Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages.

Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Recent evidence has suggested that fragments of the ECM component hyaluronan play a role in chronic inflammation by inducing macrophage expression of chemokines. Interferon-gamma (IFN-gamma), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T-cell recruitment and inhibit angiogenesis. The purpose of this investigation was to determine the effect of hyaluronan (HA) on IFN-gamma-induced Mig and IP-10 expression in mouse macrophages. We found a marked synergy between HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse macrophages. This was most significant with Mig, which was not induced by HA alone. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-alpha, was selective for Mig and IP-10, and occurred at the level of gene transcription. These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-gamma to alter macrophage chemokine expression.

Stimulation of inducible nitric oxide synthase in rat liver by hyaluronan fragments.

Hepatic injury and chronic wounding are characterized by increased synthesis of extracellular matrix proteins including hyaluronan (HA). Recently, it has been recognized that low-molecular-weight fragments of HA, but not native HA (e.g., high-molecular-weight HA), induce inflammatory gene expression, and activate the transcriptional regulator, nuclear factor kappaB (NF-kappaB). The inducible isoform of nitric oxide synthase (iNOS) is induced by cytokines and/or lipopolysaccharide (LPS) through the NF-kappaB signal transduction pathway. Because of this association, we hypothesized that HA fragments might also stimulate iNOS gene transcription. The aims of this study were therefore to determine whether HA or HA fragments induced iNOS in hepatic cells, and to characterize the signaling pathway. HA fragments (100 microg/mL) markedly stimulated iNOS messenger RNA (mRNA) in endothelial and Kupffer cells, but minimally induced this mRNA in hepatocytes and stellate cells. High-molecular-weight HA (200 microg/mL) had no effect on iNOS mRNA in any cell type. The addition of interferon gamma (IFN-gamma) to HA fragments resulted in stimulation of iNOS mRNA 2-, 3-, 4-, and 10-fold above that for HA fragments alone in hepatocytes, endothelial, Kupffer, and stellate cells, respectively. The combination of HA fragments and LPS did not result in an incremental increase in iNOS mRNA induction. iNOS protein and nitrite levels (used as a measure of NO production and NOS enzymatic activity) paralleled closely iNOS mRNA expression and increased proportionally to HA fragment concentration in a dose-dependent fashion. At 1 hour following stimulation, NF-kappaB DNA binding activity was detected in extracts from Kupffer cells stimulated with HA fragments, but not in those exposed to media alone or to high-molecular-weight HA. Finally, inhibitors of NF-kappaB blocked HA fragment-dependent iNOS mRNA induction in Kupffer and sinusoidal endothelial cells. The data indicate that HA fragments, but not high-molecular-weight HA, induce iNOS in liver, having the greatest effects on endothelial and Kupffer cells. We speculate that HA fragments may be an important stimulus for NO production in various forms of liver disease, particularly as a cofactor with inflammatory cytokines.

Limitations of epidemiologically based needs assessment. The case of prostatectomy.

OBJECTIVES: The aim of this study was to make epidemiologically based estimates of the prevalent and incident "need" for prostatectomy for lower urinary tract symptoms, defined as the numbers of men who would both benefit from and want the operation. METHODS: The methods involved a consensus panel, a two-stage postal survey of 1,480 men aged 55 years or older from eight general practices to the northwest of London, United Kingdom, and a multistate life table. RESULTS: The overall response rate was 69% (initial survey: 78%, follow-up survey: 88%). A trial-based estimate of number of candidates for prostatectomy (men with symptoms that were at least moderately severe and bothersome and who would probably or definitely want surgery) was 610 men in a population of 250,000. The corresponding incidence estimate (including men with symptoms recurring after spontaneous remission or surgery) was approximately 200 per year, including approximately 110 new cases. Consensus-based estimation, including categories of patients who have not yet been subject to a trial, gave much higher figures of approximately 3,000, 650, and 200 candidates, respectively. Adding the number of men who said they were "inclined to" choose surgery would almost double these figures. CONCLUSIONS: Estimates of need were highly sensitive to choice of indications and assumptions about patients' attitudes toward surgery. Population needs assessment for specific procedures will always involve judgment as well as epidemiological data and modeling.

Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism.

Activated macrophages play a critical role in controlling chronic tissue inflammation through the release of a variety of mediators including cytokines, chemokines, growth factors, active lipids, reactive oxygen, and nitrogen species. The mechanisms that regulate macrophage activation in chronic inflammation are poorly understood. A hallmark of chronic inflammation is the turnover of extracellular matrix components, and recent work has suggested that interactions with the extracellular matrix can exert important influences on macrophage effector functions. We have examined the effect of low molecular weight fragments of the extracellular matrix glycosaminoglycan hyaluronan (HA) on the induction of nitric-oxide synthase (iNOS) in macrophages. We found that HA fragments induce iNOS mRNA, protein and activity alone, and markedly synergize with interferon-gamma to induce iNOS gene expression in murine macrophages. In addition, we found that resident tissue alveolar macrophages respond minimally, but inflammatory alveolar macrophages exhibit a marked induction in iNOS expression in response to HA fragments. Finally, we demonstrate that the mechanism of HA fragment-induced expression of iNOS requires activation of the transcriptional regulator nuclear factor kappaB. These data support the hypothesis that HA may be an important regulator of macrophage activation at sites of chronic tissue inflammation.

Heart failure: the Cinderella of cardiology?

Heart failure is common and has a high mortality. These factors alone should make it an important public health issue. But the advent of new approaches to diagnosis and expensive forms of treatment have increased this importance to public health professionals. It has, however, received rather less attention than other manifestations of heart disease. This review summarises the major issues facing public health professionals seeking to develop strategies to tackle this condition. These include; what is known about diagnostic criteria, the prevalence of disease, including the important gaps in our knowledge about how it affects women, and the cost benefits, including the impact on quality of life, of emerging treatments. The review concludes with suggestions for research.

Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44.

Hyaluronan (HA) is a glycosaminoglycan constituent of extracellular matrix. In its native form HA exists as a high molecular weight polymer, but during inflammation lower molecular weight fragments accumulate. We have identified a collection of inflammatory genes induced in macrophages by HA fragments but not by high molecular weight HA. These include several members of the chemokine gene family: macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, cytokine responsive gene-2, monocyte chemoattractant protein-1, and regulated on activation, normal T cell expressed and secreted. HA fragments as small as hexamers are capable of inducing expression of these genes in a mouse alveolar macrophage cell line, and monoclonal antibody to the HA receptor CD44 completely blocks binding of fluorescein-labeled HA to these cells and significantly inhibits HA-induced gene expression. We also investigated the ability of HA fragments to induce chemokine gene expression in human alveolar macrophages from patients with idiopathic pulmonary fibrosis and found that interleukin-8 mRNA is markedly induced. These data support the hypothesis that HA fragments generated during inflammation induce the expression of macrophage genes which are important in the development and maintenance of the inflammatory response.

Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages.

Macrophages play an important role in the acute tissue inflammatory response through the release of cytokines and growth factors in response to stimuli such as lipopolysaccharide (LPS). Macrophage inflammatory effector functions are also influenced by interactions with the extracellular matrix (ECM). Such macrophage-ECM interactions may be important in regulating chronic inflammatory responses. Recent evidence has suggested that hyaluronan (HA), a glycosaminoglycan (GAG) component of ECM can induce inflammatory gene expression in murine macrophages. HA exists in its native form as a large polymer, but is found as smaller fragments under inflammatory conditions. The NF-kappa B/I-kappa B transcriptional regulatory system has been shown to be a critical component of the host inflammatory response. We examined the effects of high molecular weight HA and lower molecular weight HA fragments on NF-kappa B activation in mouse macrophages. Only the smaller HA fragments were found to activate NF-kappa B DNA binding activity. After HA stimulation, I-kappa B alpha mRNA was induced and I-kappa B alpha protein levels, which initially decreased, were restored. The induction of I-kappa Balpha expression was not observed for other GAGs. The time course of I-kappa B alpha protein regeneration in response to HA fragments was consistent with an autoregulatory mechanism. In support of this mechanism, in vitro translated murine I-kappa B alpha inhibited HA fragment-induced NF-kappa B DNA binding activity. The NF-kappa B DNA binding complex in HA-stimulated extracts was found to contain p50 and p65 subunits. Activation of the NF-kappa B/I-kappa B system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.

The impact of lower urinary tract symptoms on general health status and on the use of prostatectomy.

Our objective was to determine the extent to which lower urinary tract symptoms affect the general health status of men and contribute to the decision to undergo surgery. A cross-sectional population survey using postal questionnaires was conducted in the North West Thames health region, followed by a prospective cohort study of men undergoing prostatectomy (North West Thames and Oxford regions). The subjects in the first survey were 221 men aged 55 and over with previously reported mild, moderate or severe urinary symptoms; subjects in the second study were 388 men undergoing prostatectomy. Main outcome measures were self-reported symptom severity, bothersomeness and general health status (Nottingham Health Profile, Part 1). The response rate among eligible responders in the population survey was 85.7%. Increasing symptom severity was associated with worsening NHP scores for energy, emotional reactions, sleep and physical mobility (p < 0.01). Increasing bothersomeness of symptoms was associated with emotional reactions, sleep and pain (p < 0.05). Men undergoing surgery reported worse health status than men in the population with the same severity of symptoms as regards emotional reactions, energy and pain. For a given level of symptom severity, the impact of those symptoms on aspects of a man's general health status may be the determinant of seeking and undergoing surgery. Greater understanding of the factors that affect a man's response to his symptoms is needed in interpreting the decision to seek and accept treatment.

Health care sought and received by men with urinary symptoms, and their views on prostatectomy.

BACKGROUND: Urinary symptoms are common among middle aged and elderly men. AIM: A study was undertaken to describe the health care sought by men aged 55 years and over with urinary symptoms, the action taken by general practitioners and urologists, and the men's views on prostatectomy. METHOD: A postal questionnaire was sent to 516 men aged 55 years and over in the North West Thames Regional Health Authority, with previously identified mild, moderate or severe urinary symptoms. RESULTS: The response rate among eligible subjects was 83%. Of 420 respondents 45% had seen their general practitioner for their symptoms. General practitioners had referred 62% of these men to a urologist, reassured 21% and prescribed medication to 17%. The probability of a man seeking medical advice increased with increasing symptom severity. In contrast, the decision to refer was independent of symptom severity. Of the men referred to a urologist, the majority (71%) were offered and accepted surgery. The remainder were reassured (17%), or received a prescription (4%). Eight per cent were offered surgery but declined. When presented with details and information on the risks and benefits of prostatectomy, 22% of men with symptoms would probably or definitely refuse treatment, while a further 47% of men were unsure. CONCLUSION: There are many men who do not seek treatment for urinary symptoms and, of those who do, subsequent referral is not associated with symptom severity. There is scope for improving the referral process through the shared development of guidelines between general practitioners, hospitals and commissioning agencies.

Urinary symptoms: prevalence and severity in British men aged 55 and over.

OBJECTIVE: To measure the prevalence and severity of urinary symptoms among men aged 55 and over in the British population. DESIGN: Cross sectional population survey using a postal questionnaire. SETTING: North West Thames health region. SUBJECTS: 1480 men aged 55 years and over randomly selected from 8 general practices. MAIN OUTCOME MEASURES: Self reported frequency and severity of urinary symptoms, their bothersomeness and previous prostate surgery. RESULTS: The response rate among eligible subjects was 78%. The prevalence of moderate and severe symptoms was 204 per 1000, rising from 160 per 1000 in the 55-59 age group to 259 per 1000 in the 70-74 age group and declining after the age of 80 to 119 per thousand in the 85+ age group. Twelve per cent of men reported previous prostate surgery, and the probability of having had surgery increases steadily with age. About a third of those undergoing surgery have recurrence or persistence of symptoms after surgery. Of men with moderate and severe symptoms, 27.9% reported that their symptoms were a medium or big problem, 36.9% reported that their symptoms interfered with their daily activities at least some of the time, and 43.1% were unhappy or 'felt terrible' about the prospect of a future with their current symptoms. CONCLUSION: The prevalence of urinary symptoms in men is lower than previously reported, although there is a substantial number of men who are bothered by, or who find their lives adversely effected by them.

Appropriate indications for prostatectomy in the UK--results of a consensus panel.

STUDY OBJECTIVE: The use of formal consensus development to determine appropriate indications for prostatectomy and to identify factors underlying clinical decisions about appropriateness is described. DESIGN: A nominal group technique was used. SETTINGS: The study took place in an academic research institution. PARTICIPANTS: The panel consisted of six urologists and three general practitioners. MEASUREMENTS AND MAIN RESULTS: The panel identified agreed indications for prostatectomy, expressed in terms of different combinations of type of retention, type and severity of symptoms, and level of comorbidity. Agreement was reached for 67% of the indications considered. For acute on chronic retention, surgery is indicated, regardless of symptom severity, if life expectancy is greater than one year. For acute or chronic retention, surgery is generally indicated if symptoms are severe, or if symptoms are moderate and life expectancy is greater than five years. For patients with neither acute nor chronic retention, surgery is indicated if symptoms are severe, or if these are moderate and life expectancy is greater than five years. For chronic or acute retention surgery is inappropriate if symptoms are mild and life expectancy is less than one year, or if there is no retention and only mild symptoms. An "appropriateness score" was developed. This confirmed that in general the ratings were internally consistent, that the panel attached little weight to mild symptoms, that a combination of irritative and obstructive symptoms was no more indicative of surgery than obstructive symptoms alone, and that the type of symptom was less important than the other factors considered. CONCLUSIONS: The results provide a basis for population based surveys of the need for prostatectomy.

Micro-computers: availability to and use by trainees in public health medicine.

A survey of the availability to and use of micro-computers by public health medicine trainees was undertaken in February, 1989. Most departments have access to computers and trainees possess computing skills, but almost one in 15 trainees had no access to a micro-computer, and one trainee in eleven had no computing experience while a further one in eight had not progressed beyond word-processing. Departments of Public Health Medicine should review their computing resources and ensure that they are adequate for the challenges of the 1990s.

Deaths in winter in Northern Ireland: the role of low temperature.

Many European countries experience a seasonal excess in deaths each winter compared to summer. The magnitude of the excess is greater in the United Kingdom than in many other European countries. Examination of the data for Northern Ireland indicates that myocardial infarction, respiratory disease and stroke exhibit the greatest increases during winter. Excess deaths from these conditions are closely associated with low environmental temperature.

Accident and emergency attendance rates: variation among patients from different general practices.

As a consequence of the 1989 National Health Service review health authorities are likely to take a greater interest in patterns of use of secondary care services by patients of different general practitioners. Use of accident and emergency departments has been shown to predict subsequent use of other hospital services. If meaningful comparisons are to be made between practices it is important to identify factors other than variation in clinical practice which influence attendance at accident and emergency departments. A one in 20 sample of patients attending an accident and emergency department was studied. Patients were aggregated by general practice and by electoral ward of residence, and the influence of a range of variables was examined using multiple regression. For both groups of patients distance from an accident and emergency department was an important factor in the rate of attendance. It was possible to examine the effect of several socioeconomic variables in the analysis by electoral ward: these were not associated significantly with attendance rates. Similarly, in the analysis by practice, mean list size per partner could not explain variation in attendance rates. This study supports others which have indicated that distance from an accident and emergency department must be taken into account when interpreting attendance rates.

Effectiveness of intradermal hepatitis B immunization of hospital staff.

Three doses of hepatitis B vaccine were administered via an intradermal route to 316 health service staff. One month after the final dose, 89.9% of subjects had antibodies to hepatitis B surface antigen at levels of 10 IU/l or greater. A programme of hepatitis B immunization based upon the intradermal route is substantially less expensive than one using an intramuscular technique, and can enable health authorities to provide protection for increased numbers of staff without diverting resources from other programmes of health care.