Biomedical subjects

D Scholz

Publications and source records attributed to D Scholz.

At least 19 recordsLinked to original sources

PubMed2002

Conceptional considerations for a German influenza pandemic preparedness plan.

A pandemic appearance of influenza A virus must be expected at any time. The limitations of health preserving and life-saving resources, which will inevitably be reached in the event of a pandemic, will be accompanied by ethical and possibly social conflicts, which can be lessened or resolved only through precautionary planning, clearly specified competencies and transparent decisions within a social consensus. In case of a shortage of vaccines and virostatic agents, decisions will have to be made with regard to the segment of the population that absolutely must be vaccinated. It is currently estimated that a (monovalent) vaccine developed for a new pandemic strain would only suffice for the single vaccination of approximately half of the German population after a year; only 10-14 million vaccine dosages would be available to provide basic immunization and single boosters to personnel required to maintain basic medical care and essential infrastructure after half a year. In the event of local influenza outbreaks, antiviral chemotherapeutic agents could be used to close the gap until a vaccine can become effective. Even if suitable influenza vaccines and virostatic agents are not sufficiently available at the start of a pandemic, it is still possible to at least prevent an outbreak of two of the most feared secondary infections that accompany influenza: pneumococcal pneumonia or meningitis and illnesses resulting from Haemophilus influenzae. Agreement still needs to be reached with manufacturers for guaranteeing the necessary vaccine production or ensuring that they have a sufficient stock to meet the minimum demand for antiviral agents and agents for symptomatic treatment.

Antiviral Agents↗

PubMed2002

Influenza pandemic: preparedness planning in Germany.

The following conceptual framework formed the basis for a common decision made by the health ministers of Germany's 16 federal states to set up an influenza pandemic preparedness plan. The worst case scenario was used, on the basis of the data from the pandemic of 'Spanish flu', in 1918-20. The priority groups for vaccination were assessed, as well as the potentially available antiviral treatments. National policies could be highly improved by a common European view.

Disease Outbreaks↗

PubMed2001

A new structural class of selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

We describe the identification and in vitro characterization of a series of 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome. Our initial SAR data demonstrate that the 2-aminobenzylstatine core structure can effectively serve as the basis for designing potent, selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

Amino Acids↗

PubMed2001

Connexin37, not Cx40 and Cx43, is induced in vascular smooth muscle cells during coronary arteriogenesis.

W.-J. Cai, S. Koltai, E. Kocsis, D. Scholz, W. Schaper and J. Schaper. Connexin37, not Cx40 and Cx43, is Induced in Vascular Smooth Muscle Cells During Coronary Arteriogenesis. Journal of Molecular and Cellular Cardiology (2001) 33, 957-967. The hypothesis that an altered expression of gap junction (GJ) proteins, connexin37 (Cx37), Cx40 and Cx43 will contribute to adaptive arteriogenesis was tested in growing coronary collateral vessels (CV) of the dog heart by immunoconfocal microscopy and transmission electron microscopy (TEM). We found that: (1) in the normal coronary system Cx37 and Cx40 were only expressed in endothelial cells (EC) from artery to capillary; (2) during collateral growth Cx37 was significantly induced in smooth muscle cells (SMC) from small-large arteries to precapillary arterioles (Ø=15 microm), while Cx40 was still only present in EC; (3) both homogeneous and heterogeneous distribution of Cx37 was observed in normal vessels (NV) and growing vessels (GV); (4) in mature vessels (MV), Cx37 was downregulated, similar to NV; (5) dual immunostaining revealed an inverse correlation between expression of Cx37 and desmin in GV occurring prior to downregulation of alpha-smooth actin and calponin; (6) Cx43 was undetectable in any vascular cells, both in NV and GV; (7) GJ were not found in SMC by TEM. Our data for the first time show the profile of connexin expression in the coronary system and provide evidence for existence of GJ proteins in capillaries. It is a novel finding that an altered expression of Cx37 is characteristic of adaptive arteriogenesis in the dog heart and may be used as a marker of vascular growth. Induced Cx37 may be an early signal indicating that SMC are responding to haemodynamic changes, i.e. increased shear stress.

Actins↗

PubMed2001

Arteriogenesis, a new concept of vascular adaptation in occlusive disease.

The formation of collateral arteries as a process adaptive to arterial occlusion is now called 'arteriogenesis' to emphasize the difference to angiogenesis, the formation of capillaries by sprouting from pre-existent ones (W. Schaper, I. Buschmann. Cardiovasc Res 1999; 43: 835-7; I. Buschmann, W. Schaper. J Pathol 2000; 190: 338-42; D. Scholz et al. Virchows Arch 2000; 436: 257-70). The differences are that collaterals develop from pre-existing arterioles and that circulating monocytes adhere to endothelium that had been activated by the high shear stress generated by the large pressure differences between perfusion territories. Monocytes are the major producers of growth factors and of proteolytic enzymes that enable smooth muscle cells to migrate and divide. The nature of the growth factors remains uncertain. Neither FGF-1/2 nor VEGF is expressed on the transcriptional or translational level in collaterals proper and in the tissue surrounding them. Only FGF receptor 1 has a brief window of upregulation shortly after arterial occlusion. While transgenic overexpression of FGF-1 increases number and branching of arterioles, targeted disruption of FGF-1/2 does not negatively influence arteriogenesis. Cytokines that attract monocytes or prolong the life span of monocytes (MCP-1, GM CSF) are strong arteriogenic factors. Collateral vessels exhibit the same morphology whether they had formed in the heart, limbs or brain or in dogs, rabbits or mouse. They are tortuous because they also increase lengthwise in a restricted space. In animals larger than the mouse, they develop an intima, and initially, many arterioles participate in arteriogenesis, but only a few mature into large arterial channels which, when arterial occlusion had proceeded slowly enough, can replace the occluded artery to a significant proportion. Therapy with a single growth factor in animals with occluded femoral arteries significantly increases the speed of arteriogenesis but does not significantly increase the level of adaptation. It appears that the mastergene for arteriogenesis still awaits discovery.

Adaptation, Physiological↗

PubMed2001

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

Animals↗

PubMed2001

[Skelefon framework concept for defence against risks in unusual epidemics: steps by public health offices].

Necessary anti-epidemic measures have to be promulgated or taken immediately in case of a suspected case of pneumonic plague or a viral haemorrhagic fever which can be transmitted from human to human. A live threatening highly contagious infectious disease may occur at any place in Germany. Therefore each health office should have the relevant information on the available infrastructure in Germany concerning treatment and competence centres, diagnostic laboratories, dispatch of samples and patient transportation. They should also be able to give qualified recommendations to physicians and hospitals concerning the necessary measures in such a case. Contacts at risk have to be notified. Based on a risk assessment and the special living conditions of the contact person they should decide if and which further measures have to be initiated, especially in the case of post-exposure prophylaxis, separation and prohibition of work. In general, imported cases of dangerous infectious diseases quickly find the interest of the media, including all the implications resulting from this. A well-organized cooperation with the media and public relations helps to avoid unnecessary irritations and panic.

Communicable Disease Control↗

PubMed2000

Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis.

To study the role of extracellular proteolysis and antiproteolysis during adaptive arteriogenesis (collateral vessel growth) we took 58 collaterals at various developmental stages from 14 dogs with chronic occlusion of the left circumflex coronary artery (LCx) by ameroid constrictor. Immunofluorescence and quantitative immunofluorescence with antibodies against alpha-smooth muscle actin, desmin, matrix metalloproteinases 2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2), urokinase-type plasminogen activator (u-PA) and its inhibitor-1 (PAI-1) were studied with confocal microscopy. Additionally, SDS-PAGE zymography was employed. We found that in normal coronary arteries, MMP-2, MMP-9 and PAI-1 were present in all layers of the wall in small amounts. TIMP-1 was found only in smooth muscle cells. In contrast, in growing collaterals, MMP-2 and MMP-9 were 3.4-fold and 4.1-fold higher in the neointima than in the media respectively. TIMP-1 was 4.4-fold higher in the media over the growing neointima. Zymography showed MMP-2 and MMP-9 activated. PAI-1 was increased, especially in the growing neointima where it was 1.4-fold higher. In mature collaterals, MMP-2 and MMP-9 were downregulated in the neointima, 1.4-fold and 1.3-fold higher over the media. TIMP-1 was 1.4-fold increased in the neointima but PAI-1 was downregulated. Desmin and alpha-smooth muscle actin were significantly increased in the neointima compared to growing vessels. U-PA was moderately increased in growing vessels. TIMP-2 was not detectable in collaterals. We conclude that expression of MMP-2 and 9, TIMP-1 and PAI-1 showed a spatial and temporal pattern which is closely associated with the development of collateral vessels. The shift of the balance between proteolysis and antiproteolysis is regulated not only by MMPs and TIMP-1, but also by the PA-PAI system.

Adaptation, Physiological↗

PubMed2000

Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis).

Previous studies in the canine heart had shown that the growth of collateral arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ultrastructure and molecular histology of growing and remodeling collateral arteries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals had a diameter of about 50 microm. They consisted of one to two layers of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriolar thinning, followed by transformation of SMCs from the contractile- into the proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlusion, whereas adhesion molecule expression and monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosphorylation of the focal contacts after 30 min and induction of ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting that shear stress may be the initiating event. We conclude that the process of arteriogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of inflammation.

Animals↗

PubMed2000

The cytoskeleton and related proteins in the human failing heart.

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, alpha-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 alpha-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.

Cardiomyopathy, Dilated↗

PubMed1999

X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: agreement of time-resolved spectroscopy and molecular dynamics simulations.

Based on the X-ray structure of the human immunodeficiency virus type-1 (HIV-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 542 ps molecular dynamics trajectory was computed. For comparison with the 805 ps trajectory obtained for the uncomplexed enzyme, the theoretical fluorescence anisotropy decay of the unliganded protease and the inhibitor complex was calculated from the trajectories of the Trp6A/Trp6B and Trp42A/Trp42B transition dipole moments. This enabled us to directly compare the simulated data with the experimental picosecond time-resolved fluorescence data. Fitting both experimental and simulated data to the Kohlrausch-Williams-Watts (KWW) function exp(-t/tauk)beta revealed a very good agreement for the uncomplexed protease as well as for the SDZ283-910 complex. Binding of the inhibitor induced a faster decay of both the experimental and the computed protease fluorescence anisotropy decay. By this integrative approach, the atomic detail of inhibitor-induced changes in the conformational dynamics of the HIV-1 protease was experimentally verified and will be used for further inhibitor optimisation.

Anti-HIV Agents↗

PubMed1999

Isometric contraction induces the Ca2+-independent activation of the endothelial nitric oxide synthase.

Shear stress and tyrosine phosphatase inhibitors have been shown to activate the endothelial NO synthase (eNOS) in a Ca2+/calmodulin-independent manner. We report here that isometric contraction of rabbit aorta activates eNOS by a pharmacologically identical pathway. Endothelium-intact aortic rings were precontracted under isometric conditions up to 60% of the maximal phenylephrine-induced tone. The NO synthase inhibitor NGnitro-L-arginine (L-NA) and the soluble guanylyl cyclase inhibitor NS 2028 induced an additional contraction, the amplitude of which depended on the level of precontraction. The maximal production of NO by isometrically contracted aortic rings (as estimated by the increase in cGMP in detector smooth muscle cells in a superfusion bioassay) was observed during the initial phase of isometric contraction and was greater than that detected following the application of acetylcholine. The supplementary L-NA-induced increase in vascular tone was inhibited by the nonselective kinase inhibitor staurosporine and the tyrosine kinase inhibitors erbstatin A and herbimycin A. Another tyrosine kinase inhibitor, genistein, the calmodulin antagonist calmidazolium, and the selective protein kinase C inhibitor, Ro 31-8220, had no effect. Coincident with the enhanced NO formation during isometric contraction was an increase in the tyrosine phosphorylation of endothelial proteins, which also correlated with the level of precontraction. Thus, isometric contraction activates eNOS via a Ca2+-independent, tyrosine kinase inhibitor-sensitive pathway and, like shear stress, seems to be an independent determinant of mechanically induced NO formation.

1-Methyl-3-isobutylxanthine↗

PubMed1999

Ferula asa-foetida and Curcuma longa in traditional medical treatment and diet in Nepal.

Food and eating have powerful symbolic value among the hinduistically-influenced ethnic groups of Nepal. In addition, food plays a major role in the concepts of illness and curing and constitute an integral part of traditional medical prescriptions. Materials that are consumed in 0.5-1.5 g amounts in the daily diet (e.g. the spices turmeric and asafoetida) are used in minute amounts for medical purposes. Why? Three hypotheses are offered here to discuss this issue.

Animals↗

PubMed1999

Special communicationthe critical role of mechanical forces in blood vessel development, physiology and pathology

The following extended abstracts were presented at the Research Initiatives in Vascular Disease Conference, Movers and Shakers in the Vascular Tree-Hemodynamic and Biomechanical Factors in Blood Vessel Pathology, sponsored by The Lifeline Foundation and the Cardiovascular & Interventional Radiology Research and Educational Foundation; jointly sponsored by the International Society for Cardiovascular Surgery, North American Chapter, The Society for Vascular Surgery, and The Society of Cardiovascular and Interventional Radiology; in cooperation with the National Institutes of Health-National Heart, Lung &Blood Institute on Mar 11-12, 1999, in Bethesda, Md.

Journal Article↗

PubMed1999

Microvascular endothelial cells remodel cultured adult cardiomyocytes and increase their survival.

We investigated the paracrine effect of cardiac microvascular endothelial cells (MVEC) on cultured adult rat cardiomyocytes (ARC). ARC were exposed for 8 days to serum-free medium (CM) conditioned by MVEC. Controls were grown in FCS or FCS-free medium. Protein synthesis of CM-stimulated ARC increased twofold versus 5% FCS-stimulated cells until day 8. Seventy-nine percent of CM-treated myocytes survived, whereas only twenty-four percent of FCS-free ARC retained viability. The phenotype of myocytes exposed to CM was different from control. Analysis by confocal laser microscopy of CM-stimulated myocytes showed actin staining throughout the whole cell body up to the peripheral extensions, with concomitant appearance of myomesin in a cross-striated pattern. The reexpression of fetal alpha-smooth muscle actin determined immunohistochemically and by Western blot increased from day 6 in CM-treated cells, whereas ARC grown in up to 20% serum were negative. These effects could not be mimicked by any of the other cardioactive substances tested here, indicating a novel trophic factor in CM.

Actins↗

PubMed1999

Tissue-specific transcriptional activity of a pancreatic islet cell-specific enhancer sequence/Pax6-binding site determined in normal adult tissues in vivo using transgenic mice.

A pancreatic islet cell-specific enhancer sequence (PISCES) shared by the rat insulin-I, glucagon, and somatostatin genes binds the paired domain-containing transcription factor Pax6 and confers strong transcriptional activity in pancreatic islet cell lines. It was found recently that Pax6 plays a major role in islet development. In the present study, transgenic mice were used to investigate PISCES-mediated transcription in normal adult islets in vivo. In several independent mouse lines expressing a PISCES-luciferase reporter transgene, the PISCES motif directed gene expression in the adult eye, cerebellum, and discrete brain areas, consistent with the tissue distribution of Pax6. These tissues contain two Pax6 isoforms caused by alternative splicing, only one of which was found to bind the PISCES motif in electrophoretic mobility shift assays. No reporter gene expression was detected in adult pancreatic islets or in any other peripheral organ tested. RT-PCR analysis confirmed that Pax6 mRNA is present in adult islets. These results demonstrate that the PISCES motif is sufficient to direct highly tissue-specific gene expression in whole animals. The lack of PISCES-mediated transcription in adult islets indicates that the Pax6 protein(s) expressed in adult pancreatic islets function differently from the ones in the eye and cerebellum.

Alternative Splicing↗

PubMed1998

Inhibition of Fc epsilon RI-mediated activation of mast cells by 2,3,4-trihydropyrimidino[2,1-a]isoquinolines.

Assays based on reporter gene technology represent today an important tool in the pharmaceutical industry for discovering novel compound classes interfering with the activation and signaling of target cells after stimulation. Here we describe a reporter gene assay targeting mast cell activation of IgE plus antigen, established in an attempt to identify substances preventing type I allergy (allergic rhinitis, allergic conjunctivitis, allergic asthma, and acute and chronic urticaria). The assay is based on a murine mast cell line designated CPII, stimulation by IgE plus antigen, and a reporter gene construct with the TNF alpha promoter linked to luciferase as a read-out system. Via screening about 50,000 substances, compound 2 was found to inhibit the reporter gene induction in the submicromolar range in this assay. Analogues of compound 2 of the 2,3,4-trihydropyrimidino[2,1-a]isoquinoline type were synthesized starting from 2-alkyl-substituted benzonitriles via aminolysis with 1,3-diaminopropane, dimetalation of 2-substituted 2-phenyl-1,4,5,6-tetrahydropyrimidines with n- and sec-butylithium, reaction with carboxylic acid methyl esters, and finally acidic dehydration. From about 50 derivatives, compound 41 was selected as a lead structure with an IC50 of 0.2 microM and a TC50 of 2.7 microM. In a first profiling in secondary assays, it effectively interfered with the production of mediators such as TNF alpha, IL-4, IL-6, IL-13, and leukotriene synthesis as measured by the corresponding ELISAs. In addition, a passive cutaneous anaphylaxis in mice (a typical type I reaction) is inhibited to more than 90% by compound 41, when administered intradermally 90 min before challenge.

Animals↗

PubMed1998

Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb.

We have previously shown that monocytes adhere to the vascular wall during collateral vessel growth (arteriogenesis) and capillary sprouting (angiogenesis). In this study we investigated the association of monocyte accumulation with both the production of the cytokines-basic fibroblast growth factor (bFGF) and TNF-alpha-and vessel proliferation in the rabbit after femoral artery occlusion. In particular, we studied the effects of an increase in monocyte recruitment by LPS on capillary density as well as collateral and peripheral conductance after 7 d of occlusion. Monocytes accumulated around day 3 in collateral arteries when maximal proliferation was observed, and stained strongly for bFGF and TNF-alpha. In the lower limb where angiogenesis was shown to be predominant, macrophage accumulation was also closely associated with maximal proliferation (around day 7). LPS treatment significantly increased capillary density (424+/-26.1 n/mm2 vs. 312+/-20.7 n/mm2; P < 0.05) and peripheral conductance (109+/-33.8 ml/min/100 mmHg vs. 45+/-6.8 ml/min/100 mmHg; P < 0.05) as compared with untreated animals after 7 d of occlusion. These results indicate that monocyte activation plays a major role in angiogenesis and collateral artery growth.

Animals↗