Showing papers by "Heidelberg University published in 1995"
TL;DR: Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan, however, the identification of this subgroup is difficult.
Abstract: Objective. —To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting. —A total of 75 hospitals in 14 European countries. Patients. —A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT). Intervention. —Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms. Outcome Measures. —Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage. Results. —The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA—treated patients (P Conclusions. —Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients. (JAMA. 1995;274:1017-1025)
3,053 citations
TL;DR: Adding doxycycline to HeLa cells that constitutively synthesized the transactivator and that contained an appropriate, stably integrated reporter unit rapidly induced gene expression more than a thousandfold.
Abstract: A transcriptional transactivator was developed that fuses the VP16 activation domain with a mutant Tet repressor from Escherichia coli. This transactivator requires certain tetracycline (Tc) derivatives for specific DNA binding. Thus, addition of doxycycline to HeLa cells that constitutively synthesized the transactivator and that contained an appropriate, stably integrated reporter unit rapidly induced gene expression more than a thousandfold. The specificity of the Tet repressor-operator-effector interaction and the pharmacological characteristics of Tc's make this regulatory system well suited for the control of gene activities in vivo, such as in transgenic animals and possibly in gene therapy.
2,645 citations
TL;DR: It is shown here that HIV-1 Tat strongly sensitizes TCR- and CD4(gpl20)-induced apoptosis by upregulation of CD95 ligand expression, a mechanism that may contribute to CD4+ T-cell depletion in AIDS.
Abstract: The depletion of CD4+ T cells in AIDS is correlated with high turnover of the human immunodeficiency virus HIV-1 and associated with apoptosis. The molecular mechanism of apoptosis in HIV infection, however, is largely unknown. T-cell apoptosis might be affected by viral proteins such as HIV-1 Tat and gp120 (refs 10, 11). T-cell-receptor (TCR)-induced apoptosis was recently shown to involve the CD95 (APO-1/Fas) receptor. We show here that HIV-1 Tat strongly sensitizes TCR- and CD4(gp120)-induced apoptosis by upregulation of CD95 ligand expression. Concentrations of Tat found to be effective in cultures of HIV-1-infected cells were also observed in sera from HIV-1-infected individuals. Taken together, our results indicate that HIV-1 Tat and gp120 accelerate CD95-mediated, activation-induced T-cell apoptosis, a mechanism that may contribute to CD4+ T-cell depletion in AIDS.
992 citations
TL;DR: In multivariate analysis, p53 gene deletion was the strongest prognostic factor for survival and predicts for non-response to therapy with purine analogs and for poor survival in chronic B-cell leukemias.
777 citations
TL;DR: The findings suggest that liver destruction in hepatitis B may primarily involve killing of hepatocytes by T lymphocytes using the CD95 receptor-ligand system.
Abstract: Apoptosis occurs in the normal liver and in various forms of liver disease. The CD95 (APO-1/Fas) (CD95) receptor mediates apoptosis, and liver cells in animal models are acutely sensitive to apoptosis initiated by this receptor. We have used primary human hepatocytes as a model system to investigate CD95-mediated apoptotic liver damage. Treatment of fresh human hepatocytes with low concentrations of agonistic antibodies against CD95 resulted in apoptosis of > 95% of the cultured liver cells within 4 and 7.5 h. Immunohistology of a panel of explanted liver tissues revealed that hepatocytes in normal livers (n = 5) and in alcoholic cirrhosis (n = 13) expressed low constitutive levels of CD95. CD95 receptor expression was highly elevated in hepatocytes in hepatitis B virus-related cirrhosis (n = 9) and in acute liver failure (n = 8). By in situ hybridization CD95 ligand messenger RNA expression was absent in normal liver but detected at high levels in livers with ongoing liver damage. In cases of hepatitis B virus-related cirrhosis and acute hepatic failure, ligand expression was found primarily in areas with lymphocytic infiltration. In contrast, in patients with alcoholic liver damage, high CD95 ligand messenger RNA expression was found in hepatocytes. These findings suggest that liver destruction in hepatitis B may primarily involve killing of hepatocytes by T lymphocytes using the CD95 receptor-ligand system. In alcoholic liver damage, death of hepatocytes might occur by fratricide and paracrine or autocrine mechanisms mediated by the hepatocytes themselves.
727 citations
TL;DR: In this paper, the semilinear elliptic PDE in RN was studied and the existence of a positive solution under various hypotheses was proved under the assumption that the nonlinearity will be superlinear and subcritical.
Abstract: We study the semilinear elliptic PDE in RN The nonlinearity ƒ will be superlinear and subcritical We prove the existence 0f a positive solution under various hypotheses on b If and ƒ is odd in u,
706 citations
TL;DR: The data suggest that tau's amino-terminal projection domain has an important role in neuritic development and establishes tau as a mediator of microtubule-plasma membrane interactions.
Abstract: The neuronal microtubule-associated protein tau is required for the development of cell polarity in cultured neurons. Using PC12 cells that stably express tau and tau amino-terminal fragments, we report that tau interacts with the neural plasma membrane through its amino-terminal projection domain. In differentiated PC12 transfectants, tau is found in growth cone-like structures in a nonmicrotubule-dependent manner. In hippocampal neurons, tau is differentially extracted by detergent and enriched in the growth cone and the distal axon when membrane is left intact. In PC12 transfectants, overexpression of tau's amino-terminal fragment, but not of full-length tau, suppresses NGF-induced process formation. Our data suggest that tau's amino-terminal projection domain has an important role in neuritic development and establishes tau as a mediator of microtubule-plasma membrane interactions.
635 citations
TL;DR: It is shown that the increased production of Aβ results from a cellular mechanism, which differs substantially from that responsible for the production of aβ from wild-type βAPP, and is explained by a competition between α and β-secretase.
Abstract: Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production, explaining the increased A beta generation by a competition between alpha- and beta-secretase.
620 citations
TL;DR: It is concluded, that studies which do not control premorbid intelligence have to be considered as a “malpractice” and should not be accepted by scientists.
Abstract: The discrepancy between current and premorbid ability is a relevant indicator of acquired mental impairment, which itself is closely related to general cerebral dysfunction. The use of tests sensitive to cerebral dysfunction, raises relatively few problems compared with tests being resistant that are used to estimate premorbid mental ability. For premorbid ability, verbal tests assessing knowledge, especially vocabulary, have been shown to be valid. A test, possibly more insensitive to brain dysfunction than the ones usually administered, is the multiple choice vocabulary test (MWT = Mehrfachwahl-Wortschatz-Test). At present only German versions are available. They are presented in some detail because of their advantages. Construction of the MWT is simple, and it can be easily administered in about five minutes. The results correlate fairly well with global IQ in healthy adults (median of r = 0.72 in 22 samples) and are more insensitive to current disturbances than such tests as the WAIS vocabulary test. The limitations of premorbid tests with respect to diagnostic validity are discussed. It is concluded, that studies which do not control premorbid intelligence have to be considered as a "malpractice" and should not be accepted by scientists.
574 citations
TL;DR: During pregnancy a semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens, and during pregnancy maternal T Cells acquire a transient state of tolerance specific for paternal alloantigens.
Abstract: During pregnancy a semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens. A mouse transgenic for a T cell receptor recognizing the major histocompatibility (MHC) antigen H-2Kb was used to follow the fate of T cells reactive to paternal alloantigens. In contrast to syngeneic and third-party allogeneic pregnancies, mice bearing a Kb-positive conceptus had reduced numbers of Kb-reactive T cells and accepted Kb-positive tumor grafts. T cell phenotype and responsiveness were restored after delivery. Thus, during pregnancy maternal T cells acquire a transient state of tolerance specific for paternal alloantigens.
572 citations
TL;DR: A large number of studies that address the role of surgery in the management of high-grade gliomas conclude that the degree of tumor removal accomplished is solely based on the intraoperative perception of the neurosurgeon.
Abstract: IN THE VAST majority of studies that address the role of surgery in the management of high-grade gliomas, the degree of tumor removal accomplished is solely based on the intraoperative perception of the neurosurgeon. Despite its fundamental importance for a comparison of different treatment
TL;DR: The arginine residue at position 586 of the GluR-B subunit renders heteromeric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium.
Abstract: The arginine residue at position 586 of the GluR-B subunit renders heteromeric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium. The codon for this arginine is introduced at the precursor messenger RNA (pre-mRNA) stage by site-selective adenosine editing of a glutamine codon. Heterozygous mice engineered by gene targeting to harbor an editing-incompetent GluR-B allele synthesized unedited GluR-B subunits and, in principal neurons and interneurons, expressed AMPA receptors with increased calcium permeability. These mice developed seizures and died by 3 weeks of age, showing that GluR-B pre-mRNA editing is essential for brain function.
TL;DR: It is shown that B-type-cyclin degradation in yeast involves an essential nuclear ubiquitin-conjugating enzyme, UBC9, and that distinct degradation signals or regulated interaction with the ubiquitIn-protein ligase system may determine the cell-cycle specificity of cyclin proteolysi.
Abstract: CELL cycle progression in eukaryotes is controlled by the p34cdc21CDC28 protein kinase and its Short-lived, phase-specific regulatory subunits called cyclins1,2. In Xenopus oocytes, degradation of M-phase (B-type) cyclins is required for exit from mitosis and is mediated by the ubiquitin-dependent proteolytic system3. Here we show that B-type-cyclin degradation in yeast involves an essential nuclear ubiquitin-conjugating enzyme, UBC9. Repression of UBC9 synthesis prevents cell cycle progression at the G2 or early M phase, causing the accumulation of large budded cells with a single nucleus, a short spindle and replicated DNA. In ubc9 mutants both CLB5, an S-phase cyclin4,5, and CLB2, an M-phase cyclin6,7, are stabilized. In wild-type cells the CLB5 protein is unstable throughout the cell cycle, whereas CLB2 turnover occurs only at a specific cell-cycle stage8. Thus distinct degradation signals or regulated interaction with the ubiquitin-protein ligase system may determine the cell-cycle specificity of cyclin proteolysi
TL;DR: The function importance of post-synaptic GABAB receptors is highlighted by a segregation of GABAA and GABAB synapses in the mammalian brain.
TL;DR: The rapid binding kinetics lead to the conclusion that ATP-bound DnaK is the primary form initiating interaction with substrates for chaperone activity, and the special and important role for DnaJ in stabilization of DNAK-substrate interactions is indicated.
TL;DR: Brain tissue samples reveal highest Mn concentrations in the caudate nucleus, followed by the quadrigeminal plate and globus pallidus, and whole blood Mn concentrations were significantly increased, suggesting that this metal may have a role in the pathogenesis of chronic hepatic encephalopathy.
TL;DR: The properties of the excess suggest that it arises from two-pion annihilation, and in the S-Au system an enhancement over the hadronic contributions by a factor of 5.5 GeV/{ital c}{sup 2} is observed.
Abstract: We report on measurements of low-mass electron pairs in 450 GeV $p$-Be, $p$-Au, and 200 GeV/nucleon S-Au collisions at central rapidities. For the proton induced interactions, the low-mass spectra are, within the systematic errors, satisfactorily explained by electron pairs from hadron decays, whereas in the S-Au system an enhancement over the hadronic contributions by a factor of $5.0\ifmmode\pm\else\textpm\fi{}0.7(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}2.0(\mathrm{syst})$ in the invariant mass range $0.2lml1.5\phantom{\rule{0ex}{0ex}}\mathrm{GeV}{/c}^{2}$ is observed. The properties of the excess suggest that it arises from two-pion annihilation $\ensuremath{\pi}\ensuremath{\pi}\ensuremath{\rightarrow}{e}^{+}{e}^{\ensuremath{-}}$.
TL;DR: Insight is provided into how PHF-tau disturbs neuronal function, and a growing body of evidence that oxidant stress contributes to the pathogenesis of AD is added.
Abstract: Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.
TL;DR: The distinct location of both NOS isoforms in the cortex confirms that NO plays a crucial role in local glomerular signaling events in various animal species including humans.
Abstract: Nitric oxide (NO) is generated from L-arginine by NO synthase (NOS). We have investigated the localization of constitutive NOS isoforms in rat, mouse, guinea pig, rabbit, pig, and human kidney. NADPH diaphorase (NADPH-d) reaction was used for histochemical detection of NOS enzyme activity, neuronal NOS (NOS I) and endothelial NOS (NOS III) were identified by specific antibody, and in situ hybridization was applied for NOS I mRNA detection. Strong presence of NOS I in macula densa (MD), previously detected in rat, was found in all species including humans. Additional NOS I-positive cells of the thick ascending limb (TALH) were defined. A clear-cut distinction between Tamm-Horsfall-protein-positive cells of the TALH and NOS I-positive cells of the TALH was shown. Ultrastructurally, NOS I was located in the cytosol. Intimate spatial relation between NOS I-positive cells and renin-containing preglomerular afferent arteriole suggests an effect of MD-derived NO on the juxtaglomerular granular cells. In the renal vasculature, both NADPH-d and NOS III were located in the endothelium of cortical and medullary vessels, whereas the muscle layer was unreactive. The glomerular arterioles showed stronger labeling in the efferent than in the afferent endothelium, and efferent endothelium selectively contained both NOS I and NOS III. The unique morphology of efferent endothelial cells indicates a particular role for NO in this vessel segment. At the capillary level, only the glomerular tuft showed NOS-positive endothelia. A subpopulation of renal nerves containing NADPH-d and NOS I was found in perivascular connective tissue and near pelvic epithelium. These results demonstrate a wide distribution of two constitutive NOS isoforms in the kidney of various animal species including humans. The distinct location of both isoforms in the cortex confirms that NO plays a crucial role in local glomerular signaling events.
TL;DR: The design of a bidirectional promoter which would allow the simultaneous regulation of two transcriptional units from centrally located multiple tetO sequences is suggested, which may allow the co-regulation of the synthesis of two gene products in stoichiometric amounts.
Abstract: Recently, we have described a regulatory system that allows the stringent control of individual gene activities in higher eukaryotic cell lines (1), in plants (2) and in animals (3,4). The essential components of this system are (i) an RNA polymerase II minimal promoter placed downstream of multiple operator sequences (tetO) of the Escherichia coli TnlO tetracycline resistance operon and (ii) a fusion between the Tet repressor (TetR) and the herpes simplex virus protein 16 (VP16), named tTA (1). In the absence of tetracycline (Tc), tTA binds to the tet operators to activate transcription from the minimal promoter, whereas in the presence of Tc its association and consequently its transcription activation is prevented. After the binding of tTA, minimal promoters derived from the cytomegalovirus IE promoter (PhCMv; 5) and fused to seven tetO sequences reach the remarkable strength of the parent promoter in HeLa cells when compared in transient expression assays (6). This high activation potential of tTA and the arrangement of its binding sites within PhCMV*-i [(!)'»see Fig. 1A] suggested the design of a bidirectional promoter which would allow the simultaneous regulation of two transcriptional units from centrally located multiple tetO sequences (Fig. 1A). Such a promoter should be useful for a number of experimental approaches. First, it may allow the co-regulation of the synthesis of two gene products in stoichiometric amounts, frequently a prerequisite for the production of heterodimeric (or hetero-oligomeric) proteins. Second, by fusing minimal promoters of differing efficiencies to the centrally located tetO sequences, two gene products may be co-regulated at different but defined levels. Third, by integrating an appropriate reporter gene at one side of the bidirectional promoter, the regulation of a not-readily-assayable gene of interest may be monitored via the reporter function. This latter possibility may also facilitate—at the cellular as well as at the organismal level—the screening for properly integrated expression units controlling the gene of interest.
TL;DR: Multivariate analysis showed that the CD44 epitope encoded by exon v6 was a good marker for prognosis independent of progesterone receptor, lymph node status, tumour size, and grade.
15 Jun 1995-Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment
TL;DR: The performance of the ALEPH detector at the LEP e+e− collider is reviewed in this paper, where the accuracy of the tracking detectors to measure the impact parameter and momentum of charged tracks is specified.
Abstract: The performance of the ALEPH detector at the LEP e+e− collider is reviewed. The accuracy of the tracking detectors to measure the impact parameter and momentum of charged tracks is specified. Calorimeters are used to measure photons and neutral hadrons, and the accuracy obtained in energy and angle is given. An essential property of the detector is its ability to identify particles; the performance in identification of electrons, muons, neutrinos (from missing energy), charged hadrons, π0's and V0's is described.
TL;DR: Hemicraniotomy may improve survival in massive hemispheric stroke victims, decreasing mortality rates to < 35%, although some patients seem to benefit significantly.
Abstract: Objective Space-occupying hemispheric infarctions, requiring neurocritical care treatment, demonstrate high mortality and morbidity rates. This study was performed to determine the beneficial effects of decompressive craniotomy on mortality and morbidity rates.Design Open, nonrandomized, control tri
TL;DR: It is concluded that TGF‐beta s 1‐3, activin A and GDNF share a neurotrophic capacity for developing dopaminergic neurons, which is not mediated by astroglial cells and not accompanied by an increase in cell proliferation.
Abstract: The superfamily of transforming growth factors-beta (TGF-beta) comprises an expanding list of multifunctional proteins serving as regulators of cell proliferation and differentiation. Prominent members of this family include the TGF-beta s 1-5, activins, bone morphogenetic proteins and a recently discovered glial cell line-derived neurotrophic factor (GDNF). In the present study we demonstrate and compare the survival promoting and neuroprotective effects of TGF-beta 1, -2 and -3, activin A and GDNF for midbrain dopaminergic neurons in vitro. All proteins increase the survival of tyrosine hydroxylase-immunoreactive dopaminergic neurons isolated from the embryonic day (E) 14 rat mesencephalon floor to varying extents (TGF-beta s 2.5-fold, activin A and GDNF 1.6-fold). TGF-beta s, activin A and GDNF did not augment numbers of very rarely observed astroglial cells visualized by using antibodies to glial fibrillary acidic protein and had no effect on cell proliferation monitored by incorporation of BrdU. TGF-beta 1 and activin A protected dopaminergic neurons against N-methyl-4-phenylpiridinium ion toxicity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that TGF-beta 2 mRNA, but not GDNF mRNA, is expressed in the E14 rat midbrain floor and in mesencephalic cultures. We conclude that TGF-beta s 1-3, activin A and GDNF share a neurotrophic capacity for developing dopaminergic neurons, which is not mediated by astroglial cells and not accompanied by an increase in cell proliferation.
TL;DR: In this paper, the authors investigate the hypothesis that stars form in aggregates of binary systems and that the dynamical evolution of these aggregates leads to the observed properties of binary stars in the Galactic field.
Abstract: We investigate the hypothesis that stars form in aggregates of binary systems and that the dynamical evolution of these aggregates leads to the observed properties of binary stars in the Galactic field We assume that the initial distribution of periods is flat in logP, where P is the orbital period in days, and 3 75 After the cluster with R=08pc disintegrates we obtain a population which consists of about 60 per cent binary systems with a period distribution for logP>4 as is observed and in which the G-dwarf binaries have a mass ratio distribution which agrees with the observed distribution This result indicates that the majority of Galactic field stars may originate from a clustered star formation mode We invert the orbit depletion function and obtain an approximation to the initial binary star period distribution for star formation in the dominant mode cluster Comparison with the measured distribution of orbits for pre-main sequence stars suggests that the initial distribution may not depend on the star formation environment Inverse dynamical population synthesis suggests that the Galactic field stellar mass function may be related to the stellar density at birth in the most common, or dominant, mode of star formation
TL;DR: This review summarizes the structure-function relationships of podocytes and describes the general morphology and selected aspects of podocyte development and cell division.
Abstract: Glomerular visceral epithelial cells, also termed podocytes, are highly specialized epithelial cells that cover the outer aspect of the glomerular basement membrane. Recent studies point to an important role of podocytes in the physiology and pathophysiology of the glomerulus. This review summarizes the structure-function relationships of podocytes. Following a description of the general morphology of podocytes, the technical problems associated with studying these cells are discussed. A survey of podocyte function forms the center of this review. Finally, selected aspects of podocyte development and cell division are discussed.
TL;DR: In this article, the existence of free doubly or multiply charged negative ions, in particular those of small systems, has remained a curiosity and a matter of some controversy and has attracted considerable experimental and theoretical attention over the past decades.
Abstract: Singly charged negative ions in the gas phase have attracted considerable experimental and theoretical attention over the past decades. However, the existence of free doubly or multiply charged negative ions, in particular those of small systems, has remained a curiosity and a matter of some controversy. Recent experimental and quantum mechanical studies show that multiply charged negative ions of small molecules and clusters can exist as isolated entities.
TL;DR: Genistein may contribute to the preventive effect of plant-based diet on chronic diseases, including solid tumors, by inhibiting neovascularization and tumor cell proliferation and may have important applications in the treatment of solid tumors and angiogenic diseases.
Abstract: Consumption of a plant-based diet can prevent the development and progression of chronic diseases that are associated with extensive neovascularization. To determine whether prevention might be associated with dietary derived angiogenesis inhibitors, we have fractionated urine of healthy human subjects consuming a plant-based diet and examined the fractions for their abilities to inhibit the proliferation of vascular endothelial cells. One of the most potent fractions contained several isoflavonoids, which we identified by gas chromatography-mass spectrometry and subsequently synthesized. Of all synthetic compounds, the isoflavonoid genistein was the most potent and inhibited endothelial cell proliferation and in vitro angiogenesis at half maximal concentrations of 5 and 150 mumol/L, respectively. Moreover, genistein inhibited the proliferation of various tumor cells. Genistein excretion in urine of subjects consuming a plant-based diet is in the micromolar range, which is 30-fold higher than that of subjects consuming a traditional Western diet. The high concentrations of genistein in urine of vegetarians and our present results suggest that genistein may contribute to the preventive effect of plant-based diet on chronic diseases, including solid tumors, by inhibiting neovascularization and tumor cell proliferation. Thus genistein may have important applications in the treatment of solid tumors and angiogenic diseases.
TL;DR: The cloned region within Xp22.3 where the CDPX gene has been assigned and three adjacent genes showing highly significant homology to the sulfatase gene family are isolated suggest that warfarin embryopathy might involve drug-induced inhibition of the same enzyme.
TL;DR: This is the first report showing that LTP of C-fiber-evoked field potentials in the spinal dorsal horn in vivo may last for more than 8 h, and may underlie plastic changes of spinal nociception.