Citations

Abstract Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture. Introduction: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented. Materials and Methods: Postmenopausal women 50–79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk. Results: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45–0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44–0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47–0.72), and total fracture (HR, 0.71; 95% CI, 0.64–0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68–1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62–1.05; mid risk: HR, 1.09; 95% CI, 0.92–1.30; highest risk: HR, 1.04; 95% CI, 0.88–1.23; interaction, p = 0.42). Conclusions: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.

Background— Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-β type II receptor gene, BMPR2 , predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. Methods and Results— We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations ( P =0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. Conclusions— Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Abstract Background: Dietary glycemic index (GI) and glycemic load (GL) affect circulating insulin concentrations. Elevated circulating insulin concentrations can increase insulin-like growth factor-1, and both of these hormones may have growth-promoting effects within the colorectum. Methods: We examined associations of GI and GL with colorectal cancer (CRC) among participants in the Iowa Women's Health Study (n = 35,197; ages 55-69 years at baseline in 1986). Over 15 years of follow-up, we identified 757 cases of colon cancer and 209 cases of rectal cancer (954 CRC cases). Results: Overall, neither GI nor GL were significantly associated with incident CRC. However, among obese women (baseline body mass index ≥30 kg/m2) CRC incidence was increased in the highest versus lowest quintiles of GI (relative risk, 1.66; 95% confidence intervals, 1.13-2.43; P for trend = 0.02) and GL (relative risk, 1.79; 95% confidence intervals, 1.19-2.70; P for trend < 0.01). This pattern of increased risk for obese women with high GI or GL tended to hold for both colon cancer and rectal cancer, and for nondiabetic women as well. No statistically significant associations were observed between GI or GL and CRC among subjects whose baseline body mass index was <30 kg/m2. Conclusion: Our findings suggest that high GI or GL are not major CRC risk factors among older women in general, but may increase CRC risk among women who are obese. (Cancer Epidemiol Biomarkers Prev 2006;15(5):392–6)

Abstract In a population-based, cross-sectional study, we assessed age- and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by ∼15% in both sexes, whereas vBMD at these sites decreased by 39–55% and 34–46%, respectively, with greater decreases in women than in men. Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. Materials and Methods: In an age- and sex-stratified population sample of 373 women and 323 men (age, 20–97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. Results: In young adulthood, men had 35–42% larger bone areas than women (p < 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by ∼15% (p < 0.001) at central sites and by ∼16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p < 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (−55%) than in men (−46%, p < 0.001) at central sites, but were similar (−24% and −26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women (∼25%) than in men (∼18%, p < 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.

Abstract In an age- and sex-stratified population sample (n = 700), we estimated fall-related loads and bone strength indices at the UDR and FN. These load/strength ratios more closely simulated patterns of wrist and hip fractures occurring in the same population than did measurement of vBMD. Introduction: Areal BMD measurements, although associated with fracture risk, incompletely explain patterns of fragility fractures. Moreover, population-based assessments relating applied loads and whole bone strength to fracture patterns have not been made. Materials and Methods: Using QCT, we assessed volumetric BMD (vBMD), cross-sectional geometry, and axial (EA) and flexural (EI) rigidities (indices of bone's resistance to compressive and bending loads, respectively) at the ultradistal radius (UDR) and femoral neck (FN) and estimated the loads applied to the wrist and hip during a fall. We used fall load (FL)/bone strength ratios to estimate fracture risk. Results: vBMD in young adults was similar between sexes. Decreases in vBMD over life were also similar (30% and 28%) at UDR but were somewhat greater (46% and 34%) at FN in women versus men, respectively. In young adults, FL/strength ratios at UDR were 32–51% lower (better) in men than in women and increased (worsened) over life less in men (+4% to +22%) than in women (+20% to +33%). In young adults, FL/strength ratios at FN were only marginally better in men than in women but worsened less over life in men (+22% to +36%) than in women (+40% to +62%). Conclusions: The 6:1 female preponderance and the virtual immunity of men for age-related increases in wrist fractures are largely explained by the more favorable FL/strength ratios at UDR in young adult men (because of larger bone size and more favorable geometry) versus women and to maintaining this advantage over life. The 2-fold lower incidence of hip fractures in men versus women is largely explained by age-related increases (worsening) of FL/bone strength ratios that are only one-half of the increases in women. The moderate increases in these ratios with aging are insufficient to explain the >4-fold increase in hip fracture incidence after age 75 in both sexes, suggesting contributions of other factors, especially the well-documented increased frequency of injurious falls among the elderly.

Abstract Purpose: Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity. It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class. We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors. Experimental Design: We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly × 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m2 were administered on weeks 2 to 6. Results: The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included ≤ grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. ClTB was observed (1.75 ± 1.0 L/h/kg) compared with adult reports, with a mean t1/2B of 16.5 ± 9.7 hours. Mean oral bioavailability was 28.5 ± 22.5%. The apparent oral clearance (12.1 ± 13.0 L/h/kg) and volume of distribution (69.4 ± 30.6 L/kg) were substantially higher than in adults given similar oral doses. Conclusions: The maximum tolerated dose in children without bone marrow involvement was 30 mg/m2, similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.

Abstract In this review, we summarize work over the past 15 years on mucin gene expression and regulation in the lung, as well as how mucin gene expression is altered in chronic lung diseases. This field owes a great debt to Carol Basbaum for her pioneering work in dissecting signaling pathways regulating mucin gene expression and for her tremendous energy in promoting the importance of understanding the basic pathogenic mechanisms that drive mucus overproduction in cystic fibrosis, chronic obstructive pulmonary disease, and asthma.

Purpose The primary goal of this study was to evaluate the feasibility and effectiveness of a structured, multidisciplinary intervention targeted to maintain the overall quality of life (QOL), which is more comprehensive than psychosocial distress, of patients undergoing radiation therapy for advanced-stage cancer. Patients and Methods Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0% to 50% were randomly assigned to either an eight-session structured multidisciplinary intervention arm or a standard care arm. The eight 90-minute sessions addressed the five domains of QOL including cognitive, physical, emotional, spiritual, and social functioning. The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale (Linear Analog Scale of Assessment or modified Spitzer Uniscale). QOL was assessed at baseline, week 4 (end of multidisciplinary intervention), week 8, and week 27. Results Of the 103 participants, overall QOL at week 4 was maintained by the patients in the intervention (n = 49), whereas QOL at week 4 significantly decreased for patients in the control group (n = 54). This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group (P = .009). Intervention participants maintained their QOL, and controls gradually returned to baseline by the end of the 6-month follow-up period. Conclusion Although intervention participants maintained and actually improved their QOL during radiation therapy, control participants experienced a significant decrease in their QOL. Thus, a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment.

SUMMARY Real-time PCR has revolutionized the way clinical microbiology laboratories diagnose many human microbial infections. This testing method combines PCR chemistry with fluorescent probe detection of amplified product in the same reaction vessel. In general, both PCR and amplified product detection are completed in an hour or less, which is considerably faster than conventional PCR detection methods. Real-time PCR assays provide sensitivity and specificity equivalent to that of conventional PCR combined with Southern blot analysis, and since amplification and detection steps are performed in the same closed vessel, the risk of releasing amplified nucleic acids into the environment is negligible. The combination of excellent sensitivity and specificity, low contamination risk, and speed has made real-time PCR technology an appealing alternative to culture- or immunoassay-based testing methods for diagnosing many infectious diseases. This review focuses on the application of real-time PCR in the clinical microbiology laboratory.

Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4+CD25+ T cells with high levels of CTLA-4 and Foxp3 (intratumoral Treg cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4+CD25+ T cells suppressed the proliferation and cytokine (IFN-γ and IL-4) production of infiltrating CD4+CD25- T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4+CD25- T cells, and B7-H1 could be induced on intratumoral CD4+CD25+ T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4+CD25- T cells when cocultured with intratumoral Treg cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral Treg cells that express CCR4, but not CCR8. Taken together, our results suggest that Treg cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma.