Temperature effects on shape and function of human granulocytes.

Scanning microscopic and functional studies were made of granulocytes isolated from CPD anticoagulated whole blood by counterflow centrifugation in a Beckman JE-6 rotor. The collection buffer was phosphate (20 mM) buffered saline (280 mOsM) with glucose (29 mM) and human serum albumin (1.2% w/v). The final suspension contained less than 2% mononuclear cells and 5% red cells. Incubation and fixation at various temperatures revealed two distinct temperature dependent shape transformations. At 22, 37, 40 and 45 degrees C granulocytes were ameboid with extensive highly textured veils. These smoothed progressively, bullae and blebs formed, and membranes peeled finally leaving nonfunctional spheres with smooth surfaces. At 4 degrees C, granulocytes were irregular spheres, less rugose but with numerous microvilli and nodules. Veiling was absent. Phagocytosis, initially low, progressively declined over 48 h while cell surfaces become smooth. Some formed blebs, but all terminated as nonfunctional spheres with untextured surfaces containing occasional large single holes. Cellular stability estimated from changes in volume distributions, and phagocytosis by microfluorescence measurements of yeast and latex particle ingestion were also temperature dependent and paralleled the shape progressions. It is concluded that at body (37 degrees C) or fever (40 degrees C) temperatures, granulocytes have dynamic membrane surfaces characterized by extensive veiling and high function. At 4 degrees C they are relatively inactive spheres devoid of pseudopodia or veils, yet functional at slow rates.

Characterization of a truncated progesterone receptor protein in breast tumors.

The progesterone receptor (PR) mediates the actions of progesterone in the normal and malignant breast. PR is expressed as two proteins, PR B and PR A, which are expressed in normal progesterone target tissues and in breast cancers. A significant proportion of breast cancers contain, in addition, a smaller PR protein of molecular mass 78 kDa (PR78 kDa). The significance of PR78 kDa expression is unknown, and in particular, there are no data on whether PR78 kDa is able to bind ligand and therefore potentially exhibit transcriptional activity. If this smaller PR species exhibits similar differences in function as have been evidenced in vitro for PR A relative to PR B, it is possible that this PR species may be an important component in determination of progesterone response in breast cancer. The purpose of this study was to determine whether the PR78 kDa protein in breast tumors is able to bind ligand and to determine whether posttranscriptional mechanisms contribute to its formation in breast cancers. There was no evidence that PR78 kDa was derived from proteolytic activity of either PR B or PR A. Similarly, although exon-deleted PR transcripts were detected (which could, if translated, give rise to a PR protein similar in size to PR78 kDa), neither the abundance of such transcripts nor their relationship to levels of expressed PR78 kDa protein supported a role for exon deletion in formation of this truncated PR protein. PR78 kDa was not recognized by an antibody specific for PR B, indicating that, like PR A, it lacks the N-terminal portion of PR. PR78 kDa was able to bind the progestin ligand, indicating that it may have transcriptional activity. In summary, this study has shown that a truncated PR protein, found in breast cancers, is ligand-binding and seems to be derived from PR A, indicating that it may have a role in progesterone signaling, although a deeper understanding of its role, if any, in breast cancer remains to be established.

Coexpression of alternatively spliced estrogen and progesterone receptor transcripts in human breast cancer.

Primary transcripts of the human estrogen receptor (ER) and progesterone receptor (PR) are subject to a number of alternative splicing events resulting in a range of variant messenger ribonucleic acid species in receptor-positive tissues. Despite in vitro demonstrations of a possible role for some of these variants in hormonal sensitivity, the clinical significance of this process is uncertain. In this study the coexpression of variant ER and PR transcripts has been documented by RT-PCR and Southern blot analysis in a series of receptor-positive breast tumors. In 35 ER-positive tumors, a common profile of variant ER transcripts was present, with all tumors containing the delta2ER and delta7ER, 94% containing the delta4ER, and 83% containing the delta5ER. In 25 of these cases, which were also PR positive, the most highly expressed PR variants, the delta4PR, delta6PR, and delta(4/2)PR, a transcript from which a 126-bp portion of PR exon 4 was deleted, were detected in over 90% of the cases. The alternatively spliced ER variants were expressed at higher relative levels than the PR species, which had mean levels of expression less than 10% that of wild-type PR. The most abundant species was the delta7ER, which was present at levels ranging from 29-83% of the wild type. There was no relationship between the level of delta7ER in individual tumors and the pattern of expression of the estrogen-responsive proteins PR and pS2. The common profile of alternatively spliced ER and PR transcripts in breast tumors means that this feature cannot be used as a discriminator of hormone responsiveness or other clinical end points. Further, the low level of expression of the majority of variant species calls into question their potential for impacting significantly on receptor function.

Regulation of the expression and activity by progestins of a member of the SOX gene family of transcriptional modulators.

The mammalian testis-determining gene Sry and the related Sox genes define a family of transcriptional regulators widely expressed during embryogenesis. Tightly controlled temporal profiles of expression are a feature of the Sox gene family and may be required for initiation of a cascade of gene expression, yet the molecular mechanisms that control Sox gene expression are unknown. We now show that human SOX4 is expressed in the normal breast and in breast cancer cells. In these cells SOX4 is a progesterone-regulated gene, the expression of which is increased by progestins, leading to a marked increase in SOX-mediated transcriptional activity. Treatment of T-47D breast cancer cells with the synthetic progestin ORG 2058 directly increased SOX4 transcription, resulting in a 4-fold increase in SOX4 mRNA levels within 4 h of treatment. No effect of ORG 2058 was noted on other SOX genes measured, nor were other hormone-regulated HMG box proteins detected in this system, suggesting that the observed ability of progestin to increase SOX mRNA expression was confined to SOX4. The increase in SOX4 transcription was reflected in increased SOX4 protein expression, as progestin treatment of T-47D cells transfected with a SOX-responsive reporter resulted in a marked increase in reporter gene expression. Progesterone is essential for normal development and differentiation of the female reproductive system, plays an essential role in regulating growth and differentiation of the mammary gland and is required for opposing the proliferative effects of estrogen in specific cell types. The detection of SOX4 expression in the normal and malignant breast and the demonstration that SOX4 expression is under progesterone control suggests that changes in SOX4 gene expression may play a role in commitment to the differentiated phenotype in the normal and malignant mammary gland.

beta-hydroxyisobutyryl coenzyme A deacylase deficiency: a defect in valine metabolism associated with physical malformations.

An infant, born to parents who were first cousins had multiple physical malformations. An associated biochemical abnormality was suggested by the urinary excretion of cysteine and cysteamine conjugates of methacrylic acid. The coenzyme A (CoA) ester of this compound is an intermediate in the pathway of valine oxidation. Subsequent investigation revealed a deficiency of beta-hydroxyisobutyryl-CoA deacylase, an enzyme unique to valine metabolism. The enzyme defect results in accumulation of methacrylyl-CoA, a highly reactive compound, which readily undergoes addition reactions with free sulfhydryl groups. Tissue damage due to reactions between methacrylyl-CoA and important sulfhydryl-containing enzymes and cofactors may account for the teratogenic effects seen in this patient.

Weighting the seriousness of perceived health problems using Thurstone's method of paired comparisons.

An exercise carried out to weight the seriousness of perceived health problems using Thurstone's method of paired comparisons is reported. For the purposes of illustration, the sleep section of the Nottingham Health Profile containing 5 statements is used. The calculation of the scale values associated with each statement is described and a new method of deriving weights from the scale values is proposed. The judgement of comparisons was found acceptable to interviewees. The applicability of the paired comparison techniques of the field of health is discussed.

Clinical studies of color vision with Gunkel's chromagraph.

Color thresholds in a series of patients with local or systemic diseases were determined by a chromagraph method and subjected to computer analysis. When compared with normal persons, those with optic nerve disease (multiple sclerosis, optic neuritis, and optic atrophy) showed an overall weakness for all colors (enlarged neutral areas), with an additional specific defect in the orange-cyan (greenish blue) axis. Those with the two retinal diseases studied (macular degeneration and retinitis pigmentosa) also showed threshold elevation for all colors, but with a special defect in the yellow-blue axis. The general elevation was greater for patients with retinitis pigmentosa than for those with macular degeneration, regardless of the visual acuity. In patients undergoing treatment for systemic lupus erythematosus and rheumatoid arthritis, there was a mild elevation of the color threshold, especially for yellow.

Housing conditions and mental health in a disadvantaged area in Scotland.

OBJECTIVE: To examine the mental health impact of different aspects of poor housing. DESIGN: This was a post hoc analysis of data from a household interview survey. SETTING: A public sector housing estate on the outskirts of Glasgow. SUBJECTS: These comprised 114 men and 333 women aged between 17 and 65 from 451 households. MEASURES: Dependent variable: scoring > or = 5 on the 30 item general health questionnaire (GHQ30). INDEPENDENT VARIABLES: self reported data on household composition, whether ill health was a factor in the move to the current dwelling, length of time at address, household income, whether the respondent was employed, chronic illness, and 6 problems with the dwelling. RESULTS: Reporting a problem with dampness was significantly and independently associated with scores of > or = 5 on the GHQ30 after controlling for possible confounding variables. CONCLUSION: Initiatives to tackle housing dampness may be important in developing a strategy to improve mental health for the study area. More research on the mental health impact of different aspects of poor housing is required.

Reliability of a population survey tool for measuring perceived health problems: a study of patients with osteoarthrosis.

A study is described which tested the reliability of the Nottingham Health Profile, a standardised measure of perceived health status suitable for use with both large groups and individual patients. Patients with osteoarthrosis, uncomplicated by other diagnosed conditions, were given the questionnaire to fill in on two separate occasions four weeks apart. Analysis of data showed that all sections of the profile achieved a high level of reliability with coefficients of correlation ranging from 0.77 to 0.85 on part I and from 0.44 to 0.86 on part II. Patients reported many problems in the areas of physical mobility, pain, sleep, and energy, but rather fewer in the areas of social isolation and emotional reactions. With the exception of family relationships, most respondents reported a high level of disruption of their daily activities. Patients were very consistent in the number and type of problems which they affirmed.

Perceived health: age and sex comparisons in a community.

The need to find accurate and reliable indicators on which to base the planning, provision, and evaluation of health services gave impetus to the attempt to develop reliable and valid measures of the perceived health status of the consumers of health care. Subjective measures can provide an important complement to traditional statistics by giving direct access to the personal feelings of discomfort or distress that influence the use of health services. Such measures also give meaningful criteria for the evaluation of the efficacy of such services. Self assessments of health obtained from surveys and interviews have consistently found age and sex differences in the tendency to report symptoms, ill-health, disability, visits to doctors, and sickness absence. Many of these data, however, may have been misleading in using instruments of unknown or uncertain validity and reliability. Nevertheless, subjective assessments of health have been shown to have value and to add a dimension to objective measurements of health. They have been considered to be one of the better predictors of mortality and of adjustment to major episodes of illness.

A quantitative approach to perceived health status: a validation study.

The current recognition of the importance of perceived health status as a predictor of need for, and utilisation of, health services has led to attempts to produce indicators which assess subjective rather than objective health problems. The development of the Nottingham Health Profile is described, together with a study which tested the validity of the instrument on four groups of elderly people differing in health status. The results showed that the profile was capable of discriminating between groups differing in terms of diagnosed chronic illness, number of consultations at primary care level, and physiological fitness. Age, sex, and marital status were not significant overall in affecting scores. In these elderly subjects, perceived health status accorded well with objective health status. Further tests of the profile are now taking place on younger groups of subjects.

Health related behaviour in hypertension.

Three groups of patients matched for age and sex were drawn from general practitioner records. One group had been diagnosed as mild hypertensives and were not on any medication, the second group consisted of moderate to severe hypertensives on medication and the third was a quasi-control group consisting of normotensives with no diagnosed medical problem. These three groups were compared with respect to individual behaviours which may affect blood pressure levels. Patients in both hypertensive groups were less likely to be current smokers. They were also more likely to be controlling their weight than people in the control group: well over 50% of men and women in both hypertensive groups as compared with about one-third in the control group. There were no differences between the three groups with respect to reported frequency or amount of alcohol use, frequency of exercise or strategies for coping with stress, although men in the control group were significantly less likely to describe themselves as not very active. We suggest that more advice is needed for hypertensive patients concerning the adverse effects of alcohol, the benefits of exercise and successful methods of weight control. However, the greater propensity of normotensives to smoke may put them more at risk of cardiovascular disease than the hypertensive individuals.

A measure of family disruption for use in chickenpox and other childhood illnesses.

A search of the literature showed the lack of a suitable measure for assessing the impact of minor illness on children and their families. Such illness can lead to considerable disruption within the family and particularly to the parent primarily responsible for the care of the ill child. Discussion groups were run with parents who had a child who had had chickenpox within the previous 6 months. Analysis of the transcripts from the groups produced items indicating three types of disruption; parents' distress, changes in the behaviour of the ill child and general disruption to family arrangements. Items from the transcripts were formed into a questionnaire which was then used in a study of 61 families in which a child had become ill with chickenpox within the previous 7 days. The principal carer completed the measure every evening for a fortnight. The results of the study showed considerable disruption over the first few days of the child's illness, followed by a steady reduction over the whole 2-week period.(ABSTRACT TRUNCATED AT 250 WORDS)

Subjective health assessments and the perceived outcome of minor surgery.

A simple and standardised measure of perceived health status, the Nottingham Health Profile, was used to assess the effect on perceived health status of surgical intervention in a variety of non-acute medical disorders. Patients were assessed a few days before their operation and again two months later and were compared with a control group who had not undergone surgery. Results showed very little change in subjective health from before to after surgical intervention. The experimental group had similar perceived health scores to the control group on the pre- and post-tests. It is suggested that the period allowed to elapse after surgical intervention was too short, or that the level of problems experienced by patients prior to surgery was too low to show significant change. It is also possible that the particular presenting disorders were only one possible somatic representation of general feelings of minor ill-health in the group. The findings of this study point to the need to look at the differences between doctors and patients expectations of the outcome of surgery, the decision to seek care and the factors that govern wellbeing.

Cross-cultural issues in the use of socio-medical indicators.

Socio-medical indicators for the assessment of physical, psychological and social conditions have become increasingly popular as adjuncts to traditional clinical and epidemiological measures. Most such indicators have been developed in the U.S.A. or Great Britain and considerable problems may arise from attempts to use them in other cultures. The ambiguity inherent in the terms "health" and "illness" is compounded cross-culturally by differences in the meaning system of cultures, their values, expectations and historical development. Consideration of cultural differences must precede any attempt to adapt already existing instruments for use in a culture or within a sub-group whose members were not included in the development process. Reliability and validity of socio-medical measures can only be assumed after the closest attention has been paid to the technical, conceptual and linguistic issues which arise from translation. This paper details some of the issues involved together with an account of the practical problems arising from the translation of the Nottingham Health Profile into Arabic and Spanish.

The QLDS: a scale for the measurement of quality of life in depression.

It has been apparent for some time that utilisation of health services is more influenced by how people feel than by their 'objective' symptoms. Research has also shown that compliance with treatment regimens is dependent on the impact of that treatment on the patient's well-being. Such findings highlight the need to assess the patient's view of his or her progress through the health care system. This has led to a growing interest in quality of life assessment and, in particular, to the impact of illness and its treatment on the quality of life of the patient. Perhaps surprisingly, interest in quality of life measures for outcome assessment in Psychiatry has been slower to develop than in other specialties. While a number of clinician- and patient-completed measures of the severity of depressive symptoms exist, no measure of the quality of life of depressed patients is available. This paper describes the development and testing of the Quality of Life in Depression Scale (QLDS), a new measure designed to fill this gap. The theoretical basis for the instrument is that life gains its quality from the ability and capacity of the individual to satisfy his or her needs. The items included in the QLDS were derived from 30 qualitative interviews with depressed or recently recovered patients. Further interviews were held with depressed patients to establish the face and content validity of the instrument. Respondents had little trouble completing the questionnaire and found the content to be relevant to their experience of depression. The QLDS represents an important advance in our ability to understand the impact of depression on quality of life.

A new measure of quality of life in depression: testing the reliability and construct validity of the QLDS.

Our previous paper described the development of a new quality of life scale for use with people suffering from depression; the Quality of Life in Depression Scale (QLDS). This paper reports on the testing of the scale for reliability and construct validity. Reliability was assessed by giving the questionnaire to the same set of patients on two occasions 2 weeks apart. This test-retest technique yielded a correlation of 0.94, with high internal consistency at both time 1 and time 2. A test of split-half reliability also indicated very high reliability. Construct validity was measured by comparing scores on the QLDS with those on an established scale of well-being from the same group of patients. The results gave a correlation between the two measures of 0.79, giving a satisfactory validity. It is concluded that the QLDS is a reliable and valid measure which is easy to use and acceptable to patients. Further tests of discriminative, concurrent and criterion validity are planned.

Health needs in a London district.

The hospital admission rate in Inner London is higher than for the country as a whole. This could be because more beds are available or because the local population has special needs. This paper considers admission rates by electoral wards within one Inner London District. The paper shows that the high admission rates are characteristic of electoral wards which exhibit severe social deprivation and that the more affluent wards do not have high hospitalization rates despite the fact that residents of all electoral wards have equal access to hospital. Our conclusion is that the high hospitalization rates in Inner London are at least in part due to social deprivation and that any allocation of health resources needs to make adequate and additional provision for the health needs of communities which are socially deprived.

Cross-cultural adaptation of health measures. European Group for Health Management and Quality of Life Assessment.

There is increasing interest throughout Europe in measuring health needs in the general population and in the 'quality of life' of patients. This has led to a demand for questionnaires capable of measuring health status in a reliable and valid manner. Most existing measures have, however, been standardised only in the U.S.A. and, to a lesser extent, in the U.K. The issue of translation and retesting of questionnaires prepared in the English language for use in other countries has received surprisingly little attention. This paper describes some of the technical, linguistic and conceptual issues raised by translation and the processes involved in producing acceptable country-specific versions of the Nottingham Health Profile according to a systematic method.

Invasive fungal sinusitis in the acquired immunodeficiency syndrome.

Invasive fungal sinusitis can present as either an indolent or fulminant process that primarily affects immunocompromised individuals. In this article, the clinical characteristics of four cases of invasive fungal sinusitis in patients with AIDS are analyzed and 22 additional previously reported cases in the literature are reviewed. In addition to HIV infection, other variables common to these cases include facial pain or headache out of proportion to clinical or radiographic findings, CD4 lymphocyte count less than 50 cells/mm(3), absolute neutrophil count less than 1,000 cells/mm(3), subtle radiographic evidence suggesting invasion and an indolent clinical course of the invasive infection. The most common pathogen detected was Aspergillus fumigatus. Maintaining a high index of suspicion, critically assessing these clinical findings, and prudently reviewing CT scans may facilitate early diagnosis and prompt intervention in these patients.