Genetic analysis of early- versus late-stage ovarian tumors

In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.     

Fumonisin B1 induces apoptosis in cultured human keratinocytes through sphinganine accumulation and ceramide depletion

Fumonisin B1 stimulates apoptosis in a variety of cell types and tissues. We examined the role of sphingolipid changes in fumonisin B1-stimulated apoptosis. Sphinganine accumulated rapidly, sphingosine levels remained unchanged, and ceramides decreased during fumonisin B1 exposure. Increased DNA fragmentation, decreased viability, and apoptotic morphology were observed in cells exposed to fumonisin B1, sphinganine, or N-acetylsphingosine. Co-exposure to N-acetylsphingosine or beta-chloroalanine, which blocks sphinganine accumulation, partially protected cells from fumonisin B1-induced apoptosis. These results illustrate three sphingolipid-dependent mechanisms for inducing apoptosis: accumulation of excess ceramide, accumulation of excess sphinganine, and depletion of ceramide or complex sphingolipids derived from ceramide.     

Changes in plasma osteocalcin concentration following treatment with stanozolol

Treatment of healthy, adult, human volunteers with stanozolol, 5 mg twice daily, for six weeks caused a marked elevation in circulating levels of osteocalcin. Plasma osteocalcin concentrations did not fall to pretreatment values for a period in excess of four weeks after the cessation of treatment but remained similar to levels whilst on treatment. At the same time, as the rise in plasma osteocalcin was seen, plasma alkaline phosphatase activity fell; however, in this case, a return to pretreatment levels occurred within four weeks of treatment ending. These data demonstrate that stanozolol has a detectable effect on the plasma concentration of a protein thought to be a marker of osteoblast activity, and that this effect continues for a period after treatment has been discontinued.     

Breast MRI: Early experience with a 3-D fat-suppressed Gradient Echo Sequence in the evaluation of breast lesions

The early clinical experience with a 3-Dimensional Fourier Transform Gradient Echo sequence with fat suppression in the evaluation of breast masses is reported. Ten female patients with breast malignancies were pre-operatively evaluated with this sequence and the results compared with the pathological specimens. The scanning protocol included a noncontrast sequence followed by an immediate post-contrast sequence (completed 4.5 min after intravenous contrast injection) and a delayed sequence. Images were assessed for maximum lesion and parenchymal enhancement, lesion size and additional enhancing abnormalities. In six patients, malignant masses enhanced maximally on the immediate post-contrast sequence with parenchyma enhancing maximally on delayed images. In three cases, there was preferential enhancement of malignant lesions over normal parenchyma but to a similar degree on both post-contrast sequences. In one case, both the lesion and parenchyma enhanced maximally on the delayed sequence. Magnetic resonance assessed lesion size accurately and also detected satellite malignancies in one case. However, lesion grade, associated in situ carcinoma and lymphovascular invasion did not impact on lesion enhancement. In this small series, a contrast-enhanced, fat-suppressed 3-D Gradient Echo Sequence detected breast carcinoma with high sensitivity. The technique holds promise but further evaluation is required.     

Inflammatory bowel disease and predisposition to osteopenia

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.     

Selecting an equation to estimate glomerular filtration rate for use in renal dosage adjustment of drugs in electronic patient record systems

STUDY OBJECTIVE: To identify a variant of the Cockcroft-Gault equation whose estimate would agree with the Modification of Diet in Renal Disease (MDRD) estimate of glomerular filtration rate (GFR) since the MDRD equation may not be programmable in some electronic patient record systems. DESIGN: Prospective case series. SETTING: A 625-bed, adults-only, private, tertiary care teaching hospital. PATIENTS: Two hundred eight consecutive hospitalized patients with MDRD-estimated GFRs less than 90 ml/minute/1.73 m 2 . Seventeen patients were black (includes native African immigrants). INTERVENTION: Chemistry assays were performed, and patients' records were reviewed for age, ethnic background, height, and actual weight. Ideal weight, corrected weight, body mass index, body surface area (BSA), and GFR by the original MDRD equation were calculated for each patient. MEASUREMENTS AND MAIN RESULTS: Cockcroft-Gault estimates of renal clearance were calculated by using actual weight, ideal weight, and corrected weight both with and without correction for BSA. These estimates, as well as an estimate of GFR by the abbreviated MDRD equation, were compared with the original MDRD estimate. The results obtained with the abbreviated MDRD equation and with the Cockcroft-Gault equation that used corrected weight and BSA adjustment had the best agreement; both were within +/- 30% of the original MDRD equation in 80% of the 208 patients' results. All other Cockcroft-Gault variants tested were less accurate. CONCLUSION: Electronic patient record databases may not contain a nominal variable database field for black or non-black status, which is required by the MDRD equations. The Cockcroft-Gault equation that used corrected weight and BSA adjustment performed about as well as the abbreviated MDRD equation and can be programmed into electronic patient records. Given the small number of black patients included in this study, further study in this patient population is recommended before applying this Cockcroft-Gault variant to this subgroup.     

Impact of respiratory virus infections on persons with chronic underlying conditions

CONTEXT: While hospitalization rates have declined overall, hospitalizations for acute lower respiratory tract infections have increased steadily since 1980. Development of new approaches for prevention of acute respiratory tract conditions requires studies of the etiologies of infections and quantification of the risk of hospitalization for vulnerable patients. OBJECTIVE: To determine the frequency of specific virus infections associated with acute respiratory tract conditions leading to hospitalization of chronically ill patients. DESIGN: Analysis of viral etiology of patients hospitalized with acute respiratory tract conditions between July 1991 and June 1995. SETTING: Four large clinics and related hospitals serving diverse populations representative of Harris County, Texas. PATIENTS: A total of 1029 patients who were hospitalized for pneumonia, tracheobronchitis, bronchiolitis, croup, exacerbations of asthma or chronic obstructive pulmonary disease, and/or congestive heart failure. MAIN OUTCOME MEASURE: Virus infection, defined by culture, antigen detection, and significant rise in serum antibodies, by underlying condition; hospitalization rates by low- vs middle-income status. RESULTS: Ninety-three percent of patients older than 5 years had a chronic underlying condition; a chronic pulmonary condition was most common. Patients with chronic pulmonary disease from low-income populations were hospitalized at a rate of 398.6 per 10000, almost 8 times higher than the rate for patients from middle-income groups (52.2 per 10000; P<.001). Of the 403 patients (44.4% of adults and 32.3% of children) who submitted convalescent serum specimens for antibody testing, respiratory tract virus infections were detected in 181 (44.9%). Influenza, parainfluenza, and respiratory syncytial virus (RSV) infections accounted for 75% of all virus infections. CONCLUSIONS: Our study suggests that respiratory virus infections commonly trigger serious acute respiratory conditions that result in hospitalization of patients with chronic underlying conditions, highlighting the need for development of effective vaccines for these viruses, especially for parainfluenza and RSV.     

Use of confirmatory factor analysis for the identification of new components of the metabolic syndrome: the role of plasminogen activator inhibitor-1 and Haemoglobin A1c

BACKGROUND AND AIM: This study was aimed to identify additional components of metabolic syndrome from a set of cardiovascular risk markers. METHODS AND RESULTS: The homeostasis model assessment of insulin resistance (HOMA-IR), C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor, homocysteine, Haemoglobin A1c (HbA1c), and lipoprotein(a) were assessed in a population-based sample of 902 nondiabetic adult subjects. Those biomarkers that were associated with metabolic syndrome were evaluated by multiple regression analysis, along with other traditional cardiovascular risk factors. Confirmatory factor analysis (CFA) was used to test the hypothesis that both the established components of metabolic syndrome and the novel variables identified by the regression analysis were associated with a single underlying factor. HOMA-IR, PAI-1 and HbA1c were the only biomarkers independently related to metabolic syndrome. CFA validated a one-factor model that included these variables. Moreover, the indices of goodness of fit were better for this expanded model than those obtained for a previously validated one-factor model that was restricted to the conventional elements of the syndrome. CONCLUSIONS: These findings show that PAI-1 and HbA1c are singularly linked to metabolic syndrome. Their elevation is presumably another manifestation of the same pathophysiological mechanism that underlies the recognized traits of the syndrome.