Arylsulfatase B regulates versican expression by galectin-3 and AP-1 mediated transcriptional effects.

Arylsulfatase B (N-acetylgalactosamine-4-sulfatase; ARSB) removes 4-sulfate groups from chondroitin-4-sulfate (C4S) and dermatan sulfate and is required for their degradation. In human prostate stromal and epithelial cells, when ARSB was silenced, C4S, versican and versican promoter activity increased, and the galectin-3 that co-immunoprecipitated with C4S declined. Galectin-3 silencing inhibited the ARSB-silencing-induced increases in versican and versican promoter due to effects on the AP-1-binding site in the versican promoter. These findings demonstrate for the first time the transcriptional mechanism whereby ARSB can regulate expression of an extracellular matrix proteoglycan with C4S attachments. In addition, following ARSB silencing, C4S that co-immunoprecipitated with versican increased, whereas co-immunoprecipitated EGFR declined, total EGFR increased and exogenous EGF-induced cell proliferation increased, suggesting profound effects of ARSB on vital cell processes.

Arylsulfatase B (N-acetylgalactosamine-4-sulfatase): potential role as a biomarker in prostate cancer.

BACKGROUND: The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) degrades chondroitin-4-sulfate (C4S) and is reduced in malignant colonic and mammary tissues but has not previously been evaluated in prostate cancer. METHODS: ARSB immunostaining was performed on two tissue microarrays (TMAs) and analyzed by digital image analysis, generating ARSB H-scores for prevalence and intensity of epithelial, stromal and combined epithelial and stromal immunostaining. Also, paired malignant and normal prostate tissues were analyzed for ARSB activity, C4S, total sulfated glycosaminoglycans and versican content. The quantities of C4S and of the epidermal growth factor receptor (EGFR) that co-immunoprecipitated with versican were determined in the normal and malignant paired prostate tissues. RESULTS: Forty-four cases of prostate cancer were paired by age (± 5 years), race, Gleason score (in order) and pathological TNM (tumor, node, metastasis) score. The pairs differed by recurrence vs non-recurrence of elevated PSA at ≥ 4 years. When TMA cores were analyzed for ARSB H-score, 18 of the 22 pairs had lower ARSB H-scores in the recurrent member of the pair, whereas higher initial PSA values were associated with recurrence in only 65% of the paired cases. In a second TMA, Gleason scores 6 and 7 were associated with higher ARSB H-scores than Gleason scores 8 and 9 for stroma, epithelium and stroma and epithelium combined (P=0.052, P=0.015, P<0.0001, respectively) and were inversely correlated (r=-0.98, -0.97 and -0.99, respectively). In other paired normal and malignant prostate tissues, ARSB activity was significantly higher in the normal tissues, and C4S and versican values were lower (P<0.0001). C4S that co-immunoprecipitated with versican was greater in the malignant than in the normal tissue, whereas total EGFR that co-immunoprecipitated with versican was reduced. CONCLUSIONS: Study findings suggest that ARSB may be useful as a prognostic biomarker in prostate cancer and that the biological action of ARSB on chondroitin sulfate may impact upon versican's effects in the tumor microenvironment.

Exposure to the common food additive carrageenan leads to glucose intolerance, insulin resistance and inhibition of insulin signalling in HepG2 cells and C57BL/6J mice.

AIMS/HYPOTHESIS: The aim of this study was to determine the impact of the common food additive carrageenan (E407) on glucose tolerance, insulin sensitivity and insulin signalling in a mouse model and human hepatic cells, since carrageenan is known to cause inflammation through interaction with toll-like receptor (TLR)4, which is associated with inflammation in diabetes. METHODS: Male C57BL/6J mice were given carrageenan (10 mg/l) in their drinking water, and underwent a glucose tolerance test (GTT), an insulin tolerance test (ITT) and an ante-mortem intraperitoneal insulin injection. HepG2 cells were exposed to carrageenan (1 mg/l × 24 h) and insulin. Levels of phospho(Ser473)-protein kinase B (Akt), phospho(Ser307)-IRS1, phosphoinositide 3-kinase (PI3K) activity and phospho(Ser32)-inhibitor of κB (IκBα) were determined by western blotting and ELISA. RESULTS: Glucose tolerance was significantly impaired in carrageenan-treated 12-week-old mice compared with untreated controls at all time points (n = 12; p < 0.0001). Baseline insulin and insulin levels at 30 min after taking glucose during the GTT were significantly higher following carrageenan treatment. During the ITT, glucose levels declined by more than 80% in controls, but not in carrageenan-treated mice. Carrageenan exposure completely inhibited insulin-induced increases in phospho-(Ser473)-Akt and PI3K activity in vivo in mouse liver and in human HepG2 cells. Carrageenan increased phospho(Ser307)-IRS1 levels, and this was blocked when carrageenan-induced inflammation was inhibited. CONCLUSION: This is the first report of the impact of carrageenan on glucose tolerance and indicates that carrageenan impairs glucose tolerance, increases insulin resistance and inhibits insulin signalling in vivo in mouse liver and human HepG2 cells. These effects may result from carrageenan-induced inflammation. The results demonstrate extra-colonic manifestations of ingested carrageenan and suggest that carrageenan in the human diet may contribute to the development of diabetes.

Inverse relationship between density of cutaneous hair and pigmented lesion count in patients with malignant melanoma.

The aim of this study was to investigate whether there is an inverse relationship between the density of cutaneous hair and the number of pigmented lesions in patients with malignant melanoma, and to review the clinical and experimental findings with regard to this relationship. Cutaneous hair density and pigmented lesion counts were determined at nine sites by two physicians using specified criteria in 10 patients with a history of malignant melanoma and 22 control subjects. Study participants were Caucasian males of similar age, height and weight, and had similar occupational, ethnic, socioeconomic and sun exposure backgrounds. Statistical analysis was performed using combined data from all the sites and individual site data to determine whether an inverse relationship between cutaneous hair density and pigmented lesion counts exists. The results demonstrated statistically significant inverse relationships for the chest, upper back, upper arm and forearm in the melanoma patients, but not in the controls. For all the sites combined, both groups demonstrated statistically significant inverse relationships. The study findings are consistent with the hypothesis that some pigmented lesions may arise from the melanocytes of the hair follicle. This hypothesis may lead to new approaches to studying and treating melanoma.

Review of harmful gastrointestinal effects of carrageenan in animal experiments.

In this article I review the association between exposure to carrageenan and the occurrence of colonic ulcerations and gastrointestinal neoplasms in animal models. Although the International Agency for Research on Cancer in 1982 identified sufficient evidence for the carcinogenicity of degraded carrageenan in animals to regard it as posing a carcinogenic risk to humans, carrageenan is still used widely as a thickener, stabilizer, and texturizer in a variety of processed foods prevalent in the Western diet. I reviewed experimental data pertaining to carrageenan's effects with particular attention to the occurrence of ulcerations and neoplasms in association with exposure to carrageenan. In addition, I reviewed from established sources mechanisms for production of degraded carrageenan from undegraded or native carrageenan and data with regard to carrageenan intake. Review of these data demonstrated that exposure to undegraded as well as to degraded carrageenan was associated with the occurrence of intestinal ulcerations and neoplasms. This association may be attributed to contamination of undegraded carrageenan by components of low molecular weight, spontaneous metabolism of undegraded carrageenan by acid hydrolysis under conditions of normal digestion, or the interactions with intestinal bacteria. Although in 1972, the U.S. Food and Drug Administration considered restricting dietary carrageenan to an average molecular weight > 100,000, this resolution did not prevail, and no subsequent regulation has restricted use. Because of the acknowledged carcinogenic properties of degraded carrageenan in animal models and the cancer-promoting effects of undegraded carrageenan in experimental models, the widespread use of carrageenan in the Western diet should be reconsidered.

Consumption of carrageenan and other water-soluble polymers used as food additives and incidence of mammary carcinoma.

This study examined the hypothesis that the increasing incidence of mammary carcinoma in the USA in the twentieth century may be related to the consumption of carrageenan and possibly other water-soluble polymers. Widely used as food additives in the Western diet, the water-soluble polymers, also known as gums, are generally regarded as inert. However, the gum carrageenan which is comprised of linked, sulfated galactose residues has potent biological activity and undergoes acid hydrolysis to poligeenan, an acknowledged carcinogen. A time-trend analysis using age-adjusted incidence data and consumption data from established sources tested the hypothesis that increased consumption of the gums may be associated with increased incidence of mammary carcinoma. Correlations were determined using Pearson and Spearman correlation coefficients, incorporating lag intervals of 10 to 35 years. This analysis demonstrated that increasing consumption of several gums correlates positively with increased incidence of breast carcinoma.

Carrageenan-induced inclusions in mammary myoepithelial cells.

The purpose of this investigation was to characterize the ultrastructural changes that occur in mammary myoepithelial cells (MMEC) following exposure in tissue culture to low concentrations of lambda-carrageenan, a sulfated polysaccharide commonly used as a food additive. MMEC were obtained from reduction mammoplasty, grown in tissue culture, exposed for varying durations to low concentrations (0.0014%-0.0001%) of lambda-carrageenan, and examined by transmission electron microscopy, following staining for acid phosphatase and for aryl sulfatase. Carrageenan appeared to enter the cells by membrane-associated endocytic vesicles and accumulate in endosomes and lysosomes. Unusual lamellar inclusions were identified within lysosomes of the MMEC, and lysosomal vacuolation arose in association with the inclusions. The observed changes appeared to lead to destruction of the MMEC by release of proteolytic enzymes from the distorted lysosomes, similar to the process observed in lysosomal storage diseases.

Comparison of appropriateness ratings for cataract surgery between convened and mail-only multidisciplinary panels.

BACKGROUND: In this article, the authors determine the reproducibility of appropriateness ratings for cataract surgery between a multidisciplinary physician panel that convened and a multidisciplinary physician panel that completed ratings by mail. METHODS: Eighteen panelists, who constituted 2 distinct multidisciplinary panels, rated 2894 clinical scenarios as an appropriate, inappropriate, or uncertain indication to perform cataract surgery. Each panel's summary score for each scenario was calculated. Weighted kappa values were determined to assess the level of agreement between the ratings of the 2 panels. RESULTS: The panels had a substantial level of agreement overall, with a weighted kappa statistic of 0.64. There was agreement on about 68% of the scenarios, and serious disagreement, in which one panel rated an indication appropriate and the other rated it inappropriate, occurred in only 1% of the ratings. CONCLUSION: There was substantial agreement about the ratings by the 2 panels. The panel that convened rated fewer scenarios uncertain and more appropriate, suggesting the impact of group dynamics and face-to-face discussion on resolution of uncertainty.

Reproducibility of measures of overuse of cataract surgery by three physician panels.

BACKGROUND: Assess the reproducibility of methods to measure overuse of cataract surgery. OBJECTIVES: The objectives of this study are: (1) To determine the extent of agreement about clinical scenarios among, between, and within three physician panels; (2) to apply ratings of clinical scenarios from three panels to actual surgeries; and (3) to assess reproducibility of rates of appropriate use and overuse. METHODS: Three physician panels scored 2,894 clinical scenarios for the appropriate use of cataract surgery. One thousand and twenty charts were abstracted and assigned to the clinical scenario that best corresponded to the patient's clinical situation. Two hundred and fifty nine clinical scenarios were required to assign the cases. Weighted kappa values, confidence intervals, and percentages of agreement were used to measure agreement among, between, and within panels. RESULTS: The all ophthalmologist panel (OP) and the convened multispecialty panel (CM) each rate 92% of the cases as appropriate use, compared with 70% by the mail-in multispecialty panel (MM). The MM have higher uncertain (26% vs. 8% and 7%) and higher inappropriate use (3.5% vs. 0.1% and 1.9%). For the clinical scenarios, the CM and the MM have similar percentages of overuse (6.6%, 7.3%), in contrast to the OP (0.4%). The weighted kappa value for the overall level of agreement about the clinical scenarios among the three panels is 0.53, consistent with moderate agreement. CONCLUSIONS: Study results demonstrate reproducibility for assessment of appropriate use of surgery between the OP and CM. However, both multispecialty panels rate more clinical scenarios as inappropriate use than the ophthalmologist panel. Thus, reproducibility between the CM and the OP may be attributable to the low percentage of overuse of cataract surgery in the study population. The overall level of agreement about the clinical scenarios among the panels is moderate.

Visual function impairments in relation to gender, age, and visual acuity in patients who undergo cataract surgery.

PURPOSE: This study aimed to determine the relationship between visual function impairment in 776 patients who had extracapsular cataract extraction with posterior chamber intraocular lens implantation and gender, age, preoperative visual acuity (VA) of both the operative and the contralateral eye, and presence of other ocular disease in the operative eye. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: 1139 patients whose medical records were abstracted and who had cataract surgery performed at 1 of 10 participating academic medical centers in 1990. MAIN OUTCOME MEASURE: In the 776 patients who had explicit statements about impairment of visual function documented in their medical records, univariate and multivariable logistic analyses were used to assess the above relationship. RESULTS: The most severe visual functional deficit that justified the cataract operation varied in relation to gender, age, and VA. On bivariate analysis, men were more likely to have impairment with employment, driving, and glare, whereas women were more likely to have impairment with activities of daily living and recreational activities. Significant findings between visual impairment and the independent variables from the logistic regression models included: (1) employment limitation and male gender (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.08-3.40); (2) employment limitation and younger age (OR, 0.12; 95% CI, 0.050-0.28 for ages 70-79); (3) recreational impairment and older age (OR, 2.77; 95% CI, 1.64-4.70 for ages 80+); (4) impairment in performing activities of daily living and female gender (OR, 0.72; 95% CI, 0.53-0.98 for male gender); (5) impairment in performing activities of daily living and worse VA in the operative eye (OR, 5.13; 95% CI, 2.93-9.00 for VA < 20/100); (6) glare-associated impairment and younger age (OR, 0.40; 95% CI, 0.24-0.69 for age 80+); and (7) glare-associated impairment and better VA (OR, 0.16; 95% CI, 0.067-0.38 for VA < 20/100). CONCLUSION: When deciding whether to perform cataract surgery, functional impairment must be considered in relation to the age and the gender of the patient, for the type of functional impairment varies in association with age and gender.

Filament disassembly and loss of mammary myoepithelial cells after exposure to lambda-carrageenan.

Carrageenans are naturally occurring sulfated polysaccharides, widely used in commercial food preparation to improve the texture of processed foods. Because of their ubiquity in the diet and their observed preneoplastic effects in intestinal cells, their impact on human mammary myoepithelial cells in tissue culture was studied. At concentrations as low as 0.00014%, lambda-carrageenan was associated with disassembly of filaments with reduced immunostaining for vimentin, alpha-smooth muscle-specific actin, and gelsolin; increased staining for cytokeratin 14; and cell death. The absence of mammary myoepithelial cells is associated with invasive mammary malignancy; hence, the destruction of these cells in tissue culture by a low concentration of a widely used food additive suggests a dietary mechanism for mammary carcinogenesis not considered previously.

Documentation patterns before cataract surgery at ten academic centers.

PURPOSE: To determine the adequacy of documenting the preoperative evaluation for cataract surgery using criteria derived from published practice guidelines. METHODS: In 1990, 1139 surgeries that were performed on 1139 patients at ten institutions of the Academic Medical Center Consortium were reviewed for completeness of documentation of the preoperative evaluation. Criteria for completeness were derived from the American Academy of Ophthalmology Preferred Practice Pattern on cataract evaluation and the Agency for Health Care Policy and Research-sponsored guidelines. RESULTS: Twenty-six percent of charts lacked documentation of at least one of four basic elements of the preoperative evaluation. These four elements are (1) vision in the surgical eye; (2) vision in the fellow eye; (3) evaluation of the fundus, macula, or visual potential in the surgical eye: and (4) presence of some form (general or specific) of functional visual impairment. If, as stated in the guideline, a specific deficit in visual functioning should be identified, then 40% of charts fail to meet criteria. CONCLUSION: Documentation of the ocular preoperative assessment for cataract surgery is inadequate in more than one quarter of cases. The relation between lack of documentation and incompleteness of the examination is unknown. Improved documentation is needed to better measure and enhance the quality of care.

Utilization of a personal health record in a general medicine clinic.

To determine the baseline use of personal medical records maintained by patients, to initiate utilization of a personal health record (PHR), and to assess outcomes associated with its use, a survey, intervention, and outcome study was conducted with follow-up at 2, 7, and 14 months. One hundred randomly selected adult patients of the General Medicine Clinic at The University of Iowa Hospitals and Clinics were evaluated. At onset, 44% maintained no records. At 14-month follow-up, 69% maintained the PHR. The change in documentation was statistically significant (p = .013 x 10(-8), McNemar's Test for Paired Data; 95% confidence interval 0.065, 0.54). The baseline use of personal medical records was poor, but it was improved following introduction of the PHR, and most patients continued using the record 14 months later.

Assessment of appropriateness of cataract surgery at ten academic medical centers in 1990.

PURPOSE: To develop criteria for the appropriateness of cataract surgery (extracapsular cataract extraction or phacoemulsification with planned implantation of a posterior chamber intraocular lens) and to apply these criteria to patients from ten academic medical centers. METHODS: The study is a retrospective case series from ten academic medical centers. One thousand one hundred thirty-nine patients who had had cataract surgery in 1990 at the medical centers were selected randomly. Patients, identified by specific ICD-9-CM or CPT-4 codes, had no other ocular surgery performed at the same time as cataract surgery. Rates of inappropriate, uncertain, appropriate, and appropriate and crucial surgeries were determined by application of the criteria established by a multidisciplinary expert panel. RESULTS: Approximately 2% of the procedures were classified as inappropriate, after adjusting for missing or nonspecific visual function by use of discriminant analysis. Ninety-one percent of the procedures were classified as appropriate (52%) or appropriate and crucial (39%). Seven percent were designated as uncertain, either due to a median rating in the uncertain range or to disagreement in ratings among the panelists. Significant variation occurred in the results among the different institutions: inappropriate surgeries ranged from 0% to 4%, uncertain from 1% to 14%, appropriate from 35% to 66%, and appropriate and crucial from 21% to 62% (P=0.02). CONCLUSION: A small percentage of cataract surgeries was performed at these ten academic medical centers for inappropriate indications using the study criteria. Given the large number of cataract surgeries performed annually, the small percentage of uncertain and inappropriate surgeries may translate into a large number of surgeries performed for less than appropriate or appropriate and crucial indications. Significant variation existed among the institutions in the distribution of appropriate and crucial and appropriate compared with uncertain and inappropriate surgeries.

Assessment of comorbidity: a review.

Eleven clinical comorbidity indices are reviewed with attention to the development of improved assessment of comorbid conditions. Elements that are critical to the indices are reviewed, including their applicability, their inclusiveness, their validation, their correlations with outcomes of interest, their inclusion of functional assessment, their inclusion of severity assessment, and their simplicity. Improved assessment of comorbidity will enable better understanding of the processes and outcomes of medical care.

Prevention of infectious diseases in ambulatory care: immunoprophylaxis and chemoprophylaxis.

OBJECTIVE: To review the current recommendations for immunoprophylaxis and chemoprophylaxis of infection in adults, including those who are at increased risk from occupation, lifestyle, travel, or pre-existing medical conditions. DESIGN: Review of the pertinent literature. SETTING: Adult ambulatory care. CONCLUSIONS: Guidelines for the prevention of several diseases including measles, tuberculosis, and bacterial endocarditis recently have been changed. Current recommendations for immunization, immune globulin therapy, and chemotherapy for these and other common infections are reviewed.

Variation in physician opinion about scheduling of return visits for common ambulatory care conditions.

OBJECTIVE: To determine whether there is consensus about intervals between visits for adult general medicine patients with common ambulatory care conditions. DESIGN: Survey of practicing physicians and residents. SETTING: Ambulatory care at a hospital clinic, a group practice, and a physician office. PARTICIPANTS: 153 physicians, including residents, fellows, and staff from The University of Iowa Hospitals and Clinics, internists and family practitioners from three Iowa towns, and internists from Atlantic City, New Jersey. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There was wide variation in responses, with greater consensus for more acute conditions than for chronic conditions or preventive care. CONCLUSIONS: 1) Wide variation exists in proposed intervals between visits for care of patients with common ambulatory conditions. 2) Variation occurs within the same geographic area and is unassociated with year of graduation from medical school, year in training, or academic appointment 3) Further study is needed to assess the significance of this variation.

Increased use of pneumococcal vaccination in a medicine clinic following initiation of a quality assessment monitor.

OBJECTIVES: To determine the use of pneumococcal vaccination in a general medicine ambulatory clinic and the effect of a quality assessment monitor on use. DESIGN: A prospective 8-month (October 1990 through May 1991) survey and 8-month (October 1989 through May 1990) retrospective survey of use of pneumococcal vaccination in the clinic. SETTING: A general medicine clinic where patients are seen for their first internal medicine clinic visit at The University of Iowa Hospitals and Clinics, Iowa City, Iowa. PATIENTS: One thousand sixty adult patients who presented to the clinic during the study interval. INTERVENTIONS: The use of the form constituted an intervention. RESULTS: Use of pneumococcal vaccination was increased more than 5 times over the baseline level following implementation of the quality assessment monitor. CONCLUSIONS: Underuse of pneumococcal vaccination occurred in this general medicine clinic, and the introduction of a quality assessment monitor constituted an intervention that significantly increased the use of pneumococcal vaccination.

Inverse relation between density of nevi and terminal cutaneous hair. Study of male volunteer subjects and patients enrolled in a dysplastic nevus syndrome registry.

Terminal hair density was graded at seven sites in 19 male patients enrolled in a dysplastic nevus syndrome (DNS) registry and in 22 matched control subjects. An inverse relation between density of nevi and terminal hair for all sites combined was observed for both patients and control subjects (p = 0.0001, regression analysis). In addition, the registry patients had significantly less terminal cutaneous hair overall (p = 0.007, Wilcoxon rank sum test) compared with the controls.