The impact of musculoskeletal ill health on quality of life and function after critical care: a multicentre prospective cohort study.

Physical disability is a common component of post-intensive care syndrome, but the importance of musculoskeletal health in this population is currently unknown. We aimed to determine the musculoskeletal health state of intensive care unit survivors and assess its relationship with health-related quality of life; employment; and psychological and physical function. We conducted a multicentre prospective cohort study of adults admitted to intensive care for > 48 h without musculoskeletal trauma or neurological insult. Patients were followed up 6 months after admission where musculoskeletal health state was measured using the validated Musculoskeletal Health Questionnaire score. Of the 254 participants, 150 (59%) had a musculoskeletal problem and only 60 (24%) had received physiotherapy after discharge. Functional Comorbidity Index, Clinical Frailty Scale, duration of intensive care unit stay and prone positioning were all independently associated with worse musculoskeletal health. Musculoskeletal health state moderately correlated with quality of life, rs = 0.499 (95%CI 0.392-0.589); anxiety, rs = -0.433 (95%CI -0.538 to -0.315); and depression, rs = -0.537 (95%CI -0.631 to -0.434) (all p < 0.001). Patients with a musculoskeletal problem were less physically active than those without a problem (median (IQR [range]) number of 30 min physical activity sessions per week 1 (0-3.25 [0-7]) vs. 4 (1-7 [0-7]), p < 0.001, respectively). This study found that musculoskeletal health problems were common after intensive care unit stay. However, we observed that < 25% of patients received physical rehabilitation after discharge home. Our work has identified potential high-risk groups to target in future interventional studies.

Influence of cochleostomy and cochlear implant insertion on drug gradients following intratympanic application in Guinea pigs.

Locally applied drugs can protect residual hearing following cochlear implantation. The influence of cochlear implantation on drug levels in the scala tympani (ST) after round window application was investigated in guinea pigs using the marker trimethylphenylammonium (TMPA) measured in real time with TMPA-selective microelectrodes. TMPA concentration in the upper basal turn of the ST rapidly increased during implantation and then declined due to cerebrospinal fluid entering the ST at the cochlear aqueduct and exiting at the cochleostomy. The TMPA increase was found to be caused by the cochleostomy drilling if the burr tip partially entered the ST. TMPA distribution in the second turn was less affected by implantation procedures. These findings show that basal turn drug levels may be changed during implantation and the changes may need to be considered in the interpretation of therapeutic effects of drugs in conjunction with implantation.

Gentamicin Applied to the Oval Window Suppresses Vestibular Function in Guinea Pigs.

Intratympanic gentamicin therapy is widely used clinically to treat the debilitating symptoms of Ménière's disease. Cochleotoxicity is an undesirable potential side effect of the treatment and the risk of hearing loss increases proportionately with gentamicin concentration in the cochlea. It has recently been shown that gentamicin is readily absorbed through the oval window in guinea pigs. The present study uses quantitative functional measures of vestibular and cochlea function to investigate the efficacy of treating the vestibule by applying a small volume of gentamicin onto the stapes footplate in guinea pigs. Vestibular and cochlea function were assessed by recording short latency vestibular evoked potentials in response to linear head acceleration and changes in hearing threshold, respectively, 1 and 2 weeks following treatment. Histopathology was analyzed in the crista ampullaris of the posterior semi-circular canal and utricular macula in the vestibule, and in the basal and second turns of the cochlea. In animals receiving gentamicin on the stapes footplate, vestibular responses were significantly suppressed by 72.7 % 2 weeks after treatment with no significant loss of hearing. This suggests that the vestibule can be treated directly by applying gentamicin onto the stapes footplate.

Epithelial dysplasia in nipple aspirates of breast fluid: association with family history and other breast cancer risk factors.

Because of the strong association of epithelial dysplasia and breast cancer, the extent to which dysplasia of breast fluid epithelial cells obtained by nipple aspiration is associated with breast cancer risk factors was investigated. A significantly higher proportion of women who had a first-degree family history of breast cancer had dysplastic cells in breast fluid than women who had no such history. When family history status was correlated with various breast cancer risk factors, higher proportions of women with dysplasia were found among those who had a first degree family history of breast cancer and for whom certain other risk factors were present, which suggested additive and synergistic effects of these factors on breast epithelium. Breast epithelia of women with a first-degree family history of breast cancer may be more prone to abnormal differentiation in response to environmentally conditioned risk factors.

Nipple aspirate cytology for the study of breast cancer precursors.

The association of abnormal nonmalignant cells in nipple aspirate fluid (NAF) and atypical proliferative disease (APD) of breast ducts was examined in the presence and absence of breast cancer in 134 patients. A high frequency of NAF samples with cellular abnormalities (atypical hyperplasia) was found when APD occurred with either breast cancer (70%) or benign breast biopsy specimens (54%). APD was present in 27 malignant cases (80%) and in 39 benign cases (39%). Inasmuch as APD may represent an intermediate step in the malignant transformation of duct epithelium, the cytologic examination of NAF offers a new approach with which to study the spectrum of breast cancer precursors and to assist in identifying women at risk for breast cancer.

Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid.

BACKGROUND: We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow-up in the original study group (n = 4046) and presents the first follow-up for a second group of women (n = 3627). METHODS: We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided. RESULTS: For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825) and 3.3% (65 of 1950) for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457) and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3). CONCLUSION: The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer.

Epidemiology of breast fluid secretion: association with breast cancer risk factors and cerumen type.

The epidemiology of breast fluid secretion was studied on the basis of nipple aspirates of breast fluid obtained from 3,929 nonlactating women of various racial groups. The results confirmed and extended earlier findings by our group: Variation in the proportion of secretors was related to most breast cancer risk factors, including age, race, age at menarche, age at first pregnancy, age at menopause, clinically diagnosed fibrocystic disease, menopausal estrogen use, and cerumen phenotype. Secretory activity as measured by nipple aspiration appeared to reflect hormonal and genetic effects on breast epithelium.

Benign and malignant breast disease: initial study results of serum and breast fluid analyses of endogenous estrogens.

Design, methods, and study population of a long-term multidisciplinary investigation of benign and malignant breast disease were reported. This initial report focused on the relation of menstrual, reproductive, and other factors to serum and breast fluid estrogen measures [estradiol (E2), estrone (E1), percent free estrogen, and sex hormone binding globulin] among control women. After adjustment for the factors found to be related to the various estrogen measures, estrogen levels in women with benign and malignant disease were compared to those of controls. Findings were as follows: a) little evidence of any relation of most breast cancer risk factors with the various serum estrogen parameters studied; b) differences in breast fluid estrogen levels that may be relevant to the protective effect of parity on breast cancer risk; c) markedly higher levels of E2 and E1 in breast fluid than in serum and no evidence of a correlation of serum with breast fluid measures; d) no support for the hypothesis that breast cancer patients have higher serum percent free E2 than controls or women with benign breast disease; and e) higher breast fluid E2 and E1 levels in women with biopsied benign breast disease than in controls.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Breast fluid cholesterol and cholesterol beta-epoxide concentrations in women with benign breast disease.

Because cholesterol 5,6-epoxides have been reported to be mutagenic, carcinogenic, and cytotoxic, we investigated the relationship of these substances in breast fluid to histopathologically defined breast disease. We measured cholesterol and its oxidation product, 5 beta,6 beta-epoxide, in breast fluids from 68 women with biopsied benign breast disease (BBD) and 135 women with no history of breast disease (controls). Each biopsy was classified according to the most severe epithelial change: (a) nonproliferative epithelia; (b) hyperplasia without atypia; or (c) hyperplasia with atypia. Similar to our previous findings in control women, breast fluid cholesterol and beta-epoxide concentrations in women with BBD were associated with factors of interest in relation to breast cancer: concentrations increased with age and were higher in white than nonwhite women and in women who were past or current smokers; concentrations were lower in women who had given birth or breastfed within 2 yr. Increased breast fluid cholesterol and beta-epoxide concentrations were significantly associated with proliferative BBD (hyperplasia with or without atypia) compared to controls. After adjustment for covariates, the odds ratio for proliferative BBD associated with detectable versus nondetectable beta-epoxide concentrations was 8.5 (95% confidence intervals, 1.1, 68.8). Our findings suggest that the histological progression from normal epithelium to hyperplasia without atypia to atypical hyperplasia is associated with progressively increasing concentrations of both cholesterol and cholesterol beta-epoxide.

Association of abnormal nipple aspirate cytology and mammographic pattern and density.

The pattern and density of mammograms have been shown to be associated with proliferative histopathology and an increased risk of breast cancer. We recently found that epithelial atypia in nipple aspirate fluid obtained 10-18 years earlier was associated with an increased risk of breast cancer. In the present study we examined the association between the cytology of nipple aspirate fluid and mammographic patterns in 588 volunteers recruited from the mammography clinic at the University of California. Nipple aspirate fluid cytology was classified according to the most severe epithelial change present and mammograms were classified by the Wolfe method and the percentage area of density. A direct relationship was found between mammographic density and cytological abnormality. When controlled for age, body mass index, previous biopsy, and calcification, the odds ratios of high density mammograms (over 50%) with nipple aspirate fluid cytological atypia was 4.4 (95% confidence interval, 0.9-21.5; P = 0.08) when normal cytology was the referent. These preliminary findings indicate that highly dense mammograms are associated with cytological atypia and are consistent with studies reporting an association of histological hyperplasia and atypical hyperplasia with severe mammographic findings. If confirmed by further studies, nipple aspirate cytology may be a useful adjunct to mammographic patterns in the prediction of breast cancer risk, especially among premenopausal women.

Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women.

Soy foods have been reported to have protective effects against premenopausal breast cancer in Asian women. No studies have been reported on potential physiological effects of dietary soy consumption on breast gland function. We evaluated the influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to resemble those previously found in Asian women. At monthly intervals for 1 year, 24 normal pre- and postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and 24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months 4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, gross cystic disease fluid protein (GCDFP-15) concentration, and NAF cytology were used as biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study protocol was obtained. Compared with NAF volumes obtained in months 1-3, a 2-6-fold increase in NAF volume ensued during months 4-9 in all premenopausal women. A minimal increase or no response was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin, cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with concentrations found in months 1-3 (no soy), plasma estradiol concentrations were elevated erratically throughout a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in premenopausal women during the months of soy ingestion. Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women (29.2%) during the months they were consuming soy protein isolate. The findings did not support our a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells, and elevated levels of plasma estradiol. These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate.

Gross cystic disease fluid protein in nipple aspirates of breast fluid of Asian and non-Asian women.

Gross cystic disease fluid protein 15 (GCDFP-15) is universally present in the apocrine metaplastic epithelium of cystic breast disease and breast cancer, but it is rarely found in normal breast epithelium. Therefore GCDFP-15 detected in nipple aspirates of breast fluid (NAF) could serve as a biochemical marker of the presence and possibly extent of apocrine metaplasia within the breast. GCDFP-15 levels were measured in NAF from 37 Asian and 78 non-Asian women using radioimmunoassay. GCDFP-15 (range, 0-81,643 micrograms/ml) was found in the NAF of all but 1 woman and was highly correlated between right and left breasts. Mean concentrations of GCDFP-15 were significantly lower in NAF from Asian compared with non-Asian women. Markedly reduced levels of GCDFP-15 were found in the 17 women who had been parous in the previous 2 years. In women not parous within the prior 2 years, no relationship was found between GCDFP-15 levels and age, weight, age at menarche, first-degree family history of breast cancer, parity, oral contraceptive use, or smoking history. High concentrations of GCDFP-15 were found in the NAF of women with a history of a benign breast biopsy. Because similarly high levels of GCDFP-15 were found in NAF in over 40% of women without a history of benign breast biopsy, and because GCDFP-15 in the breast is produced only by apocrine metaplastic epithelium, we infer that the breasts of these women likely contain a significant degree of apocrine metaplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

A cytomorphologic approach to standardization of cell dispersal evaluation for gynecologic specimens.

Dispersal of cells in gynecologic specimens is a major concern in sample preparation for automated systems. A variety of dispersal techniques has been tested, with varying degrees of success reported by many laboratories. In order to have a more meaningful comparison of the results of different techniques and among investigators, a standardized evaluation procedure is desirable. The cytomorphologic element of evaluation of cell dispersal has been developed and tested in this laboratory and might be applied toward this purpose. This evaluation reveals the changes in relative numbers of single cells according to cell type and estimates cell loss as well as changes in cellular preservation. Groups of cells are tabulated according to whether they appear as definite tissue groups or as clumps of single cells. Because abnormal cells and cells from the transformation zone often occur in tissue groups, special emphasis is placed on dispersal analysis by cell type to reveal whether the diagnostically important cells and cells relating to specimen adequacy were optimally dispersed. Furthermore, the format of evaluation allows assessment of the applicability of dispersal procedures to preparation for both flow and slide-based systems of automated cytology.

Flow cytometry of human gynecologic specimens using log chromomycin A3 fluorescence and log 90 degrees light scatter.

Flow cytometry and electronic cell sorting are being investigated to screen gynecologic specimens for cervical neoplasia. Cellular DNA content is quantitated by Chromomycin A3 fluorescence and cell size is quantitated by 90 degrees light scatter; the logarithms of the measured intensities are used to produce a two parameter histogram. To determine the cell types responsible for signals in various histogram regions, systematic electronic cell sorting is performed. The sorted fractions are sedimented into microscope slides and stained by the Papanicolaou technique. The cells in each fraction are identified by conventional cytomorphologic criteria. Morphologic analysis of sorted cells reveals histogram regions corresponding to specific cell types. One very important region contains the highest concentration of signals from abnormal cells and is therefore the best region to analyze for specimen abnormality. However, because a significant number of signals in this region are from normal cells, specimens cannot be diagnosed by their analysis. Another important histogram region is composed primarily of signals from endocervical columnar and metaplastic cells. The presence of such cells is a good criterion for specimen adequacy, therefore analysis of signals in this region is essential to assess specimen adequacy for automatic screening.

Cellular composition of the nipple aspirate specimen of breast fluid. II. Abnormal findings.

Studies of cellular findings in nipple aspirate specimens from 796 women revealed 50 women with abnormal cells and/or microcalcifications. The clinical correlation of these abnormalities with breast cancer appears to be highly significant: abnormal cells were found in 50% of the satisfactory specimens from women who had breast cancer or who had had a previous mastectomy for breast cancer. Continued observation of the women for evidence of regression, persistence, or progression of the cytologic abnormalities is required to determine the significance of the abnormalities. Microcalcifications were present in nipple aspirates from 27% of the women whose mammograms were interpreted as showing calcification. The absence of mammographic confirmation of the cytologic findings of microcalcifications may be an indication for re-evaluation of the existing mammograms and repeat clinical and mammographic examination at more frequent intervals for early localization of small lesions.

Cellular composition of the nipple aspirate specimen of breast fluid. I. The benign cells.

A nipple aspirator device was used to obtain breast secretions for cytologic examination, as well as for viral and biochemical analysis. Examination of the first 1,456 specimens from 796 women revealed ductal epithelium in 54%. Ductal epithelial cells were often absent in specimens from normal women; however, 78.5% of women with benign breast disease on tissue biopsy had specimens containing ductal epithelium. Apocrine metaplastic cells were a further indication of the presence of breast disease, and were rarely found in specimens from asymptomatic women. Foam cells were often abundant in specimens from normal breasts, but were found in decreased numbers in specimens from women benign breast disease. Differences in the occurrence of ductal epithelial cells, apocrine metaplastic cells, and foam cells suggest an alteration in the rate of maturation of ductal epithelium in women with both benign and malignant breast disease. The finding of a relative abundance of cells in nipple aspirate specimens from women with breast disease and few or no cells in specimens from women with normal breasts is believed to be of great importance in the cytologic evaluation of nipple aspirate specimens.

Seed migration and the structure of plant populations : An experimental study on Thymus vulgaris L.

We use chemical typing to compare sub-populations of thyme (Thymus vulgaris L.) growing in the channels of several ravines where seed migration is expected from sub-populations on the plateu to associated basin subpopulations. The results indicate that seed migration does occur. However, there is little effective gene flow between sub-populations. We discuss the implications of restricted gene flow for population dynamics and structure.

Significance of endometrial cells in cervicovaginal smears.

A study was undertaken to determine the significance of finding normal endometrial cells in routine cervicovaginal smears. The results indicate that the presence of normal endometrial cells in cervicovaginal smears in patients under 40 is generally not of significance, but similar findings in older patients correlate significantly with pathologic changes in the endometrium. In the older age group, therefore, such findings clearly indicate a need for further evaluation, including tissue sampling of the endometrium.

Cytologic diagnosis of multiple myeloma and macroglobulinemia in effusions.

The presence of effusion in association with multiple myeloma or macroglobulinemia is an unusual finding which generally occurs late in the course of the disease. Occasionally, cytoligic detection is a diagnostic problem. In both conditions, the fluid is characrerized by a high specific gravity and high protein content. In myeloma, plasma cells at varying stages of differentiation are present, while in macroglobulinemia atypical lymphocytes and plasma cells resembling those found in the blood and bone marrow are seen. Generally, the diagnosis can be readily made on the basis of clinical features, characteristics of the fluid and cytologic findings. In difficult cases, additional procedures helpful in establishing a definite diagnosis include methyl green pyronine stain, fluid electrophoresis and electron microscopy.