Regional differences in mechanical and material properties of femoral head cancellous bone in health and osteoarthritis.

Osteoarthritis (OA) is a debilitating condition common among the aging population. In this study we have determined mechanical and material properties of cancellous bone cores from two differently loaded regions of femoral heads obtained from healthy subjects and those with end-stage osteoarthritis. Densitometric properties were determined prior to compression testing for Young's modulus (EC) and yield strength (sigma(y)), after which bones were powdered for analysis of collagen and mineral content. In both OA and normal cancellous bone, volumetric bone mineral density (BMDv), apparent density (rhoA), E(C), and sigma(y) were systematically greater in the superior than in the inferior region (P<0.05). In the OA inferior region, median BMDv (0.434 g-cm(-3)) and rA (0.426 g-cm(-3)) were significantly greater than in normals (0.329 and 0.287 g-cm(-3), respectively, both P<0.05) reflecting an increased amount of tissue. The mineral:collagen ratio was decreased in OA, but this was only significant in the superior region (P<0.008). Relationships between EC and both BMDv and rho(A) were weaker in OA bone cores (r(2) = 0.66 and r(2) = 0.59) than in normals (r(2) = 0.86 and r(2) = 0.77, respectively). Likewise, sigma(y) and both BMDv and rho(A) were weaker in OA (r(2) = 0.74 and r(2) = 0.70) than in normals (r(2) = 0.83 and r(2) = 0.77, respectively). For the same value of density measure, EC and sigma(y) tended to be lower in OA bone when compared with normal bone. In conclusion, femoral head cancellous bone mass in end-stage osteoarthritis is increased but undermineralized, and is neither stiffer nor stronger than normal cancellous bone.

Laboratory analyses of the potential toxicity of sediment-associated polydimethylsiloxane to benthic macroinvertebrates.

Polydimethylsiloxane (PDMS) is widely used in a number of industrial processes and consumer products that result in down-the-drain disposal. The log p value for the PDMS used in the present study was 10, and the vapor pressure and water solubility values were below detection limits. These physicochemical characteristics and a measured degradation rate of 3% after six months in moist soils suggest that PDMS may accumulate in aquatic sediments. Sediment toxicity tests with the amphipod Hyalella azteca and with larvae of the midge Chironomus tentans were used to assess the potential for toxicity of PDMS-amended sediments to benthic invertebrates in short-term (10-d) and whole-life-cycle (28 d for H. azteca, 50-65 d for C. tentans) exposures. Endpoints for short-term tests included survival and growth, while life-cycle assays considered survival, growth, reproduction, and, for C. tentans only, emergence. Short-term and life-cycle exposures to concentrations of > or = 1,000 mg PDMS/kg sediment (dry wt) indicated that PDMS will not reduce survival, growth, or reproduction in H. azteca or C. tentans.

Fate and effects of polydimethylsiloxane (PDMS) in marine environments.

Polydimethylsiloxanes (PDMS) defoamers are used to improve process efficiency under extreme conditions during gas-oil separation, when other chemicals fail to perform. They are also used to reduce the oil content of process waters discharged to the marine environment, thereby serving an important function in reducing oil pollution. As a consequence of these applications small quantities of PDMS may also be released into the environment. This paper reviews the fate of PDMS in the marine environment and the extensive effect studies that have been conducted. These demonstrate the absence of adverse effects on a wide range of marine species.

Aortic valve replacement in patients with aortic stenosis and severe left ventricular dysfunction.

BACKGROUND: The outcome of aortic valve replacement for severe aortic stenosis is worse in patients with impaired left ventricular function. Such dysfunction in aortic stenosis may be reversible if caused by afterload mismatch, but not if it is caused by superimposed myocardial infarction. METHODS: From our echocardiography database, 55 patients with severe aortic stenosis (valve area < or =0.75 cm2) and ejection fractions of 30% or lower who subsequently underwent aortic valve replacement were included. The operative mortality and clinical follow-up were detailed. RESULTS: There were 10 perioperative deaths (operative mortality, 18%). Twenty (36%) of the 55 patients had a prior myocardial infarction. In the 35 patients without prior myocardial infarction, there was only 1 death (3%). In contrast, 9 of 20 patients with prior myocardial infarction died (mortality rate, 45%; P< or =.001). The factors significantly associated with perioperative death on univariate analysis (functional class, mean aortic gradient, and prior myocardial infarction) were entered into a model for stepwise logistic regression. This multivariate analysis showed that only prior myocardial infarction was independently associated with perioperative death (odds ratio, 14.9; 95% confidence interval, 2.4-92.1; P = .004). CONCLUSIONS: The risk of aortic valve replacement in patients with severe aortic stenosis and severely reduced left ventricular systolic function is extremely high if the patients have had a prior myocardial infarction. This information should be factored into the risk-benefit analysis that is done preoperatively for these patients, and it may preclude operation for some.

Plasma osteocalcin in healthy Nigerian children and in children with calcium-deficiency rickets.

Osteocalcin is an osteoblast-specific protein believed to be associated with events occurring during bone mineralization, which has been widely used clinically as an indicator of osteoblast function. Plasma osteocalcin concentrations (pOC) were studied in 94 (59 male, 35 female) healthy and 44 (21 male, 23 female) rachitic Nigerian children, all one to five years of age. The study was aimed at establishing a reference range for healthy Nigerian children determining any changes in plasma osteocalcin levels occurring in children with calcium-deficiency rickets. In the controls, pOC levels ranged from 3-89 ng/ml, with a mean value of 23 +/- 19 ng/ml. The values were higher in girls (29 +/- 21 ng/ml) than in boys (21 +/- 18 ng/ml), though not significantly. The controls had values consistent with other published pediatric ranges from Europe and North America. In the younger rachitic children (under 3 years) the mean pOC was lower than in the controls (P = 0.04) despite the much elevated plasma levels of 1,25(OH)2D. In the controls, pOC correlated with 1,25(OH)2D (r = 0.59, P = 0.003), alkaline phosphatase (r = 0. 22, P = 0.03), and inorganic phosphate (r = 0.27, P = 0.01). These correlations were lost in the rickets group. The findings in the controls confirm the known association between plasma 1,25(OH)2D and circulating osteocalcin levels, whereas the findings in the rickets group suggest that the stimulatory effects of 1,25(OH)2D on osteocalcin may depend on other permissive factors, such as normal circulating levels of calcium and phosphate.

Female pseudohermaphroditism due to congenital adrenal hyperplasia complicated by adenocarcinoma of the prostate and clear cell carcinoma of the endometrium.

The presence of prostatic glandular tissue in female pseudohermaphrodites has previously been documented. However, prostatic neoplasia in this clinical setting has not been reported. A karyotypic female with congenital adrenal hyperplasia due to 21-hydroxylase deficiency developed a prostatic adenocarcinoma associated with elevated serum prostatic specific antigen levels and osteoblastic skeletal metastases. This demonstrates that this tissue in pseudohermaphrodites can become malignant. In addition, the patient subsequently developed clear cell carcinoma of the endometrium, possibly related to radiation therapy for the prostatic adenocarcinoma. This demonstrates that female pseudohermaphrodites may be at risk not only for malignancies seen in genotypic females but also prostate cancer.

Etiology of rickets in Nigerian children.

We studied 26 Nigerian children with active rickets (13 boys, 13 girls), aged 1 to 5 years, and compared results of biochemical studies with those of healthy control subjects. The plasma 1,25-dihydroxyvitamin D level was elevated (568 +/- 317 pmol/L) and the 25-hydroxyvitamin D level was (36 +/- 28 mol/L) in the children with rickets compared with the control subjects (369 +/- 134 nmol/L and 69 +/- 22 nmol/L, respectively). The results suggest that rickets in Nigeria is largely the result of calcium deficiency and that vitamin D deficiency and possibly end organ resistance may be contributory factors.

Genetic alterations distinguish different types of ovarian tumors.

Seventy-four sporadic ovarian tumors were studied for loss of heterozygosity (LOH) and microsatellite instability (MI) with 20 polymorphic markers on chromosome 17 and at least I marker on every other chromosome. Additionally, activation of the K-ras oncogene was examined through mutation analysis of codon 12. A majority of the tumors analyzed were low grade and/or of the mucinous histologic type. A negative correlation between LOH on chromosome 17 and K-ras activation was observed, with the former alteration present in the majority of high grade serous and endometrioid tumors and the latter most commonly found in the mucinous and low malignant potential (LMP) tumors. In 60% of cases where LOH on chromosome 17 was present, it was observed at all informative markers, indicating chromosome loss. In these cases, frequent events of LOH were observed on the other chromosomes. When confined events of LOH were observed on chromosome 17, fewer events of LOH were observed on the other chromosomes. In the absence of LOH on chromosome 17, LOH on other chromosomes was rare. K-ras activation was most commonly observed in tumors with no LOH events. Two endometrioid tumors and 2 mucinous tumors demonstrated MI. Our data support the involvement of different molecular pathways in the development of different types of ovarian tumors.

Loss of heterozygosity and genomic instability in synchronous endometrioid tumors of the ovary and endometrium.

BACKGROUND: The unknown etiology of endometrioid carcinomas of the ovary and the relatively high frequency of a concomitant carcinoma of the endometrium in these patients warrants study of such tumors. The aim of this study was to identify the genetic alterations involved in endometrioid ovarian cancer development, and to determine whether primary tumors of the endometrium and synchronous primary endometrioid tumors of the ovary could be distinguished based on differing patterns of genetic alterations. The distinction of metastatic carcinoma of the ovary from other synchronous primary tumors is often difficult but has important therapeutic and prognostic implications. METHODS: This study examined the genetic alterations at 28 polymorphic DNA markers in the DNA of tumors of 17 patients with endometrioid carcinoma of the ovary, including 5 nonmetastatic ovarian tumors, 5 ovarian tumors metastatic to the uterus, and 7 endometrioid ovarian tumors with a synchronous primary endometrial tumor. RESULTS: Chromosomes 17 and 22 were found to be the most common sites of loss of heterozygosity (LOH) in the 17 patients studied. Loss of heterozygosity on chromosome 17 was associated with advanced stage ovarian tumors. In 96% of LOH events in the metastatic tumors, LOH was observed in the primary tumor and in the metastatic site. Conversely, in four of seven synchronous tumors in which LOH was observed, LOH was confined to the ovarian tumor. Genomic instability was identified in two of seven patients with synchronously occurring tumors that did not demonstrate LOH. A positive family history was noted for these two patients. CONCLUSIONS: A lack of shared genetic alterations and in synchronously occurring endometrial and endometrioid ovarian tumors indicates independent developmental pathways for these tumors. Loss of heterozygosity on chromosome 17 in endometrioid ovarian carcinoma may indicate transition to a more aggressive tumor.

Genetic alterations on chromosome 17 distinguish different types of epithelial ovarian tumors.

Epithelial tumors of the ovary are the most common ovarian tumors of adult women. They exist in several different histological patterns and exhibit varying degrees of aggressiveness. Molecular genetic studies in epithelial ovarian cancer have shown that loss of heterozygosity (LOH) for regions of chromosome 17 is a common event, probably reflecting the inactivation of one or more tumor suppressor genes present on this chromosome. We examined 87 sporadic epithelial ovarian tumors of different grade and histological type at 16 loci on this chromosome and found that 35% of them showed LOH for chromosome 17. Of these, 84% showed LOH for all informative markers, suggesting that loss of the entire chromosome 17 homologue may have occurred. Interestingly, chromosome 17 loss was observed frequently in serous tumors (49%), was less common in endometrioid tumors (15%), and was rare in mucinous tumors (4%) (P = .01 and P = .0002, respectively). Our findings support the concept that the histological subtypes of epithelial ovarian cancer may be the result of different molecular genetic events.

Hypermethylation at a chromosome 17 "hot spot" is a common event in ovarian cancer.

Alterations of normal DNA methylation patterns have been reported in various types of human tumors. These alterations are represented by genome wide hypomethylation and by region specific hypermethylation. One commonly hypermethylated region is 17p13.3 (D17S5), the putative site of a tumor suppressor gene. In this study we report that hypermethylation at this locus occurs frequently (33%) in ovarian tumors. We reported previously that loss of chromosome 17 is a common event in serous epithelial ovarian tumors. A correlation of the methylation event and chromosome 17 loss suggests that hypermethylation at D17S5 precedes chromosome 17 loss.

Proliferation-associated nucleolar antigen P120: a prognostic marker in node-negative breast cancer.

BACKGROUND: P120 is a nucleolar proliferation antigen found in rapidly dividing cells and in a variety of malignancies. METHODS: Our purpose was to determine whether P120 expression is a prognostic factor for patients with node-negative breast cancer by testing pathologic material from 90 patients for P120 immunoreactivity, histologic grade, and estrogen receptors. RESULTS: P120 was detected in 52 of the 90 specimens (58%). Node-negative cancer patients with tumors that did not express the P120 antigen had a significantly better overall survival rate than node-negative cancer patients with tumors that did express P120 (92% vs 69%; p = 0.035). Histologic studies indicated that 36 tumors were grade I, 28 were grade II, and 26 were grade III. The presence of P120 correlated significantly with the nuclear grade of the tumor: 73% of grade III tumors, 64% of grade II tumors, and 42% of grade I tumors stained positive for P120 (p = 0.033). The correlation between nuclear grade and overall survival rate was also significant (grade 1, 94%; grade II, 79%; grade III, 58%); (p = 0.003). No significant correlation was found between P120 expression and estrogen receptors. Multivariate analysis shows that P120 expression and histologic grade together are the strongest predictors of survival. CONCLUSIONS: The biologic marker P120 may play an important role in determining which patients with node-negative cancer will benefit most from adjuvant therapy.

Different signaling pathways for CD18-mediated adhesion and Fc-mediated phagocytosis. Response of neutrophils to LPS.

The regulation of CD11b/CD18 adhesive and phagocytic functions on human polymorphonuclear leukocytes (PMN) in response to LPS was examined. Adhesion of PMN to surfaces coated with LPS had little or no effect on the cells, but pretreating the LPS-coated surfaces with either diluted serum or LPS-binding protein strongly enhanced their ability to bind C3bi-coated E (EC3bi), a ligand for CD11b/CD18. LPS-binding protein is known to enable responses of cells to LPS by facilitating binding of LPS to CD14. Consistent with this, we found that preformed complexes of LPS with soluble rCD14 stimulated binding of ligand by CD11b/CD18 in a concentration-dependent manner. Known agonists that stimulate CD11b/CD18 binding activity on PMN all cause simultaneous enhancement of Fc-mediated phagocytosis. However, LPS presented in complex with either serum proteins or CD14 failed to stimulate the ingestion of ElgG by PMN. The number of FcRs and their ability to bind ligand were not affected by treatment with LPS, nor were they compromised in their ability to respond to other agonists. These results suggest that LPS generates intracellular signals that alter the ability of CD11b/CD18 to bind ligand, but this alteration is not sufficient to promote phagocytosis of IgG-coated particle. This conclusion was confirmed by showing that PMN treated with LPS and serum produced a lipid with the properties of integrin-modulating factor 1: acetone extracts of these cells stimulated CD11b/CD18 adhesive capacity on PMN. However, the lipid did not enhance Fc-mediated phagocytosis. These studies suggest that CD14 affects CD11b/CD18 function by inducing the synthesis of a lipid such as IMF-1, and that this lipid affects only the binding activity, not the phagocytosis-promoting capacity of CD11b/CD18.

Ovarian cancer screening in asymptomatic postmenopausal women.

From 1987 to 1992, 3220 asymptomatic postmenopausal women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume > 10cm3 or (2) a papillary projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. If the repeat sonogram was abnormal, a morphology index score was assigned to each tumor, and a serum CA-125 was obtained. The patient then had a pelvic examination and an exploratory laparotomy. Forty-four patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy. Twenty-one patients had serous cystadenomas and 3 had primary ovarian cancers. Two patients with primary ovarian cancer had Stage IA disease and one had Stage IIIB disease. All patients with ovarian cancer had normal pelvic examinations and normal serum CA-125 levels, and are presently alive and well 32, 31, and 8 months after conventional therapy. Over 5000 screening years have been accumulated at this institution, and there have been no ovarian cancer deaths in the screened population. TVS screening has produced a decrease in stage at detection and case-specific mortality from ovarian cancer. A multi-institutional trial to test the efficacy of TVS as a screening method for ovarian cancer is indicated.