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.

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.

Diversity of autoantibodies in patients with antimitochondrial antibody and their diagnostic value.

A retrospective analysis of clinical and laboratory features of 102 patients, whose sera contained antibody to mitochondria, showed that primary biliary cirrhosis was diagnosed in 50% of them. Immunofluorescence showed that the sera of the patients with primary biliary cirrhosis all had the M2 antimitochondrial antibody staining pattern. A new staining pattern, designated M2(1), which could be mistaken for the M2 pattern, was not found in any patients with either primary biliary cirrhosis or chronic active hepatitis. Other serological variables such as antibody to mitochondria in IgM class, to multiple nuclear dots, and to the XR antigen, were associated with primary biliary cirrhosis, and taken in association with antimitochondrial antibody of M2 type, contribute to the diagnosis of the disease.

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.

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.

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.

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.

Serum zinc and venous occlusion.

Serum zinc was measured with and without venous occlusion in 100 subjects. During venous occlusion serum zinc was 0.79 ug/ml and without venous occlusion it was 0.75 ug/ml (p less than 0.001).

Hepatitis B immunisation in northern Ireland: an epidemiological and economic analysis.

The availability of active immunisation against hepatitis B has stimulated demand for protection among health care workers. The vaccine remains expensive, and widespread immunisation will divert scarce resources from elsewhere. The arguments in favour of widespread immunisation of health care workers are based on studies from areas with prevalences of infection and carriage which are much higher than in Northern Ireland. This study was carried out to provide a rational basis for deciding who should be offered immunisation. The epidemiology of hepatitis B infection in Northern Ireland is examined. The incidence of hepatitis B in Northern Ireland is one of the lowest in the world. The evidence for an increased risk of infection among health care workers throughout the world is reviewed. The risk of infection varies widely among different countries and there is evidence that increased awareness of the hazards of sharps injuries and the introduction of safe handling techniques have substantially reduced the risk. An economic analysis suggests that a widespread programme of hepatitis B immunisation in Northern Ireland compares unfavourably with other health care interventions.

Increasing mortality from malignant melanoma among women in Northern Ireland.

Deaths from malignant melanoma in each part of the British Isles between 1969 and 1984 have been examined. There has been a substantial increase of deaths among women in each part, and an increase of similar magnitude among men in all areas except Northern Ireland. It is suggested that this difference requires further study. The increasing number of deaths from this disease indicates a need for greater public and professional awareness of this potentially preventable and curable condition.

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.

Deaths in winter: can Britain learn from Europe?

There is a substantial increase in the number of deaths in winter in the United Kingdom. This is also seen in some, but not all, European countries. Almost 60% of the variation among countries can be explained by the minimum average monthly temperature and the gross national product per capita. Seasonal variation is lowest in those countries with cold winters, suggesting that insulation may be important. It is also low in the more wealthy countries. The implications for health service policy of these finding are discussed. Some of the residual variation may be explained by known factors, such as low cost geo-thermal energy in Iceland, but much remains unexplained. There is a need for more research in this field.

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.

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.