Citations

Abstract Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3′,5′-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals. (Cancer Res 2006; 66(24): 11571-5)

Background— The 2000 European Society of Cardiology/American College of Cardiology definition for myocardial infarction (MI) combines ischemic symptoms, electrocardiographic changes, and troponin rather than creatine kinase levels. The use of troponins will increase the detection of MI by a magnitude to be quantified, and the clinical acceptance of the new definition is unknown. Method and Results— Subjects presenting to an Olmsted County facility with a troponin T value ≥0.03 ng/mL between November 2002 and March 2005 were prospectively classified through the use of standardized MI criteria, relying on cardiac pain, Minnesota coding of the ECG, and troponin, creatine kinase, and its MB fraction measured simultaneously. Through the use of dynamic changes in troponin, 538 MIs were identified versus 327 with creatine kinase and 427 with only the MB fraction of creatine kinase. This represents a 74% (95% confidence interval [CI], 69% to 79%) increase above the number of MIs identified with creatine kinase and a 41% (95% CI, 37% to 46%) increase above the number identified with criteria including only its MB fraction. When relying on single values of troponin, increases in the number of MIs were always large but varied widely according to the threshold used for troponin. Cases meeting only troponin-based criteria were less likely to have electrocardiographic ST-segment elevation and had better survival than those identified with previous criteria. Clinician diagnoses mentioned MI in 42% (95% CI, 34% to 49%) of cases meeting only troponin-based criteria versus 74% (95% CI, 69% to 78%) for MIs meeting the previous criteria ( P <0.001). Conclusions— The prospective application of the new criteria in the community results in a large increase in the number of MIs and a change in case mix. The clinical acceptance of the new criteria is incomplete, and studies that rely exclusively on dismissal diagnoses to assess MI rates may underestimate the burden of disease as presently defined.

To determine whether receptor-mediated endocytosis occurs in vasopressin-responsive cells, we developed a model system using synthetic fluorescent-labeled vasopressin analogs and A10 (smooth muscle) and LLC-PK1 (kidney epithelial) cells in culture; these cell lines express V1 and V2 vasopressin cell surface receptor types, respectively. We used epifluorescence microscopy to examine the binding, internalization, and intracellular destination of [1-(2-mercapto)propionic acid,8-lysine-N6-carboxytetramethylrhodamine] vasopressin (R-MLVP) and [1-(2-mercapto)propionic acid,8-lysine-N6-carboxyfluorescein]vasopressin (F-MLVP) in these cells. The rhodamine-labeled fluorescent vasopressin analog, R-MLVP, initially bound in a diffuse manner at the cell surface of both A10 and LLC-PK1 cells and could be displaced by excess unlabeled [8-arginine]vasopressin. After incubation at 37 degrees C, bound ligand rapidly aggregated into small clusters or patches, which were internalized in a manner consistent with receptor-mediated endocytosis. Subsequent processing of internalized ligand-receptor complexes appeared to differ between A10 and LLC-PK1 cells. In the case of LLC-PK1 cells, ligand was delivered to a tightly focused lysosome compartment in the perinuclear region of the cell, and receptor molecules were replenished at the cell surface. The lysosomal location of ligand was supported by the quenching of fluorescence in the internalized vesicles when F-MLVP was used as a fluorescent tracer. In the case of A10 cells, ligand became localized to a vesicular compartment and reappearance of receptor at the cell surface was limited. Our data are consistent with the occurrence of receptor-mediated endocytosis of vasopressin in cells with V1 and V2 receptors.

Abstract Background: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. Experimental Design: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. Results: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference χ2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. Conclusions: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.

Abstract The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of ∼42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD. Introduction: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk. Materials and Methods: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted β coefficients. Results: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD. Conclusion: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.

Abstract The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of ∼39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. Introduction: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. Materials and Methods: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. Results: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. Conclusions: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.

Respiration contributes importantly to short-term modulation of sympathetic nerve activity. However, the relationship between spontaneous breathing rate, chemoreflex function, and direct measures of sympathetic traffic in healthy humans has not been studied previously. We tested the hypothesis that muscle sympathetic nerve activity and chemoreflex sensitivity are linked independently to respiratory rate in normal subjects. We studied 69 normal male subjects aged 29.6±8.1 years. Subjects were subdivided according to the tertiles of respiratory rate distributions. Mean respiration rate was 10.6 breaths/min in the first tertile, 14.8 breaths/min in the second tertile, and 18.0 breaths/min in the third tertile. Subjects from the third tertile (faster respiratory rate) had greater sympathetic activity than subjects from the first tertile (slower respiratory rate; 29±3 versus 17±2 bursts/min; P <0.001). Stepwise multiple linear regression analysis revealed that only respiratory rate was linked independently to sympathetic activity ( r =0.42; P <0.001). In comparison to subjects with slow respiratory rate, subjects with fast respiratory rate had greater increases in minute ventilation during both hypercapnia (7.3±0.8 versus 3.2±1.0 L/min; P =0.005) and hypoxia (5.7±0.8 versus 2.4±0.7 L/min; P =0.007). Muscle sympathetic nerve activity and chemoreflex sensitivity are linked to spontaneous respiratory rate in normal humans. Faster respiratory rate is associated with higher levels of sympathetic traffic and potentiated responses to hypoxia and hypercapnia. Spontaneous breathing frequency, central sympathetic outflow, and chemoreflex sensitivity exhibit significant and hitherto unrecognized interactions in the modulation of neural circulatory control.

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.