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PubMed2003

Hormone regulation of endothelial apoptosis and proliferation in vessel regression and angiogenesis.

Apoptosis and endothelial proliferation represent two adverse events which take place during vessel regression and angiogenesis, respectively. Apoptosis, an intrinsically activated programmed cell death, regulates cell elimination during vessel regression. In contrast, angiogenesis involves endothelial cell proliferation, migration, and vascular formation. Several molecules, including growth factors and cytokines, produced by endothelial cells and by other cells within the vicinity of the capillary network, regulate apoptosis and angiogenesis. Hormones and endocrine peptides acting via specific receptors located on the endothelial and perivascular stromal cells also have been found to be involved in the regulation of these two major antagonistic processes. The need for a better understanding of the mechanisms involved in hormone regulation of endothelial cell during apoptosis and angiogenesis is of great importance. The accumulating knowledge of hormone regulation may contribute to the introduction of new therapeutic strategies targeting the endothelial cells.

Animals↗

PubMed1978

Intra and extracranial meningiomas involving the temporal bone.

Meningiomas involving the temporal bone are very rare. Until 1964, only 39 cases had been reported in the world literature. Most series reported are very small and a physician is unable, based on his own experience, to acquire a sufficient knowledge about this entity and may raise serious doubts regarding the diagnosis and management of these tumors. In the past nine years the author has encountered five cases of meningiomas involving the temporal bone. This became a stimulus for a thorough research of the world literature of meningiomas in general, with emphasis on temporal bone involvement. Nine more cases were collected from cooperative physicians with whom the author has been associated. These 14 cases are the clinical material analysed in this study. This thesis is divided into three sections: 1. Exhaustive review of the world literature on meningiomas with emphasis on involvement of the temporal bone. 2. A detailed presentation and discussion of the clinical material stressing the importance of the newer diagnostic methods available and the most modern microsurgical techniques used in otological and neurological surgery procedures, applied to the treatment of those lesions. A light microscopic histopathological study of all cases reported is presented. Electronmicroscopy demonstrates the true intracellular nature of an atypical, recurrent meningioma occurring in a child. 3. A critical evaluation of the cases presented and the value of the diagnostic and therapeutic methods applied in this series of patients are here analysed. Conclusions are then drawn based on the experience and knowledge accumulated in this study. The histopathological diagnosis of meningiomas sometimes is difficult. Probably those tumors involve the temporal bone more commonly than has been reported in the literature. Some of these lesions probably are being misdiagnosed as chemodectomas or other neoplasias. Computerized axial tomography, particularly applied to the diagnosis of brain lesions, is the major break-through of recent modern medicine. A noninvasive technique, when used with contrast enhancement, offers great diagnostic possibilities. Early diagnosis of meningiomas and their complete surgical excision are the key factors necessary for a successful result with a good prognosis and a low recurrence rate. Although these tumors are classically considered radioresistant, radiotherapy may play a role in the treatment of incompletely excised lesions or in patients of a poor surgical risk. Further experiences and time will probably lead to more definite conclusions regarding the role of radiation therapy or the combined surgical and postoperative radiation treatment. Of all brain tumors, meningiomas offer the best prognosis.

Adolescent↗

PubMed2002

Cell surface heparan sulfate and its roles in assisting viral infections.

Heparan sulfate, a highly sulfated polysaccharide, is present on the surface of mammalian cells and in the extracellular matrix in large quantities. The sulfated monosaccharide sequences within heparan sulfate determine the protein binding specificity and regulate biological functions. Numerous viruses and parasites utilize cell surface heparan sulfate as receptors to infect target cells. Due to the structural complexity of heparan sulfate, it was considered a nonspecific cell surface receptor by interacting with the positive motifs of viral proteins. However, recent studies reveal that heparan sulfate plays multiple roles in assisting viral infection, and the activities in promoting viral infections require unique monosaccharide sequences, suggesting that heparan sulfate could serve as a specific receptor for viral infection. The currently available techniques for the structural analysis of heparan sulfate provide essential information about the specific roles of heparan sulfate in assisting viral infections. The knowledge accumulated in this fast growing field will permit us to have a better understanding of the mechanism of viral infection and will lead to the development of new antiviral agents.

Carbohydrate Conformation↗

PubMed2003

Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts.

The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) technique has been extensively used for the detection and quantification of apoptosis in histological tissue sections. However, the interpretation and specificity of this assay have been controversial. With accumulating knowledge of the molecular mechanisms of cell death and the discovery of the caspases as key mediators of apoptosis, more direct and earlier measurements of apoptosis in tissue sections have emerged. This study, using antibodies that specifically recognize activated caspase-3 and caspase-cleaved cytokeratin (CK) 18, evaluated whether immunohistochemical stains would improve the detection and quantification of apoptosis in tissue sections, compared with the TUNEL assay. Tumour xenografts of the prostate cancer cell line PC-3 were used as an example, since these tissues contain large numbers of cells undergoing apoptosis. Apoptotic cells were quantified and apoptotic indices were calculated by computer-assisted image analysis following identification of apoptotic cells by morphological analysis, the TUNEL assay, activated caspase-3 and cleaved CK18 immunohistochemistry. The results indicated that activated caspase-3 immunohistochemistry was an easy, sensitive, and reliable method for detecting and quantifying apoptosis in this model. An excellent correlation (R = 0.89) between the apoptotic indices obtained using activated caspase-3 and cleaved CK18 immunostaining was observed. A good correlation (R = 0.75) between the apoptotic indices obtained using activated caspase-3 immunostaining and the TUNEL assay was also found. Activated caspase-3 immunohistochemistry is therefore recommended for the detection and quantification of apoptosis in tissue sections.

Animals↗

PubMed1993

Toward universal ecology disturbance measures. Basis and outline of a universal measure.

In the past, environmental risk assessments of materials were primarily based upon known or suspected toxic and/or ecotoxic effects. When considering the restructuring of economies to function within ecological boundary conditions, the accumulated knowledge about hazardous materials is not sufficient because science can never predict, simulate, and quantify all possible environmental consequences in terms of nature, intensity, time, and space for releasing a multitude of different material streams. The comparison of the environmental impact intensities of different materials on the basis of toxicological hazard considerations is therefore quite limited. Moreover, since our knowledge about toxic effects is continuously expanding, economic restructuring decisions of today may turn out to be shortsighted tomorrow. This paper introduces the material intensity per unit service--the MIPS--as a universal measure for the initial estimation and comparison of the environmental impact intensities of infrastructures, goods, and services. This paper further argues that Western infrastructures, goods, and services must be dematerialized by an average factor of 10 or more in order to begin restabilizing the ecosphere. With the concept of MIPS, and a goal for long-range economic planning, robust and consistent ecological policies could be developed and internationally harmonized, and actual progress toward sustainability could be monitored.

Animals↗

PubMed2003

Design, synthesis, and biological studies of the A-ring-modified 1,25-dihydroxyvitamin D3 analogs.

Antitumor effects of 1alpha,25-dihydroxyvitamin D3 analogs have recently become one of the major topics of the vitamin D research field. We focused on the structure-activity relationships of the A-ring moiety of the vitamin D molecule and found several strong agonists of the vitamin D receptor, using a design of introducing a functional group into the C2 position. In the first step, all eight possible diastereomers of novel 2-methyl-1,25-dihydroxyvitamin D3 were synthesized using the convergent method with palladium catalyzed coupling reaction. We studied conformational analysis of each isomer based on 1H NMR and computer calculations; and biologically, VDR binding affinity, potency of induction of HL-60 cell differentiation, and apoptosis were investigated in detail. The biological effect of double modification in a combination of the CD-ring side chain (20-epi, 20-epi-22R-methyl, and KH-1060 types) and the 2-methyl group was then evaluated. In this context, 5,6-trans derivatives of 2-methyl analogs were also synthesized and tested. Through these experiments, our accumulated knowledge that the 2a-methylated analog with the natural la,3fl-dihydroxyl groups possesses a strong and unique biological profile guided us the next synthetic goal, i.e., three kinds of longer functional groups: 2alpha-alkyl, 2alpha-hydroxyalkyl, and 2alpha-hydroxyalkoxyl groups, which were introduced into 1alpha,25-dihydroxyvitamin D3, stereoselectively. We found that five of our new 2alpha-modified analogs show higher VDR-binding affinity than that of the natural hormone. HL-60 cell differentiation induction activities and calcium mobilization were studied for some of these compounds. These are the first examples, including the pioneer 2a-methyl analog, that exhibit higher VDR-binding affinity than 1alpha,25-dihydroxyvitamin D3 with pure A-ring modifications. To explain the effect, docking studies of the synthetic ligands to VDR are also described. This study could stimulate the development of antitumor medicines of the vitamin D analogs.

Cell Differentiation↗

PubMed2005

Microbial isoprenoid production: an example of green chemistry through metabolic engineering.

Saving energy, cost efficiency, producing less waste, improving the biodegradability of products, potential for producing novel and complex molecules with improved properties, and reducing the dependency on fossil fuels as raw materials are the main advantages of using biotechnological processes to produce chemicals. Such processes are often referred to as green chemistry or white biotechnology. Metabolic engineering, which permits the rational design of cell factories using directed genetic modifications, is an indispensable strategy for expanding green chemistry. In this chapter, the benefits of using metabolic engineering approaches for the development of green chemistry are illustrated by the recent advances in microbial production of isoprenoids, a diverse and important group of natural compounds with numerous existing and potential commercial applications. Accumulated knowledge on the metabolic pathways leading to the synthesis of the principal precursors of isoprenoids is reviewed, and recent investigations into isoprenoid production using engineered cell factories are described.

Bioreactors↗

PubMedDate not supplied

Is cysteine residue important in FITC-sensitive ATP-binding site of P-type ATPases? A commentary to the state of the art.

Treatment of P-type ATPases (from mammalian sources) by fluorescein isothiocyanate (ITC) revealed the ITC label on a lysine residue that was than considered as essential for binding of ATP in the ATP-binding site of these enzymes. On the other hand, experiments with site directed mutagenesis excluded the presence of an essential Iysine residue that would be localized in the ATP binding sites of ATPases. Other previous studies, including those of ourselves, indicated that the primary site of isothiocyanate interaction may be the sulfhydryl group of a cysteine residue and this may be essential for binding of ATP. In addition considerable knowledge accumulated since yet also about the differences in stability of reaction product of isothiocyanates with SH- or NH2- groups. Based upon evaluation of the data available up to now, in present paper the following tentative roles for lysine and cysteine residues located in the ATP-binding site of P-type ATPases are proposed: The positively charged micro-domain of the lysine residue may probably attract the negatively charged phosphate moiety of the ATP molecule whereas the cysteine residue may probably be responsible for recognition and binding of ATP by creation of a proton bridge with the amino group in position 6 on the adenosine ring of ATP.

Adenosine Triphosphatases↗

PubMed1981

Experimental methods in behavioral teratology.

The possibility that the exposure of the embryo to certain chemical substances can lead to behavioral disturbances is known from human epidemiological studies, e.g., in chronic poisoning with mercury and ethanol. Therefore, efforts are made to develop toxicological techniques with which new behavioral teratogens can be recognized. The review describes the most important experimental methods which are presently explored, and which are based on a rich body of knowledge accumulated by experimental psychologists. Most of the tests were developed with small animals, mostly with rats. They range from a rather straightforward determination of various reflexes to complex behavioral situations involving mechanical devices, operant conditioning techniques and procedures evaluating social behavior. In applying these methods in routine toxicology, it is important to remember, that many behavioral effects determined in newborn and adult animals are subtle. Moreover, they are influenced by a large variety of environmental factors affecting the health and the behavior of the mothers and of the offspring in the early and later phases of development. Therefore, the experiments must be conducted under highly standardized conditions and must be controlled rigorously. It is concluded that the best experimental strategy for the evaluation of potential behavioral teratogens is not yet established. Therefore, it would be premature to decide on a fixed protocol to be included in routine animal safety experiments for drugs and other chemical substances.

Animals↗

PubMed1989

Kinetic analysis of excitation-contraction coupling.

Recent studies of isolated muscle membrane have enabled induction and monitoring of rapid Ca2+ release from sarcoplasmic reticulum (SR)5 in vitro by a variety of methods. On the other hand, various proteins that may be directly or indirectly involved in the Ca2+ release mechanism have begun to be unveiled. In this mini-review, we attempt to deduce the molecular mechanism by which Ca2+ release is induced, regulated, and performed, by combining the updated information of the Ca2+ release kinetics with the accumulated knowledge about the key molecular components.

Animals↗

PubMed1989

Structure-function relationships of icosahedral plant viruses.

X-ray diffraction studies on single crystals of a few viruses have led to the elucidation of their three dimensional structure at near atomic resolution. Both the tertiary structure of the coat protein subunit and the quaternary organization of the icosahedral capsid in these viruses are remarkably similar. These studies have led to a critical re-examination of the structural principles in the architecture of isometric viruses and suggestions of alternative mechanisms of assembly. Apart from their role in the assembly of the virus particle, the coat proteins of certian viruses have been shown to inhibit the replication of the cognate RNA leading to cross-protection. The coat protein amino acid sequence and the genomic sequence of several spherical plant RNA viruses have been determined in the last decade. Experimental data on the mechanisms of uncoating, gene expression and replication of several classes of viruses have also become available. The function of the non-structural proteins of some viruses have been determined. This rapid progress has provided a wealth of information on several key steps in the life cycle of RNA viruses. The function of the viral coat protein, capsid architecture, assembly and disassembly and replication of isometric RNA plant viruses are discussed in the light of this accumulated knowledge.

Capsid↗

PubMed1995

Oscillating between denial and recognition of PTSD: why are lessons learned and forgotten?

Consistent observations suggest that denial of PTSD and blaming of its victims are not isolated omissions or distortions but a pattern that spans over time, crosses national and cultural boundaries, and defies accumulated knowledge. This article traces the origins of these attitudes and offers three explanations: (a) mental health professionals are unable to transcend prevailing cultural and social norms; (b) they are "blinded" by professional theories; and (c) denial may stem from a fundamental human difficulty in comprehending and acknowledging our own vulnerability.

Anxiety↗

PubMed2006

The role of VEGF receptors in angiogenesis; complex partnerships.

Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have profound effects on neural cells. VEGFs are predominantly produced by endothelial, hematopoietic and stromal cells in response to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of these proteins more than 20 years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial cells during cell migration, growth and differentiation.

Animals↗

PubMed2001

Forest ecosystem development in post-mining landscapes: a case study of the Lusatian lignite district.

The restoration of surface mining landscapes requries the (re)creation of ecosystems. In Lusatia (eastern Germany), large-scale open-cast lignite mining operations generated spoil dumps widely consisting of acidified, phytotoxic substrates. Amelioration and rehabilitation measures have been developed and applied to these substrates since the 1950s. However, it is still not clear whether these approaches are sustainable. This paper reports on collaborative research work into the ecological potential of forest ecosystem development on typical minesites in the Lusatian lignite district. At first sight, pine stands on minesites along a chronosequence comprising about 35 years did not show differences when compared with stands on non-mined sites of the general region. Furthermore, with some modification, conceptual models for flora and fauna succession in forest stands on non-mined sites seem to be applicable, at least for the early stages of forest ecosystem development. For example, soil organism abundance and activity at minesites had already reached levels typical of non-mined sites after about 20-30 years. In contrast, mine soils are very different from non-mined soils of the test region. Chemically, mine soil development is dominated by processes originating from pyrite oxidation. Geogenic, i.e. lignitic, soil organic carbon was shown to substitute for some functions of pedogenic soil organic matter. Rooting was hampered but not completely impeded in strongly acidified soil compartments. Roots and mycorrhizae are apparently able to make use of the characteristic heterogeneity of young mine soils. Considering these recent results and the knowledge accumulated during more than 30 years of research on minesite rehabilitation internationally, it can be stated that minesite restoration might be used as an ideal case study for forest ecosystem development starting at "point zero" on "terra nova".

Coal Mining↗

PubMed2005

[Quality of life after radical urologic pelvic surgery and impact of inpatient rehabilitation].

Health-related quality of life (QOL) has become a pivotal criterion for assessing quality of specific therapy for prostate and bladder cancer in urology and serves increasingly as a basis for therapeutic decisions reached by urologists and patients. To aid in comprehension, we present the development of QOL research, the accumulated knowledge, and needs for further investigations by offering a broad review of the literature. In Germany, established inpatient rehabilitation has dealt with QOL for decades, but proof of efficacy was lacking. We clearly demonstrated in a prospective study the beneficial effects on QOL achieved with a specific modular urologic inpatient rehabilitation program after radical prostatectomy within 3-4 weeks and stability of these effects over time. Inpatient rehabilitation provides the best generic and disease-specific QOL after radical urologic surgery and completes the surgeon's performance.

Cystectomy↗

PubMed2004

[The anatomy of the ulnocarpal complex].

The ulnocarpal complex (triangular fibrocartilage complex; TFCC) represents an intricate system of structures which secures motion guidance, stability and pressure transmission in the ulnocarpal compartment of the wrist joint. Anatomically, this complex consists of the ulnocarpal disc (triangular disc), palmar and dorsal radioulnar ligaments, ulnolunate, ulnotriquetral and ulnocapitate ligaments, ulnocarpal meniscus homologue, ulnar recess (prestyloid recess), ulnocarpal collateral ligament and tendon sheath of the extensor carpi ulnaris. The distal radioulnar joint and the interosseous membrane of the forearm, which lie close together, also belong functionally to the ulnocarpal complex. Together with the proximal radioulnar joint, they permit rotational movements of the hand (pronation and supination). This review highlights all components of the ulnocarpal complex systematically. Distinctive characteristics involving size, as well as variations, are listed, and their functional meaning analyzed. The accumulated knowledge serves as a basis for possible interventions both at the ulnocarpal complex and the distal radioulnar joint.

Carpal Bones↗

PubMed2005

Acute mesenteric ischemia: the challenge of gastroenterology.

Intestinal ischemia has been classified into three major categories based on its clinical features, namely, acute mesenteric ischemia (AMI), chronic mesenteric ischemia (intestinal angina), and colonic ischemia (ischemic colitis). Acute mesenteric ischemia is not an isolated clinical entity, but a complex of diseases, including acute mesenteric arterial embolus and thrombus, mesenteric venous thrombus, and nonocclusive mesenteric ischemia (NOMI). These diseases have common clinical features caused by impaired blood perfusion to the intestine, bacterial translocation, and systemic inflammatory response syndrome. Reperfusion injury, which exacerbates the ischemic damage of the intestinal microcirculation, is another important feature of AMI. There is substantial evidence that the mortality associated with AMI varies according to its cause. Nonocclusive mesenteric ischemia is the most lethal form of AMI because of the poor understanding of its pathophysiology and its mild and nonspecific symptoms, which often delay its diagnosis. Mesenteric venous thrombosis is much less lethal than acute thromboembolism of the superior mesenteric artery and NOMI. We present an overview of the current understanding of AMI based on reported evidence. Although AMI is still lethal and in-hospital mortality rates have remained high over the last few decades, accumulated knowledge on this condition is expected to improve its prognosis.

Acute Disease↗

PubMed2006

A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. The cause of KD is largely unknown, but its higher incidence in the Asian population and increased risk in patients' families suggests the existence of underlying genetic factors. To determine the loci of a susceptibility gene for KD, a genomewide linkage analysis with affected sib pairs was performed on 78 family samples collected from all over Japan. Multipoint linkage analysis using MAPMAKER/SIBS 2.0 identified evidence of linkage on 12q24 [maximum lod score (MLS) = 2.69]. Possible linkage (MLS > 1.0) was also found on 4q35, 5q34, 6q27, 7p15, 8q24, 18q23, 19q13, Xp22, and Xq27. This is the first large-scale study of the genetic susceptibility to KD, and our results, combined with the accumulated knowledge of the human genome, could greatly promote research on identification of the molecular pathogenesis of KD.

Chromosome Mapping↗