Effizienz konnte aufgrund einer schwachen Datenbasis nicht beantwortet werden. Kombinations-HT kann nicht zur Primärprävention von Osteoporose und Herz-Kreislauferkrankungen bei postmenopausalen Frauen empfohlen werden, da die negativen (erhöhtes Brustkrebs- und allgemeines kardiovaskuläres Risiko) durch die positiven (reduziertes Fraktur- und Darmkrebsrisiko) Effekte nicht aufgewogen werden. Diskussion Die Mehrzahl der Studien zur Therapie von Hitzewallungen und nächtlichen Schweißausbrüchen war zu kurz, um langfristige Therapierisiken zu beurteilen. Die ökonomischen Untersuchungen variierten stark hinsichtlich der Methodik und wurden nicht vor dem Hintergrund des deutschen Gesundheitswesens durchgeführt. Schlussfolgerung Die HT kann zur kurzfristigen Behandlung von Hitzewallungen und nächtlichen Schweißausbrüchen empfohlen werden. Zu den ökonomischen Auswirkungen der HT bei dieser Indikation besteht für Deutschland erheblicher Forschungsbedarf. Als primärpräventive Maßnahme bei gesunden Frauen in der Postmenopause kann sie nicht empfohlen werden.
    Keywords: HORMONE ; HORMONES ; HORMONE REPLACE THER ; HORMONE REPLACEMENT THERAPY ; HORMONE REPLACEMENT THERAPIES ; HORMONE REPLACEMENT THERAPY, POST MENOPAUSAL ; HORMONE REPLACEMENT THERAPY, POST-MENOPAUSAL ; MENOPAUSE ; CLIMACTERIC ; CLIMACTERICS ; PREVENTIVE MEDICINE ; RISK ; RISKS ; HORMONE ; HORMONE ; HORMON-SUBSTITUTIONSBEHANDLUNG ; HORMON-SUBSTITUTIONSBEHANDLUNG ; HORMON-SUBSTITUTIONSBEHANDLUNG ; ÖSTROGENSUBSTITUTIONSTHERAPIE ; ÖSTROGENSUBSTITUTIONSTHERAPIE ; MENOPAUSE ; KLIMAKTERIUM ; KLIMAKTERIUM ; PRÄVENTIVMEDIZIN ; RISIKO ; RISIKO ; Hormone ; Hormon-Substitutionsbehandlung ; Hormonsubstitutionstherapie ; Post-Menopause ; Menopause ; Klimakterium ; Praeventivmedizin ; Risisko ; ddc: 610
    Language: German
    Type: article
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  • 2
    facet.materialart.
    Unknown
    German Medical Science; Düsseldorf, Köln
    In:  GMS Current Topics in Otorhinolaryngology - Head and Neck Surgery; VOL: 3; DOC06 /20041228/
    Publication Date: 2004-12-29
    Description: Hearing loss from occupational and leisure noise numbers amongst the most frequent causes of an acquired sensorineural hearing loss. Here we present a review of up-to-date findings on the pathophysiology of acoustic injury to the inner ear, with special attention being paid to its molecular-biological and genetic aspects. Epidemiological aspects shall also be dealt with, as shall the roles of lacking recovery from occupational noise due to additional exposure by leisure noise and the combined exposure of noise and chemicals. Based on the epidemiological and pathophysiological findings and against the background of published animal-experimental, pre-clinical and clinical findings, the various approaches for prevention, protection and therapeutic intervention with acoustic trauma are discussed. Pharmacological strategies involving anti-oxidative, anti-excitotoxic and anti-apoptotic substances as well as non-pharmacological strategies like "sound conditioning" are given attention. Furthermore, systemic and local substance application as well as the therapy of acute acoustic trauma and chronic hearing problems (including modern therapy forms for comorbidities such as tinnitus) shall be delved into.
    Keywords: acute acoustic trauma ; noise-induced hearing loss ; recreational ; leisure noise ; occupational ; prevention ; protection ; therapy ; animal ; human ; ddc: 610
    Language: English
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  • 3
    ISSN: 1573-904X
    Keywords: methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
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  • 4
    ISSN: 1573-7322
    Keywords: hypertrophy ; pacing ; hemodynamics ; review ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ventricular hypertrophy due to genetic mutations of sarcomeric proteins or that associated with long-standing hypertension typically yields a cavity with hyperdynamic ejection, elevated diastolic pressures, and limited filling volumes. The net result is reduced reserve capacity, dyspnea with exertional intolerance, and chest discomfort despite normal appearing coronary vessels. In addition to pharmacologic therapy by agents having negative inotropic effects, recent studies have examined the potential of ventricular pacing using right apical pre-excitation as a treatment for these disorders. This form of pacing can increase end-systolic volume and reduce cavity obliteration in both forms of the disease, yet has no demonstrable acute benefit on diastolic function. Chronic therapy trials have yielded mixed results, with more favorable responses observed in older patients particularly those with hypertensive hypertrophic disease. These data have also highlighted the importance of enhancing systolic reserve rather than diastolic function as a key therapeutic effect from pacing therapy. This review discusses the mechanisms by which pacing with ventricular pre-excitation acutely influences ventricular function, and summarizes results of recent clinical trials, putting the data into perspective regarding the relative role of systolic versus diastolic effects in these patients.
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  • 5
    ISSN: 1573-7330
    Keywords: Apoptosis ; CD44 ; human ; hyaluronic acid ; granulosa cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: This study was designed to examine whether hyaluronicacid (HA) inhibits apoptosis in cumulus and muralgranulosa cells and to examine whether this effect of HAwas mediated through CD44. Methods: Mural and cumulus granulosa cells were obtainedfrom in vitro fertilization patients. The cells were culturedwith various concentrations of HA or HA plus variousconcentrations of anti-CD44 antibody without serum supplement.After 24 hr of culture, the cells were fixed and stainedwith Hoechst 33258. One thousand granulosa cells of eachconditions were observed by fluorescence microscopy. Results: HA inhibited apoptosis in both kinds of granulosacells, and anti-CD44 antibody prevented this effect of HA.Conclusions: The incidence of apoptotic granulosa cellswith fragmented condensed nuclei was reduced by HA viaCD44.
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  • 6
    ISSN: 1573-742X
    Keywords: osteonectin ; acute myocardial infarction ; thrombolysis ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet α-granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447.7±20.6 ng/ml) and AMI patients (425.7±43.3 ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4±26.9 ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this α-granule constituent, challenge the postulate of uniform platelet activation in AMI patients.
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  • 7
    ISSN: 1573-7276
    Keywords: bone metastasis ; breast carcinoma ; histomorphometry ; human ; immunohistochemistry ; MMP ; TIMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP- 1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.
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  • 8
    ISSN: 1573-7322
    Keywords: heart failure ; human ; cytoskeleton ; contractile dysfunction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, α-actinin, myomesin, and M-protein. 3) True ‘cytoskeletal’ proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and α-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.
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  • 9
    ISSN: 1573-8221
    Keywords: human ; embryogenesis ; blood vessels ; encephalon ; electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It was found that intracerebral blood vessels in human embryo telencephalon first appear on the 7th week of prenatal development as capillaries with poorly differentiated walls and signs of functional immaturity. The formation of the basal capillary membrane consisting of laminin and type IV collagen starts immediately after the formation of primary capillary network.
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  • 10
    ISSN: 1573-8221
    Keywords: human ; Body surface area
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A novel universal mathematical model for calculation of human body surface area with maximum accuracy is proposed.
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  • 11
    ISSN: 1573-742X
    Keywords: alcohol ; platelets ; acute myocardial infarction ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Moderate alcohol consumption (MAC) and platelet inhibition have been independently associated with a reduced risk for the development of acute myocardial infarction (AMI). The effects of MAC on the initial platelet status in patients presenting with AMI are not elucidated. Here we sought to define the effects of MAC on platelet characteristics in AMI patients before applying any reperfusion strategies. The study was designed as an analysis within the cohort study in 23 patients with AMI enrolled in the GUSTO-III. Platelets were investigated by different techniques, including aggregometry, flow cytometry, and ELISA. MAC patients exhibited mild, but consistent, inhibition of platelet aggregability, surface receptor expression, and released substances as compared to non-alcohol consuming patients. These differences were significant for 5 µM ADP (p = 0.04), 10 µM ADP-induced aggregation (p = 0.02); P-selectin (p = 0.01), and PECAM-1 (p = 0.02) platelet-bound expression. Our study confirms that moderate alcohol consumption is associated with diminished platelet activation in patients presenting with AMI. The ability of MAC to favorably modulate the pre-reperfusion platelet status in such patients is of clinical importance, and further investigation in large-scale clinical trials seem warranted.
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  • 12
    ISSN: 1573-4943
    Keywords: Creatine kinase ; human ; expression ; brain ; muscle ; purification ; kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We report the expression of the human muscle (CK-MM) and brain (CK-BB) creatine kinases in Escherichia coli. The proteins have been purified to apparent homogeneity and several of their physical and kinetic properties investigated. In the process, we have conclusively verified the correct DNA sequence of the genes encoding the respective isozymes, and determined the correct primary structure and mass of the gene products. Alignment of the primary sequences of these two enzymes shows 81% sequence identity with each other, and no obvious gross structural differences. However, Western blot analyses demonstrated the general lack of antigenic cross-reactivity between these isozymes. Preliminary kinetic analyses show the K m and k cat values for the creatine and MgATP substrates are similar to values reported for other isozymes from various tissues and organisms. The human muscle and brain CKs do not, however, exhibit the synergism of substrate binding that is observed, for example, in rabbit muscle creatine kinase.
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  • 13
    ISSN: 1573-4919
    Keywords: apolipoprotein C-III ; hepatic plasma membranes ; specific binding ; human ; mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Apo C-III plays an important role in the metabolism of plasma triglyceride, which can delay the catabolism of triglyceride-rich lipoproteins by interfering with apo E-mediated receptor clearance of remnant particles from plasma. The mechanism of the interference has not yet been defined. To further explore the role of apo C-III, we first injected mice with 125I-apo C-III. The measurement of radioactivity showed that liver took up 3.3-10 fold as much radioactivity as other organs such as heart, spleen, lung, kidney, stomach, large intestine, small intestine, and muscle. This was confirmed by incubating the tissue homogenates of the organs with 125I-apo C-III that the radiolabeled apo C-III specifically bound to only hepatic homogenate. To investigate which subcellular part or parts of hepatic cells play the role of binding to apo C-III, hepatic cell components of nucleus, mitochondria, microsomes and plasma membranes were then incubated with 125I-apo C-III. The radiolabeled apo C-III could specifically bind to only hepatic plasma membranes. Finally hepatic plasma membranes were purified to study the characteristics of the specific binding with apo C-III. Addition of increasing concentration of 125I-apo C-III to human hepatic plasma membranes revealed saturable binding to membranes with a Kd of 0.31±0.07 μmol/l. The maximum specific binding capacity was 1.74±0.45 μ apo C-III/mg membrane protein. In competition studies using unlabeled apo C-III and isolated lipoproteins HDL, LDL and VLDL, only apo C-III and VLDL effectively competed with 125I-apo C-III for membrane binding. The binding of 125I-apo C-III to human liver plasma membranes was Ca2+-independent, and was abolished when plasma membranes were treated with trypsin. The characteristics of 125I-apo C-III binding to mouse liver plasma membranes were similar to those of human liver plasma membranes with the exception of a binding maximum of 1.52±0.39 μapo C-III/mg membrane protein. We conclude that apo C-III exhibits high-affinity binding to hepatic plasma membranes, which is saturable, reverse and specific.
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  • 14
    ISSN: 1572-8773
    Keywords: Al ; human ; lymphocytes ; urine concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The purpose of this study was to examine whether oral exposure to aluminum (Al) can affect the human immune system. Eighteen healthy volunteers (mean age 42, 28–57 yr) were divided into a test group (9 females, 4 males) and a referent group (3 females, 2 males). Over 6 weeks, the test subjects ingested 10 ml of antacid (aluminum hydroxide, 59 mg Al/ml) three times daily. Aluminum was analyzed in urine before and during the exposure period (ICP-MS). Blood samples were used for analysis of lymphocyte subpopulations, mitogen-induced lymphocyte proliferation and in vitro production and circulating plasma concentrations of immunoglobulin (Ig) A, IgG, IgM, interleukin (IL) -2 and IL-4. Urinary Al concentration in the test subjects was approximately 10- to 20-fold higher than in the referent group during exposure. This indicates that ingestion of an Al-containing antacid is associated with an Al absorption far above that originating from food and drinking water. In both referents and test subjects the lymphocyte subpopulations, lymphocyte proliferation and the in vitro Ig and IL production showed similar, time-dependent changes before as well as during the exposure period. No major differences were seen between the referent and test groups regarding the immune parameters, except for a slightly smaller CD8+CD45R0+ population (primed cytotoxic T-cells), in the exposed individuals as compared to the referents. The results also show that subjects on antacid therapy may constitute a suitable population for studying biological effects of high-dose oral exposure to Al.
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  • 15
    ISSN: 1573-6849
    Keywords: chimpanzee ; chromatin condensation ; human ; mouse ; XY body
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We used multicolour fluorescence in-situ hybridization on air-dried pachytene nuclei to analyse the structural and functional domains of the sex vesicle (SV) in human, chimpanzee and mouse. The same technology associated with 3-dimensional analysis was then performed on human and mouse pachytene nuclei from cytospin preparations and tissue cryosections. The human and the chimpanzee SVs were very similar, with a consistently small size and a high degree of condensation. The mouse SV was most often seen to be large and poorly condensed, although it did undergo progressive condensation during pachynema. These results suggest that the condensation of the sex chromosomes is not a prerequisite for the formation of the mouse SV, and that a different specific mechanism could be responsible for its formation. We also found that the X and Y chromosomes are organized into two separate and non-entangled chromatin domains in the SV of the three species. In each species, telomeres of the X and Y chromosomes remain clustered in a small area of the SV, even those without a pseudoautosomal region. The possible mechanisms involved in the organization of the sex chromosomes and in SV formation are discussed.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Biogerontology 1 (2000), S. 103-121 
    ISSN: 1573-6768
    Keywords: human ; immortalization ; senescence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Following a limited number of population doublings(PD), human diploid somatic cells enter the terminalproliferation arrest state of senescence. This is anintrinsic mechanism which involves p53- andpRB/p16INK4-mediated pathways. The mostpopular candidate for the counting mechanism whichmeasures the age of a cell in PD is telomereshortening. Recent studies have shown that senescencecan also be induced independently of a PD levelby various factors; this premature senescence alsoappears to involve the activity of p53 and/orp16INK4. Immortalization of cells requiresabrogation of p53 and pRB-mediated terminalproliferation arrest and/or activation of a telomeremaintenance mechanism. The central role of telomeresin human cell senescence and immortalization hasreceived much attention; however there is evidencethat senescence can occur independently of telomerelength and that genes that are not necessarily involved in telomere maintenance are involved in immortalization.
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  • 17
    ISSN: 1573-675X
    Keywords: Apoptosis ; differential display ; human ; placenta.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Placenta is a transient feto-maternal association that develops during mammalian pregnancies. Human placental tissue during the first trimester of pregnancy is an actively dividing and differentiating tissue, while near term, it represents a fully differentiated unit performing many life-sustaining functions for the fetus. Previous studies have demonstrated that the percentage of placental cells that undergo apoptosis is greater at full term as compared to the first trimester of pregnancy. In this study, we undertook a study aimed at gaining an insight into the kind of genes expressed in the two developmentally distinct stages of gestation ie, the first trimester and term using Differential Display RT-PCR. Cloning and sequencing of one of the differentially expressed cDNAs from term placental tissue revealed that it is a novel gene, referred to as T-18 in the text. In this study, we also examined the regulation of this gene during apoptosis in the human placenta. A model for analysis of placental apoptosis was established by incubating placental villi in serum-free culture medium. It was observed that apoptosis occurred rapidly following incubation of placental villi without tropic support, and the proposed free-radical scavenger, superoxide dismutase (SOD) suppressed apoptosis in the placenta. Interestingly, the levels of T-18 mRNA increased significantly during spontaneous induction of apoptosis and decreased when apoptosis was blocked by SOD. These data clearly suggest that there is a strong correlation between the expression of T-18 and placental apoptosis and that T-18, may play a significant role in this process. Furthermore, the establishment of a defined in vitro explant culture model should facilitate elucidation of factors, which regulate apoptosis in human placenta.
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  • 18
    ISSN: 1573-6849
    Keywords: gene mapping ; human ; R-banding ; river buffalo ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 19
    ISSN: 1573-6849
    Keywords: cat ; chromosome painting ; comparative mapping ; dog ; evolution ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Domestic cats and dogs are important companion animals and model animals in biomedical research. The cat has a highly conserved karyotype, closely resembling the ancestral karyotype of mammals, while the dog has one of the most extensively rearranged mammalian karyotypes investigated so far. We have constructed the first detailed comparative chromosome map of the domestic dog and cat by reciprocal chromosome painting. Dog paints specific for the 38 autosomes and the X chromosomes delineated 68 conserved chromosomal segments in the cat, while reverse painting of cat probes onto red fox and dog chromosomes revealed 65 conserved segments. Most conserved segments on cat chromosomes also show a high degree of conservation in G-banding patterns compared with their canine counterparts. At least 47 chromosomal fissions (breaks), 25 fusions and one inversion are needed to convert the cat karyotype to that of the dog, confirming that extensive chromosome rearrangements differentiate the karyotypes of the cat and dog. Comparative analysis of the distribution patterns of conserved segments defined by dog paints on cat and human chromosomes has refined the human/cat comparative genome map and, most importantly, has revealed 15 cryptic inversions in seven large chromosomal regions of conserved synteny between humans and cats.
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  • 20
    ISSN: 1573-6792
    Keywords: conductivity ; skull ; human ; inhomogeneity ; spongiosum ; compact layer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study, electrical conductivities of compact, spongiosum, and bulk layers of cadaver skull were determined at varying electric fields at room temperature. Current was applied and withdrawn over the top and bottom surfaces of each sample and potential drop across different layers was measured using the four-electrode method. We developed a model, which considers of variations in skull thicknesses, to determine the conductivity of the tri-layer skull and its individual anatomical structures. The results indicate that the spongiform and the two compact layers of the skull have significantly different and inhomogeneous conductivities ranging from 0.76 ∓ .14 to 11.5 ∓ 1.8 milliS/m.
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  • 21
    ISSN: 1573-6849
    Keywords: autoantibodies ; cell cycle ; DNA replication ; human ; MCP1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Metaphase chromosome protein 1 (MCP1) is a nuclear autoantigen that is associated with condensed chromosomes throughout mitosis. During interphase, this antigen shows a speckle distribution in the nucleus, excluding the nucleolus. Additionally, MCP1 binds tightly to the scaffold/matrix component of nuclei and isolated chromosomes. In order to determine the in-vivo localization of the antigen, we have expressed MCP1 fused to EGFP in tissue culture cells. The results demonstrate that MCP1 is located in the nucleus during interphase and during mitosis associates tightly to condensed chromosomes. Furthermore, microinjection of specific antibody confirms these results. We have used a specific monoclonal antibody (mAb 402) against MCP1 to assess the function of this antigen during cell cycle progression. HeLa and Ptk-2 cells that were microinjected into the nucleus and/or cytoplasm at G1/S and very early S phase were not able to progress and complete DNA replication. However, injection of mAb 402 at mid or late S phase does not prevent completion of DNA replication and subsequent progression into mitosis. Microinjection of mAb 402 in Ptk-2 cells synchronized in mitosis did not interfere with progression of mitosis and cells divided. Our results suggest that MCP1 is required at the G1/S transition and during early S phase.
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  • 22
    ISSN: 1573-6903
    Keywords: Isoprostanes ; thromboxanes ; norepinephrine ; human ; iris-ciliary body
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Isoprostanes (IsoP's) are prostaglandin-like compounds that are derived from free-radical catalyzed peroxidation of arachidonic acid independent of the cyclcooxygenase enzyme. In the present study, we investigated the effect of IsoP's on norepinephrine (NE) release from human isolated iris-ciliary bodies. Isolated human iris-ciliary bodies were prepared for studies of [3H]NE release using the superfusion method. Both 8-iso-prostaglandin F2α (F2-IsoP) and the thromboxane (Tx) receptor agonist, U46619 enhanced field-stimulated [3H]NE release from isolated, superfused human iris-ciliary bodies without affecting basal tritium efflux. On the other hand, an equimolar concentration (10 μM) of 8-iso-prostaglandin E2 (E2-IsoP) inhibited evoked [3H]NE overflow. The Tx-receptor antagonist, SQ 29548 blocked the enhancements of electrically-evoked [3H]NE release induced by F2-IsoP and U46619. However, the inhibitory responses elicited by E2-IsoP was not antagonized by SQ 29548. We conclude that IsoP's can produce both excitatory and inhibitory effects on sympathetic neurotransmission in human isolated iris-ciliary bodies. The stimulatory effects of IsoP' on NE release may be mediated by Tx-receptors.
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  • 23
    ISSN: 1573-2568
    Keywords: growth hormone ; intestinal absorption ; intestinal secretions ; human ; jejunum ; intestinal perfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies in rats showed that the administration of recombinant human growth hormone markedly increased intestinal absorption of electrolytes and water and suggested that growth hormone would be a useful antidiarrheal agent. We therefore examined the effect of recombinant human growth hormone on the human jejunum in vivo, using a triple lumen nonabsorbable marker technique. Healthy subjects were studied on two different test days, one as a control and a second where recombinant human growth hormone was injected subcutaneously in a dose of 100 μg/kg. With this dose we achieved equal or higher growth hormone serum levels than in previous rat studies. However the administration of recombinant human growth hormone did not stimulate absorption or inhibit secretion of water and electrolytes in the human jejunum in vivo. We believe that the discrepancy between humans and rats is most likely due to the species difference rather than to differences in methods that were used. Therefore recombinant human growth hormone cannot be considered a useful proabsorptive antidiarrheal agent in humans.
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  • 24
    ISSN: 1573-2592
    Keywords: IL-18 ; sepsis ; human ; endotoxemia ; cytokines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1β and acts in part by inducing interferon-gamma (IFN-γ). Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge. In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1122 ± 259 pg/ml) in nine septic patients compared to six healthy adults (191 ± 42 pg/ml), P 〈 0.01). Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor. Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response. Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis.
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  • 25
    ISSN: 1573-2622
    Keywords: diabetes ; ERG ; glucose ; human ; photopic ; retina
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Circulating glucose was manipulated in young human volunteers with clinically normal vision. Fasting achieved a concentration range of 45-91 mg/dl. And sugar loading produced a range of 79-108 mg/dl. Glucose increased in all subjects. A nonparametric ANOVA provided a p=0.0005 for the significance of the concentration differences between group glucose concentrations under the two conditions in the sample. Each volunteer participated in each condition of the repeated-measures design. Clinical tests were completed before electroretinograms were recorded under photopic and scotopic adaptation conditions. Measures were made from 12 eyes. Only photopic adaptation conditions with maximal stimuli produced significant results. Inter-individual differences were robust and constrained to reduced implicit times for b-wave peaks and 30 Hz flicker implicit times. Under the elevated glucose conditions. Other variables showed very strong trends. These results confirm and extend other human indications of photopic retinal sensitivity to variations within the normal range of circulating glucose concentrations.
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  • 26
    Electronic Resource
    Electronic Resource
    Springer
    Annals of clinical psychiatry 12 (2000), S. 171-173 
    ISSN: 1573-3238
    Keywords: serotonin uptake inhibitors ; pharmacology ; testosterone ; metabolism ; human ; antidepressive agents ; adverse effects ; case report ; paraphilia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We report on a patient with a low testosterone level which occurred during treatment with venlafaxine. The testosterone level increased when the medication was discontinued. Possible clinical correlation with amelioration of paraphilia is discussed.
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  • 27
    ISSN: 1435-1463
    Keywords: Keywords: Mouse ; cat ; human ; rat ; striatum ; adenosine A2A receptors ; 6-OH-dopamine.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Adenosine A2A receptors are present on enkephalinergic medium sized striatal neurons in the rat and have an important function in the modulation of striatal output. In order to establish more accurately whether adenosine transmission is a generalized phenomenon in mammalian striatum we compared the A2A R expression in the mouse, rat, cat and human striatum. Secondly we compared the modulation of enkephalin gene expression and A2A receptor gene expression in rat striatal neurons after 6-OH-dopamine lesion of the substantia nigra. Hybridization histochemistry was performed with a 35S-labelled radioactive oligonucleotide probe. The results showed high expression of A2A adenosine receptor genes only in the medium-sized cells of the striatum in all examined species. In the rat striatum, expression of A2A receptors was not significantly altered after lesion of the dopaminergic pathways with 6-OH-dopamine even though enkephalin gene expression was up-regulated. The absence of a change in A2A receptor gene expression after 6-OH-dopamine treatment speaks against a dependency on dopaminergic innervation. The maintained inhibitory function of A2A R on motor activity in spite of dopamine depletion could be partly responsible for the depression of locomotor activity observed in basal ganglia disorders such as Parkinson's disease.
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  • 28
    ISSN: 1432-0428
    Keywords: Keywords Islets ; pig ; xenograft ; human ; lymphocytes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The intensity and mechanisms of cell-mediated rejection of pig islet cells were studied in 49 Type I diabetic and 34 healthy subjects. Human peripheral mononuclear cells proliferated strongly in response to pig islet cells (p 〈 0.001), though with notable interindividual variations (stimulation index 2 to 215). The variance of stimulation index was higher in diabetic than healthy subjects (p 〈 0.0001). The response to islet cells was stronger (p 〈 0.01) than that to pig splenocytes. Proliferation in response to islet cells was strongly decreased (p 〈 0.01) when CD4 + T cells were blocked with monoclonal antibodies, whereas the blocking of CD8 + cells or NK cells gave less pronounced effects. The response to islet cells was decreased (p 〈 0.01), but not abolished, after antigen-presenting cells were removed. Purified CD4 + cells alone did not proliferate in response to islet cells but recovered their proliferative ability when mixed with antigen-presenting cells, whereas CD8 + cells alone proliferated in the presence of interleukin-2 in response to islet cells. Proliferation was blocked (p 〈 0.01) by anti-DR monoclonal antibodies. During proliferation in response to islet cells, interleukin-10 increased 43-fold (p 〈 0.01) but interferon-γ increased only slightly. No statistical differences were detected between diabetic and control subjects with respect to lymphocyte subsets and the recognition mechanisms or to interferon-γ / interleukin-10 production in response to islet cells. These results provide the first detailed information on human cell-mediated xenoreaction to pig islet cells. This situation involves a dominant CD4 class II-restricted Th2 response, with an indirect recognition pathway, as well as a CD8 T-cell response resulting from direct recognition. This strong reaction constitutes a serious obstacle which may vary in degree among subjects. [Diabetologia (1999) 42: 330–335]
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  • 29
    ISSN: 1573-899X
    Keywords: Thalamus ; human ; ventrolateral nucelus ; single and network neuron activity ; voluntary movement ; rhythmic spike processes ; Parkinson's tremor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The responses of neurons in the ventrolateral nucleus (VL) of the thalamus were studied in humans during performance of voluntary motor tests; recordings were made with microelectrodes during stereotaxic operations in patients with Parkinson's disease. Two previously classified types of polyvalent neurons (A, B) were found to show different patterns of responses during the functional stages of carrying out a voluntary movement (preparation, initiation, performance). A and B neurons showed concordant changes in the dynamics of ongoing network activity in the form of linked (activation-inhibition) and synergic (activation) response patterns, correlating with the preparation-trigger and performance phases of movements. It is suggested that the simultaneous activity of both types of neuron, with their common functional nature, reflects integrative processes occurring in the ventrolateral nucleus and associated with programming and processing of general signal parameters but not with the performance of any particular movement. The anterior (Voa nucleus) and posterior (Vop) parts of the ventrolateral nucleus were found to have different roles in organizing voluntary movements, associated with differences in their cellular organization and mechanisms of transmitting motor signals. It is suggested that the concordant changes in the activities of the two types of neurons in these areas seen during the performance of voluntary movements gives the ventrolateral nucleus a key role in the motor control system in humans.
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  • 30
    ISSN: 1573-904X
    Keywords: Cereport ; bradykinin B2 receptor ; human ; brain endothelium ; permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability. Methods. HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [I4C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000). Results. Cereport increased the HBMEC permeability to [l4C]-inulin, but not to [3H]-dextran. The effect was transient, maximal at 15 min (i.e., 79.3% increase), and polarized to the basolateral membrane. An inverted U, dose-response curve was observed with active concentrations of Cereport from 0.01 to 0.5 nmol/L, the plateau maximal effect between 0.5 and 10 nmol/L, and loss of activity at the highest concentration, i.e., 20 nmol/L. Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 μmol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 μmol/L) enhanced by 31 % (p 〈 0.05) the effect of 0.1 nmol/L Cereport. Unlabeled Cereport displaced [12 5I]-bradykinin and/or [125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side. Conclusions. Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its effects can be further modulated through changes in cAMP and cGMP second messenger systems.
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  • 31
    ISSN: 1573-7217
    Keywords: α2‐adrenergic agonists ; α2‐adrenergic antagonists ; α2‐adrenoceptor ; breast cancer ; catecholamines ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract (-)Epinephrine (Epi) and –Norepinephrine (NEpi) significantly stimulated tritiated Thymidine incorporation in MCF‐7 cells at concentrations 10–30 pM to 10 nM, with an EC50 of 10 pM for Epi and 14.2 pM for NEpi. To characterize this action, cells were incubated in the presence of NEpi or Epi and different antagonists. The β‐adrenergic antagonist Propanolol showed no effect on the agonist's stimulation, whereas the α‐adrenergic antagonist Phentolamine, reverted it completely at high concentrations (100 μM). The α1‐adrenergic antagonist Prazosin (Pra) acted only at high concentrations, while the α2‐adrenergic antagonist Yohimbine (Yo) reverted the stimulation at an EC50 of 0.11μM. Likewise, when the cells were incubated in the presence of the specific α2‐adrenergic agonist Clonidine (Clo), Thymidine incorporation was significantly stimulated at an EC50 of 0.298 pM. Again, the incubation of the cells in the presence of the α1‐adrenergic antagonist Pra exerted its action at high concentrations, whereas the α2‐adrenergic antagonist Yo showed a clear reversal of the agonist's enhancement at an EC50 of 0.136 μM. Moreover, Clo caused a clear and significant inhibition of stimulated cAMP levels both in the intracellular and the extracellular fractions. Yo showed a complete reversion of cAMP levels to control values in the presence of Clo, while Pra had the opposite effect. These data suggest that the stimulation provoked in Thymidine incorporation by the agonists Epi, NEpi, and Clo is, at least in part, due to an α2‐adrenergic mechanism directly on tumoral cells, and that the effect is coupled with inhibition of cAMP levels, as described for this kind of receptors.
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  • 32
    ISSN: 1573-7330
    Keywords: human ; medium ; ICSI ; embryo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Our purpose wax to evaluate the efficiency of a medium, devoid of any human or animal compound and specially designed for early embryo development (from the zygote to the eight-cell stage), SMART2, in intracytoplasmic sperm injection (ICSI) and to compare it with a medium containing human serum albumin (EllioStep2). Methods: Oocytes from 50 ICSI attempts were randomly placed, after sperm injection, into either SMART2 or EllioStep2. After a 48-hr incubation, the embryos were examined for quality scoring before transfer or freezing. Results: The percentage of normally fertilized oocytes per intact oocytes was slightly higher using SMART2 (139/199 vs. 135/224, respectively, for SMART2 and EllioStep2: P 〈 0.05). The distribution of embryo scores and the percentage of embryos with a fair morphology (71/143 vs. 72/148, respectively, for SMART2 and EllioStep2; not significant) were identical in both media. Conclusions: These data show that SMART2 medium can be successfully used for early embryo growth and, because it is devoid of any human or animal compound, offers better safety for patients than conventional media.
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  • 33
    Electronic Resource
    Electronic Resource
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    Sepsis 3 (1999), S. 335-344 
    ISSN: 1573-7411
    Keywords: human ; inflammation ; bacterial infections ; peritonitis ; immunology ; genetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Normal peritoneal response to microorganisms is characterized by hyperemia, exudation of protein-rich fluid into the peritoneal cavity and marked influx of neutrophils, universally known as peritonitis. Under favorable circumstances for the host, peritoneal and systemic defense mechanism can remove infection from peritoneal cavity (resolution) or at least manage to contain infection (intra-abdominal abscess). Normal peritoneal response to infection may be altered by local peritoneal and systemic factors resulting in a non-efficient mechanism that interfere with the ability of the host to eradicate infection from the peritoneal cavity or further damage the peritoneal interface.
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  • 34
    Electronic Resource
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    Neurochemical research 24 (1999), S. 1385-1395 
    ISSN: 1573-6903
    Keywords: Epilepsy ; human ; amino acids ; glutamate ; GABA ; polyamines ; phosphoinositol ; metabotropic glutamate receptors ; microdialysis ; nuclear magnetic resonance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Studies of neuroactive amino acids and their regulatory enzymes in surgically excised focally epileptic human brain are reviewed. Concentrations of glutamate, aspartate and glycine are significantly increased in epileptogenic cerebral cortex. The activities of the enzymes, glutamate dehydrogenase and aspartate aminotransferase, involved in glutamate and aspartate metabolism are also increased. Polyamine synthesis is enhanced in epileptogenic cortex and may contribute to the activation of N-methyl-D-aspartate (NMDA) receptors. Nuclear magnetic resonance spectroscopy (NMRS) reveals that patients with poorly controlled complex partial seizures have a significant diminution in occipital lobe gamma aminobutyric acid (GABA) concentration. The activity of the enzyme GABA-aminotransaminase (GABA-T) which catalyzes GABA degredation is not altered in epileptogenic cortex. NMRS studies show that vigabatrin, a GABA-T inhibitor and effective antiepileptic, significantly increases brain GABA. Glutamate decarboxylase (GAD), responsible for GABA synthesis, is diminished in interneurons in discrete regions of epileptogenic cortex and hippocampus. In vivo microdialysis performed in epilepsy surgery patients provides measurements of extracellular amino acid levels during spontaneous seizures. Glutamate concentrations are higher in epileptic hippocampi and increase before seizure onset reaching potentially excitotoxic levels. Frontal or temporal cortical epileptogenic foci also release aspartate, glutamate and serine particularly during intense seizures or status epilepticus. GABA in contrast, exhibits a delayed and feeble rise in the epileptic hippocampus possibly due to a reduction in the number and/or efficiency of GABA transporters.
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  • 35
    ISSN: 1573-7233
    Keywords: melanoma ; skin ; reconstructs ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Melanoma develops from a series of architectural and phenotypically distinct stages and becomes progressively aggressive. Considerable progress has been made in understanding the biological, pathological, and immunological aspects of human melanoma. Genetic and cytogenetic studies have revealed broad chromosomal abnormalities and wide mutational spectra. Precise biological and molecular determinants responsible for melanoma progression are not yet known. This is in part due to lack of experimental models that mimic human melanomas. Experimental models in melanoma should not only identify cause and origin of malignancy, but also should represent the ordered progression steps that culminate in metastasis to distant organs. Currently, there are several mouse and other vertebrate melanoma models under investigation; several of them promise to shed light on mechanisms of melanomagenesis. However, many of them suffer from lack of context to human skin architecture and hence, are of basic interest. The lack of appropriate models impeded the efforts to understand origin, etiology, progression and ultimately therapeutic benefits to humans. Development of human skin–mouse chimeric models has appeal because it mimics human diseases. In addition, human artificial skin constructs in vitro promises to be a versatile and efficient model to study not only origin and mechanisms of melanoma, but also progression. This review will focus on the recent progress in establishing tumor models in melanoma in general and their relevance to human melanoma as molecular determinants of tumor progression.
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  • 36
    ISSN: 1573-7330
    Keywords: calcium signaling ; preimplantation development ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Cell cycle-related calcium signals, bearing some similarity to those previously described in other animal species, have also been observed in human preimplantation embryos. These signals follow those occurring in both gametes during the period preceding fertilization and those induced by the fertilizing spermatozoon in the oocyte after gamete fusion. Even though the signals occurring during each of these distinct developmetal periods have different temporal and spatial characteristics, there may be a relationship between them; in fact, abnormalities of calcium signals occurring in an earlier developmental period may be at the origin of abnormal signals during later developmental periods. Methods: Possible mechanisms by which inadequate or truncated calcium signals can impair embryo development are discussed. Results: These mechanisms include complete failure of the second meiotic division, leading to triploidy; incomplete failure of the second meiotic division, leading to de novo chromosomal numerical abnormalities; abnormal pronuclear development and function; abnormalities of the blastomere cell cycle, possibly leading to embryo cleavage arrest; and problems with blastomere allocation to embryonic cell lineages, leading to disproportionate development of the inner cell mass and trophectoderm derivatives, which can be the origin of implantation failure or miscarriage. Conclusions: Future research should make it possible to decipher the nature of normal developmental signals, to determine the key checkpoints at which these signals are required to prevent the switch to apoptosis, and to examine the possibilities of therapeutic action at these checkpoints to rescue the endangered embryo for normal development.
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  • 37
    Electronic Resource
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    Molecular and cellular biochemistry 191 (1999), S. 21-28 
    ISSN: 1573-4919
    Keywords: protein kinase CK2 ; intersubunit contact ; holoenzyme structure ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Chemical crosslinking and analysis of CNBr-digested fusion products by immunoblotting with sequence-specific antibodies identifies an interaction between positions 55-70 of subunit β (β55-70) and 65-80 of subunit α (α65-80). This has been supported by crosslinking of subunits with peptides α65-80 and β55-70, by binding of subunits to immobilized peptides, and by the hindrance of coprecipitation with peptide-raised antibodies (anti-α65-80; anti-β55-70). Functionally, β55-70 is a negative regulatory region for the kinase activity of subunit α. The opposite, stimulatory property of subunit β has been assigned to its C-terminal part. Subdivision of peptide β155-181, that has stimulatory effect, into overlapping peptides and assaying for a binding and binding competition revealed a tight physical contact at β162-175. This region, however, is non-stimulatory indicating binding a necessary but not sufficient quality for stimulation. A contact might exist to regions surrounding C147 and/or C220 at subunit a as indicated by crosslinking and peptide competition. The crosslinking data also confirm a β-β contact in CK2 holoenzyme. Effects by non-ionic detergents show hydrophobic interactions to play an important role in catalytic activity adjustment.
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  • 38
    ISSN: 1573-4919
    Keywords: protein kinase CK2 ; gene structure and organization ; gene promotor activation ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Two CK2α loci are present in the human genome. First, locus 20p13, that contains the CK2α coding gene. It spans around 70 kb, is composed of 13 exons and shows homology to the respective gene in the nematode Caenorhabditis elegans. The translation start site is located in the second exon, the stop codon in exon 13. Two transcription start sites were identified, the further 5′ located site defines position 1 of the gene, the second site is located at position 50, respectively. The promoter region shows characteristics of a so-called house keeping gene: A high GC content, lack of a TATA-box and presence of several GC-boxes. By reporter gene assays, the promoter region of the CK2α gene could be located between position -256 and 144 relative to the first transcription start site. In the 3′ noncoding region of the CK2α gene, six polyadenylation signals were identified. As indicated by Northern blot analysis and by comparison with expressed sequence tags from the EMBL databank, the most 3′ located, active polyadenylation signal seems to be the fourth defining the end of the CK2α gene. The second CK2α locus is at 11p15. It contains a processed pseudogene, which shows all typical features of a processed sequence, such as absence of introns, short poly-A tail and direct flanking repeats. Interestingly, it contains a complete open reading frame and has potential promoter elements in its 5′ region. Nevertheless, no promoter activity could be detected in reporter gene assays.
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  • 39
    ISSN: 1573-0743
    Keywords: body height ; body weight ; cardiac output ; gender ; heart mass ; human ; stroke volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To obtain normal values of left ventricular (LV) end-diastolic volume (EDV), stroke volume (SV), cardiac output (CO) and LV mass, in relation to gender, weight (W), length (L) and body surface area (BSA). Methods: Sixty-one healthy volunteers (32 male, 22.4 ± 2.2 years) were examined, weight was 70.9 ± 12.2 kg, length was 1.78 ± 0.09 m, BSA was 1.88 ± 0.19 m2. Segmented k-space breathhold cine MRI was used to obtain a stack of parallel short-axis images, from which LV volumes and end-diastolic mass were derived by slice summation. Four different body size indices were studied: W, L, L2 and BSA. Results: After indexing for L, L2 and BSA, the gender differences in all LV parameters are still persisting. After indexing for W, gender differences persist for EDV and EDM, but are no longer observed for SV and CO. Separate regression analyses for males and females were performed. EDV, SV, CO and EDM correlated significantly with each body size index, both in males and in females. L or BSA were in general better predictors for LV parameters than W. Linear regression equations of EDV (ml) vs. L(m) were for males: EDV = 275 × L − 359 and for females: EDV = 190 × L − 215. Equations of SV(ml) vs. L were for males: SV = 186 × L − 237 and for females: SV = 118 × L − 121. Equations of LV mass(g) vs. L were for males: Mass = 175 × L − 179 and for females: Mass = 65.8 × L − 10.9. Conclusion: Most gender differences in LV parameters remain even after correction for body size indices. Normal reference values for LV parameters are given in relation to body size indices, by calculating regression coefficients separately for males and females. These normal values serve to obtain more accurate reference values for a patient with given gender, weight and length, and thus to improve the differentiation between normal and abnormal LV parameters.
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  • 40
    ISSN: 1573-0778
    Keywords: alpha-2-macroglobulin ; α2M ; bait region ; CHO cells ; human ; lysyl endopeptidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Alpha 2-macroglobulin (α2M), a plasma glycoprotein produced in the liver, inhibits a variety of proteinases and thus considered to play important homeostatic roles in the body. This broad inhibitory spectrum has been explained by the trapping theory by which a proteinase recognizes a region of 25–30 amino acid peptide in α2M called bait region and cleaves it, leading to the conformational change of α2M, and to the subsequent entrapment and inhibition of the proteinase. We constructed α2M cDNAs with mutated DNA sequences in the bait region, and obtained recombinant CHO cell lines producing either wild type α2M, or mutant α2Ms, i.e., α2M/K692 and α2M/K696, each with substitution of Arg with Lys at codons 692 and 696, respectively. We tested if lysyl endopeptidase is not inhibited by wild type α2M, but could be inhibited by these engineered mutant α2Ms. Thus, recombinant α2M/K696 protein successfully inhibited lysyl endopeptidase activity, while recombinant α2M/K692 protein was not sensitive to lysyl endopeptidase, suggesting that not all bait region peptide bonds can equally be accessible and susceptible to proteinases. The present results not only provided the trapping theory with additional supportive evidence, but the first experimental evidence for the value of engineered α2M-derived proteinase inhibitor with an artificial proteinase inhibitory spectrum of potential industrial and/or therapeutic usefulness.
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  • 41
    ISSN: 1570-7458
    Keywords: Culex quinquefasciatus ; Culicidae ; host preference ; human ; calf ; goat ; host odour ; carbon dioxide ; Tanzania
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Field experiments to determine the host preference of Culex quinquefasciatus Say (Diptera: Culicidae) between man, calf and goat, were conducted in Muheza, north-east Tanzania. The responses of the mosquito to the three hosts were also compared to their responses to carbon dioxide. A total of 2565 unfed female mosquitoes were collected, of which Cx quinquefasciatus accounted for 96.6% of the catch. A human-baited tent caught a larger number of host-seeking Cx quinquefasciatus than a calf-baited or goat-baited tent (P〈0.05). The man:calf ratio was 7.8:1 while the man:goat ratio was 10:1. The difference in response to either a calf- or goat-baited tent was not statistically significant (P〉0.05). The number of mosquitoes attracted to a human-baited tent was significantly larger than that attracted to carbon dioxide released at 300 ml min−1. Only 25.3% of the human host attractancy was attributed to carbon dioxide. The number of Cx quinquefasciatus responding to a tent baited with a calf or goat was not significantly different from the number responding to a tent baited with carbon dioxide. It can be concluded that with equal availability of the three vertebrate hosts, Cx quinquefasciatus would respond more to volatile cues from a human host than from either a calf or goat, thereby supporting earlier data about its high degree of anthropophily. The major olfactory cue from a goat or a calf to which this mosquito responds is probably carbon dioxide.
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  • 42
    ISSN: 1573-6849
    Keywords: chromosome microdissection ; donkey ; horse ; human ; Zoo-FISH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A pilot study comparing horse and donkey karyotypes on a molecular basis was initiated using the chromosomal microdissection approach. All equine meta- and submetacentric chromosomes, viz. ECA1 to ECA13 and the X and Y chromosomes, were microdissected. The DNA was PCR amplified, non-radioactively labelled and used as probes on equine metaphase chromosomes to confirm their origin. Once tested, the paints were used as probes on donkey metaphase chromosomes to detect homologous chromosomal segments between the two species. The results not only detected conservation of whole chromosome and/or arm synteny between the two karyotypes, but also highlighted varying degrees of rearrangements. The findings also enable deduction of homology between parts of donkey and human karyotypes. In light of the molecular evidence, this study examines the accuracy of the available comparative cytogenetic data between horse and donkey.
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  • 43
    ISSN: 1573-6903
    Keywords: Calmodulin ; human ; localization ; phosphodiesterase ; brain ; cAMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The amplification of cyclic nucleotide ‘second messenger’ signals within neurons is controlled by phosphodiesterases which are responsible for their degradation. Calmodulin-dependent phosphodiesterase (CaMPDE) is an abundant enzyme in brain which carries out this function. For the first time, we have localized CaMPDE in the normal human brain at various ages, using a monoclonal antibody designated A6. This antibody was generated using standard techniques, purified, and applied to tissue sections. Autopsy specimens of human brain with no neuropathological abnormalities were selected representing a range of pre- and postnatal ages. Sections of various brain regions were evaluated for immunoreactivity, graded as nil, equivocal, or definite. We demonstrated definite CaMPDE immunohistochemical staining in neocortex, especially in neurons in layers 2 and 5. There was definite neuronal immunoreactivity in the hippocampus, and in the subiculum. The striatum had definite patchy neuronal staining. Definite terminal staining in the globus pallidus externa and substantia nigra pars reticulata outlined resident neurons, interpreted as axonal terminal staining. Cerebellar Purkinje cells showed definite immunoreactivity. In the developing brain, definite immunohistochemical staining was seen in the cerebellar external granular layer. The expression of CaMPDE in specific subsets of neurons suggests they may correlate with cells having dopaminergic innervation and/or high levels of neuronal integration.
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  • 44
    ISSN: 1573-6849
    Keywords: chromosome 22q ; clone resource ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 45
    ISSN: 1573-6784
    Keywords: baboon ; chimpanzee ; COII ; DNA ; fecal ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Mitochondrial COII DNA was amplified by PCR from total DNA extracted from field collected primate fecal samples (n=24) which had been stored without refrigeration for over 30 days. High molecular weight DNA total DNA was obtained from samples stored in 70% (v/v) ethanol, SDS lysis buffer (LB) and guanidine isothiocyanate buffer (GTB) than from samples stored in 10% formalin. Fecal DNA quality and COII amplification varied according to storage solution (formalin, ethanol, LB and GTB), extraction method (LB-based and GTB-based) and primate species (chimpanzee, baboon, human). It is recommended that fecal samples be collected in LB for DNA analysis. However, GTB-based protocols are suitable when total RNA is needed for epidemiological studies of viral diseases or gene expression analysis.
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  • 46
    ISSN: 1573-2614
    Keywords: Compliance ; human ; lung ; mechanical ventilation ; mechanics ; resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Medicine
    Notes: Abstract Objective. To evaluate and further develop a method for determination and mathematical characterisation of the elastic pressure-volume (Pel-V) relationship in mechanically ventilated human subjects during one single modified insufflation with simultaneous determination of resistance of the respiratory system. Subjects. Eight adult non-smoking human subjects without heart, lung, or thoracic cage disease scheduled for non-thoracic surgery. The study was performed in anaesthetised and muscle-relaxed subjects. Measurements and Main Results. The Pel-V curve was determined with a computer-controlled Servo Ventilator 900C during a modified insufflation with either constant or sinusoidally varying flow. Pressure and flow were measured with the built-in sensors of the ventilator. Tracheal pressure (Ptr) was calculated by subtracting the pressure drop over the tracheal tube. The elastic recoil pressure in the peripheral lung, Pel, was obtained from the calculated Ptr by subtracting the pressure drop over the airways. Ptr was also directly measured through a catheter. The calculated Ptr gave similar results as the directly measured Ptr, thus indicating the reliability of the signal originating from the ventilator sensor for computation of downstream pressures. The inflection points of the sigmoidal Pel-V curve and the compliance of the linear segment were determined with high reproducibility. Conclusions. Using one single modified insufflation allows a fast and accurate determination of respiratory mechanics. The Pel-V curves were determined with high reproducibility and were adequately described by a three-segment model of the curve incorporating a linear segment between two asymmetrical non-linear segments.
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  • 47
    ISSN: 1573-2614
    Keywords: occlusion pressure ; P0.1 ; monitor ; human ; automatic measurement ; mechanical load ; software
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Medicine
    Notes: Abstract Objective. To design and evaluate a clinical monitor of respiratory drive (P0.1) and other respiratory variables in a simple way, using a commercial ventilator. Methods. Nine healthy males were studied as they were breathing spontaneously in a Servo 900C Ventilator, at rest and during light exercise (50 W). The ventilator was slightly modified to improve its mechanical performance during spontaneous breathing, and was used as a measuring instrument. All the relevant information was retrieved, calculated and monitored by a PC. Respiratory drive was assessed as occlusion pressures from the inspiratory airway pressure signal. The equipment was compared with a two-way non-rebreathing laboratory system. Furthermore, negative and positive inspiratory pressures were applied from the ventilator, to study respiratory responses to mechanical loads. Results. At rest, the ventilator introduced a minor influence on inspiratory time and P0.1, but not in ventilatio n, tidal volume, expiratory duration and respiratory frequency. During exercise, the influence was more evident. This effect could also be noticed in the coefficients of variation. The responses to mechanical loads were easily recorded and can be used as a simple test of central load-compensating mechanisms. Conclusions. The ventilator, with limitations, may be an alternative to conventional techniques, especially in clinical studies of the central inspiratory activity with and without respiratory loading.
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  • 48
    ISSN: 1435-1463
    Keywords: Keywords: Aromatic L-amino acid decarboxylase ; brain ; colocalization ; GTP cyclohydrolase I ; human ; immunohistochemistry ; tetrahydrobiopterin ; tyrosine hydroxylase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. Guanosine triphosphate (GTP) cyclohydrolase I (GCH) is the first and rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, the cofactor of tyrosine hydroxylase (TH). Our previous study reported the presence of GCH in several neuronal groups in animal brains using a newly raised anti-GCH antibody. The present study aims at elucidating whether GCH and TH coexist in the same neurons of the human brain with the aid of immunohistochemical dual labeling. GCH-immunoreactivity was observed in the cell bodies and fibers of monoaminergic neurons of the human brain. Neurons which contain both enzymes are seen in the human substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and zona incerta. In these regions, almost all the cells also show immunoreactivity for aromatic L-amino acid decarboxylase (AADC), the second step enzyme for catecholamine synthesis, indicating that these neurons are catecholaminergic. However, some neurons in the dorsal and dorsomedial hypothalamic nuclei are stained only for GCH or TH. They appear to constitute an independent cell group in the human brain. The present observation suggests that L-dopa is not produced in the cells immunoreactive for TH but not for GCH, and that TH in these cells which lack GCH may have an unidentified role other than dopa synthesis.
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  • 49
    ISSN: 1435-5604
    Keywords: Key words: alendronate ; bisphosphonate ; human ; osteoclasts ; morphology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Alendronate is a powerful therapeutic agent for the treatment of hypercalcemia in malignancy and osteoporosis and has recently been developed as a treatment for hypercalcemia of malignancy. In this study, time-lapse cinemicrography was used to investigate the effects of this agent on the morphology and the motility of human osteoclast-like multinucleated cells (MNCs) from human bone marrow. Alendronate at 10−5 M induced contraction of the cells starting 7.5 h after its addition. contraction was markedly induced immediately after alendronate removal. However, contraction almost disappeared 18 h after removal, and osteoclast-like MNCs recovered their original sizes and shape. There was only partial recovery from contraction after alendronate treatment at 10−4 M. In contrast, untreated control cells did not change their morphology after washing with culture medium. Motility analysis showed that osteoclast-like MNCs treated with 10−5 M alendronate moved actively after washing, but at 10−4 M the motility locus was very narrow. At 10−4 M, the actin ring in the cells began to break down, beginning 6 h after addition. The effects of alendronate on human osteoclast-like MNCs morphology and motility were reversible at 10−5 M, suggesting that alendronate dose not cause any cellular damages in human osteoclasts up to 10−5 M, which is an effective dose for bone resorption.
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  • 50
    ISSN: 1432-0428
    Keywords: Keywords Dietary fibre ; thiamine ; thiamine deficiency ; glucose tolerance test ; sex ; insulin resistance ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Epidemiologic studies have shown an association between the intake of dietary fibres and 2-h glucose values. Food rich in dietary fibres is often also rich in thiamine. Animal studies have shown that thiamine deficiency can induce glucose intolerance. Our aim was to investigate the association between fibre consumption and thiamine intake on the one hand and glucose tolerance on the other hand. We used data from the Hoorn Study, a study of glucose tolerance among 1008 men and 1188 women, aged 50–75 years, without diabetes. In linear regression analyses, fibre intake was inversely associated with fasting glucose. There was also an inverse association between fibre intake and 2-h glucose but it disappeared for the greater part after adjustment for fasting glucose. Fibre intake appeared to be strongly correlated with thiamine intake, and this correlation explained the remaining part of the association between fibre intake and 2-h glucose. Thiamine intake appeared to have a strong and relevant association with 2-h glucose, which was independent of fibre intake and fasting glucose. This association was borderline after adjustment for potential confounders. In women, but not in men, the effect of thiamine intake on 2-h glucose seemed to be modified by fibre intake, independent of potential confounders. In conclusion, part of the association between fibre intake and glucose tolerance is possibly attributable to concomitant thiamine intake. [Diabetologia (1998) 41: 1168–1175]
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  • 51
    ISSN: 1573-904X
    Keywords: absorption ; intestinal intubation ; propanolol ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 52
    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
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  • 53
    ISSN: 1573-904X
    Keywords: amphotericin B ; pharmacokinetics ; human ; gender-differences ; disposition function differences ; interspecies scaling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.
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  • 54
    ISSN: 1573-904X
    Keywords: carbamazepine ; human ; bioavailability: gender, dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if three marketed generic carbamazepine tablets were bioequivalent to the innovator formulation, as well as to each other. In addition, to examine in vivo-in vitro relationships among the four formulations. Methods. Each formulation was given as a single dose to 18 healthy male and female subjects using a crossover design. Blood samples were collected for 169 hr. Carbamazepine was assayed by HPLC with UV detection. Results.In vivo fraction absorbed plots indicated that the three generic formulations were absorbed more rapidly than the innovator product, and the mean time of maximum plasma concentration was 6−7 hr sooner for the generic formulations. The mean maximum plasma concentration ranged from 17−19 percent higher for the generic products compared to the innovator, and the 90% confidence limits for Cmax data ranged from 111% to 126%. The mean AUC(0−∞) for the generic products ranged from 101−104% compared to the innovator, and the confidence limits for AUC ranged from 97−108%. Conclusions. The generic products were all more rapidly absorbed than the innovator, but simulations of steady-state concentrations indicated that it would be unlikely that these differences would have any significant clinical effect. An excellent association was seen between the Cmax and the percent of drug dissolved in vitro. The correlation was used to accurately predict the Cmax of four other 200 mg tablets evaluated in an earlier study.
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  • 55
    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
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  • 56
    ISSN: 1573-904X
    Keywords: nucleosides ; transport ; choroid ; plexus ; human ; HIV
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 57