bluuebunny/crossref_metadata_2025 huggingface dataset:
Faith, Aging, and Dementia
Authors: Stuckey Jon C.
Published: September 2003

Research consistently documents positive relationships among religion, spirituality, and outcomes related to well-being. The purpose of this study was to determine the degree to which spousal dementia caregivers and other older adults rely on religion and spirituality as coping resources. A total of 52 Christian, Jewish, and non-religious dementia caregivers - as well as matched comparison groups of non-caregivers - were interviewed. Qualitative data analysis yielded both common themes among the three religious groups as well as themes of distinction. The findings suggest that the search for meaning and purpose during stressful life events knows no religious or spiritual borders. Even among the non-religious and non-spiritual, purpose and meaning were found in other areas, including in caring for others, in friendships, or simply in the aesthetic joys of life.
Religion, Spirituality, and Ethnicity
Authors: Nightingale Marcie C.
Published: September 2003

Caregivers of persons with Alzheimer's disease (AD) provide an inordinate and escalating level of care. It has been postulated that: (1) religious beliefs and/or spirituality may assist individuals in their caregiving efforts; and (2) coping strategies may vary depending on ethnicity. The intent of this pilot study was to examine these theories by interviewing five African-American and five white caregivers of persons with AD using demographic and open-ended questions regarding spirituality, religious practices, and ethnicity. Five themes were identified regarding the development of the caregivers' beliefs and practices: 1. later life development of beliefs; 2. religious training and practices; 3. family influences; 4. impact of ethnicity on caregiving; and 5. impact of spirituality and religion on caregiving.

All caregivers felt their spirituality and/or religious practices shaped how they approached providing care and all reported that they were influenced by their ethnic background. Most stated that religious practices and spirituality affected how they felt about providing care and that religion and spirituality helped them deal with difficult challenges. Through a better understanding of the importance of different coping mechanisms among caregivers, professionals are able to provide more sensitive care to persons of diverse groups.
Living Alone with Dementia
Authors: Gilmour Helen , Gibson Faith , Campbell Jim
Published: September 2003

As the number of people with dementia is increasing alongside the social trend of a greater proportion of the population living on their own, this article seeks to explore a number of issues arising from these circumstances. It summarizes a qualitative study of ten people with dementia who live alone in their own homes. The views of these individuals, their families and care staff, GPs, district nurses and social workers are described and analysed, providing insights into the different perceptions of risk. The findings and discussion highlight issues relating to assessing and managing risk and problems and opportunities related to living alone with dementia. In this study no incidents of major harm were reported and daily contact with others was considerable. However, resources and support are needed to enable professionals, families and people with dementia to achieve a sense of shared negotiated responsibility for risk taking.
Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression
Authors: Kaser Arthur , Kaser Susanne , Kaneider Nicole C. , Enrich Barbara , Wiedermann Christian J. , Tilg Herbert
Published: September 2003

In vivo evidence suggests that interleukin-18 (IL-18) shapes the development of adaptive immunity toward T-helper cell type 1 (Th1) responses. Monocyte-derived dendritic cells 1 (DC1s) preferentially induce a Th1 response, while plasmacytoid DC-derived DC2s have been linked to a Th2 response. We analyzed the role of IL-18 during the initiation phase of a Th response in vitro to elucidate the basis of these in vivo observations. IL-18 was constitutively released from DC1s, but not DC2s. Neutralization of IL-18 in coculture experiments of DC1s with allogeneic naive T lymphocytes did not alter the Th1/Th2 phenotype, while anti–IL-12 efficiently down-regulated the Th1 response. Unexpectedly, IL-18 receptor (IL-18R) α and β chains were expressed on DC2 lineage. IL-18R expression was functional, as IL-18 induced chemotaxis in plasmacytoid DCs (pre-DC2s) and enhanced the allostimulatory capacity of IL-3–differentiated DC2s. Pre-DC2s exposed to IL-18 skewed the development of Th cells toward Th1 in coculture experiments of DC2s and allogeneic naive T cells, which was inhibited by IL-12 p70 neutralization. IL-18 might have a profound role during the initiation phase of an immune response by recruiting pre-DC2s and modulating the function of DC2s.
Identification of the primary collagen-binding surface on human glycoprotein VI by site-directed mutagenesis and by a blocking phage antibody
Authors: Smethurst Peter A. , Joutsi-Korhonen Lotta , O'Connor Marie N. , Wilson Erica , Jennings Nicola S. , Garner Stephen F. , Zhang Yanjun , Knight C. Graham , Dafforn Timothy R. , Buckle Ashley , IJsseldijk Martin J. W. , de Groot Philip G. , Watkins Nicholas A. , Farndale Richard W. , Ouwehand Willem H.
Published: September 2003

Glycoprotein (GP) VI is the major receptor responsible for platelet activation by collagen, but the collagen-binding surface of GPVI is unknown. To address this issue we expressed, from insect cells, the immunoglobulin (Ig)–like ectodomains (residues 1-185) of human and murine GPVI, called hD1D2 and mD1D2, respectively. Both proteins bound specifically to collagen-related peptide (CRP), a GPVI-specific ligand, but hD1D2 bound CRP more strongly than did mD1D2. Molecular modeling and sequence comparison identified key differences between hD1D2 and mD1D2. Ten mutant hD1D2s were expressed, of which 4 had human residues replaced by their murine counterpart, and 6 had replacements by alanine. CRP binding studies with these mutants demonstrated that the exchange of lysine at position 59 for the corresponding murine glutamate substantially reduced binding to CRP. The position of lysine59 on the apical surface of GPVI suggests a mode of CRP binding analogous to that used by the related killer cell Ig-like receptors to bind HLA. This surface was confirmed as critical for collagen binding by epitope mapping of an inhibitory phage antibody against GPVI. This anti-GPVI, clone 10B12, gave dose-dependent inhibition of the hD1D2-collagen interaction. Clone 10B12 inhibited activation of platelets by CRP and collagen in aggregometry and thrombus formation by the latter in whole blood perfusion. Antibody 10B12 showed significantly reduced binding to the hD1D2-E59, and, on that basis, the GPVI:10B12 interface was modeled.
Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment
Authors: Mazurier Frédéric , Gan Olga I. , McKenzie Joby L. , Doedens Monica , Dick John E.
Published: September 2003

Knowledge of the composition and interrelationship of the various hematopoietic stem cells (HSCs) that comprise the human HSC pool and the consequence of culture on each class is required for effective therapies based on stem cells. Clonal tracking of retrovirally transduced HSCs in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice revealed heterogeneity in the repopulation capacity of SCID-repopulating cells (SRCs). However, it is impossible to establish whether HSC heterogeneity is intrinsic or whether the culture conditions required for retroviral transduction induce qualitative and quantitative alterations to SRCs. Here, we report establishment of a clonal tracking method that uses lentivectors to transduce HSCs with minimal manipulation during overnight culture without cytokine stimulation. By serial bone marrow (BM) sampling of mice receiving transplants, short-term SRCs (ST-SRCs) and long-term SRCs (LT-SRCs) were identified on the basis of repopulation dynamics demonstrating that their existence is not an experimental artifact but reflects the state of the HSC pool. However, 4 days of culture in conditions previously used for SRC retroviral transduction significantly reduced SRC number as assessed by clonal analysis. These studies provide a foundation to understand the molecular and cellular determinants of human HSC development and to develop therapies targeted to specific HSC classes.
The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46
Authors: Arnon Tal I. , Achdout Hagit , Lieberman Niva , Gazit Roi , Gonen-Gross Tsufit , Katz Gil , Bar-Ilan Ahuva , Bloushtain Noga , Lev Marianna , Joseph Aviva , Kedar Eli , Porgador Angel , Mandelboim Ofer
Published: September 2003

The destruction of viral-infected and tumor cells is mediated in part via the lysis receptor of natural killer (NK) cells, NKp46. The nature, however, of its lysis ligands expressed on target cells is poorly defined. Recently, we have identified a novel functional interaction between the lysis receptors NKp46 and NKp44 and the hemagglutinin of influenza and hemgglutininneuroaminidase of Sendai viruses. This recognition depends on the sialylation of NKp46 and NKp44 receptors. In this study, we expand the significance of these observations by demonstrating a conserved pattern of NKp46 and NKp44 recognition by various hemagglutinins derived from different viral strains. We further establish that this recognition is direct and mainly mediated via α2,6-linked sialic acid carried by NKp46. In addition, we demonstrate that the ability of NKp46 to recognize target cells is confined to the membrane proximal domain, and largely relies on the highly conserved sugar-carrying residue, Thr 225. This residue plays a critical dual role in NKp46 interactions with both viral hemagglutinins and the unknown tumor ligands via different mechanisms. These results may explain the ability of NK cells to kill such a broad spectrum of viral-infected and tumor cells.
Trypsin-modulating oostatic factor: a potential new larvicide for mosquito control
Authors: Borovsky D.
Published: September 2003

Trypsin-modulating oostatic factor (TMOF), a mosquito decapeptide,terminates trypsin biosynthesis in the mosquito gut. The hormone is secreted from the ovary, starting 18 h after the blood meal, circulates in the hemolymph, binds to a gut receptor and stops trypsin biosynthesis by exerting a translational control on trypsin mRNA. Because of the unique primary amino acid sequence of the hormone (YDPAPPPPPP) and its stable three-dimensional conformation, TMOF is not degraded by gut proteolytic enzymes and can traverse the gut epithelial cells into the hemolymph of adults and larvae. Using this unique property, hormone fed to different species of mosquito larvae stops food digestion and causes larval mortality. To determine the shortest amino acid sequence that can bind to the gut receptor and still cause high larval mortality, 25 analogues of TMOF were synthesized and tested. The tetrapeptide(YDPA) was as effective as the decapeptide, indicating that the binding to the gut receptor is at the N-terminus of the molecule. Cloning and expressing the hormone on the coat protein of tobacco mosaic virus (TMV) in Chlorella sp. and Saccharomyces cerevisiae cells and feeding the recombinant cells to mosquito larvae caused larval mortality. These results indicate that TMOF can be used as a new biorational insecticide against mosquito larvae.
Towards genetic manipulation of wild mosquito populations to combat malaria: advances and challenges
Authors: Riehle Michael A. , Srinivasan Prakash , Moreira Cristina K. , Jacobs-Lorena Marcelo
Published: September 2003

Malaria kills millions of people every year, yet there has been little progress in controlling this disease. For transmission to occur, the malaria parasite has to complete a complex developmental cycle in the mosquito. The mosquito is therefore a potential weak link in malaria transmission, and generating mosquito populations that are refractory to the parasite is a potential means of controlling the disease. There has been considerable progress over the last decade towards developing the tools for creating a refractory mosquito. Accomplishments include germline transformation of several important mosquito vectors, the completed genomes of the mosquito Anopheles gambiae and the malaria parasite Plasmodium falciparum, and the identification of promoters and effector genes that confer resistance in the mosquito. These tools have provided researchers with the ability to engineer a refractory mosquito vector, but there are fundamental gaps in our knowledge of how to transfer this technology safely and effectively into field populations. This review considers strategies for interfering with Plasmodium development in the mosquito, together with issues related to the transfer of laboratory-acquired knowledge to the field, such as minimization of transgene fitness load to the mosquito, driving genes through populations, avoiding the selection of resistant strains, and how to produce and release populations of males only.
Utilization of genomic sequence information to develop malaria vaccines
Authors: Doolan D. L. , Aguiar J. C. , Weiss W. R. , Sette A. , Felgner P. L. , Regis D. P. , Quinones-Casas P. , Yates J. R. , Blair P. L. , Richie T. L. , Hoffman S. L. , Carucci D. J.
Published: September 2003

Recent advances in the fields of genomics, proteomics and molecular immunology offer tremendous opportunities for the development of novel interventions against public health threats, including malaria. However, there is currently no algorithm that can effectively identify the targets of protective T cell or antibody responses from genomic data. Furthermore, the identification of antigens that will stimulate the most effective immunity against the target pathogen is problematic, particularly if the genome is large. Malaria is an attractive model for the development and validation of approaches to translate genomic information to vaccine development because of the critical need for effective anti-malarial interventions and because the Plasmodium parasite is a complex multistage pathogen targeted by multiple immune responses. Sterile protective immunity can be achieved by immunization with radiation-attenuated sporozoites, and anti-disease immunity can be induced in residents in malaria-endemic areas. However, the 23 Mb Plasmodium falciparum genome encodes more than 5300 proteins, each of which is a potential target of protective immune responses. The current generation of subunit vaccines is based on a single or few antigens and therefore might elicit too narrow a breadth of response. We are working towards the development of a new generation vaccine based on the presumption that duplicating the protection induced by the whole organism may require a vaccine nearly as complex as the organism itself. Here, we present our strategy to exploit the genomic sequence of P. falciparum for malaria vaccine development.
Gene vector and transposable element behavior in mosquitoes
Authors: O'Brochta David A. , Sethuraman Nagaraja , Wilson Raymond , Hice Robert H. , Pinkerton Alexandra C. , Levesque Cynthia S. , Bideshi Dennis K. , Jasinskiene Nijole , Coates Craig J. , James Anthony A. , Lehane Michael J. , Atkinson Peter W.
Published: September 2003

The development of efficient germ-line transformation technologies for mosquitoes has increased the ability of entomologists to find, isolate and analyze genes. The utility of the currently available systems will be determined by a number of factors including the behavior of the gene vectors during the initial integration event and their behavior after chromosomal integration. Post-integration behavior will determine whether the transposable elements being employed currently as primary gene vectors will be useful as gene-tagging and enhancer-trapping agents. The post-integration behavior of existing insect vectors has not been extensively examined. Mos1 is useful as a primary germ-line transformation vector in insects but is inefficiently remobilized in Drosophila melanogaster and Aedes aegypti. Hermes transforms D. melanogaster efficiently and can be remobilized in this species. This element is also useful for creating transgenic A. aegypti, but its mode of integration in mosquitoes results in the insertion of flanking plasmid DNA. Hermes can be remobilized in the soma of A. aegypti and transposes using a common cut-and-paste mechanism; however, the element does not remobilize in the germ line. piggyBac can be used to create transgenic mosquitoes and occasionally integrates using a mechanism other than a simple cut-and-paste mechanism. Preliminary data suggest that remobilization is infrequent. Minos also functions in mosquitoes and, like the other gene vectors,appears to remobilize inefficiently following integration. These results have implications for future gene vector development efforts and applications.
Transport mechanisms of diuresis in Malpighian tubules of insects
Authors: Beyenbach Klaus W.
Published: September 2003

We have studied Malpighian tubules of Aedes aegypti using a variety of methods: Ramsay fluid secretion assay, electron probe analysis of secreted fluid, in vitro microperfusion and two-electrode voltage clamp. Collectively, these methods have allowed us to elucidate transepithelial transport mechanisms under control conditions and in the presence of diuretic peptides. Mosquito natriuretic peptide (MNP), a corticotropin-releasing factor (CRF)-like diuretic peptide, selectively increases transepithelial secretion of NaCl and water, meeting the NaCl loads of the blood meal. The intracellular messenger of MNP is cAMP, which increases the Na+ conductance and activates the Na+/K+/2Cl--cotransporter in the basolateral membrane of principal cells. Leucokinin non-selectively increases transepithelial NaCl and KCl secretion, which may deal with hemolymph volume expansions or reduce the flight pay load upon eclosion from the aquatic habitat. The non-selective NaCl and KCl diuresis stems from the increase in septate junctional Cl- conductance activated by leucokinin using Ca2+ as second messenger. Fundamental to diuretic mechanisms are powerful epithelial transport mechanisms in the distal segment of the Malpighian tubules, where transepithelial secretion rates can exceed the capacity of mammalian glomerular kidneys in the renal turnover of the extracellular fluid compartment. In conjunction with powerful epithelial transport mechanisms driven by the V-type H+-ATPase, diuretic hormones enable hematophagous and probably also phytophagous insects to deal with enormous dietary loads, thereby contributing to the evolutionary success of insects.
Antimalarial compounds: from bench to bedside
Authors: Olliaro Piero L. , Taylor Walter R. J.
Published: September 2003

The emergence and spread of drug-resistant malaria parasites is the major threat to effective malaria control. So far, malaria control has relied heavily on a restricted number of chemically related drugs belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin-type compounds been used widely, predominantly in Southeast Asia. Experience has shown that resistance eventually curtails the life span of antimalarial drugs. If measures are not applied to contain resistance, the investment put into the development of new drugs will be squandered.

Current efforts focus, on the one hand, on research into novel compounds with mechanisms of action that are different to the traditionally used drugs,and, on the other hand, on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and expensive ventures. Whilst very few new antimalarial drugs were developed in the last quarter of the 20th century (only four of the nearly 1400 drugs registered worldwide during 1975-1999), various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial pipeline is relatively healthy. Projects are underway at different stages of drug development, from pre-development to registration. However, there is relatively little novelty, as current development projects still rely upon the traditional quinoline, antifolate and, in particular, artemisinin compounds. New structures are expected from the more upstream discovery efforts but it will take time before they become drugs.

Therefore, whilst waiting for the drugs of tomorrow, there is a pressing need for immediately available, effective and affordable drugs that will have long life spans. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance.

Most research work has focussed on the use of artesunate combined with currently used standard drugs, namely mefloquine, amodiaquine,sulfadoxine/pyrimethamine and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and are dependent on the level of resistance of the standard drug. From these studies,further work is underway to produce fixed dose combinations that will be packaged in blister packs. Malaria control programmes need efficacious drugs that can be used with ease by the populations of endemic countries.

This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.
Radiographic measurement of joint space height in non-osteoarthritic tibiofemoral joints
Authors: Deep K. , Norris M. , Smart C. , Senior C.
Published: September 2003

There have been many reports which suggest that in patients with tibiofemoral osteoarthritis, a reduction in joint space is demonstrated better on weight-bearing radiographs taken with the knee in semiflexion than in full extension. The reduction has been attributed to the loss of articular cartilage in the contact area in a semiflexed arthritic knee. None of these studies have, however, included normal knees. We have therefore undertaken a prospective, double-blind, randomised study in order to evaluate the difference in the joint-space of arthroscopically-proven normal tibiofemoral joints as seen on weight-bearing full-extension and 30° flexion posteroanterior radiographs. Twenty-two knees were evaluated and the results showed that there may be a difference of up to 2 mm in the two views. This difference could be attributed to the inherent differential thickness of the articular cartilage in different areas of the femoral and tibial condyles and a change in the areas of contact between them.
Venous leg ulcers after hip replacement
Authors: Mehta J. S. , Nicolaou N. , Kiryluk S. , Fordyce M. J. F.
Published: September 2003

Venous ulceration is a chronic disabling complication of deep-vein thrombosis. The aim of this study was to estimate the incidence of venous leg ulcers five years or more after total hip replacement (THR) and to investigate some of the clinical features associated with their development.

We carried out a postal survey of all patients who had undergone a THR 5 to 12 years previously. Replies from 816 patients showed that 66 (8.1%) had a history of leg ulcers. The prevalence of active ulceration was 2.6% and 43 patients (5.3%) reported developing ulceration since their hip replacement. A clinical review determined that 31 (3.8%) of these were true venous ulcers. The ulcers occurred more commonly on the operated side and developed at a mean of 5.8 years (18 months to 12 years) after the first arthroplasty. A mean of 1.9 arthroplasties (1 to 5) (primary and revision) were carried out before the ulcers appeared. The overall incidence of ulcers was similar to that in the general population.
NON-OPERATIVE MANAGEMENT OF A PERI-PROSTHETIC SUBCAPITAL FRACTURE AFTER METAL-ON-METAL BIRMINGHAM HIP RESURFACING
Authors: Cumming D. , Fordyce M. J. F.
Published: September 2003

We describe a patient who sustained a peri-prosthetic fracture of the femoral neck two weeks after undergoing a resurfacing procedure for osteoarthritis of the hip. The fracture was minimally displaced and a satisfactory outcome was obtained following conservative treatment.
Experimental study of maleation of polypropylene in various twin‐screw extruder systems
Authors: Chang Dohoon , White James L.
Published: September 2003

A range of continuous mixing machines were used as continuous reactors for grafting maleic anhydride onto polypropylene. The machines used were (1) a nonintermeshing modular counterrotating twin‐screw extruder, (2) an intermeshing modular corotating twin‐screw extruder, (3) intermeshing modular counterrotating twin‐screw extruder, and (4) a Kobelco Nex‐T continuous mixer. The grafting reaction of maleic anhydride onto polypropylene and degradation of polypropylene during the grafting reaction were investigated as means for comparing these different machines for reactive extrusion. The influence of processing variables such as screw speed and processing temperature on polymer characteristics also was investigated. Generally, in a comparison of the different machines, the intermeshing counterrotating twin‐screw extruder had the lowest levels of grafted maleic anhydride, whereas the Kobelco Nex‐T continuous mixer under the conditions used had the highest levels of grafted maleic anhydride. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 1755–1764, 2003
Ultrasonic oscillations effect on rheological and processing properties of metallocene‐catalyzed linear low density polyethylene
Authors: Wu Hong , Guo Shaoyun , Chen Guangshun , Lin Jia , Chen Wei , Wang Hongtao
Published: September 2003

The effects of ultrasonic oscillations and die materials on die pressure, productivity of extrusion, melt viscosity of metallocene‐catalyzed linear low density polyethylene (mLLDPE), as well as their mechanism were studied in a special ultrasonic oscillations extrusion system developed in our lab. Die materials used in our experiment included steel, brass, and polytetrafluoroethylene (PTFE). The experimental results showed that ultrasonic oscillations as well as die materials have great influence on the rheological and processing behavior of mLLDPE. Ultrasonic oscillations can greatly increase the productivity of mLLDPE melt extruded through different dies, and can decrease the die pressure and the melt viscosity of mLLDPE. Compared with steel or brass die, mLLDPE melt extruded through PTFE die is more sensitive to ultrasonic oscillations. A possible mechanism for the improved processability of mLLDPE is proposed in this article. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 1873–1878, 2003
Reaction time does not predict surgical skill
Authors: Shah J , Buckley D , Frisby J , Darzi A
Published: September 2003

Fast is not always best
Alcohol consumption and the risk of nosocomial infection in general surgery
Authors: Delgado-Rodríguez M , Mariscal-Ortiz M , Gómez-Ortega A , Martínez-Gallego G , Palma-Pérez S , Sillero-Arenas M , Medina-Cuadros M
Published: September 2003

Background

Alcohol consumption increases community-acquired infections and affects the immune system. The aim of this report was to analyse whether drinking increases the risk of nosocomial infection.

Methods

This was a prospective study of 1505 patients admitted consecutively to a general surgical department. Alcohol consumption was assessed by a structured questionnaire. Postoperative infection was classified using the Centers for Disease Control criteria. Confounding was controlled for by logistic regression analysis, and the results were stratified by gender and drinking pattern.

Results

Most women were light drinkers and no increased risk of postoperative infection was noted. In men, drinking was associated with a lower American Society of Anesthesiologists grade and fewer co-morbidities. Heavy alcohol consumption (more than 108 g/day) in men increased the rate of all-site nosocomial infection (adjusted odds ratio (OR) 2·51, 95 per cent confidence interval (c.i.) 1·06 to 5·96) and the rate of in-hospital surgical-site infection (SSI) (adjusted OR 2·16, 95 per cent c.i. 0·84 to 5·58). An intake of above 72 g/day increased the rate of lower respiratory tract infection (adjusted OR 5·22, 95 per cent c.i. 1·04 to 26·2). Alcohol consumption was not related to the rate of SSI after hospital discharge. When drinking was limited to weekends, there was no relationship with nosocomial infection.

Conclusion

Heavy alcohol consumption increased the risk of nosocomial infection in men who underwent general surgical procedures.
Effect of endoscopic ultrasonography on the management of 100 consecutive patients with oesophageal and junctional carcinoma
Authors: Preston S R , Clark G W B , Martin I G , Sue Ling H M , Harris K M
Published: September 2003

Background

Endoscopic ultrasonography (EUS) offers very accurate tumour and node staging information for oesophagogastric cancer. The aim was to determine whether the addition of EUS directly influenced the definitive management plan for individual patients.

Methods

Personal and staging information from 100 consecutive patients with carcinoma of the oesophagus or oesophagogastric junction were summarized and blinded. Three consultant oesophagogastric surgeons independently made a management decision for each patient, in the presence and absence of the EUS data. All scored their perceived value of the EUS staging data for each patient.

Results

EUS was deemed useful in 63–87 per cent of patients and its addition resulted in an increased number of concordant management plans (from 53 to 62 per cent), and increased agreement between surgeons. The greatest change in concordant management was an increased referral of patients for non-surgical palliation.

Conclusion

The addition of EUS to the staging of patients with oesophageal and oesophagogastric junction cancer significantly altered the management strategy for some of these patients.
Gastrointestinal stromal tumours
Authors: Connolly E M , Gaffney E , Reynolds J V
Published: September 2003

Background

Gastrointestinal stromal tumours (GISTs), previously classified as benign or malignant smooth muscle tumours, are the most common mesenchymal tumours of the gastrointestinal tract. GISTs express a growth factor receptor with tyrosine kinase activity, termed KIT. Mutations of KIT are common in malignant GISTs and lead to constitutional activation of tyrosine kinase function, which causes cellular proliferation and resistance to apoptosis. GISTs are notoriously unresponsive to chemotherapy and, until the recent introduction of the KIT inhibitor imatinib, there has been no effective therapy for advanced, metastatic disease.

Methods

A Medline literature search was preformed to locate all articles relating to gastrointestinal tumours, GISTs, KIT and imatinib.

Results and conclusions

The 5-year survival rate after complete resection of GISTs is approximately 50 per cent. The median duration of survival for patients with a metastatic GIST is approximately 20 months, and 9–12 months for patients with local recurrence. Phase II trials have investigated the effect of imatinib on irresectable or metastatic GISTs. In these trials more than 50 per cent of patients responded to imatinib within a few months and approximately 12 per cent had disease progression. Uptake of [18F]fluoro-2-deoxy-d-glucose demonstrated by positron emission tomography has been found to be reduced after starting imatinib. The potential for cure and the optimal length of treatment is currently unknown. Imatinib is the first effective systemic therapy for metastatic and locally irresectable GISTs. Large multi-institutional clinical trials to investigate the efficacy of imatinib as adjuvant or neoadjuvant therapy for GISTs are now required.
Role of peritoneal mesothelial cells in peritonitis
Authors: Yao V , Platell C , Hall J C
Published: September 2003

Background

Peritoneal mesothelial cells have a remarkable capacity to respond to peritoneal insults. They generate an intense biological response and play an important role in the formation of adhesions. This review describes these activities and comments on their relationship to surgical drainage, peritoneal lavage and laparostomy in the management of patients with peritonitis.

Methods and results

Material was identified from previous review articles, references cited in original papers and a Medline search of the literature. The peritoneal mesothelium adapts to peritonitis by facilitating the clearance of contaminated fluid from the peritoneal cavity and inducing the formation of fibrinous adhesions that support the localization of contaminants. In addition, the fluid within the peritoneal cavity is a battleground in which effector mechanisms generated with the involvement of peritoneal mesothelial cells meet the contaminants. The result is a complex mix of cascading processes that have evolved to protect life in the absence of surgery.

Conclusion

Future advances in the management of patients with severe peritonitis may depend upon molecular strategies that modify the activity of peritoneal mesothelial cells.
Macaque monkey retrosplenial cortex: II. Cortical afferents
Authors: Kobayashi Yasushi , Amaral David G.
Published: September 2003

We investigated the cortical afferents of the retrosplenial cortex and the adjacent posterior cingulate cortex (area 23) in the macaque monkey by using the retrograde tracers Fast blue and Diamidino yellow. We quantitatively analyzed the distribution of labeled neurons throughout the cortical mantle. Injections involving the retrosplenial cortex resulted in labeled neurons within the retrosplenial cortex and in areas 23 and 31 (∼78% of the total labeled cells). In the remainder of the cortex, the heaviest projections originated in the hippocampal formation, including the entorhinal cortex, subiculum, presubiculum, and parasubiculum. The parahippocampal and perirhinal cortices also contained many labeled neurons, as did the prefrontal cortex, mainly in areas 46, 9, 10, and 11, and the occipital cortex, mainly area V2. Injections in area 23 also resulted in numerous labeled cells in the posterior cingulate and retrosplenial regions (∼67% of total labeled cells). As in the retrosplenial cortex, injections of area 23 led to many labeled neurons in the frontal cortex, although most of these cells were in areas 9 and 46. Larger numbers of retrogradely labeled cells were also distributed more widely in the posterior parietal cortex, including areas 7a, 7m, LIP, and DP. There were some labeled cells in the parahippocampal cortex. These connections are consistent with the retrosplenial cortex acting as an interface between the working memory functions in the prefrontal areas and the long‐term memory encoding in the medial temporal lobe. The posterior cingulate cortex, in contrast, may be more highly associated with visuospatial functions. J. Comp. Neurol. 466:48–79, 2003. © 2003 Wiley‐Liss, Inc.
MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll‐like receptor 2 signaling
Authors: de Veer Michael J. , Curtis Joan M. , Baldwin Tracey M. , DiDonato Joseph A. , Sexton Adrienne , McConville Malcolm J. , Handman Emanuela , Schofield Louis
Published: September 2003

Leishmania major is an obligate intracellular eukaryotic pathogen of mononuclear phagocytes. Invasive promastigotes gain entry into target cells by receptor‐mediated phagocytosis, transform into non‐motile amastigotes and establish in the phagolysosome. Glycosylphosphatidylinositol‐anchored lipophosphoglycan (LPG) is a virulence factor and a major parasite molecule involved in this process. We observed that mice lacking the Toll‐like receptor (TLR) pathway adaptor protein MyD88 were more susceptible to infection with L. major than wild‐type C57BL/6 mice, demonstrating a central role for this innate immune recognition pathway in control of infection, and suggesting that L. major possesses a ligand for TLR. We sought to identify parasite molecules capable of activating the protective Toll pathway, and found that purified Leishmania LPG, but not other surface glycolipids, activate innate immune signaling pathways via TLR2. Activation of cytokine synthesis by LPG required the presence of the lipid anchor and a functional MyD88 adaptor protein. LPG also induced the expression of negative regulatory pathways mediated by members of thesuppressors of cytokine signaling family SOCS‐1 and SOCS‐3. Thus, the Toll pathway is required for resistance to L. major and LPG is a defined TLR agonist from this important human pathogen.
HLA class I‐restricted recognition of an HIV‐derived epitope peptide by a human T cell receptor α chain having a Vδ1 variable segment
Authors: Ueno Takamasa , Tomiyama Hiroko , Fujiwara Mamoru , Oka Shinichi , Takiguchi Masafumi
Published: September 2003

A subset of human peripheral α β T cells have been shown to express TCR α chains containing Vδ1 segments, although what antigens the Vδ1+ α β T cells recognize via these TCR is not known yet. We eventually established a human CD8 T cell clone that expressed α β TCR and Vδ1 antigens. Corroboratively, a unique in‐frame Vδ1.1JαCα transcript was found in the clone. The clone showed cytotoxic activity and IFN‐γ production towards cells expressing HLA‐B*3501 pulsed with an HIV Pol‐derived epitope peptide (IPLTEEAEL). By flow‐cytometric analysis ex vivo using an HLA‐B*3501 tetramer, a fraction of Vδ1+CD8+tetramer+ cells was found in peripheral lymphocytes of an HIV‐infected patient, indicating the existence of HLA‐restricted and HIV‐specific Vδ1+ CD8 T cells in vivo. Moreover, retrovirus‐mediated transfer of the TCR‐encoding genes into TCR‐negative hybridoma cells showed that the transduced cells were stained by the tetramer and were activated in response to the Pol peptide, further confirming the ligand specificity of the TCR. Together, these results clearly demonstrate that Vδ1+ α β TCR are restricted to engaging peptide antigens in the context of classical MHC class I molecules, highlighting the difference in the ligand specificity between Vδ1+ α β TCR and Vδ1+ γ δ TCR.
Kinetics and signaling requirements of CD40‐mediated protection from B cell receptor‐induced apoptosis
Authors: Eeva Jonna , Postila Ville , Mättö Mikko , Nuutinen Ulla , Ropponen Antti , Eray Mine , Pelkonen Jukka
Published: September 2003

In the present study we used a human follicular lymphoma cell line, HF1A3, as an in vitro model for the antigen‐driven selection process in germinal centers. Apoptosis can be induced in HF1A3 cells by B cell receptor (BCR) stimulation, but the molecular mechanisms and kinetics of this process are largely unknown. We demonstrate here that there is over 12 h delay between receptoractivation and the execution phase of apoptosis, i.e. disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria, caspase‐3 activation and DNA fragmentation.New protein synthesis is required for mitochondrial alterations and subsequent apoptosis to occur, as these processes are completely blocked by the protein synthesis inhibitor cycloheximide. All the apoptotic events induced by BCR triggering are completely reversed by CD40 ligation with anti‐CD40 antibody. CD40 ligation can reverse the apoptotic process in HF1A3 cells almost until the first mitochondrial events take place demonstrating that CD40‐mediated protection operates very fast and at or before mitochondrial phase of apoptosis. Using specific inhibitors of cell signaling we coulddemonstrate that Raf‐extracellular signal‐regulated kinase, phosphatidylinositol 3‐kinase, p38 or protein kinase C activation pathways are not involved in CD40‐mediated protection from BCR‐induced apoptosis in HF1A3 cells.
Mini‐review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross‐priming and direct priming?
Authors: Melief Cornelis J. M.
Published: September 2003

Cross‐priming is the process whereby professional APC, mainly dendritic cells (DC), prime T cells by presenting antigens processed from proteins of other cells such as tumor cells or virus‐infected cells. It has been argued that the importance of cross‐priming of CD8+ CTL responses has been overemphasized, despite strong evidence that these mechanisms operate when infectious organisms, tumors or self antigens cannot efficiently access the biosynthetic MHC class I processing pathway of DC. Since DC are ideally equipped to capture exogenous antigen and also, particularly in the mature state, express costimulatory molecules, itis difficult to distinguish whether effects are due to cross‐presentation, costimulation, or both. Whether cross‐priming or cross‐tolerance occurs depends on the maturation state of the DC, as wellas the levels of MHC class I‐bound peptides they present. Cross‐presentation of tumor‐derived antigens has been demonstrated but, importantly, requires adequate APC activation to prime CTL responses. Similarly, cross‐presentation of antigens from infectious organisms appears to be common, and frequently leads to cross‐priming. Interactions between cross‐presenting DC, CD4+ cellsand CD8+ T cells in the establishment of immunological memory are still not well defined. Experiments utilizing DC depletion are needed to further examine the role of processes such as cross‐priming and costimulation in the immune response.
Enzyme activity of α‐chymotrypsin after derivatization with phenolic compounds
Authors: Rohn Sascha , Rawel Harshadrai M. , Wollenberger Ulla , Kroll Jürgen
Published: September 2003

α‐Chymotrypsin was allowed to react with selected phenolic and related compounds (chlorogenic acid, m‐, o‐, p‐dihydroxybenzene, p‐benzoquinone). The derivatized enzymes obtained were characterized in terms of their activity. In vitro experiments illustrated that the enzymatic activity of the derivatives was adversely affected. The kinetics of the enzymatic reactions showed that the hydrolysis of selected food proteins becomes slower and the affinity of the enzyme to these substrates declined as measured by Michaelis‐Menten constant and maximum velocity of the enzymatic reaction. This enzyme inhibition depended on the reactivity of the phenolic and related substances tested as well as on the degree of the derivatization. Further, influence of the enzyme‐substrate ratio was also demonstrated. The effects of the derivatization are more pronounced with increasing concentration of the substrates.
Chemical and biochemical changes in prickly pears with different ripening behaviour
Authors: Silos‐Espino Héctor , Fabian‐Morales Lourdes , Osuna‐Castro Juan Alberto , Valverde María Elena , Guevara‐Lara Fidel , Paredes‐López Octavio
Published: September 2003

Chemical and biochemical changes were studied in ripening prickly pears from three Opuntia morphospecies with different ripening behaviour: Naranjona (O. ficus‐indica( Blanca Cristalina (Opuntia sp.( and Charola (O. streptacantha( of early, intermediate, and late ripening, respectively. At fullyripe stage (commercial maturity( Blanca Cristalina showed the biggest fruits, the hardest texture, and its pulp had the highest protein content. There were no significant differences among morphospecies in pH or total soluble solids in fully ripe fruits. The three species exhibited considerable levels of vitamin C, dietary fibre, and minerals such as calcium, iron, and zinc. Protein expression was analysed in pulp and skin from every species at physiological and commercial maturity. Some proteins appeared at both stages, while many others expressed differentially. This study evaluated prickly pear components important for human nutrition and health, and provided basic information on pricky pear ripening, with a view to its control and to improving shelf life.
Assay of gliadin by real‐time immunopolymerase chain reaction
Authors: Henterich Nadine , Osman Awad A. , Méndez Enrique , Mothes Thomas
Published: September 2003

Patients with coeliac disease (gluten‐sensitive enteropathy) are intolerant against gliadins from wheat and the respective proteins from related cereals and have to keep a lifelong gluten‐free diet. For control of gliadin in gluten‐free food sensitive assay techniques are necessary. We developed an immunopolymerase chain reaction (iPCR) assay for gliadin. In this technique immunological detection of gliadin by a monoclonal antibody R5 conjugated with an oligonucleotide is amplified by PCR. For quantification, iPCR was performed as real‐time PCR (real‐time iPCR) in one step. By means of real‐time iPCR, the sensitivity of gliadin analysis was increased more than 30‐fold above the level reached by enzyme immunoassay. Real time‐iPCR using R5 directly conjugated with oligonucleotide was clearly more sensitive than real time‐iPCR applying sequentially biotinylated R5, streptavidin, and biotinylated oligonucleotide. With directly conjugated R5 gliadin was detected at a concentration as low as 0.16 ng/mL corresponding to 16 μg gliadin/100 g food or 0.16 ppm (corresponding to 0.25 g of food extracted in 10 mL of solvent and 25‐fold dilution of the extract prior to analysis). This is the first report applying the highly sensitive technique of iPCR for gliadin analysis. Furthermore, this is the first approach to perform real‐time iPCR in one step without changing the reaction vessels after enzyme immunoassay for subsequent PCR analysis thus minimizing risks of contamination and loss of sensitivity.
Synthesis and Properties of Oligodeoxynucleotide Analogs with Bis(methylene) Sulfone Bridges
Authors: Eschgfäller Bernd , Schmidt Jürgen G. , König Marcel , Benner Steven A.
Published: September 2003

A convergent, solution‐phase synthesis was developed for the bis(methylene) sulfone‐bridged oligodeoxynucleotide analogs (SNA) 5′‐d(HOCH2‐Tso2Tso2Tso2Cso2Tso2Tso2Tso2T‐CH2SO$\rm{_{3}^{-}}$)‐3′ (35b) and 5′‐d(HOCH2‐Tso2Tso2Tso2Tso2Tso2Tso2Tso2T‐CH2SO$\rm{_{3}^{-}}$)‐3′ (34c) (SO2 corresponds to CH2SO2CH2 instead of OP(O)(O−)(O). In these, the phosphodiester linkages are replaced by non‐ionic bis(methylene) sulfone linkers. The general strategy involved convergent coupling of 3′,5′‐bishomo‐β‐D‐deoxyribonucleotide analogs functionalized at the 6′‐end (CH2C(5′)) as bromides or mesylates and at the CH2C(3′) position as thiols, with the resulting thioether being oxidized to the corresponding sulfone. A single charge was introduced at the terminal CH2C(3′) position of the octamers to increase their solubility in water. During the synthesis, it became apparent that the key intermediates generated secondary structures through either folding or aggregation in a variety of solvents. This generated unusual reactivity and was unique for very similar structures. For example, although the dimeric thiol d(BzOCH2‐Tso2C‐CH2SH) (14b) was a well‐behaved synthetic intermediate, the tetrameric thiol d(TrOCH2‐Tso2Tso2Tso2toC‐CH2SH) derived from the corresponding thioacetate was rapidly converted to a disulfide by very small amounts of oxidant (28→29, Scheme 6), while the analogous tetrameric thiol d(BzOCH2‐Tso2TsTso2T‐CH2SH) (26), differing only by a single heterocycle, was oxidized much more slowly (Bz=PhCO, Tr=Ph3C, to=2‐MeC6H4CO (at N4 of dc)). The sequence‐dependent reactivity, well known in many classes of natural products (including polypeptides), is not prominent in natural oligonucleotides. These results are discussed in light of the proposal that the repeating negative charge in nucleic acids is key to their ability to serve as genetic molecules, in particular, their capability to support Darwinian evolution. The ability of 5′‐d(HOCH2‐Tso2Tso2Tso2Cso2Tso2Tso2Tso2T‐CH2SO$\rm{_{3}^{-}}$)‐3′ (35b) to bind as a third strand to duplex DNA was also examined. No triple‐helix‐forming propensity was detected in this molecule.