bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of early bisphosphonate administration and irradiation leads to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model
Authors: Krempien Robert , Huber Peter E. , Harms Wolfgang , Treiber Martina , Wannenmacher Michael , Krempien Burkhardt
Published: September 2003

BACKGROUND

The goal of the current study was to analyze the combined effect of bisphosphonates (BPs) and irradiation on remineralization and restabilization of osteolytic bone metastases in an animal tumor model.

METHODS

Bone metastases were induced in male Wistar rats via intraosseous injection of the Walker carcinosarcoma 256B cell line into both proximal tibia metaphyses on Day 1 of the study. Three treatment groups were analyzed. All animals received a single radiation dose of 17 grays (in the form of 6‐megaelectron‐volt electrons) on Day 7 and were sacrificed on Day 49. Group 1 (the control group) was treated with irradiation only. Groups 2 and 3 received additional BPs (clodronate; daily intraperitoneal injection dose, 20 mg/kg per day). In Group 2, BPs were given before irradiation, on Days 3–6; this schedule later was referred to as early BP treatment. In Group 3, BPs were administered simultaneously with irradiation, on Days 7–10; this schedule later was referred to as simultaneous BP treatment. The endpoints of the study were bone density and microstructural parameters of bone on Day 49. Bone density was measured using X‐ray absorption. Microstructural parameters of bone were assessed using histomorphometry. A total of thirty tibiae were analyzed in each group.

RESULTS

After irradiation, bone density was significantly higher among animals in the early BP treatment group compared with those in the control group and those in the simultaneous BP treatment group (P = 0.001). Histomorphometric analysis of bone showed significantly better‐preserved (P < 0.001) microstructural parameters (bone area, trabecular number, and trabecular separation) in the early BP treatment group compared with the control and simultaneous BP treatment groups.

CONCLUSIONS

Early BP administration in combination with irradiation led to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model. Cancer 2003;98:1318–24. © 2003 American Cancer Society.

DOI 10.1002/cncr.11646
Extraocular retinoblastoma: A 13‐year experience
Authors: Antoneli Célia Beatriz Gianotti , Steinhorst Flávio , de Cássia Braga Ribeiro Karina , Novaes Paulo Eduardo R. S. , Chojniak Martha M. M. , Arias Victor , de Camargo Beatriz
Published: September 2003

BACKGROUND

The current study was performed to evaluate two regimens of treatment and to describe clinical and epidemiologic characteristics in patients with extraocular retinoblastoma.

METHODS

Eighty‐three patients with extraocular retinoblastoma according to Childrens Cancer Group (CCG) classification were admitted to the Pediatric Department of the A. C. Camargo between 1987–2000. The age, gender, race, lag time, first clinical presentation, staging, laterality, and treatment regimen were analyzed. Treatment was comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide during the first treatment period (1987–1991) or cisplatin and teniposide with alternating courses of ifosfamide and etoposide during the second treatment period (1992–2000).

RESULTS

The mean age of the patients was 32.9 months (range, 2–145 months). The mean lag time was 10.5 months. Forty‐three patients were treated in the first period and 40 patients were treated in the second period. Locally advanced tumors (Class I–III) were present in 83.1% of the patients. There was a positive correlation between lag time and age for unilateral tumors (correlation coefficient [r] = 0.35; P = 0.006), whereas the correlation was negative for bilateral tumors (r = −0.12; P = 0.63). The 5‐year overall survival was 55.1% in the first treatment period and 59.4% in the second treatment period (P = 0.69). No significant differences with regard to survival rates were noted for unilateral tumors between the two treatment periods (44.6 noted for unilateral tumors vs. 59.1 noted for unilateral tumors).

CONCLUSIONS

In the current study, the addition of ifosfamide and etoposide to a treatment regimen comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide did not appear to improve the survival of patients with extraocular retinoblastoma. Patients with dissemination to the central nervous system or metastatic disease remain incurable and die of progressive disease, despite the aggressive treatment. A multicenter trial should be considered to evaluate the best strategy for these situations. Cancer 2003;98:1292–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11647
Prognostic significance of psychosocial factors in African‐American and white breast cancer patients
Authors: Soler‐Vila Hosanna , Kasl Stanislav V. , Jones Beth A.
Published: September 2003

BACKGROUND

It has been suggested that psychosocial factors, such as coping and emotional support, influence cancer survival, but results have been inconclusive. Given the scarce data from racially/ethnically diverse populations, the authors investigated the prognostic significance of selected psychosocial variables in a cohort of African‐American women and white women with breast cancer.

METHODS

The authors examined the effects of coping styles, perceived emotional support, fatalism, and health locus of control on survival for a population‐based cohort of 145 African‐American women and 177 white women who were diagnosed with breast cancer in Connecticut between January 1987 and March 1989 and were followed for survival for approximately 10 years. Cox proportional hazards models were adjusted for sociodemographic factors, biomedical factors (American Joint Committee on Cancer stage at diagnosis, histologic grade, comorbidity, obesity, menopausal status, and treatment), and lifestyle factors.

RESULTS

Fully adjusted models showed that lower perceived emotional support (disagreeing with the statement, “cancer is a topic I can talk about freely with my friends/relatives”) at diagnosis was associated with a higher risk of death from any cause (hazard ratio, 1.39; 95% confidence interval, 1.09–1.79). Adjustment for additional tumor characteristics (nuclear grade, estrogen and progesterone receptor status) and genetic alterations (p53, HER‐2) did not alter the findings. No other psychosocial factors significantly predicted survival in patients with breast cancer.

CONCLUSIONS

Higher levels of perceived emotional support showed a moderate but significant association with increased survival in African‐American and white women with breast cancer who were followed for 10 years after diagnosis when adjusting for known prognostic factors. Survival was not related to coping styles, fatalism, or health locus of control. Cancer 2003;98:1299–308. © 2003 American Cancer Society.

DOI 10.1002/cncr.11670
Optimal call admission control under packet and call level QoS constraints and effect of buffering
Authors: Spitler Stephen L. , Lee Daniel C.
Published: September 2003

For a single network switch allocating link bandwidth to connections of a single class, an optimal call admission control (CAC) policy is found by the solution of a linear programming (LP) problem. Our optimization differs from previous work in that we include the effect of an output buffer in the switch for the temporary storage of packets bound for transmittal across the link. We find a policy that is optimal in the sense of minimizing call blocking subject to a packet level quality of service (QoS) requirement that limits the packet loss ratio. Such a policy's call blocking probability, if it is small enough to satisfy a call level QoS requirement, then establishes the feasibility of satisfying both the packet and call level QoS requirements for a given call request rate. We show with a previously described example that the addition of even a small output buffer can significantly increase the range of call request rates for which there exists a feasible policy, i.e. one that satisfies both QoS requirements. Also presented is an upper bound, valid for any fixed buffer size, on the range of call request rates for which there exists a feasible CAC policy. Copyright © 2003 John Wiley & Sons, Ltd.
The end‐user application toolkit: a QoS portal for the next generation Internet
Authors: Tsetsekas Charilaos A. , Maniatis Sotirios I. , Venieris Iakovos S.
Published: September 2003

The support of quality of service (QoS) in the Internet has become one of the most important topics within the Internet community. The introduction of the Integrated Services (IntServ) and the Differentiated Services (DiffServ) architectures was a major breakthrough in this direction. Enhanced by the Bandwidth Broker concept, DiffServ aims to provide QoS in the Internet through the prioritization of some IP flows over others. However, up to now the DiffServ architecture lacks a standard mechanism for the interaction between users/applications and the Bandwidth Brokers (BB), so that end‐to‐end QoS can be achieved.

In this paper we present a distributed middleware architecture for the transparent support of QoS in the Internet. The paper focuses on bridging the gap that currently exists between applications and the network and presents the end‐user application toolkit (EAT). The EAT middleware provides a framework for the presentation of network services to users, the description and selection of QoS parameters, the forwarding of reservation requests and the verification of the accredited QoS level. Through the concept of application profiles, it aims to support QoS for legacy applications, that is, commercial applications that cannot be modified to support QoS. Copyright © 2003 John Wiley & Sons, Ltd.
Waiting time distribution of an ATM switch routing two‐class traffic with two service rates
Authors: Nassar Hamed , Ali Ahmed Mohamed
Published: September 2003

In this article we analyse the waiting time of an arbitrary packet in an output buffered space division switch routing two‐class traffic, e.g. in a multimedia environment. For the purpose of the analysis, the switch is modelled as a priority, discrete time, batch arrival queueing system, with a single server having two service rates. The results of the analysis are verified in various ways, including obtaining previously published results as special cases.

The fundamental contribution of this article is the assumption of two service rates, one for each class, rather than the typical assumption of one service rate for both classes. This assumption is useful in that it accounts for the different quality of service (QoS) needs of each class. Another contribution is the introduction of a new approach to analyse the waiting time—an approach not based on the system occupancy as is typical in the published literature. Copyright © 2003 John Wiley & Sons, Ltd.
Performance analysis of an improved multi‐carrier CDMA system under frequency‐selective Rayleigh fading channels
Authors: Chen Hsiao‐Hwa
Published: September 2003

In this article, an analytical method is proposed to study an improved orthogonal multi‐carrier DS/CDMA system, which uses QPSK for both spreading and carrier modulations without redundant sub‐carriers and time interleavers in each sub‐channel. The article concerns in particular such a system and its performance under frequency‐selective Rayleigh fading channels with various delay‐power profiles. The bit error probabilities under varying multipath‐diversity orders (using maximal ratio combing RAKE reception) and different numbers of resolvable multipaths are derived. It has been shown that the system, despite of its structural simplicity, performs well in mitigating frequency‐selective fading. The performance is also evaluated taking into account various other parameter sets, such as numbers of users and sub‐carriers, lengths of PN codes and the number of fingers in an RAKE receiver, etc. Copyright © 2003 John Wiley & Sons, Ltd.
Proteinase‐activated receptors (PARs): An evolving hormonal system
Authors: Hollenberg Morley D.
Published: September 2003

An overview of the articles presented in this two‐part special issue of Drug Development Research is provided here. This two‐part series focuses on the discovery, molecular pharmacology, and physiology of the Proteinase‐activated Receptor (PAR) family. This recently discovered G‐protein‐coupled receptor family mediates the signaling properties of a number of serine proteinases, including thrombin. PARs are responsible for a variety of physiological roles that proteinases may now be seen to play in their capacity as “signaling molecules.” It is the aim of the Special Issue articles to illustrate PARs' unique pharmacological properties and to alert the scientific community to the widespread physiological roles this receptor family can play in a variety of settings. Drug Dev. Res. 59:334–335, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors: Tethered ligands and receptor‐activating peptides
Authors: Hollenberg Morley D.
Published: September 2003

Proteinase‐activated receptors (PARs), newly‐discovered members of the G‐protein‐coupled receptor superfamily, comprising four cloned family members (PARs 1 to 4), are activated by the proteolytic unmasking of a “tethered ligand” sequence situated in the N‐terminal extracellular receptor domain. Furthermore, synthetic peptides with sequences based on the revealed tethered ligands can, in the absence of proteolysis, trigger receptor signaling. This report reviews the data supporting the tethered ligand mechanism of receptor activation, outlines the utility of the receptor‐activating peptides (so‐called PAR‐APs) for exploring the potential physiological roles of the PARs, and discusses the potential differences between the activation of the receptors via their tethered ligands as opposed to activation by the soluble peptides having the same amino acid sequences. Drug Dev. Res. 59:336–343, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptor domains and signaling
Authors: Hollenberg Morley D. , Compton Steven J.
Published: September 2003

Given that the proteinase‐activated receptors (PARs) are activated by a “tethered ligand mechanism,” an important question to answer is: Which other extracellular domains of the receptors are involved in this novel signaling mechanism? Further, as for other G‐protein‐coupled receptors (GPCRs), it is of importance to know about the intracellular receptor domains that are involved in coupling receptor activation to signal transduction. Studies summarized in this article have singled out the importance of extracellular loop‐2 of PAR1 and PAR2 for tethered‐ligand signaling. In human PAR1, but not in PAR2, a short sequence in the extracellular N‐terminal domain (Q83 to G94) is also important for receptor activation. As for other GPCRs, intracellular loops 2 and 3 mediate receptor‐G‐protein coupling, and the C‐terminal sequence, with a putative “palmitoylation” site and target residues for kinase C phosphorylation, plays a role in receptor signaling and desensitization. This article provides an overview of the experiments leading to the current understanding of the PAR domains involved in signal transduction. Drug Dev. Res. 59:344–349, 2003. © 2003 Wiley‐Liss, Inc.
Glycosylation and proteinase‐activated receptor function
Authors: Compton Steven J.
Published: September 2003

N‐linked glycosylation is a post‐translational modification that enables the cell to regulate protein function without recourse to the genome. The Proteinase‐Activated Receptors (PAR) each possesses a number of N‐linked glycosylation sites on their extracellular domains. However, little is currently known about the relative glycosylation status of each family member and about the influence that glycosylation may confer on receptor function. Interestingly, each PAR possesses an N‐linked glycosylation site in close proximity to the cleavage/activation site on the receptor N‐terminus. Recent studies focusing on PAR2 have pointed out a role for glycosylation on the N‐terminus in influencing receptor activation. Consequently, shifts in tissue and/or cell glycosylation patterns in health and disease could play an important role in regulating PAR function. Drug Dev. Res. 59:350–354, 2003. © 2003 Wiley‐Liss, Inc.
Design and evaluation of potent peptide‐mimetic PAR1 antagonists
Authors: Derian Claudia K. , Maryanoff Bruce E. , Andrade‐Gordon Patricia , Zhang Han‐Cheng
Published: September 2003

The serine protease α‐thrombin is a powerful mediator of cellular responses, not only playing a key regulatory role in the maintenance of normal hemostasis, but also contributing more broadly to a range of physiological and potentially pathological conditions. Most of the cellular actions attributed to α‐thrombin have been linked to the activation of a family of seven‐transmembrane G‐protein‐coupled protease‐activated receptors, termed PARs. Of the four family members identified, PAR1 has received recognition as the most significant receptor for mediating thrombin's cellular actions. Thus, the development of a potent, selective antagonist of PAR1 would be an important and essential tool to probe the physiological and potential pathological roles of PAR1. In this review, we provide a synopsis of our de novo design approach to the discovery of selective PAR1 antagonists, exemplified by RWJ‐58259, along with the in vitro and in vivo studies performed to demonstrate the important role of this receptor in thrombosis and vascular injury. RWJ‐58259 demonstrated antithrombotic activity in a model of vascular injury‐induced thrombosis in cynomolgus monkeys and prevented neointimal proliferation in a rat balloon angioplasty model. These seminal studies clearly lay the groundwork for more detailed preclinical in vivo studies and ultimately, advancing PAR1 antagonists into human clinical studies. Expanded chemical synthetic efforts and other novel technologies targeted to PAR1 and its intracellular signaling pathways are already on the horizon in an effort to further modulate thrombin's biological actions. Drug Dev. Res. 59:355–366, 2003. © 2003 Wiley‐Liss, Inc.
Intracellular signalling by the G‐protein coupled proteinase‐activated receptor (PAR) family
Authors: Macfarlane Scott R. , Plevin Robin
Published: September 2003

The proteinase‐activated receptor (PAR) family are novel members of the G‐protein coupled receptor superfamily that are activated by a mechanism involving specific proteolytic cleavage of their N‐terminal. Activation of intracellular signalling pathways by the PAR family has received relatively little attention compared with the other aspects of their function. Along with activation of intracellular calcium, diacylglycerol, and inositol 1,4,5‐trisphosphate, PARs have been reported to activate signalling pathways closely linked to both cell proliferation and inflammation. Here we attempt to describe these signalling pathways and the G‐proteins involved in coupling the receptors to these intracellular events. Drug Dev. Res. 59:367–374, 2003. © 2003 Wiley‐Liss, Inc.
The inflammatory response
Authors: Vergnolle Nathalie
Published: September 2003

Inflammation, which constitutes the body's response to injury, is characterized by a series of events where several different cell types are playing distinct roles. Proteinase‐activated receptors (PARs) are expressed in all the cell types that are involved in inflammatory processes. The expression of PARs is up‐regulated during inflammatory processes. Activation of PARs can lead to inflammation or, in some circumstances, can be protective against uncontrolled inflammatory reaction. Most recently, studies have shown that inflammatory responses were altered in PAR‐deficient mice. Thus, a crucial role for PARs seems to emerge from the most recent literature and presents PARs as novel and interesting therapeutic targets for the treatment of inflammation. Drug Dev. Res. 59:375–381, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors and nociceptive pathways
Authors: Vergnolle Nathalie
Published: September 2003

The discovery of Proteinase‐Activated receptors (PARs) in the nervous system has led to new insights about the potential physiological role that these enzymes could play in relation to nerve functions. Here, we summarize evidence that proteinases, through the activation of PARs, interact with the nervous system, playing a role in pain perception and modulation of nociceptive pathways. New potential roles are suggested for the members of the PAR family, highlighting proteinases and their receptors as potential therapeutic targets for pain relief. Drug Dev. Res. 59:382–385, 2003. © 2003 Wiley‐Liss, Inc.
Intestinal epithelial secretory function: Role of proteinase‐activated receptors
Authors: Buresi Michelle C. , MacNaughton Wallace K.
Published: September 2003

The ability of enterocytes to secrete electrolytes and water into the intestinal lumen represents a critical feature of mucosal defense. During disease, this function may be altered and may initiate or exacerbate pathological conditions. Although many of the intracellular mechanisms linking stimulation to secretion have been elucidated, novel pathways continue to be revealed. These pathways provide potential for therapeutic manipulation of cellular function. In addition, the importance of the microenvironment surrounding enterocytes is increasingly being acknowledged, and the interactions between epithelial cells and their milieu are proving to be essential to the regulation of secretory function, both in health and disease. In this way, epithelial ion transport functions can be modulated by mediators released from neighboring nerves, inflammatory cells, and pathogens, or by endocrine factors. Much interest has recently been elicited by the discovery that proteinases can regulate cellular functions through the activation of proteinase‐activated receptors (PARs). Because of the abundance of proteases within the gastrointestinal tract, particularly in the setting of development, inflammation, and healing, it is likely that PARs have an important role to play in these processes. PARs have been localized to a variety of cell types in the gastrointestinal tract, and have been shown to influence epithelial secretory function on several levels. In this review, we discuss the mechanisms by which proteases and PARs regulate intestinal secretory function, and the manner in which these modulations might contribute to inflammatory processes. Drug Dev. Res. 59:386–394, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors (PARs), platelets and angiogenesis
Authors: Perini Rafael , Wallace John L.
Published: September 2003

With respect to the role of proteinase‐activated receptors (PARs), few cells have been as thoroughly studied as the platelet. PARs appear to act as the key receptors mediating the pro‐aggregatory and pro‐secretory effects of thrombin, but there is considerable variation from species to species in terms of which PARs are involved in these processes. In addition to contributing to hemostasis, platelets are increasingly being viewed as important contributors to healing and to tumor growth. This can be attributed to the many pro‐ and anti‐angiogenic factors that are stored within platelets and are released as sites of injury and new vessel growth. There is emerging evidence for an important role for PARs in regulating the release of growth factors from platelets, raising the specter that PARs may be a rational target for new therapies that will modulate repair processes and tumour growth. Drug Dev. Res. 59:395–399, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptor activation by coagulation proteinases
Authors: Riewald Matthias , Ruf Wolfram
Published: September 2003

Coagulation proteinases signal through proteinase activated receptors (PARs). Thrombin‐dependent PAR signaling on platelets is essential for hemostasis, but regulation of inflammation by PAR‐signaling is increasingly recognized as an important aspect of other pro‐ and anticoagulant pathways. In tissue factor (TF)‐dependent initiation of coagulation, factor Xa is the PAR1 or PAR2 activating proteinase while associated in the transient TF‐VIIa‐Xa complex. In the anticoagulant protein C (PC) pathway, the thrombin‐thrombomodulin complex activates PC bound to the endothelial PC receptor (EPCR) and EPCR functions as an essential co‐receptor for activated PC‐mediated signaling through endothelial cell PAR1. Thus, the pro‐ and anti‐inflammatory receptor cascades are mechanistically coupled to cell signaling that precedes systemic coagulant or anticoagulant effects. In contrast with the substrate‐like recognition of PARs by thrombin, TF, or EPCR targeted activation of PARs generates cell‐type specificity, PAR selectivity, and proteinase receptor co‐signaling with the G‐protein coupled PAR response. Cellular proteinase receptors are thus major determinants of the biological outcome of coagulation factor signaling on vascular cells. Drug Dev. Res. 59:400–407, 2003. © 2003 Wiley‐Liss, Inc.
Role of proteinase‐activated receptors in cutaneous biology and disease
Authors: Rattenholl Anke , Steinhoff Martin
Published: September 2003

The skin is the largest organ of the human body. It makes up of about 15% of the body weight. Proteinase‐activated receptor‐1 (PAR1) and PAR2 have been discovered in various constitutive or transient cells within the epidermis as well as the dermis. In fact, epidermal keratinocytes were among the first cells in which the presence of PAR2 was reported. Several observations advanced our knowledge of PARs as regulators of skin homeostasis and disease. For example, PARs are expressed by keratinocytes and regulate growth, differentiation, pigmentation, and release of growth factors and cytokines. Mast cells release tryptase, which activates PAR2 on keratinocytes and endothelial cells, thereby contributing to inflammation and probably allergic reactions. PAR2 is also involved in leukocyte/endothelial interactions within the skin by modulating the functions of both microvascular endothelial cells and neutrophils. Thus, PARs may be implicated in skin pathophysiology such as wound healing, cutaneous inflammation, pruritus, tumorigenesis (e.g. melanoma, squamous cell carcinoma) and bacterial infections. Functional PAR1 and PAR2 were recently demonstrated on primary afferent neurons in the skin, thereby regulating neurogenic inflammation. PAR2 agonists induce release of neuropeptides from cutaneous sensory nerves, leading to pain and itch. This review highlights the recent knowledge of PARs in cutaneous physiology and disease, and discusses the possibility of PAR agonists or antagonists as novel tools for the treatment of skin diseases. Drug Dev. Res. 59:408–416, 2003. © 2003 Wiley‐Liss, Inc.
Radiation toxicity and proteinase‐activated receptors
Authors: Wang Junru , Hauer‐Jensen Martin
Published: September 2003

Despite recent technological advances, the cure rates that can be achieved with radiation therapy are limited by the risk of injury to the normal tissues that surround the tumor. This review summarizes current knowledge regarding proteinase‐activated receptors (PARs) and their possible role in the pathogenesis of normal tissue radiation injury. In particular, data are presented indicating that activation of PAR1 by thrombin, and PAR2 by trypsin and mast cell proteinases, may be involved both in acute radiation responses, as well as in the chronic fibroproliferative processes that lead to the development of radiation‐induced tissue fibrosis and clinical complications. If effective pharmacologic modulators of PAR1 or PAR2 were available, these compounds would be potentially useful as preventive or therapeutic agents in patients receiving radiation therapy, especially if blockade could be targeted to specific tissues or cellular compartments. Drug Dev. Res. 60:1–8, 2003. © 2003 Wiley‐Liss, Inc.
Modulation of gastric function by proteinase‐activated receptors
Authors: Nishikawa Hiroyuki , Kawabata Atsufumi
Published: September 2003

Proteinase‐activated receptor (PAR)1 and PAR2 are abundantly expressed in the gastric mucosa and smooth muscle. PAR2 modulates a variety of gastric functions, mediating secretion of mucus and pepsinogen, suppression of acid output, an increase in mucosal blood flow, and smooth muscle contraction/relaxation. PAR2 is considered primarily protective in the gastric mucosa. PARs other than PAR2 might also be involved in the modulation of gastric functions. PARs, especially PAR2, would thus appear to be novel targets for the development of drugs for treatment of gastric mucosal diseases. Drug Dev. Res. 60:9–13, 2003. © 2003 Wiley‐Liss, Inc.
Searching for the physiological role and therapeutic potential of vascular proteinase‐activated receptor‐2 (PAR2)
Authors: McGuire John J. , Triggle Chris R.
Published: September 2003

The intercellular interactions of endothelial and vascular smooth muscle cells are interesting to many scientists who seek to develop new drugs to treat cardiovascular diseases. Of particular interest is the regulation of blood flow by the paracrine actions of the endothelium on the underlying vascular smooth muscle cells of blood vessels. The development and further understanding of drugs that mimic or potentiate endothelial‐derived factors, in particular vasodilators such as nitric oxide (NO), have proved to be of therapeutic benefit (e.g., sildenafil, nitroglycerin). On the other hand, endothelial‐derived proinflammatory substances are released in response to tissue insult or during the progression of vascular diseases such as atherosclerosis. Proteinase‐activated receptor 2 (PAR2) represents a novel target for vascular biology because of 1) its unique mechanism of activation by proteinases, 2) questions regarding the identity of the endogenous agonist(s), and 3) its apparent multiple activities in the vasculature. Whether it will be agonists or antagonists of PAR2 that will serve as the basis for a new class of therapeutic agents for the treatment of vascular diseases is an open question for further research and drug development. Drug Dev. Res. 60:14–19, 2003. © 2003 Wiley‐Liss, Inc.
Upregulation of proteinase‐activated receptors (PARs) and cardiovascular function
Authors: Cirino Giuseppe , Cicala Carla
Published: September 2003

Proteinase activated receptors (PARs) have attracted particular attention for their possible role in cardiovascular physiology and disease. The aim of this article is to review what is known up to now about the upregulation of PARs that are targets for thrombin (PARs 1, 3, and 4) and PAR2, which is not activated by thrombin. Particular emphasis will be given to what is the “state of the art” on the upregulation of these receptors within the cardiovascular system and their relationship to those phenomena that can be encompassed under the term “cardiovascular inflammation.“ Drug Dev. Res. 60:20–23, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors (PARs) and bronchial smooth muscle functions
Authors: Geppetti Pierangelo , Trevisani Marcello
Published: September 2003

Proteinase‐activated receptors (PARs) have been found to be present in the airway tissue of different mammal species. As for many other receptors, including the bradykinin or tachykinin receptors, their distribution is not restricted to one single cell type, and accordingly, their activation results in the production of diverse and often opposing responses. Remarkable variations have been found in different mammal species regarding the distribution and function of PARs. This first observation may explain the substantial differences observed occasionally in the role of various PARs and their agonists in the modulation of bronchomotor activity and in other airway functions. In addition, these considerations should result in caution in drawing conclusions from findings obtained in one single mammal species and applying them to human tissues and human diseases. The present article will focus on the distribution and function of PARs in the airway tissues from experimental animals and humans. Particular emphasis will be given to the distribution and function of PAR2 because this receptor type has been shown to produce a large variety of responses of potential interest for airway pathophysiology. Drug Dev. Res. 60:24–28, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors and the pathophysiology of pulmonary fibrosis
Authors: Chambers Rachel C.
Published: September 2003

Interest in the role of proteinase‐activated receptors (PARs) in the pathogenesis of fibrotic lung disease was fuelled by two central observations: first, the recognition that the coagulation cascade is activated in a number of these disorders; and second, the long‐standing observation that thrombin, a principal regulator of coagulation, is a potent mitogen for fibroblasts, the key cell type responsible for the production of interstitial collagens in the fibrotic lung. This article will briefly review this evidence and focus on recent studies suggesting an important role for PAR1‐mediated cellular responses in the pathophysiology of lung fibrosis. Drug Dev. Res. 60:29–35, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors (PARs) and the kidney
Authors: Hollenberg Morley D. , Wijesuriya Suranga J. , Gui Yu , Loutzenhiser Rodger
Published: September 2003

It has been discovered that the kidney is an organ that is particularly rich in proteinase‐activated receptor‐2 (PAR2) and that also expresses PARs 1 and 4. Notwithstanding this fact, the potential physiologic role that PARs play in regulating renal function is largely unknown. This article summarizes much about what is known in terms of the expression of mRNA for PARs 1, 2 and 4 in the kidney, the cellular distribution of PARs 1 and 2, and the renal vascular actions of PARs 1, 2, and 4. The ability of PARs 1 and 2 to exert a bidirectional action on renal perfusion flow and glomerular filtration rate and the wide distribution of PARs 1 and 2 in both vascular and epithelial elements of the kidney imply not only that the PARs may play an important pathophysiologic role in the kidney, but that the individual PARs may each play distinct roles in this regard. Drug Dev. Res. 60:36–42, 2003. © 2003 Wiley‐Liss, Inc.
Signal transduction by serine proteinases in astrocytes: Regulation of proliferation, morphologic changes, and survival via proteinase‐activated receptors
Authors: Wang Hong , Reiser Georg
Published: September 2003

Astrocytes, in addition to their conventionally known function as supporting cells in the brain, have recently been revealed to play a much more pivotal role in maintaining the brain's vitality than has been previously assumed. Astrocytes, an intimate partner of neurons, coordinate neuronal activity across cellular networks in the central nervous system (CNS). Proteinases like thrombin can act on astrocytes via activation of plasma membrane proteinase‐activated receptors (PARs), thereby mediating cellular responses such as morphologic changes, proliferation, and survival. These astrocyte responses may have an important influence on neuronal development, plasticity, and repair after injury. These effects may be mediated either through distinct or overlapping signal transduction cascades, after activation of PARs. In this article, we summarize recent findings regarding the widespread distribution of PARs in the brain, as well as the underlying signaling events initiated by proteinases in astrocytes. Such studies provide a better understanding of the intracellular signaling machinery linking PARs to their potential physiologic and pathologic functions in the CNS. Drug Dev. Res. 60:43–50, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptor expression and function in the brain
Authors: Noorbakhsh Farshid , Power Christopher
Published: September 2003

Proteinase‐activated receptors (PARs) represent a novel family of G‐protein coupled receptors that mediate the diverse biologic effects of proteinases on target cells. Four different members of the PAR family have been identified so far: PAR1, PAR3, and PAR4 act as receptors for thrombin, and PAR2 is activated by trypsin/tryptase. It is now known that all four subtypes of PARs are widely expressed in the central nervous system, and there is increasing evidence to suggest roles for proteinases and PARs in development and pathogenesis in the nervous system. Harnessing different G proteins and a variety of signal transduction cascades, PARs can affect neural cell proliferation, morphology, and electrical activities. PARs have also been considered as major players in neuroinflammatory/degenerative processes in which they play both neuroprotective and neuropathogenic roles. The advent of PARs agonistic and antagonistic peptides, which selectively activate their cognate receptor and mediate a broad spectrum of PAR‐executed effects in the nervous system, makes these peptides attractive therapeutic possibilities. Herein we review different aspects of PARs activities in the normal development and function of the brain and address some evidence related to PARs roles in nervous system pathogenesis with a focus on neuroinflammatory/degenerative disorders. Drug Dev. Res. 60:51–57, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors (PARs) in the nervous system: Roles in neuroplasticity and neurotrauma
Authors: Festoff Barry W.
Published: September 2003

A brief overview is presented of the rapidly evolving effects of thrombin, other serine proteinases, their proteinase‐activated receptors (PARs), and their downstream signaling pathways in the peripheral (PNS) and central nervous system (CNS). In other articles presented in this volume of Drug Development Research, emphasis on the role of thrombin and PARs in astrocyte and microglial function is emphasized and will only be touched upon herein. This overview focuses on the PAR family, principally PAR1, in neuronal dysfunction and what appears to be a differential vulnerability to thrombin in neuronal subsets. It also emphasizes upregulation of PARs in neurodegeneration and neurotrauma as part of a neuroplastic response, but which may be maladaptive as well as adaptive in effect. Finally, regulation of PAR signaling will be mentioned—through one or more G‐protein‐coupled receptor regulated protein kinases—as they relate to microglial responses. The role(s) of thrombin and PAR signaling in neuroplasticity is in keeping with emerging roles for these pathways in pathophysiologic responses, and demands a careful evaluation by the pharmacologic community in terms of drug development in the CNS. Drug Dev. Res. 60:58–64, 2003. © 2003 Wiley‐Liss, Inc.
Proteinase‐activated receptors (PARs) and immune function
Authors: Fiorucci Stefano , Distrutti Eleonora
Published: September 2003

Proteinase‐activated receptors (PARs) function as cell sensors for proteinases. Expression of PARs in immune cells suggests a role in innate immunity. PAR1 mediates the cellular effects of thrombin and causes cytokine and chemokine production by endothelial cells and macrophages. Expression of PAR1 on fibroblasts mediates the profibrogenic activity of thrombin and triggers extracellular matrix protein deposition. PAR2 activation by trypsin, tryptase, and coagulation proteinases triggers both pro‐ and antiinflammatory activities by regulating monocyte recruitment/activation in inflamed tissues. Drug Dev. Res. 60:65–70, 2003. © 2003 Wiley‐Liss, Inc.
Detecting and tracing illegal access by using traffic pattern matching technique
Authors: Takei Yohsuke , Ohta Kohei , Kato Nei , Nemoto Yoshiaki
Published: September 2003

Illegal access on the Internet has become a problem in recent years. Since illegal access aimed at the network significantly affects the entire network, there has been an urgent need to establish countermeasures. Observing network traffic is considered an effective means for detecting this type of illegal access. However, problems presented by the kinds of illegal access represented by a DoS (Denial of Service) attack are that the attacker can alter the packet source address. Acquiring and analyzing packet information is also difficult due to the increased network speed. Therefore, there is an urgent need to establish a reliable and low‐impact observation technique and a technique that enables attackers to be traced in future high‐speed network environments. In this paper, the authors propose an algorithm for detecting illegal access by extracting and comparing changes in traffic patterns and show that illegal access can be detected and traced by applying this algorithm. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 61–71, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10014
Consideration of the local SAR and radiation characteristics of a helical antenna using a cylindroid whole body phantom at 150 MHz
Authors: Koyanagi Yoshio , Kawai Hiroki , Ogawa Koichi , Ito Koichi
Published: September 2003

A cylindroid whole body phantom is proposed to evaluate the local specific absorption rate (SAR) and radiation characteristics when a small normal‐mode helical antenna (NHA) of a 150‐MHz wireless terminal is in the vicinity of the abdomen of a human body. For their investigations, the distance between the NHA and phantom was set to the value in actual usage conditions. The thermography method is employed to evaluate the local SAR. It was confirmed that the local SAR of a wireless terminal with a transmission output of 5 W did not exceed 5 W/kg even in impedance‐matched conditions. In addition, to check the interrelationship between the local SAR and radiation characteristics in actual usage conditions, an analysis that considered impedance mismatch loss was employed. The results show that the rise of the local SAR decreased by deterioration of the radiated power due to mismatch loss when accompanying a phantom approach. Although the local SAR for a mismatch condition did not exceed 1.2 W/kg regardless of the distance, the maximum gain deteriorated at least 10 dB compared with the matching condition. The authors show that by setting the target value of the local SAR to at most 2 W/kg and controlling the matching condition or available power of the power supply, the gain can be improved 5 dB or more. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 48–60, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10084
Environment‐adaptive personal communications realizing ubiquitous computing networks
Authors: Kamioka Eiji , Yamada Shigeki
Published: September 2003

This paper is concerned with the realization of a ubiquitous computing network designed to improve the reachability of communications and to eliminate complex setup and manipulation related to communications. The new communication system EAPEC (environment‐adaptive personal communications) is proposed. The communications context of the user, which changes from time to time, is automatically acquired. Based on that information, the communications terminal and the communications service/medium that are optimal for the receiver to receive the message are automatically selected. Then, according to the selection, the communications service or the communications medium is automatically converted. It is shown in this paper that EAPEC can be realized under the 3GPP (third‐generation partnership project) IP network architecture. Placement of five functional modules in the network and the automatic acquisition procedure for communications context are described. As a means of performance evaluation, the call setup delay is evaluated by simulation, and guidelines for network design are obtained. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 34–47, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10087
Frequency stability measuring technique using digital signal processing
Authors: Uchino Masaharu , Mochizuki Ken
Published: September 2003

To measure the frequency stability of an atomic oscillator having high‐frequency stability, a technique using a pair of mixers and a time interval counter is widely used. This technique shares the signals of a local oscillator, uses a pair of mixers to convert the signals of the reference oscillator and the signals of the test oscillator to beat signals, and then uses a time interval counter to measure the phase difference between the beat signals. In this paper, the authors propose a frequency stability measuring technique that uses a two‐channel audio band digitizer in place of the time interval counter. This technique uses the local oscillator and pair of mixers to convert the test signals and reference signals to audio‐band beat signals, and then performs an analog‐to‐digital conversion on the beat signals. When the phase difference between two beat signals is numerically calculated, not only the effect of the local oscillator's phase noise can be eliminated, but the DC offset voltage generated from the mixers is not a critical problem for frequency stability measurements. The authors developed a prototype frequency stability analyzer based on this technique and obtained an Allan deviation (square root of the Allan variance) of σy(τ) = 5 × 10−17at τ = 1000 seconds as a result of measuring its residual noise at a frequency of 100 MHz. This technique can be used to analyze a wide range of properties such as the clock quality of digital devices that operate at high speed, as well as the frequency stability of atomic oscillators at arbitrary nominal frequencies. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 21–33, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10097
Use of optical orthogonal codes with 2‐PPM and BCH codes for time‐hopping optical CDMA system
Authors: Iwata Ayako , Sawagashira Hiroshi , Sonoda Toshio , Kamakura Koji , Sasase Iwao
Published: September 2003

In this paper, we propose the use of 2‐PPM for time‐hopping optical code division multiple access (CDMA) where the transmission bits are embedded in the weighted positions of signature sequences. To use 2‐PPM, each chip is composed of two slots, and an optical pulse is transmitted in either slot, according to a bit transmitted in the corresponding weighted position. In the receiver, threshold detection is used, which makes bits that have suffered multiple access interference (MAI) erasure bits. By using codeword bits of the BCH codes for the transmitted bits, the effect of MAI is removed in the decoding of BCH codes. Since the effect of MAI is treated as erasure bits, the proposed method reduces the effect of MAI more than the decoding procedures treating them as error bits. In addition, the use of extended BCH (eBCH) codes allows us to reduce the effect of MAI more efficiently. We analyze the bit error rate (BER) of the proposed system, assuming that the photodetector outputs follow the Poisson distribution. The numerical results show that the proposed system achieves better BER performance than the system without Manchester signaling. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 11–20, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10123
OFDM transmission characteristics in multipath environment where the delay spreading exceeds the guard interval analyzed based on the ETP model
Authors: Gejoh Noriyuki , Karasawa Yoshio
Published: September 2003

By establishing a guard interval, the OFDM method shows excellent characteristics in a multipath environment. However, if the delay spreading exceeds that guard interval, intersymbol interference occurs. In this paper, we propose a method of extending the “equivalent transmission path model” to analyze the OFDM transmission characteristics in this kind of multipath environment in which the delay spreading exceeds the guard interval and show that the results obtained by using this method match the exact simulation results to a sufficient approximation precision. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 87(1): 1–10, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10131