Citations

Abstract Background: Mammographic density is a strong risk factor for breast cancer. However, whether changes in mammographic density are associated with risk remains unclear. Materials and Methods: A study of 372 incident breast cancer cases and 713 matched controls was conducted within the Mayo Clinic mammography screening practice. Controls were matched on age, exam date, residence, menopause, interval between, and number of mammograms. All serial craniocaudal mammograms 10 years before ascertainment were digitized, and quantitative measures of percent density (PD) were estimated using a thresholding method. Data on potential confounders were abstracted from medical records. Logistic regression models with generalized estimating equations were used to evaluate the interactions among PD at earliest mammogram, time from earliest to each serial mammogram, and absolute change in PD between the earliest and subsequent mammograms. Analyses were done separately for PD measures from the ipsilateral and contralateral breast and also by use of hormone therapy (HT). Results: Subjects had an average of five mammograms available, were primarily postmenopausal (83%), and averaged 61 years at the earliest mammogram. Mean PD at earliest mammogram was higher for cases (31%) than controls (27%; ipsilateral side). There was no evidence of an association between change in PD and breast cancer risk by time. Compared with no change, an overall reduction of 10% PD (lowest quartile of change) was associated with an odds ratio of 0.9997 and an increase of 6.5% PD (highest quartile of change) with an odds ratio of 1.002. The same results held within the group of 220 cases and 340 controls never using HT. Among the 124 cases and 337 controls known to use HT during the interval, there was a statistically significant interaction between change in PD and time since the earliest mammogram (P = 0.01). However, in all groups, the risk associated with the earliest PD remained a stronger predictor of risk than change in PD. Conclusion: We observed no association between change in PD with breast cancer risk among all women and those never using HT. However, the interaction between change in PD and time should be evaluated in other populations. (Cancer Epidemiol Biomarkers Prev 2007;16(5):921–8)

AbstractPrevious studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation. (Cancer Epidemiol Biomarkers Prev 2007;16(5):969–78)

Background: This study reviewed the results, complications, and patient satisfaction rates of a modified technique of flexor-to-extensor tendon transfer for correction of lesser-toe deformities. Methods: Records of 38 patients (79 toes; 46 feet) were identified and reviewed retrospectively. The mean duration of clinical followup was 33 (range 6 to 121) months. The average age of patients was 65 (range 27 to 82) years; 32 were women (84%) and six were men. Results: In 89% of the toes (70 toes; 34 patients; 42 feet) patients were satisfied with the procedure and would have it again. Conclusions: The technique described for flexor-to-extensor transfer for correction of lesser-toe deformities resulted in few complications, no “floating” toes and high patient satisfaction.

AbstractThe molecular structure and agonist-induced conformational changes of class II G protein-coupled receptors are poorly understood. In this work, we developed and characterized a series of dual cyan fluorescent protein (CFP)-tagged and yellow fluorescent protein (YFP)-tagged secretin receptor constructs for use in various functional and fluorescence analyses of receptor structural variants. CFP insertions within the first or second intracellular loop domains of this receptor were tolerated poorly or partially, respectively, in receptors tagged with a carboxyl-terminal yellow fluorescent protein that itself had no effect on secretin binding or cAMP production. A similar CFP insertion into the third intracellular loop resulted in a plasma membrane-localized receptor that bound secretin and signaled normally. This fully active third-loop variant exhibited a significant decrease in fluorescence resonance energy transfer signals that were recorded with an acousto-optic tunable filter microscope after exposure to secretin agonist but not to a receptor antagonist. These data demonstrate changes in the relative positions of intracellular structures that support a model for secretin receptor activation.

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a novel marker and participant in vascular inflammation. Inflammation also is associated with coronary atherosclerosis. We tested the hypothesis that local coronary production of Lp-PLA 2 is enhanced in patients with early coronary atherosclerosis and associated with local endothelial function. Methods and Results— Coronary angiography, blood flow, flow reserve, endothelial function assessment, and intravascular ultrasound with volumetric analysis were performed in 15 patients with mild coronary atherosclerosis and in 15 control subjects. Plasma samples were collected simultaneously from the left main coronary artery and coronary sinus for measurement of Lp-PLA 2 , lysophosphatidylcholine (a product of Lp-PLA 2 ), and C-reactive protein. Hemodynamic parameters and cholesterol were similar in both groups. Arterial Lp-PLA 2 levels were similar in patients and control subjects: 225 ng/mL (interquartile range [IQR], 196 to 273 ng/mL) versus 221 ng/mL (IQR, 177 to 294 ng/mL). Lp-PLA 2 net production in the coronary circulation was higher in patients compared with control subjects: 519 ng/min (IQR, 198 to 1276 ng/min) versus −529 ng/min (IQR, −872 to −79 ng/min; P =0.001) and correlated with percent atheroma volume ( r s =0.37, P =0.04). Net production of lysophosphatidylcholine was higher in patients compared with control subjects: 199 ng/min (IQR, −592 to 470 ng/min) versus −505 ng/min (IQR, −1119 to 0 ng/min; P =0.03) and correlated with coronary endothelial dysfunction ( r s =0.5, P =0.005). C-reactive protein was not significantly different between the groups. Conclusions— Early coronary atherosclerosis in humans is characterized by local production of Lp-PLA 2 . Local coronary production of lysophosphatidylcholine, the active product of Lp-PLA 2 , is associated with endothelial dysfunction. These results support the role for Lp-PLA 2 in the mechanism of regional vascular inflammation and atherosclerosis in humans.

Background— Long-QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. We sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis. Methods and Results— Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic’s LQTS Clinic, patients were categorized as having definite LQTS (D-LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% compared with 34% for P-LQTS and 0% among No-LQTS patients ( P <0.0001). The average QTc was greater in either D-LQTS or P-LQTS than in No-LQTS (461 versus 424 ms, P <0.0001). Vasovagal syncope was more common among the No-LQTS subset (28%) than the P-LQTS/D-LQTS group (8%; P =0.04). Determinants for discordance (ie, positive outside diagnosis versus No-LQTS) included overestimation of QTc, diagnosing LQTS on the basis of “borderline” QTc values, and interpretation of a vasovagal fainting episode as an LQTS-precipitated cardiac event. Conclusions— Diagnostic concordance was present for less than one third of the patients who sought a second opinion. Two of every 5 patients referred with the diagnosis of LQTS departed without such a diagnosis. Miscalculation of the QTc, misinterpretation of the normal distribution of QTc values, and misinterpretation of symptoms appear to be responsible for most of the diagnostic miscues.

Patients with hypertension have a blunted sensitivity of baroreflex control of heart period. In these patients, baroreflex sensitivity is positively related to heart rate variability and inversely related to blood pressure variability. We hypothesized that this relationship would also be evident in healthy normotensive subjects and that individuals with higher baroreflex sensitivity would have lower ambulatory 24-hour blood pressure. Twenty-four-hour ambulatory blood pressure and heart rate were recorded in 50 healthy, normotensive, nonobese individuals (31 women and 19 men). The baroreflex was assessed using sequential bolus administration of sodium nitroprusside and phenylephrine, and baroreflex sensitivity was calculated as the slope of the relation between systolic blood pressure and R-R interval during the resulting blood pressure transients. Baroreflex sensitivity was inversely correlated to 24-hour average mean arterial pressure ( R =0.49; P <0.001) and positively related to daytime heart rate variability ( R =0.33; P =0.02). In contrast, no relationship was found between baroreflex sensitivity and 24-hour heart rate or blood pressure variabilities. We conclude that the relationship between baroreflex sensitivity and daytime heart rate variability was similar to that reported previously in hypertensive subjects. Furthermore, the inverse relation between baroreflex sensitivity and mean arterial pressure supports the idea that the baroreflex may exert longer-term effects on blood pressure than thought previously.

AbstractTLRs are usually thought to recognize substances produced by microorganisms and thus, to initiate host defenses. This concept, however, fails to explain some functions of this family of receptors. Recognition of endogenous substances may explain the broader functions of TLRs in physiology and disease. Activation of TLRs by endogenous substances necessitates vigorous control of the function of the receptors. This communication will summarize a line of research, which points to an endogenous agonist for TLR4 and a putative mechanism for controlling the function of that receptor.