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PubMed1989

Taurine modulates platelet aggregation in cats and humans.

To explore the relationship between whole-body taurine status and function, the taurine concentration in plasma and platelets was measured and evaluated in terms of ex vivo collagen-induced platelet aggregation in taurine-depleted cats and taurine-supplemented humans. Taurine status exerted a significant effect on platelet aggregability. Platelets from taurine-depleted cats were twice as sensitive to aggregation as platelets from cats receiving taurine. On the other hand, platelets from humans with normal taurine status increased resistance to aggregation by 30-70% when supplemented with taurine at 400 or 1600 mg/d, respectively. Decreased platelet aggregability was associated with increased platelet taurine and glutathione concentrations and decreased thromboxane release on aggregation. These data indicate that taurine in vivo stabilizes platelets against aggregation such that during taurine depletion platelets become overly sensitive whereas during supplementation their tendency to aggregate is depressed.

Adult↗
PubMed2006

Surgical procedures for melanoma in public and private New South Wales hospitals, 2001-2002.

BACKGROUND: Evidence suggests that there is considerable variation in the types of procedures used to treat cancer. This variation may result in suboptimal or cost-ineffective care. The present study examined the variation in surgical treatment of melanoma before the establishment of a Melanoma Network that could promote more uniform high-quality care in New South Wales (NSW). The variations in the use of surgical procedures for melanoma by NSW Area Health Service of patient residence were examined. METHODS: Data in the Health Information Exchange of NSW Health collected on procedures carried out on patients with a diagnosis of melanoma in NSW public and private hospitals from 1 July 2001 to 30 June 2002 were examined. Data were aggregated by Area Health Services of patient residence. These data were compared with the numbers of new cases of melanoma notified to the NSW Central Cancer Registry in the same areas in 2001-2002. Excision of skin lesions, skin grafting and numbers and types of lymph node procedures were examined. RESULTS: During the study period, the Central Cancer Registry reported that there were 3085 notifications of melanoma, whereas hospital inpatient data recorded that 6864 procedures were carried out for patients with a melanoma diagnosis in NSW public and private hospitals. Sixty-seven per cent of procedures were carried out in private hospitals. A total of 852 skin grafting procedures were recorded. Of these, 60% were carried out in private hospitals. The average proportion of skin grafts associated with excisions in NSW was 30% (range, 0-53%). Eight hundred and fifty-eight lymph node procedures were recorded for 747 NSW residents. These were biopsies, excisions or both. Forty per cent were carried out in private hospitals. The average proportion of new cases of melanoma associated with a lymph node procedure in NSW was 28% (range, 0-47%). CONCLUSION: Most of the inpatient procedures for patients with melanoma were carried out in private hospitals. The proportions of new cases that underwent skin grafting after excision, or underwent lymph node dissection, varied more than fivefold from one Area Health Service to another. This may indicate variations in casemix, variations in clinical practice or both.

Hospitals, Private↗
PubMed2003

Effects of barbiturates on human platelet aggregation differ depending on their chemical structures.

The effects of barbiturates on human platelet function are not fully understood. Since we have already revealed the effects and mechanisms of thiopental, thiamylal, and pentobarbital in platelets, the present study attempted to elucidate (i) the effects of other barbiturates on human platelet aggregation, (ii) the underlying mechanisms, and (iii) the structure-function relationship of barbiturates in platelets. Barbiturates, including amobarbital, butalbital, secobarbital, barbital, phenobarbital, metharbital, and primidone, were examined. Human platelet aggregation induced by adenosine diphosphate (ADP), epinephrine, and (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2), a thromboxane A2 analog, was measured using an 8-channel light-transmission aggregometer. The cytosolic free calcium concentration ([Ca2+]i) was measured by fluorometer using fura-2 loaded platelets. Inositol 1,4,5-trisphosphate (IP3) formation induced by STA2 was determined by a commercially available IP3 assay kit. Amobarbital, butalbital, and secobarbital suppressed ADP-, epinephrine- and STA2-induced platelet aggregation and the STA2-induced [Ca2+]i increase, even when Ca2+ influx was blocked by Ni2+. However, they did not affect STA2-induced IP3 formation. Barbital, phenobarbital, metharbital, and primidone (up to 1 mM) had no effect on ADP- and epinephrine-induced platelet aggregation. Thus, we conclude that amobarbital, butalbital, and secobarbital inhibit platelet aggregation by suppressing [Ca2+]i increase without affecting IP3 formation. However, these antiaggregatory effects may not have clinical importance, since the barbiturate concentrations used were higher than clinically relevant ones. The other tested barbiturates had no effects on platelet aggregation. The data indicate that the effects of barbiturates on platelet aggregation differ depending on their chemical structures.

Adult↗
PubMed1992

Endothelium-derived relaxing factor inhibits thrombin-induced platelet aggregation by inhibiting platelet phospholipase C.

Endothelium-derived relaxing factor (EDRF) inhibits platelet function, but the mechanism underlying this inhibitory effect is not known. To examine this, cultured acetylsalicylic acid (ASA)-treated endothelial cells (EC) from bovine aorta (BAEC) or from human umbilical vein (HUVEC) were incubated with washed, ASA-treated human platelets. Incubation of platelets with either BAEC or HUVEC resulted in inhibition of thrombin-induced platelet aggregation that was dependent on the number of EC added. This effect was potentiated by superoxide dismutase and reversed by treating EC with NG-nitro-L-arginine or by treating platelets with methylene blue, indicating that the inhibition of platelet aggregation was due to the release of EDRF by EC. EC significantly blocked the thrombin stimulated breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) and the production of phosphatidic acid in [32P]orthophosphate-labeled platelets and of inositol trisphosphate in [3H]myoinositol-labeled platelets. In addition, the thrombin-mediated activation of protein kinase C (PKC) and phosphorylation of myosin light chain were inhibited in the presence of EC. Finally, thrombin stimulated an increase in cytosolic ionized calcium concentration ([Ca2+]i) in fura2-loaded platelets that was abolished by concentrations of EC which also blocked thrombin-induced aggregation. These data indicate that EDRF blocks thrombin-induced platelet aggregation by inhibiting the activation of PIP2-specific phospholipase C and thereby suppressing the consequent activation of PKC and the mobilization of [Ca2+]i.

Animals↗
PubMed2006

Use of cigarettes and other tobacco products among students aged 13-15 years--worldwide, 1999-2005.

The use of tobacco in any form is a major preventable cause of premature death and disease. Globally, nearly 5 million persons die every year from tobacco-related illnesses, with disproportionately higher mortality occurring in developing countries. The Global Youth Tobacco Survey (GYTS), initiated in 1999 by the World Health Organization (WHO), CDC, and the Canadian Public Health Association, is a school-based survey that includes questions on prevalence of cigarette and other tobacco use; attitudes toward tobacco; access to tobacco products; exposure to secondhand smoke, school curricula on tobacco, media, and advertising; and smoking cessation. This report presents estimates of self-reported cigarette and other tobacco-product use during 1999-2005 in 132 different countries and the Gaza Strip/West Bank. The data are aggregated within each of the six WHO regions. GYTS data indicate that nearly two of every 10 students reported currently using a tobacco product, with no statistically significant difference between the proportion of those reporting cigarette smoking (8.9%) and other tobacco use (11.2%). Use of tobacco by adolescents is a major public health problem in all six WHO regions. Worldwide, more countries need to develop, implement, and evaluate their tobacco-control programs to address the use of all types of tobacco products, especially among girls.

Adolescent↗
PubMed1994

A commentary on the NRC report "Science and judgment in risk assessment".

This article provides a brief overview of the report "Science and Judgment in Risk Assessment," prepared by a Committee of the National Research Council/National Academy of Science in response to a U.S. Environmental Protection Agency request mandated by the Clean Air Act Amendments of 1990 (CAAA-1990). The report critiques EPA's current approaches for characterizing human cancer risks from exposure to chemicals and offers recommendations for the conduct of future cancer risk assessments, especially those required in implementing the CAAA-1990 provisions which are concerned with hazardous air pollutants. The report offers specific recommendations that address the role of default options, data needs, methods and models, uncertainty, variability, and the aggregation of data. A cross-cutting theme of the report is the use of an iterative approach in which screening assessments with limited data and, of necessity, default options used in the absence of specific scientific data may be performed initially followed by subsequent assessments, as needed, in which increasing amounts of data are developed and incorporated. In some instances, the specific data on a given chemical or pollutant source will replace conservative default options used in earlier assignments. The report includes two authored appendices that address issues related to the use of default options and their replacement by specific scientific information. One appendix by Finkel advocates a principle of "plausible conservatism" for choosing and altering default options and in making cancer risk estimates. A second appendix by McClellan and North advocates the full use of scientific information in the risk assessment process. This article gives major attention to the key aspects of the NRC/NAS report, especially those dealing with the use and replacement of default options. The default options and the extent to which the options are replaced with specific science have major impact on the final quantitation of cancer risk for exposure to chemicals.

Air Pollution↗
PubMed1998

The aggregation in human lens proteins blocks the scavenging of UVA-generated singlet oxygen by ascorbic acid and glutathione.

One hour of UVA irradiation of air-saturated solutions of 2 mg/mL solubilized lens protein aggregates from aged human lens is able to produce on accumulated concentration of more than 2mM 1O2, along with oxidation of 120 nmol/mL of both Trp and His amino acid residues. Increasing concentrations of either sodium azide or ascorbic acid (up to 10 mM) during the irradiation decreased th His destruction by no more than 50-60% with the intact aggregates, but completely prevented the His loss with proteolyzed aggregates. Glutathione (up to 10 mM) was able to protect less than 10% of the aggregate His residues from oxidative damage, whereas His loss was almost completely prevented in the proteolyzed aggregates. Similar data were obtained for teh UVA photolysis of the Trp residues. This finding led us to study the role a protein conformation of these aggregates plays in the diminishing of antioxidant ability to prevent UVA-mediated photolysis of 1O2-sensitive amino acid residues. We found that Trp, His, and Cys are buried in the aggregates and cannot be oxidized by a relatively high concentration of 1O2 generated externally to the protein. Increasing urea denaturation of the aggregates caused exposure of the buried Trp residues as determined by the red shift of the fluorescence maximum and by a marked increase in the acrylamide and iodide fluorescence quenching. The ability of glutathione to prevent Trp oxidation by UVA light correlated directly with the extent of Trp exposure. These data suggest that the aggregation of the lens crystallins during aging produces a barrier, which prevents the access of water-soluble antioxidants to the sites of UVA-dependent singlet oxygen generation. In this case UVA proteolysis of the lens proteins can proceed even in the presence of physiological levels of antioxidants.

Aging↗
PubMed2001

Heterogeneous database integration in biomedicine.

The rapid expansion of biomedical knowledge, reduction in computing costs, and spread of internet access have created an ocean of electronic data. The decentralized nature of our scientific community and healthcare system, however, has resulted in a patchwork of diverse, or heterogeneous, database implementations, making access to and aggregation of data across databases very difficult. The database heterogeneity problem applies equally to clinical data describing individual patients and biological data characterizing our genome. Specifically, databases are highly heterogeneous with respect to the data models they employ, the data schemas they specify, the query languages they support, and the terminologies they recognize. Heterogeneous database systems attempt to unify disparate databases by providing uniform conceptual schemas that resolve representational heterogeneities, and by providing querying capabilities that aggregate and integrate distributed data. Research in this area has applied a variety of database and knowledge-based techniques, including semantic data modeling, ontology definition, query translation, query optimization, and terminology mapping. Existing systems have addressed heterogeneous database integration in the realms of molecular biology, hospital information systems, and application portability.

Computational Biology↗
PubMed2003

[Spatial distribution of leptospirosis in Rio Grande do Sul, Brazil: recovering the ecology of ecological studies].

Leptospirosis is an endemic disease in the State of Rio Grande do Sul, Brazil, and presents a broad diversity of exposure routes, reservoirs, etiological agents, and clinical features. The main objective of this work is to identify transmission areas and possible ecological components of leptospirosis transmission. This was accomplished through the aggregation of epidemiological data into spatial units that represent the State's socio-environmental diversity. The 1,274 confirmed leptospirosis cases that occurred in 2001 were georeferenced in the counties of residence. The county maps were overlaid on environmental units characterizing land use, altitude, and river basins. Incidence rates for each environmental class were calculated, along with their statistical significance, through GIS aggregation operations. The highest incidence rates were verified in coastal sedimentary areas with low altitude and predominantly agricultural land use. In these areas, most of the cases were associated with irrigated farming. The results suggest the existence of favorable ecological characteristics for leptospirosis transmission in places involving proliferation of peri-domiciliary rodents and intensive agricultural production. The article discusses the effects of data aggregation into environmental units, as well as strategies to control the endemic in the State.

Animals↗
PubMed1985

An analysis of the evidence on competition in the physician services markets.

By comparing aggregated physician utilization data in Michigan with a disaggregated measure of the intensity with which physicians treat their patients, the article shows that the availability effect found in many studies of the physician services markets is due to the larger number of providers seen by patients in physician dense markets. Although the aggregated data are consistent with the concept of induced demand, the data from individual practices do not indicate that doctors treat their patients more intensively as the availability of physicians increases. The paper discusses and interprets these results within the context of current issues in health care policy.

Economic Competition↗
PubMed1978

Electron microscopic morphology of immunoglobulin aggregates and their interactions in rheumatoid articular collagenous tissues.

Immunoelectron microscopy for IgG and IgA was combined with plain electron microscopy and light microscopy to study a variety of articular collagenous tissues from 14 cases of classic rheumatoid arthritis. Numerous extensive aggregates of IgG and IgA positive material were found widely spread in locations that coincided with immunofluorescent staining for these immunoglobulins and B1c. This Ig positive material is thought to represent deposits of immune complexes. As great and greater amounts were seen in fibrocartilage menisci as in hyaline cartilage. A single specimen of disease tendon was also positive. Severe pathologic changes of the matrix characterized by loss of normal morphology, alterations in collagen, and overall reduced density were observed in regions of aggregate deposition with a consistent replacement and disappearance of collagen in the locale of the aggregates themselves. Polymorphonuclear cells in regions of degraded hyaline and tendon matrix were seen to have phagocytosed aggregates. These data give some credence to a direct role of immune aggregates in rheumatoid arthritis articular collagenous tissues in disease pathogenesis.

Adult↗
PubMed1994

Effect of link protein and free hyaluronic acid binding region on spacing of proteoglycans in aggregates.

Aging of articular cartilage results in accumulation of aggrecan fragments of various sizes that retain their ability to aggregate even though they may have relatively few glycosaminoglycan chains. Residual binding of partially degraded aggrecan may prevent binding of newly synthesized aggrecan subunits that have greater numbers of glycosaminoglycan chains. This study was undertaken to determine the effects of various relative molar ratios of intact aggrecan, link proteins, and hyaluronic acid binding region fragments on the structure of reconstituted aggregates. High molar ratios of link proteins relative to aggrecan decreased the spacing between adjacent aggrecan subunits; low molar ratios of hyaluronic acid binding region relative to aggrecan (4:1 or less) had no significant effect on spacing, and high molar ratios resulted in an increase in the spacing and a decrease in the percentage of aggrecan subunits found in aggregates. These data suggest that the density of aggrecan subunits on the aggregate is determined primarily by steric hindrance of the glycosaminoglycan chains of the aggrecan subunits and that, to a limited extent, partial degradation of aggrecan in an aggregate allows attachment of more aggrecan subunits.

Aggrecans↗
PubMed2000

[Establishment of a national database for ICU-associated infections. First results from the "Krankenhaus-Infections-Surveillance-System" (KISS)].

OBJECTIVES: To establish a surveillance system as an element of internal quality management, participating intensive care units (ICUs) report their ICU-associated infection surveillance data for aggregation into a national database. METHODS: In order to provide data on ICU-associated infections, a nosocomial surveillance system in German intensive care units (Krankenhaus-Infections-Surveillance-System (KISS)) started in 1997. The method of data collection is based on the (adult) ICU surveillance component from the National Nosocomial Infections Surveillance (NNIS)-System. Until now 113 German ICUs (most of them medical/surgical ICUs) were included in this system. We continuously collected and calculated the data from site-specific infections (device-associated pneumonias, blood stream infections and urinary tract infections). RESULTS: There are now a total of 393,177 patient-days (100,015 patients) among them 176,415 ventilator-days, 295,221 central line-days and 316,799 urinary catheter-days in the data base. The data analysis showed the following device-associated infection rates: 11.2 pneumonias/1000 ventilator-days, 1.8 primary bloodstream infections/1000 central line-days and 4.0 urinary tract infections/1000 urinary catheter-days. CONCLUSION: The project has reached high interest in Germany and animated more ICUs to take part or to apply the same method in order to use the reference data for comparison.

Cross Infection↗
PubMed1999

Solution structure of copper ion-induced molecular aggregates of tyrosine melanin.

Melanin, the ubiquitous biological pigment, provides photoprotection by efficient filtration of light and also by its antioxidant behavior. In solutions of synthetic melanin, both optical and antioxidant behavior are affected by the aggregation states of melanin. We have utilized small-angle x-ray and neutron scattering to determine the molecular dimensions of synthetic tyrosine melanin in its unaggregated state in D(2)O and H(2)O to study the structure of melanin aggregates formed in the presence of copper ions at various copper-to-melanin molar ratios. In the absence of copper ions, or at low copper ion concentrations, tyrosine melanin is present in solution as a sheet-like particle with a mean thickness of 12.5 A and a lateral extent of approximately 54 A. At a copper-to-melanin molar ratio of 0.6, melanin aggregates to form long, rod-like structures with a radius of 32 A. At a higher copper ion concentration, with a copper-to-melanin ratio of 1.0, these rod-like structures further aggregate, forming sheet-like structures with a mean thickness of 51 A. A change in the charge of the ionizable groups induced by the addition of copper ions is proposed to account for part of the aggregation. The data also support a model for the copper-induced aggregation of melanin driven by pi stacking assisted by peripheral Cu(2+) complexation. The relationship between our results and a previous hypothesis for reduced cellular damage from bound-to-melanin redox metal ions is also discussed.

Biophysical Phenomena↗
PubMed1998

Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in ataxin-1. In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 accumulates in a single, ubiquitin-positive nuclear inclusion. In this study, we show that these inclusions stain positively for the 20S proteasome and the molecular chaperone HDJ-2/HSDJ. Similarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize with the 20S proteasome and endogenous HDJ-2/HSDJ. Overexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases the frequency of ataxin-1 aggregation. These data suggest that protein misfolding is responsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promotes the recognition of a misfolded polyglutamine repeat protein, allowing its refolding and/or ubiquitin-dependent degradation.

Animals↗
PubMed2003

Function-modulating human monoclonal antibodies against platelet-membrane receptors isolated from a phage-display library.

Monoclonal antibodies to platelet membrane receptors have been used extensively for analysis of receptor structure and function. Function-blocking human antibodies are being used for the development of antiplatelet drugs. We isolated human monoclonal antibodies from a library of single-chain Fv (scFv) antibodies displayed on the surface of filamentous phage, by selection on whole platelets. Eight different platelet-binding clones were isolated, of which three bound to the platelet-membrane glycoprotein (GP) GPIb in an ELISA assay. Specific elution with a recombinant polypeptide of von Willebrand factor (VWF) spanning the GPIbalpha binding site, yielded the same three phage clones. Two of the three anti-GPIb clones could be purified as scFv monoclonal antibodies, and they competed with each other for binding to intact platelets, suggesting that they bind at or near the same site on GPIb. Their binding affinities differed, however, and the clone with higher affinity inhibited ristocetin-induced platelet aggregation. These data indicate that selection from a phage display library of human scFvs using whole platelets can be applied for the isolation of functional antiplatelet-GPIb antibodies useful for the development of new therapeutic and diagnostic strategies.

Amino Acid Sequence↗
PubMed1989

Platelet aggregation induced by type IIb platelet von Willebrand factor.

Platelet lysates from five patients with a form of type IIb von Willebrand's disease (vWd), associated with spontaneous platelet aggregation and thrombocytopenia, induced platelet aggregation of normal and other vWd's platelet-rich plasma (PRP). Platelet lysate from normals, type I or type IIa vWd did not cause platelet aggregation of normal PRP. When polyclonal monospecific antibodies directed against plasma von Willebrand factor (vWf) were incubated with the type IIb platelet lysate, they inhibited the platelet aggregation. Monoclonal antibodies directed against the glycoprotein (GP) Ib binding domain of plasma vWf incubated with the type IIb platelet lysate did not inhibit the platelet aggregation. Normal platelets suspended in afibrinogenaemic plasma did not aggregate when type IIb vWd platelet lysate was added. Normal platelets incubated with monoclonal antibodies directed against the fibrinogen and vWf binding site(s) on the GPIIb/IIIa were not aggregated by the type IIb platelet lysate. Bernard-Soulier PRP aggregated when type IIb vWd platelet lysate was added, while Glanzmann's thrombasthenic platelets did not. Peptides containing the RGDS sequence or the sequence of the carboxy terminal 15 amino acids of the gamma chain of fibrinogen inhibited the type IIb vWd platelet lysate-induced platelet aggregation. These data suggest that type IIb platelet vWf can cause platelet aggregation of PRP without the addition of any agonist. This interaction is different from that observed with the plasma vWf from these patients.

Antibodies, Monoclonal↗