bluuebunny/crossref_metadata_2025 huggingface dataset:
Social Insurance for Health Service
Authors: Roemer Milton I.
Published: February 2009

Implementation of social insurance for financing health services has yielded different patterns depending on a country's economic level and its government's political ideology. By the late 19th century, thousands of small sickness funds operated in Europe, and in 1883 Germany's Chancellor Bismarck led the enactment of a law mandating enrollment by low-income workers. Other countries followed, with France completing Western European coverage in 1928. The Russian Revolution in 1917 led to a National Health Service covering everyone from general revenues by 1937. New Zealand legislated universal population coverage in 1939. After World War II, Scandinavian countries extended coverage to everyone and Britain introduced its National Health Service covering everyone with comprehensive care and financed by general revenues in 1948. Outside of Europe Japan adopted health insurance in 1922, covering everyone in 1946. Chile was the first developing country to enact statutory health insurance in 1924 for industrial workers, with extension to all low-income people with its “Servicio Nacional de Salud” in 1952. India covered 3.5 percent of its large population with the Employees' State Insurance Corporation in 1948, and China after its 1949 revolution developed four types of health insurance for designated groups of workers and dependents. Sub-Saharan African countries took limited health insurance actions in the late 1960s and 1970s. By 1980, some 85 countries had enacted social security programs to finance or deliver health services or both.
Weak and strong holism
Authors: Täljedal Inge-Bert
Published: February 2009

Dissatisfaction with the health care system, in combination with an increasing academic status of paramedical professions, is currently inspiring the analysis of central medical terms by philosophers. One interesting result is the formulation of equilibrium theories that define health without reference to disease. It is argued here that the alleged holism of such theories is in fact weaker than the strong holism represented by the irreductive materialism inherent in traditional medicine. Strong holism resolves certain anomalies in the weakly holistic description of the Human Being, notably the claim that perfect health is compatible with having a deadly disease.
Why was the perinatal mortality rate higher in Denmark than in Sweden? The development in the 1970s and 1980s
Authors: Vallgårda Signild
Published: February 2009

The purpose of this article is to identify factors explaining why the perinatal mortality rate ceased to fall in Denmark during the 1980s, while it continued to do so in Sweden, and to study the ability of known risk factors to predict this development. My analysis is based on routinely collected published data on all births, where I have studied the levels and changes in known risk factors for perinatal deaths in the two countries. The results of the study are: The proportion of low birth weight infants and the mothers' age and parity did not differ or change in a way that explains the higher perinatal mortality rate in Denmark during the 1980s. The weight specific perinatal mortality rate was the same in the two countries, with the exception of very low birth weight babies, i.e. below 1,500 grammes, where the perinatal mortality rate was higher in Denmark; this difference increased during the 1980s. The proportion of very low birth weight infants increased in Denmark from the 1970s to the 1980s while it remained stable in Sweden. The Danish increase in the proportion of low birth weight infants can be due to changed registration practices with more very small infants being registered in the 1980s. Among the factors studied registration practices, smoking and neonatal care seemed to be able to explain part of the differences between the two countries. The relative risk of perinatal death associated with the mothers' age and parity varied depending on the size of the groups at risk: the more women in high age and parity groups the lower the relative risk, which indicates that a selection as well as a causal effect was present. A conclusion is that the changes in relative risk over time associated with age and parity should lead to a closer investigation of the characteristics actually associated with an increased risk in order not to treat all old and multiparous women as patients at risk.
Relationships between health behavior, knowledge, and beliefs among Swedish blue-collar workers
Authors: Näslund Görel K.
Published: February 2009

The main objective of this study was to assess the health behavior, risk awareness and beliefs concerning the importance of positive health practices among blue-collar workers, and to examine the relationships between behavior, knowledge and beliefs. Data were gathered from 1359 workers aged 18-65 years using a postal questionnaire to 2493 randomly selected members of two labor unions.

A high prevalence of negative health practices was noted among the respondents. While no relationship was found between health behaviors and awareness of risks associated with such behaviors, there was a relationship between positive health practices and strong beliefs about the importance of those practices. Awareness of the influence of a positive behavior on disease risk was associated with a stronger belief concerning the importance of that behavior. Women were characterized by having more positive health behavior, a higher level of risk awareness and stronger beliefs concerning the importance of positive health practices.
HIV/AIDS — Information and knowledge
Authors: Eriksson Torbjörn , Sonesson Andreas , Isacsson Åke
Published: February 2009

Knowledge of hiv/aids, exposure to hiv/aids information and appreciation of given information was studied, by a questionnaire, among 326 Kenyan and 146 Swedish teenage school students in 1994. The aim of the study was to examine differences and similarities in knowledge in the two populations and to examine which sources of information about hiv and aids the respondents had been exposed to and which were most appreciated.

The overall knowledge about hiv/aids was high but in specific items the knowledge and awareness of different risk behaviours for contracting hiv/aids differed for the Kenyan and Swedish teenagers. The dissemination of hard factual information about hiv/aids has thus been successful in reaching out although not in stopping the spread of hiv/aids. This calls for new strategies in disease prevention and health promotion. Those strategies should focus much more on lifestyle changes. The health care system, the school and the existing strong civil and voluntary information structures have an important role to play in that work.
Determinants of willingness to pay taxes for a community-based prevention programme
Authors: Lindholm Lars A. , Rosén Måns E. , Stenbeck Magnus E.
Published: February 2009

Prevention can reduce the risk of disease, but has other consequences as well. Willingness-to-pay (WTP) is one method to analyse these multi-dimensional consequences, if the stated WTP is assumed to be a function of all the expected positive and negative effects perceived. An interview study of a community-based cardiovascular disease prevention programme in northern Sweden shows that expectations regarding reduced mortality in the community and future savings in public health care spending increase the perceived value of the programme. Among personal benefits, decreased disease risk was not positively associated with WTP, while a low level of anxiety was.
Lifestyle as regards physical exercise, smoking and drinking, of adult insulin-treated diabetic people compared with non-diabetic controls
Authors: Gåfvels Catharina , Lithner Folke
Published: February 2009

Chronic complications in diabetes are sometimes associated with living habits. To investigate whether diabetic people's habits of smoking, drinking alcohol and taking physical exercise differed from those of the general population, a questionnaire was sent to 561 insulin-treated diabetic people and to 1,125 controls, matched for age, sex and domicile. Diabetic people were current smokers as often as controls (21% vs 23%; ns), but they drank less alcohol and more of them were non-drinkers (22% vs 13%; p<0.001). Diabetic people more often took physical exercise than did controls (40% vs 28%; p< 0.001). Diabetic women were more seldom smokers (18% vs 26%; p<0.05), more often non-drinkers (26% vs 14%; p<0.001) and exercised regularly more (44% vs 28%; p<0.001) than female controls. Diabetic men were more similar to male controls in their habits. Young diabetic people drank less alcohol and were more often non-drinkers (22% vs 9%; p<0.001) compared with their controls. Comparison within the diabetic group showed that men drank alcohol more frequently and in greater amounts, and that more women were non-drinkers (26% vs 18%; p<0.05). People with chronic complications drank less frequently and exercised less regularly (34% vs 44%; p<0.05) than those without complications. These findings suggest that diabetic people's smoking, drinking and exercise habits are rather similar to general people's. However, diabetic women seem to take risk factors for developing complications into consideration more than men, which could reflect a true gender pattern and/or be an effect of worrying more about diabetes.
Incidence of long-term sick-listing in an urban area of Sweden and its relationship with demographic data of the population
Authors: Lurie Miroslaw , Gustafsson Marianne , Lindh Margareta , Sanne Harald
Published: February 2009

By checking the card indexes of seven out of twelve Social Insurance Offices covering 66% of the total wage-earning population in the city of Göteborg the patients recorded for 90 days of continuous sick-listing were classified into four diagnostic categories according to the doctor's certificate: “non-specific pain” and “specific pain” of the musculoskeletal system, “other pain” and “non-pain” diagnoses. The overall yearly incidence of 90 days' sick-listing averaged 5.4%. A significant correlation was found between the incidence of 90 days' sick-listing due to “non-pain” and musculoskeletal pain diagnoses and the proportion of demographic characteristics of the areas. The hypothesis of presuming the highest association between non-specific pain diagnoses and demographic factors was rejected.
Health examinations and health services for asylum seekers in Sweden
Authors: Hjern Anders , Allebeck Peter
Published: February 2009

With an influx of several hundred thousand refugees during the last two decades, care for asylum seekers and refugees has become an important part of health and medical care in Sweden. The Swedish government spent 377 million Swedish crowns (SEK) on medical expenses for asylum seekers and refugees in 1990–91, 427 million SEK in 1991–92 and 804 million in 1992–93 (1 US$ is approximately 6 SEK). The annual cost per asylum seeker was 11,387 SEK in 1992, to be compared with the average cost of health and medical care for Swedish residents in the age 0–49 years which was around 8,000 SEK at that time (1). Despite the large amounts of money and the large number of patients involved in the medical reception programme for refugees in Sweden in recent years, there has been little research about the quality and adequacy of this programme.

The Swedish reception programme for asylum seekers is centered around state-run refugee camps in different parts of the country. To be able to describe the structure and content of the health care service offered to asylum seekers, a semi-structured questionnaire was sent to all health units in refugee camps in Sweden in May 1995. Health units in 30 of the 33 refugee camps in Sweden responded to the questions about the health care service offered to asylum seekers (2).
Doctors' attitudes towards empirical data-a comparative study
Authors: Lynöe Niels , Svensson Tomas
Published: February 2009

In the assessment of the effects of medical technologies, the focus is most often on the quality of the empirical data. In order to shed light on the question whether medical researchers are really so empirically oriented we conducted the following study. 600 questionnaires were sent by mail to three groups, selected at random: 1) preclinical researchers; 2) clinical researchers who received research grants from The Swedish Medical Research Council; and 3) general practitioners. The questionnaire was built around three cases concerning the assessment of the effects of: a) H-2-receptor antagonists, b) coronary by-pass surgery and c) the homeopathic treatment of hay fever.

The results indicate that there are rather small differences in how the three groups assessed the three technologies and larger differences within one and the same group concerning different cases. The tendency is that the more one considers that empirical data should be assessed independent of theoretical considerations, the higher are the demands which are placed on the quality and quantity of the empirical documentation, and vice-versa.
Medical ethics-an endeavour for social medicine?
Authors: Lynöe Niels
Published: February 2009

In this paper twelve themes are pointed out as background for the increased interest for medical ethics: New medical knowledge, the democratisation of doctor-patient relationship, changes in the disease panorama, autonomy and its limits, research ethics, collegiate concern, prioritisation, ethics of clinical training, immigration and cultural conflicts, changes in the view of the rationality of ethical reasoning, changes in the view of nature in relation to culture and medical students' requests for teaching in medical ethics. It is discussed whether teaching in medical ethics is a matter for social medicine or whether one should pass it on to hospital priests or philosophers?
Long-term economic effects of team-based clinical case management of patients with chronic minor disease and long-term absence from working life
Authors: Timpka Toomas , Leijon Margareta , Karlsson Göran , Svensson Lilian , Bjurulf Per
Published: February 2009

Objectives: To examine the socio-economic effects of team-based clinical case management of patients with chronic minor disease bound for early retirement.

Design: Marginal analysis of programme costs and benefits to society compared with no-programme baseline of costs occurring in society due to productivity loss. Prospective patient data collection on admission, discharge, and at one year and five years after discharge to determine programme effectiveness.

Setting: Out-patient clinic at the department of social medicine in tertiary care hospital.

Subjects: 239 patients with minor disease and long-term vocational absence consecutively admitted to the study. At the one-year evaluation, 17 patients had been readmitted to the team, 7 could not be found, 6 declined the interview and 2 were deceased. At the five-year evaluation of 49 patients who were active after one year, one was deceased and 10 were unable to be found.

Main outcome measures: Vocational activity. Programme costs. Benefits to society measured by decrease in indirect costs.

Results: The one-year vocational rehabilitation rate from the program was 20.5% and the five-year rehabilitation rate was 11.3%. The total discounted cost for case management of the 239 patients was 7.6 MSEK (£600,000). The decrease in the indirect costs to society from the 28 patients found active after five years was 35.1 MSEK (£2,500,000). The net present value of the programme at the 1991 price level was 27.5 MSEK (£2,365,000).

Conclusions: Tertiary care level team-based clinical case management for vocational rehabilitation of patients with chronic minor disease has a positive cost-benefit ratio. A cross-boundary awareness at a health policy level is needed of the societal costs involved for this group of patients who fall between the traditional services in health care and social work.
Unemployment and sexual risk-taking among adolescents
Authors: Hammarström Anne , Janlert Urban
Published: February 2009

Sexual risk-taking can lead to serious consequences. This study addressed the question of how sexual risk-taking was influenced by unemployment. A cohort of 1060 adolescents were followed from their last term in compulsory, school and five years ahead until the age of 21. Sexual risk-taking, defined as unprotected intercourse without wishing to conceive, was studied with the help of a questionnaire at the beginning and at the end of the period. For men there was a positive correlation between the length of unemployment and increase in risk-taking during the period, but for women there was a (statistically non-significant) negative correlation. In a logistic regression analysis, having children also had a significant effect on increased risk-taking among men. Unemployment thus implies increased sexual risk-taking among adolescent men.
New UV Absorber for PET Packaging: Better Protection With Less Discoloration
Authors: Coughlin Greg , Schambony Simon
Published: February 2009

``UVA S-Pack'' is a new UV absorber additive designed to protect PET packaging content from the damaging effects of UV radiation. Compared to conventional UV absorbers that have been used for this purpose, this new product offers broader UV protection with less discoloration. The performance of this new UV absorber in content protection was demonstrated in exposure tests with vitamins and colorants. The product is also FDA-cleared for use in PET for food-contact applications. Due to this product's unique absorption and emission profile, it is expected to also offer suitable performance in polyester-based films and sheets.
Structure of the AML1-ETO eTAFH domain–HEB peptide complex and its contribution to AML1-ETO activity
Authors: Park Sangho , Chen Wei , Cierpicki Tomasz , Tonelli Marco , Cai Xiongwei , Speck Nancy A. , Bushweller John H.
Published: February 2009

AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein–associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO–mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.
Reflections on Northern Rock: The Bank Run that Heralded the Global Financial Crisis
Authors: Shin Hyun Song
Published: February 2009

The U.K. bank Northern Rock became the first high-profile casualty of the global financial crisis of 2007–2008 when it suffered its depositor run in September 2007. In spite of the television images of long lines of depositors outside its branch offices, the run on Northern Rock was unlike the textbook retail depositor run caused by coordination failure. Also, contrary to received wisdom, its reliance on securitization was not an immediate factor in its failure. Rather, its problems stemmed from its high leverage coupled with reliance on institutional investors for short-term funding. When the de-leveraging in the credit markets began in August 2007, Northern Rock was uniquely vulnerable to the shrinking of lender balance sheets arising from the tick-up in measured risks. Financial regulation that relies on risk-weighted capital requirements is powerless against such runs. The Northern Rock case also offers lessons concerning the economics of short-term debt.
Markets: Red Light States: Who Buys Online Adult Entertainment?
Authors: Edelman Benjamin
Published: February 2009

This paper studies the adult online entertainment industry, particularly the consumption side of the market. In particular, it focuses on the demographics and consumption patterns of those who subscribe to adult entertainment websites. On the surface, this business would seem to face a number of obstacles. Regulatory and legal barriers have already been mentioned. In addition, those charging for access to adult entertainment face competition from similar content available without a fee. In the context of adult entertainment, free access offers consumers an extra benefit: online payments tend to create records documenting the fact of a customer's purchase; consumers of free content may feel more confident that their purchases will remain confidential. More broadly, measured levels of religiosity in American are high. On the other hand, social critics often argue that the rise of Internet pornography is contributing to a coarsening of American culture. Do consumption patterns of online adult entertainment reveal two separate Americas? Or is the consumption of online adult entertainment widespread, regardless of legal barriers, potential for embarrassment, and even religious conviction?
Retrospectives: On the Definition of Economics
Authors: Backhouse Roger E , Medema Steven G
Published: February 2009

Modern economists do not subscribe to a homogeneous definition of their subject. Surveying definitions of economics from contemporary principles of economics textbooks, we find that economics is the study of the economy, the study of the coordination process, the study of the effects of scarcity, the science of choice, and the study of human behavior. At a time when economists are tackling subjects as diverse as growth, auctions, crime, and religion with a methodological toolkit that includes real analysis, econometrics, laboratory experiments, and historical case studies, and when they are debating the explanatory roles of rationality and behavioral norms, any concise definition of economics is likely to be inadequate. This lack of agreement on a definition does not necessarily pose a problem for the subject. Economists are generally guided by pragmatic considerations of what works or by methodological views emanating from various sources, not by formal definitions: to repeat the comment attributed to Jacob Viner, economics is what economists do. However, the way the definition of economics has evolved is more than a historical curiosity. At times, definitions are used to justify what economists are doing. Definitions can also reflect the direction in which their authors want to see the subject move and can even influence practice.
The Rise in Mortgage Defaults
Authors: Mayer Christopher , Pence Karen , Sherlund Shane M
Published: February 2009

The first hints of trouble in the mortgage market surfaced in mid-2005, and conditions subsequently began to deteriorate rapidly. Mortgage defaults and delinquencies are particularly concentrated among borrowers whose mortgages are classified as “subprime” or “near-prime.” The main factors underlying the rise in mortgage defaults appear to be declines in house prices and deteriorated underwriting standards, in particular an increase in loan-to-value ratios and in the share of mortgages with little or no documentation of income. Contrary to popular perception, the growth in unconventional mortgages products, such as those with prepayment penalties, interest-only periods, and teaser interest rates, does not appear to be a significant factor in defaults through mid-2008 because borrowers who had problems with these products could refinance into different mortgages. However, as markets realized the extent of the poor underwriting, underwriting standards tightened and borrowers began to face difficulties refinancing; this dynamic suggests that these unconventional products could pose problems going forward.
Crisis and Responses: The Federal Reserve in the Early Stages of the Financial Crisis
Authors: Cecchetti Stephen G
Published: February 2009

Realizing that their traditional instruments were inadequate for responding to the crisis that began on August 9, 2007, Federal Reserve officials improvised. Beginning in mid-December 2007, they implemented a series of changes directed at ensuring that liquidity would be distributed to those institutions that needed it most. Conceptually, this meant America's central bankers shifted from focusing solely on the size of their balance sheet, which they use to keep the overnight interbank lending rate close to their chosen target, to manipulating the composition of their assets as well. In this paper, I examine the Federal Reserve's conventional and unconventional responses to the financial crisis of 2007–2008.
Medication dispensing errors at a public pediatric hospital
Authors: Costa Lindemberg Assunção , Valli Cleidenete , Alvarenga Angra Pimentel
Published: February 2009

OBJECTIVE: assess the safety of medication dispensing processes through the dispensing error rate. METHOD: Cross-sectional study carried out at a pharmaceutical service of a pediatric hospital in Espírito Santo, Brazil. Data collection was performed between August and September 2006, totaling 2620 prescribed medication doses. Any deviation from the medical prescription in dispensing medication was considered a dispensing error. THE CATEGORIES OF MEDICATION ERRORS WERE: content, labeling, and documentation errors. The dispensing error rate was computed by dividing the number of errors by the total of dispensed doses. RESULTS: From the 300 identified errors, 262 (87.3 %) were content errors. The rate of errors in the labeling and documentation categories was 33 (11%) and 5 (1.7%), respectively. CONCLUSION: The total dispensing error rate was higher than rates reported in international studies. The most frequent category was "content error".
Arthroscopic shoulder assessment in Turkish amateur boxers
Authors: Özkan Hüseyin , Yanmış İbrahim , Kürklü Mustafa , Şehirlioğlu Ali , Tunay Servet , Kömürcü Mahmut , Başbozkurt Mustafa
Published: February 2009

The most common injuries reported in the literature regarding the sport of boxing are to the brain, eyes, kidneys and hands. Shoulder injuries have not been fully reported in the literature until recently, as a result we aimed to present our arthroscopic findings in amateur boxers. Ten amateur boxers with complaints of pain in the shoulder region and decreased performance during sportsplay were enrolled. They were evaluated by physical examination, radiology and arthroscopy. There were no clinical findings of instability. One patient was found to have subacromial impingement; six had crepitation at various degrees during shoulder movements. At arthroscopy, all patients had a variety of pathological findings. Five patients had Grade 1, three had Grade 2, and two had Grade 3 chondropathy. Various degrees of fraying of the anterosuperior and posterosuperior regions of the glenoid labrum were noted in all cases. Three patients had superior labrum anterior and posterior lesions, one patient had a posterior labroligamentous lesion, and one had chondral erosion in the anterosuperior portion of the humeral head. In conclusions, although the injury mechanism of the shoulder during boxing is unknown, this study shows that shoulder complaints in boxers should be considered as possible indicators of serious intra-articular lesions.
Pharmacologic responses of the mouse urinary bladder
Authors: Canda A. , Chapple Christopher , Chess-Williams Russ
Published: February 2009

The aim of the study was to determine pathways involved in contraction and relaxation of the mouse urinary bladder. Mouse bladder strips were set up in gassed Krebs-bicarbonate solution and responses to various drugs and electrical field stimulation were obtained. Isoprenaline (b-receptor agonist) caused a 63% inhibition of carbachol precontracted detrusor (EC50=2nM). Carbachol caused contraction (EC50=0.3µM), responses were antagonised more potently by 4-DAMP (M3-antagonist) than methoctramine (M2-antagonist). Electrical field stimulation caused contraction, which was inhibited by atropine (60%) and less by guanethidine and α,β-methylene-ATP. The neurogenic responses were not potentiated by inhibition of nitric oxide synthase. Presence of an intact urothelium significantly depressed responses to carbachol (p=0.02) and addition of indomethacin and L-NNA to remove prostaglandin and nitric oxide production respectively did not prevent the inhibitory effect of the urothelium. In conclusion, b-receptor agonists cause relaxation and muscarinic agonists cause contraction via the M3-receptor. Acetylcholine is the main neurotransmitter causing contraction while nitric oxide has a minor role. The mouse and human urothelium are similar in releasing a factor that inhibits contraction of the detrusor muscle which is unidentified but is not nitric oxide or a prostaglandin. Therefore, the mouse may be used as a model to study the lower urinary tract.
Inflation of diagnostic tests in hypertensive young adults: a need for diagnostic guideline?
Authors: Kirkpantur Alper , Arici Mustafa , Altun Bulent , Turgan Cetin
Published: February 2009

The cause of hypertension in young adults (age:18–29 years) is mostly a primary condition although secondary causes are frequent in this population. Clinical files of 100 patients were reviewed to evaluate the use of diagnostic tests after completion of diagnostic work-up for hypertension. Seventy-nine patients had primary hypertension while 21 patients had secondary hypertension. Renal imaging studies, serum levels of aldosterone and plasma renin activity, and screening tests for pheochromocytoma were more likely to be performed in patients younger than 24 years, in female patients and in patients without familial history of hypertension in primary hypertensive patients (p<0.05). Renal imaging studies and screening tests for pheochromocytoma were done more frequently in patients with Stage 2 hypertension (p<0,05). Among secondary hypertensives, renal imaging studies and renal biopsy were more ordered in patients younger than 24 years, in female patients, in patients with Stage 2 hypertension and in patients without family history for hypertension (p<0.05). Mean body mass index was higher in patients with primary hypertension than patients with secondary hypertension (p<0.05). Seventy patients (70%) had undergone several screening interventions with negative results. In conclusion, a simple, stepwise diagnostic evaluation would greatly benefit the management of young hypertensives.
Highly Variable Immune-Response Proteins (185/333) from the Sea Urchin,Strongylocentrotus purpuratus: Proteomic Analysis Identifies Diversity within and between Individuals
Authors: Dheilly Nolwenn M. , Nair Sham V. , Smith L. Courtney , Raftos David A.
Published: February 2009

185/333 genes and transcripts from the purple sea urchin, Strongylocentrotus purpuratus, predict high levels of amino acid diversity within the encoded proteins. Based on their expression patterns, 185/333 proteins appear to be involved in immune responses. In the present study, one- and two-dimensional Western blots show that 185/333 proteins exhibit high levels of molecular diversity within and between individual sea urchins. The molecular masses of 185/333-positive bands or spots range from 30 to 250 kDa with a broad array of isoelectric points. The observed molecular masses are higher than those predicted from mRNAs, suggesting that 185/333 proteins form strong associations with other molecules or with each other. Some sea urchins expressed >200 distinct 185/333 proteins, and each animal had a unique suite of the proteins that differed from all other individuals. When sea urchins were challenged in vivo with pathogen-associated molecular patterns (PAMPs; bacterial LPS and peptidoglycan), the expression of 185/333 proteins increased. More importantly, different suites of 185/333 proteins were expressed in response to different PAMPs. This suggests that the expression of 185/333 proteins can be tailored toward different PAMPs in a form of pathogen-specific immune response.
Cyclical Expression of EBV Latent Membrane Protein 1 in EBV-Transformed B Cells Underpins Heterogeneity of Epitope Presentation and CD8+ T Cell Recognition
Authors: Brooks Jill M. , Lee Steven P. , Leese Alison M. , Thomas Wendy A. , Rowe Martin , Rickinson Alan B.
Published: February 2009

CD8+ T cells specific for EBV latent cycle epitopes can be reactivated in vitro by stimulating with the autologous EBV-transformed B lymphoblastoid cell line (LCL). The resultant CD8+ clones kill epitope peptide-loaded targets, but frequently do not kill or show only low levels of lysis of the unmanipulated LCL in 5-h cytotoxicity assays. However, they reproducibly show clear LCL recognition in cytokine (IFN-γ) release assays and inhibit LCL outgrowth in long-term coculture assays. We show that this growth inhibition is not mediated by cytokines, but by slow killing detectable in extended cytotoxicity assays. The paradoxical earlier findings reflect the fact that cytokine assays are more sensitive indicators of Ag-specific recognition in situations in which the target population is heterogeneous at the single-cell level in terms of epitope display. Such heterogeneity exists within LCLs with, at any one time, subpopulations showing large differences in sensitivity to T cell detection. These differences are not cell cycle related, but correlate with differing levels of EBV latent membrane protein (LMP)1 expression at the single-cell level. In this study, LMP1 is not itself a CD8+ T cell target, but its expression enhances Ag-processing capacity and HLA class I expression. We propose that LMP1 levels fluctuate cyclically in individual cells and, over time, all cells within a LCL pass through a LMP1high T cell-detectable phase.
CREB Mediates Prostaglandin F2α-Induced MUC5AC Overexpression
Authors: Chung Wen-Cheng , Ryu Seung-Hee , Sun Hongxia , Zeldin Darryl C. , Koo Ja Seok
Published: February 2009

Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE2 and PGF2α. PGE2-induced mucin production has been well studied, but the effect of PGF2α on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF2α on MUC5AC production, we investigated the signal transduction of PGF2α associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF2α induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF2α-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF2α receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE2 and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.
Synergistic Induction of Inflammation by Bacterial Products Lipopolysaccharide and fMLP: An Important Microbial Pathogenic Mechanism
Authors: Chen Ling-Yu , Pan Warren W. , Chen Miao , Li Jain-Dong , Liu Wei , Chen Guoqiang , Huang Shuang , Papadimos Thomas J. , Pan Zhixing K.
Published: February 2009

A wide variety of stimuli have been shown to induce inflammation, but bacteria products/components are considered the major inducers during bacterial infections. We previously demonstrated that bacterial products/components such as LPS, a glycolipid component of the bacterial outer membrane, and formylated peptides (fMLP), a bacterial-derived peptide, induced proinflammatory cytokine gene expression in human peripheral blood monocytes. We now present evidence that mixtures of bacterial products/components LPS and fMLP behave synergistically in the induction of inflammation in vitro and in vivo. Furthermore, our results indicate that the TLR4 and the IKKβ-IκBα signaling pathways are involved in the synergistic induction of inflammatory cytokines. The mechanism of synergistic activation of NF-κB is depended on nuclear translocation of p65 and phosphorylation of p65 at both Ser536 and Ser276 sites. These results demonstrate an important role for bacterial products/components from lysed bacteria in the pathogenesis of infectious diseases. We believe that this synergistic induction of inflammation by bacterial products LPS and fMLP represents an important pathogenic mechanism during bacterial infection, which may suggest novel therapeutic strategies or targets to minimize host injury following bacterial infection.
A Phase I-II Study of α-Galactosylceramide-Pulsed IL-2/GM-CSF-Cultured Peripheral Blood Mononuclear Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer
Authors: Motohashi Shinichiro , Nagato Kaoru , Kunii Naoki , Yamamoto Heizaburo , Yamasaki Kazuki , Okita Kohsuke , Hanaoka Hideki , Shimizu Naomi , Suzuki Makoto , Yoshino Ichiro , Taniguchi Masaru , Fujisawa Takehiko , Nakayama Toshinori
Published: February 2009

To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.
LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis
Authors: Workman Creg J. , Wang Yao , El Kasmi Karim C. , Pardoll Drew M. , Murray Peter J. , Drake Charles G. , Vignali Dario A. A.
Published: February 2009

Lymphocyte activation gene 3 (LAG-3) is a CD4-related, activation-induced cell surface molecule expressed by various lymphoid cell types and binds to MHC class II with high affinity. We have previously shown that LAG-3 negatively regulates the expansion of activated T cells and T cell homeostasis, and is required for maximal regulatory T cell function. In this study, we demonstrate for the first time that LAG-3 is also expressed on CD11clow/B220+/PDCA-1+ plasmacytoid dendritic cells (pDCs). Lag3 expression, as determined by real time PCR, was ∼10-fold greater in pDCs than in either regulatory T cells or activated T effector cells. Activated pDCs also generate ∼5 times more sLAG-3 than activated T cells. LAG-3-deficient pDCs proliferate and expand more than wild-type pDCs in vivo in response to the TLR9 ligand, CpG. However, the effect of LAG-3 appears to be selective as there was no effect of LAG-3 on the expression of MHC class II, TLR9, and chemokine receptors, or on cytokine production. Lastly, adoptive transfer of either Lag3+/+ or Lag3−/− T cells plus or minus Lag3+/+ or Lag3−/− pDCs defined a role for LAG-3 in controlling pDC homeostasis as well as highlighting the consequences of deregulated Lag3−/− pDCs on T cell homeostasis. This raised the possibility of homeostatic reciprocity between T cells and pDCs. Collectively, our data suggests that LAG-3 plays an important but selective cell intrinsic and cell extrinsic role in pDC biology, and may serve as a key functional marker for their study.
Naive Mouse Macrophages Become Activated following Recognition of L5178Y Lymphoma Cells via Concurrent Ligation of CD40, NKG2D, and CD18 Molecules
Authors: Buhtoiarov Ilia N. , Rakhmilevich Alexander L. , Lanier Lewis L. , Ranheim Erik A. , Sondel Paul M.
Published: February 2009

Under different circumstances, tumors can inhibit or activate macrophage (Mφ) effector functions. We studied the mechanisms of tumor-Mφ interactions leading to Mφ activation. The results show that L5178Y mouse T cell lymphoma cells can prime naive mouse Mφ to subsequent LPS stimulation, resulting in increased NO production and antilymphoma effects in vitro. L5178Y cells, but not naive splenocytes, primed Mφ to ligation of TLR4 but not TLR9. L5178Y-primed Mφ incubated with LPS showed down-regulation of CD40 and up-regulation of NKG2D expression. Although L5178Y T cell lymphoma cells primed naive mouse Mφ, several other mouse and human cells lines failed to prime mouse Mφ. Neither L5178Y-conditioned supernatants nor coculture of Mφ and L5178Y cells in Transwells resulted in priming, indicating that direct L5178Y cell-Mφ contact was needed. Several receptor-ligand pairs are reciprocally expressed on Mφ and L5178Y cell membranes and can be potentially involved in Mφ priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro Mφ priming. Furthermore, simultaneous blocking of interactions between CD40-CD154, NKG2D-H60, and CD18-ICAM-1/2 led to complete abrogation of Mφ-mediated NO secretion and complete inhibition of Mφ-mediated tumor cell cytostasis. The priming of Mφ to LPS with L5178Y cells was also observed in vivo. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the Mφ may facilitate Mφ-mediated antitumor immune surveillance.
Trypanosoma cruzi Triggers an Early Type I IFN Response In Vivo at the Site of Intradermal Infection
Authors: Chessler Anne-Danielle C. , Unnikrishnan Meera , Bei Amy K. , Daily Johanna P. , Burleigh Barbara A.
Published: February 2009

Early interactions between the protozoan parasite Trypanosoma cruzi and mammalian hosts at primary sites of infection (skin and mucosal membranes) are predicted to be critical determinants of parasite survival and dissemination in the host. To investigate the early host response triggered by three different strains of T. cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes was observed in excised skin 24 h postinfection where the level of IFN-stimulated gene induction was parasite strain-dependent, with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFN-γ-producing cells or infection of IFN-γ-deficient mice had minimal impact on the IFN response generated in T. cruzi-infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi at the site of inoculation and their role in shaping the early transcriptional response to this pathogen.
TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal
Authors: Mercier Blandine C. , Cottalorda Anne , Coupet Charles-Antoine , Marvel Jacqueline , Bonnefoy-Bérard Nathalie
Published: February 2009

TLR are involved in the detection of microbial infection as well as endogenous ligands that signal tissue and cell damage in mammals. This recognition plays an essential role in innate immune response and the initiation of adaptive immune response. We have previously shown that murine CD8 T cells express TLR2, and that costimulation of Ag-activated CD8 T cells with TLR2 ligands enhances their proliferation, survival, and effector functions. We also demonstrated that TLR2 engagement on CD8 T cells significantly reduces their need for costimulatory signals delivered by APC. We show in this study that TLR2 engagement on CD8 T cells lowers the Ag concentration required for optimal activation, and converts a partial activation into a productive process leading to a significant expansion of cells. Using altered peptide ligands, we demonstrate that TLR2 engagement increases CD8 T cell activation and enables the generation of functional memory cells in response to a low TCR signal. This increased activation is associated with an augmented activation of the PI3K. Taken together, our results demonstrate that TLR2 engagement on CD8 T cells lowers their activation threshold for TCR signal strength and enables efficient memory cell generation in response to a weak TCR signal.
The Role of Hepatic Invariant NKT Cells in Systemic/Local Inflammation and Mortality during Polymicrobial Septic Shock
Authors: Hu Caroline K. , Venet Fabienne , Heffernan David S. , Wang Yvonne L. , Horner Brian , Huang Xin , Chung Chun-Shiang , Gregory Stephen H. , Ayala Alfred
Published: February 2009

NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jα18−/−) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3+α-galactosylceramide CD1d tetramer+ cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.