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Resumen: Objetivo: medir el impacto de la terapia de resincronización cardiaca en términos de variables ecocardiográficas en pacientes de países latinoamericanos. Método: se realizó un estudio prospectivo, multicéntrico, intervencionista, en el que los pacientes elegibles fueron llevados, por primera vez, a implante de un dispositivo de resincronización cardiaca. El objetivo primario fue valorar los cambios del tamaño y la función del ventrículo izquierdo por medio de un ecocardiograma previo al implante del dispositivo y en el sexto mes. Los objetivos secundarios evaluados fueron hospitalizaciones, cambios en la clase funcional, mortalidad, calidad de vida y un score compuesto clínico basado en estos factores de evaluación global del paciente. Resultados: para cumplir el objetivo primario se analizaron datos de 75 sujetos. La edad promedio fue de 63,7 años; 21.3% fueron mujeres y 30.7% tuvieron cardiopatía isquémica. Al sexto mes de seguimiento las mediciones de volumen de fin de diástole y sístole del ventrículo izquierdo disminuyeron en promedio 37.6 ml y 37.8 ml, respectivamente. La fracción de eyección del ventrículo izquierdo en promedio se incrementó un 11%. El puntaje compuesto clínico mostró mejoría en el 86.4% de los pacientes en el sexto mes postimplante del resincronizador. Conclusiones: se observó remodelado inverso del ventrículo izquierdo y mejoría en el estado clínico de los pacientes con insuficiencia cardiaca y disfunción sistólica del ventrículo izquierdo que recibieron terapia de resincronización cardiaca en el ámbito de la práctica clínica de rutina. Abstract: Objective: To measure the impact of cardiac resynchronisation therapy in terms of cardiac ultrasound variables in patients from Latin-American countries. Method: A prospective, multicentre, interventionist study was conducted, in which the eligible patients were those that had a cardiac resynchronisation device implanted for the first time. The primary objective was to assess the changes in size and left ventricular function by means of a cardiac ultrasound carried out prior to implanting the device and in the sixth month. The secondary objectives evaluated were hospital admissions, change in functional class, mortality, quality of life, and an overall assessment of the patient using a combined clinical score based on these factors. Results: A total of 75 subjects were analysed in order to complete the primary objective. The mean age was 63.7 years; 21.3% were female, and 30.7% had ischaemic heart disease. At the sixth month, the left ventricular end-diastolic and systolic volume decreased by a mean of 37.6 ml and 37.8 ml, respectively. The left ventricular ejection fraction increased by a mean of 11%. The combined clinical score showed an improvement in 86.4% of the patients in the sixth month after the implantation of the synchronisation device. Conclusions: A reverse remodelling of the left ventricle was observed, as well as an improvement in the clinical stage of patients with heart failure and left ventricular systolic dysfunction that received cardiac resynchronisation treatment in the setting of routine clinical practice.

Background Estrogen may inhibit cell senescence that contributes to age‐related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. Methods Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead‐based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β‐estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. Results Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [−108 pg/mL (p = .008), −234 pg/mL (p = .0006), and −1374 pg/mL (p, Hormonal treatments reduced the levels of selected markers of aging in the blood of recently menopausal women.

Background Administrative databases that capture diagnostic codes are increasingly being used worldwide for research because they can save time and reduce costs. However, assessing validity is necessary before defining diseases using only diagnostic codes in research applications. Objective Our objective was to assess the validity of using diagnostic codes to identify incident Parkinson's disease (PD) cases in Olmsted County, Minnesota using an established standard for comparison (1976–2005). Methods Cases were identified solely using computer programs applied to administrative diagnostic code indexes from the Rochester Epidemiology Project (REP). Two codes >30 days apart or one code on the death certificate constituted PD. The standard was a clinical diagnosis by movement disorders specialists based on medical record review. Validity was assessed using positive predictive value (PPV) and sensitivity. Numbers of incident cases and incidence rates were compared between the two ascertainment methods by sex. Results The codes only method over-counted the number of incident PD cases by 73% (804 versus 464), and this over-counting generally increased with calendar year. Sensitivity was 80% (95% CI [76%, 84%]) and PPV was 46% (95% CI [34%, 50%]). Disease status misclassification accounted for two-thirds of falsely identified cases, where individuals were found to not have PD (43%) or even parkinsonism (23%) after medical record review. The codes only method also over-estimated the incidence rate time trend for men and women by approximately two-fold. Conclusion In our context, using administrative diagnostic codes only to identify incident PD cases is not recommended unless more accurate algorithms are developed.

Implantable cardioverter-defibrillator (ICD) shocks are associated with increased anxiety, health care utilization, and potentially mortality.The purpose of the Shock-Less Study was to determine if providing feedback reports to physicians on their adherence to evidence-based shock reduction programming could improve their programming behavior and reduce shocks.Shock-Less enrolled primary prevention (PP) and secondary prevention (SP) ICD patients between 2009 and 2012 at 118 study centers worldwide and followed patients longitudinally after their ICD implant. Center-specific therapy programming reports (TPRs) were delivered to each center 9 to 12 months after their first enrollment. The reports detailed adherence to evidence-based programming targets: number of intervals to detect ventricular fibrillation (VF NID), longest treatment interval (LTI), supraventricular tachycardia (SVT) discriminators (Wavelet, PR Logic), SVT limit, Lead Integrity Alert (LIA), and antitachycardia pacing (ATP). Clinicians programmed ICDs at their discretion. The primary outcome measure was the change in utilization of evidence-based shock reduction programming before (phase I, n = 2694 patients) and after initiation of the TPR (phase II, n = 1438 patients).Patients implanted after feedback reports (phase II) were up to 20% more likely to have their ICDs programmed in line with evidence-based shock reduction programming (eg, VF NID in PP patients 30/40 in 33.5% vs 18.6%, P.0001). Patients implanted in phase II had a lower risk of all-cause shock (adjusted hazard ratio 0.72, 95% confidence interval 0.58-0.90, P = .003).Providing programming feedback reports improves adherence to evidence-based shock reduction programming and is associated with lower risk of ICD shocks.

Introduction Radiofrequency (RF) ablation is effective for slow pathway ablation, but carries a risk of inadvertent AV block requiring permanent pacing. By comparison, cryoablation with a 4 mm distal electrode catheter has not been reported to cause permanent AV block but has been shown to be less effective than RF ablation. We sought to define the safety and efficacy of a 6 mm distal electrode cryoablation catheter for slow pathway ablation in patients with atrioventricular nodal reentry tachycardia (AVNRT). Methods and results Twenty-six US and eight Canadian centers participated in the study. Patients with supraventricular tachycardia (SVT) thought likely to be AVNRT were enrolled. If AVNRT was inducible and confirmed to be the clinical SVT, then the slow pathway was targeted with a cryoablation catheter using a standardized protocol of best practices. Acute success was defined as inducibility of no more than one echo beat after cryoablation. Primary efficacy was defined as acute success and the absence of documented recurrent AVNRT over 6 months of follow-up. Primary safety was a composite of serious procedure-related adverse events and/or device-related complications. 397 subjects met enrollment criteria after the EP study and received cryoablation. Mean ablation procedure duration (including a waiting period) was 89 ± 40 min, and mean fluoroscopy time was 4.8 ± 5.9 min. Isoproterenol was administered before cryoablation in 53% and after the last lesion in 85% of cases. Acute procedural success was realized in 95% (378/397) of subjects. No subject received a permanent pacemaker due to AV block. The slow pathway could not be ablated in 19 subjects, including: 12 due to inefficacy, 2 due to transient AV block, and 5 due to both inefficacy and transient AV block. RF ablation was used in the same procedure in 11 of 19 failed subjects, and was ineffective in 3 subjects. Among the group with acute success, 10 subjects (2.7%) had documented recurrent AVNRT over the 6-month follow-up period, and all occurred within 3 months of the index cryoablation. Serious procedure-related adverse events occurred in 4 subjects (1.0%), including one each: tamponade, pulmonary embolism, femoral vein hemorrhage, and diagnostic EP catheter knotting. None of these serious adverse events were related to use of the cryoablation catheter. Overall, 93% of subjects had successful slow pathway ablation at 6 months with the study cryoablation catheter. Conclusions Cryoablation for AVNRT using a focal 6 mm catheter was safe and effective. It resulted in a low risk of recurrence over 6 months of follow-up with no incidence of AV block requiring permanent pacing. This article is protected by copyright. All rights reserved

Aims This cross-sectional study evaluated the application of accepted international implantable cardioverter defibrillator (ICD) guidelines for primary prevention of sudden cardiac death in patients with heart failure. Methods and results The PLASMA (Probabilidad de Sufrir Muerte Arritmica) study was designed to characterize management of cardiac patients in Latin America. Twelve centres included 1958 consecutively admitted patients in cardiology units in 2008 and 2009. Discharged patients were evaluated for primary prevention, ICD indication and prescription by general cardiologists. Of 1711 discharged patients, 1525 (89%) had data available for evaluating indication status. Class I indications for ICD therapy were met for 153 (10%) patients based on collected data. Only 20 (13%, 95% confidence interval: 7.7–18.4%) patients with indication were prescribed an ICD. Patients prescribed an ICD were younger than patients who were not prescribed an ICD (62 vs. 68 years, P < 0.01). The reasons given by cardiologists for not prescribing an ICD for 133 patients with an indication were: indication criteria not met (75%), life expectancy

Objectives The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) ≤30%. Background Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. Methods This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non–life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. Results Analyses were conducted on 575 patients (84% male; average age ± SD = 65 ± 11 years; average LVEF ± SD = 0.24 ± 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 ± 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). Conclusions In MADIT-II–indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I–Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240 )

We investigated the risk of cancer after the diagnosis of Parkinson's disease (PD) through a historical cohort study. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of PD in Olmsted County, Minnesota from 1976 through 1995. Patients with PD were matched by age (+/- 1 year) and gender to referent subjects from the same population. For 196 patients and 185 referent subjects, we ascertained the incidence of cancer through medical records abstraction between the date of diagnosis (or index date) and death, loss to follow-up, or end of study. The risk of cancer was higher among patients than in referent subjects (relative risk [RR] = 1.64; 95% confidence interval [CI] = 1.15-2.35; P = 0.007). The RR did not change noticeably after adjustment for smoking. The increased risk was significant for nonmelanoma skin cancer (RR = 1.76; 95% CI = 1.07-2.89; P = 0.03), but not for other more severe types of cancer; therefore, we cannot exclude the occurrence of a surveillance bias. Among PD patients, there was no relation between the risk of cancer and the cumulative dose of levodopa received or the use of other PD medications.

Background Circulating testosterone plays an important role in maintenance and growth of prostate cells. Luteinizing hormone (LH), secreted from the anterior pituitary, signals testicular Leydig cells to secrete testosterone. A genetic variant of the LH-β protein, LH-βV, exists in up to 40% of Caucasians and is more bioactive than the wild-type protein. We hypothesized that genetically determined variation in LH function might affect susceptibility to prostate cancer via altered testosterone secretion. Methods We determined the frequency of the LH-βV polymorphism (two linked polymorphisms: Trp8 Arg and Ile15 Thr) in familial prostate cancer patients (n = 446), in sporadic prostate cancer patients (n = 388), and in population-based controls without prostate cancer (n = 510) to assess the role of this polymorphism in susceptibility to prostate cancer. Results A higher frequency of this variant genotype (LH-βV: Arg8/Thr15) was observed in familial prostate cancer patients (18.6%) than in controls (13.7%), and after taking into account the correlation of the familial cases and adjusting for age and body mass index (BMI), there was a weak positive association between the variant LH-β genotype, and risk of familial prostate cancer (OR = 1.29; 95% CI 0.96–1.75). The sporadic case group was also slightly more likely to have a variant genotype (15.2%) compared to the controls (13.7%), and after adjustment for age and BMI, a similar association with this variant was found (OR = 1.33; 95% CI 0.86–02.07). Surgical cases showed a slightly stronger association for the variant LH-β genotype compared to non-surgical cases, but among the surgical cases there was little variability in risk across nodal status, stage, and tumor grade. Conclusions These data are consistent with the hypothesis that the LH-β variant is a weak risk factor for prostate cancer. Prostate 56: 30–36, 2003. © 2003 Wiley-Liss, Inc.

The DNA-damage–signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage–signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus–transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage–signaling pathway may play an important role in the development of prostate cancer.

The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (χ 2 trend test=1.42; P =.23) or the Asp541 variant (χ 2 =1.52; P =.22). However, significant differences were detected for the Arg462Gln genotypes (χ 2 =5.20; P =.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32–0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis ≤64 years) ( P =.0008; OR=0.29; 95% CI=0.13–0.66), in node-negative patients ( P =.01; OR=0.48; 95% CI 0.27–0.84), patients with stage T 1 /T 2 disease ( P =.008; OR=0.39; 95% CI 0.2–0.75), and patients with low-grade disease ( P =.01; OR=0.40; 95% CI 0.20–0.78). To evaluate whether this variant was also associated with sporadic PC, we genotyped an additional 499 patients with sporadic PC. Differences in frequency were not detected between patients with sporadic disease and control subjects. However, the same association was observed between patients with familial disease and patients with sporadic disease for the entire group (χ 2 =4.82; P =.03), as well as in the subset analyses. These results suggest that polymorphic changes within the RNASEL gene may be associated with increased risk of familial but not sporadic PC.

We applied the incidence rates of parkinsonism and Parkinson's disease (PD) from Olmsted County, MN (1976–1990) to a hypothetical cohort undergoing the mortality rates observed in Minnesota, and computed the lifetime risk and the remaining lifetime risk of developing parkinsonism and PD. These risks were compared to cumulative incidences that do not take competing risks of death into account. The lifetime risk of developing parkinsonism from birth was 4.4% for men and 3.7% for women (ratio = 1.2). The corresponding risk of developing PD was 2.0% for men and 1.3% for women (ratio = 1.5). Because of the opposite effect of higher incidence and higher mortality rates in men, the lifetime risks were only slightly higher in men than in women. Lifetime cumulative incidences were consistently higher than lifetime risks; this difference was more pronounced in men and in older subjects. Lifetime risk estimates are useful in clinical practice, epidemiologic research, and public health.

We studied the association of Parkinson's disease (PD) with type of menopause (natural or surgical), age at menopause, and postmenopausal estrogen replacement therapy using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 72 women who developed PD in Olmsted County, MN, during the twenty years 1976-1995. Each incident case was matched by age (+/- 1 year) to a general population control subject. We collected exposure data through review of the complete medical records of cases and control subjects in the system. PD cases had undergone hysterectomy (with or without unilateral oophorectomy) significantly more often than control subjects (odds ratio [OR] = 3.36; 95% confidence interval [CI] = 1.05-10.77). In addition, PD cases had experienced early menopause (< or = 46 years) more commonly than control subjects (OR = 2.18; 95% CI = 0.88-5.39). Finally, PD cases had used estrogens orally or parenterally for at least 6 months after menopause less frequently (8%) than control subjects (14%; OR = 0.47; 95% CI = 0.12-1.85). However, the findings for early menopause and estrogen replacement therapy were not statistically significant. Despite the limited sample size of this exploratory study, we hypothesize that there is an increased risk of PD in conditions causing an early reduction in endogenous estrogen. This hypothesis needs to be confirmed in a larger study.

Objective: To investigate time trends in the incidence of parkinsonism and PD over a 15-year period (1976 to 1990).Methods: The authors used the medical records–linkage system of the Rochester Epidemiology Project to identify incidence cases of parkinsonism in Olmsted County, MN, over three 5-year periods, 1976 to 1980, 1981 to 1985, and 1986 to 1990. PD and other types of parkinsonism were classified using defined criteria. Population denominators were derived from census data and were corrected by removing prevalent cases of parkinsonism.Results: Over the 15 years of the study, 364 cases of parkinsonism were identified; 154 (42%) of them had PD. The incidence of parkinsonism remained stable over the three 5-year periods for the age classes 0 to 39, 40 to 59, and 60 to 69 years. For the age class 70 to 99 years, there was some increase over time mainly owing to an increased incidence of drug-induced parkinsonism. The incidence of PD remained stable over the three 5-year periods for all age classes. Results were similar when considering men and women separately. No birth-cohort effect was present for parkinsonism. Comparison with three previous studies in the same population did not reveal any major long-term secular trends in the incidence of parkinsonism.Conclusions: The findings for PD over 15 years and comparison of the findings with historical data for parkinsonism over half a century suggest that no major environmental risk factors for PD (e.g., environmental toxins, drugs, diet constituents, or infectious agents) were introduced or removed from this population during these periods.

A recent study of hereditary prostate cancer has provided evidence for a prostate cancer–susceptibility locus, HPC20, which maps to 20q13. To assess further the potential contribution of this locus to prostate cancer susceptibility, we studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. Parametric analysis, allowing for heterogeneity, resulted in an overall HLOD score of 0.09 (P=.39) at D20S171, under the assumption of linkage in 6% of families. Mode-of-inheritance–free analysis of the entire data set resulted in a maximal Zlr score of 0.76 (LOD 0.13; P=.22) at the same location. The strongest evidence for linkage was seen in the subset of 16 black families (LOD 0.86; Zlr=1.99; P=.023) between markers D20S893 and D20S120, near the putative location of HPC20. Although some positive results were observed, our linkage study does not provide statistically significant support for the existence of a prostate cancer–susceptibility locus HPC20 at 20q13.

To study the association of PD with preceding smoking, alcohol, and coffee consumption using a case-control design.The authors used the medical records linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, during the years 1976 to 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control subject. The authors reviewed the complete medical records of cases and control subjects to abstract exposure information.For coffee consumption, the authors found an OR of 0.35 (95% CI = 0.16 to 0.78, p = 0.01), a dose-effect trend (p = 0.003), and a later age at PD onset in cases who drank coffee compared with those who never did (median 72 versus 64 years; p = 0.0002). The inverse association with coffee remained significant after adjustment for education, smoking, and alcohol drinking and was restricted to PD cases with onset at age72 years and to men. The OR for cigarette smoking was 0.69 (95% CI = 0.45 to 1.08, p = 0.1). The authors found no association between PD and alcohol consumption. Extreme or unusual behaviors such as tobacco chewing or snuff use and a diagnosis of alcoholism were significantly more common in control subjects than cases.These findings suggest an inverse association between coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered.

We studied the association between preceding psychiatric disorders and Parkinson's disease (PD) using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, Minnesota, during the years 1976-1995. Each case was matched by age (+/-1 yr) and sex to a general population control. We reviewed the complete medical records of cases and control subjects to detect preceding psychiatric disorders. The frequency of psychiatric disorders was higher in cases than in control subjects; the odds ratio was 2.2 for anxiety disorders (95% confidence interval [95% CI] = 1.4-3.4; p = 0.0003), 1.9 for depressive disorders (95% CI = 1.1-3.2; p = 0.02), and 2.4 for both anxiety disorders and depressive disorders occurring in the same individual (95% CI = 1.2-4.8; p = 0.02). When we restricted analyses to disorders present 5 years or more before the onset of motor symptoms of PD, the association with depressive disorders lost statistical significance. However, the association with anxiety disorders remained significant for disorders present 5, 10, or 20 years before onset of motor symptoms. Our results suggest that anxiety disorders and depressive disorders are associated with PD and that the causative process or the risk factors underlying PD are present many years before the appearance of motor symptoms.

Recent studies suggest that hereditary prostate cancer (PRCA) is a complex disease, involving multiple susceptibility genes and variable phenotypic expression. Through linkage analysis, potential prostate cancer susceptibility loci have been mapped to 3 regions on chromosome 1. To investigate the reported linkage to these regions, we conducted linkage studies on 144 PRCA families by using microsatellite markers in regions 1q24-25 (HPC1) and 1q42.2-43 (PCAP). We also examined the 1p36 (CAPB) region in 13 PRCA families with at least one case of brain cancer. No significant evidence of linkage to the HPC1 or PCAP region was found when the entire data set was analyzed. However, weak evidence for linkage to HPC1 was observed in the subset of families with male-to-male transmission (n=102; maximum multipoint nonparametric linkage [NPL] 1.99, P=.03). Weak evidence for linkage with heterogeneity within this subset was also observed (HLOD 1.21, P=.02), with approximately 20% of families linked. Although not statistically significant, suggestive evidence for linkage to PCAP was observed for the families (n=21) that met the three criteria of male-to-male transmission, average age of diagnosis66 years, and/=5 affected individuals (maximum multipoint NPL 1.45, P=.08). There was no evidence for linkage to CAPB in the brain cancer-prostate cancer subset. These results strengthen the argument that prostate cancer is a heterogeneous disease and that multiple genetic and environmental factors may be important for its etiology.

Cardiac resynchronization therapy (CRT) can improve clinical and cardiac structural status in heart failure patients. The role of baseline diastolic echocardiographic parameters to characterize the likelihood of positive outcomes is not well known. We explored relationships between diastolic parameters and outcomes 6 months after CRT implant in the Predictors of Response to CRT (PROSPECT) Trial.We hypothesized that diastolic echocardiographic parameters were associated with clinical and structural outcomes in CRT patients.For 426 patients in PROSPECT, a prospective observational trial of CRT, baseline E/A ratio, left atrial (LA) area, isovolumic relaxation time, left ventricular inflow deceleration time, E' velocity, and E/E' ratio were evaluated and related to 6-month clinical composite score (CCS) and left ventricular end-systolic volume (LVESV) reduction using Spearman rank-order correlations. Parameters associated with outcomes were analyzed further by discrete categorization.As continuous variables, only E/A ratio and LA area correlated with CCSs (P = 0.017, P = 0.045, respectively) and relative change in LVESV at 6 months (P0.0001, P = 0.001, respectively). As discrete variables, E/A ratio and LA area also correlated with CCSs and LVESV.Diastolic echo parameters E/A ratio and LA area were associated with clinical and structural outcomes in CRT patients at 6 months.

Background— For patients with symptomatic New York Heart Association class III or IV, ejection fraction ≤35%, and QRS ≥130 ms, cardiac resynchronization therapy (CRT) has become an established treatment option. However, use of these implant criteria fails to result in clinical or echocardiographic improvement in 30% to 45% of CRT patients. Methods and Results— The Predictors of Response to CRT (PROSPECT)-ECG is a substudy of the prospective observational PROSPECT trial. ECGs collected before, during, and after CRT implantation were analyzed. Primary outcomes were improvement in clinical composite score (CCS) and reduction of left ventricular end systolic volume (LVESV) of >15% after 6 months. Age, sex, cause of cardiomyopathy, myocardial infarction location, right ventricular function, mitral regurgitation, preimplantation QRS width, preimplantation PR interval, preimplantation right ventricular–paced QRS width, preimplantation axis categories, LV-paced QRS width, postimplantation axis categories, difference between biventricular (Bi-V) pacing and preimplantation QRS width, and QRS bundle branch morphological features were analyzed univariably in logistic regression models to predict outcomes. All significant predictors (α=0.1), age, and sex were used for multivariable analyses. Cardiomyopathy cause interaction and subanalyses were also performed. In multivariable analyses, only QRS left bundle branch morphological features predicted both CCS (odds ratio [OR]=2.46, P =0.02) and LVESV (OR=2.89, P =0.048) response. The difference between Bi-V and preimplantation QRS width predicted CCS improvement (OR=0.89, P =0.04). LV-paced QRS width predicted LVESV reduction (OR=0.86, P =0.01). Specifically, an LV-paced QRS width of ≤200 ms was predictive of nonischemic LVESV reduction (OR=5.12, P =0.01). Conclusions— Baseline left bundle branch QRS morphological features, LV-paced QRS width, and the difference between Bi-V and preimplantation QRS width can predict positive outcomes after CRT and may represent a novel intraprocedural method to optimize coronary sinus lead placement. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00253357.

We investigated whether primary prevention implantable cardioverter defibrillator (ICD) patients with atrial arrhythmias are at higher risk for ICD shocks and mortality compared to patients without atrial arrhythmias in a subanalysis of the PREPARE study.Details of the PREPARE study design and results have been previously reported. We now included 537 of the 700 patients enrolled in PREPARE. These patients had a dual or biventricular device and at least one device follow-up after implantation. Continuously collected device diagnostics data were used to classify patients into two groups during follow-up: with (n = 133) or without (n = 404) atrial tachycardia/atrial fibrillation (AT/AF). The primary outcomes were ICD shocks and mortality. Subjects were followed for a mean of 333 ± 73 (range 5-365) days. During a follow-up of 1 year, ICD shocks occurred in 44 (8%) patients. Significantly, more patients with AT/AF received a shock (13.0% vs 6.9%, P = 0.03), with inappropriate shocks accounting for the majority of the difference (6.9% vs 2.6%, P = 0.02). There was no difference in prevalence of shocks between patients with and without a history of AF. Mortality was similar in patients with and without AT/AF, whether detected during the study or prior to the study. In addition, the 34 subjects with high average ventricular rate (≥110 beats per minute) during AT/AF had a higher risk of an inappropriate shock (21.0% vs 2.1%, P0.01).Primary prevention ICD patients with AT/AF are more likely to receive shocks, especially inappropriate shocks. Mortality was not higher in AT/AF patients. (PACE 2011; 34:1070-1079).

Cardiac resynchronization therapy (CRT) is currently limited to those with left ventricular ejection fraction (LVEF) < 35%. To evaluate whether patients with LVEF > 35% might benefit from CRT, we performed a retrospective analysis of the predictors of response to CRT (PROSPECT) database. PROSPECT was a prospective, multicentre study that enrolled CRT patients based on enrolling centre-evaluated LVEF < 35%, but all echocardiograms were subsequently analysed by a core laboratory. Patients with core laboratory-measured LVEF > 35% (OVER35) were compared with those whose LVEF was < 35% (UNDER35). Clinical composite score (CCS) and change in LV end systolic volume (LVESV) were analysed from baseline to 6-month follow-up. Of 361 patients, 86 (24%) had LVEF > 35%. At entry, OVER35 had smaller LV volumes, shorter QRS duration, shorter 6-min walk distance, and were more likely to have ischaemic aetiology than UNDER35. Outcomes were comparable between the groups, with 62.8% of OVER35 improved in CCS (70.2% in UNDER35) and 50.8% of OVER35 improved in LVESV (57.8% in UNDER35). Patients with LVEF > 35%, New York heart association functional Class III-IV status, and QRS > 130 ms appear to derive clinical and structural benefit from CRT. As CRT may offer a valuable option for these patients, this hypothesis should be formally tested in a prospective, randomized multicentre trial.

A surface electrocardiogram (SECG) for pacing threshold measurements during routine implantable cardioverter-defibrillator (ICD) follow-up can be cumbersome. This study evaluated the use of an intrathoracic far-field electrogram (EGM) derived between the Can and superior vena cava (SVC) electrode -- the Leadless electrocardiogram (LLECG), in dual chamber ICDs in performing pacing threshold tests.The LLECG was evaluated prospectively during atrial and ventricular pacing threshold testing as a substudy of the Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter-Defibrillators trial (EMPIRIC) in which dual chamber ICDs were implanted in 888 patients. Threshold tests were conducted at 1 volt by decrementing the pulse width. Follow-up at three months compared pacing thresholds measured using LLECG with those using Lead I of the surface ECG (SECG). The timesaving afforded by LLECG was assessed by a questionnaire.The median threshold difference between LLECG and SECG measurements for both atrial (0.00 ms, P = 0.90) and ventricular (0.00 ms, P = 0.34) threshold tests were not significant. Ninety percent of atrial and ventricular threshold differences were bounded by +/- 0.10 ms and -0.10 to +0.04 ms, respectively. We found that 99% of atrial and ventricular thresholds tests at six and 12 months attempted using LLECG were successfully completed. The questionnaire indicated that 65% of healthcare professionals found LLECG to afford at least some timesaving during device follow-ups.Routine follow-up can be performed reliably and expeditiously in dual chamber Medtronic (Minneapolis, MN, USA) ICDs using LLECG alone, resulting in overall timesaving.

International audience; The putative association between pesticide exposures and Parkinson's disease (PD) remains controversial. We identified all subjects who developed PD in Olmsted County, Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year) and sex to general population controls. We assessed exposures to chemical products by means of telephone interview with cases, controls, or their proxies (149 cases; 129 controls). Exposure to pesticides related or unrelated to farming was associated with PD in men (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.04). The association remained significant after adjustment for education or smoking. Analyses for the other six categories of industrial and household chemicals were all nonsignificant. This population-based study suggests a link between pesticides use and PD that is restricted to men. Pesticides may interact with other genetic or nongenetic factors that are different in men and women.

The authors studied the association of markers of inflammation with the later development of Parkinson disease (PD) using a case-control design (196 cases and 196 matched controls). The frequency of diseases of immediate-type hypersensitivity was significantly higher in cases than controls. In addition, cases used anti-inflammatory agents less frequently than controls (nonsignificant trend). The results may support the hypothesis that there is an inflammatory component in the pathogenesis of PD.

We established a historical cohort of 7,216 subjects who completed the Minnesota Multiphasic Personality Inventory (MMPI) at the Mayo Clinic from 1962 through 1965 for research (not clinical indication), and who resided within a 120-mile radius centered in Rochester, Minnesota. We describe here the overall cohort design and sampling, we report results concerning reliability and validity, and we describe age and sex patterns at baseline for four MMPI scores of primary interest (depression, anxiety, social introversion, and negativity). Subjects excluded from the cohort because of missing data had MMPI scores similar to subjects included (after appropriate rescaling). A cut-off specific for age and sex at the 75th percentile of the distribution of raw scores was valid compared with the traditional clinical cut-off (T scores plus one standard deviation). Baseline scores for all four scales were higher in women than in men at all ages (all p < 0.0001). Depression and social introversion scores showed an increasing trend with age in both sexes (Spearman rank correlation, rho = 0.05 and 0.08, respectively, p < 0.0001 for both). Baseline scores on the anxiety scale showed a decreasing trend with age in both sexes (rho = –0.06, p < 0.0001). Negativity scores remained relatively stable with age in both sexes (rho = 0.03, p = 0.01). We found a high correlation between the anxiety score and the negativity score (rho = 0.90, p < 0.0001) even after the exclusion of overlapping items (rho = 0.68, p < 0.0001). This newly established historical cohort study provides opportunities to test hypotheses regarding the link between personality and aging, aging-related diseases, and overall mortality.

International audience; OBJECTIVE: To investigate the association of Parkinson disease (PD) with education and occupations using a case-control study design. METHODS: The authors used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control. The authors collected information about education and occupations using two independent sources of data: a review of the complete medical records in the system and a telephone interview. Occupations were coded using the 1980 Standard Occupational Classification. RESULTS: Subjects with 9 or more years of education were at increased risk of PD (OR = 2.0; 95% CI = 1.1 to 3.6; p = 0.02), and there was a trend of increasing risk with increasing education (test for linear trend, p = 0.02; medical records data). Physicians were at significantly increased risk of PD using both sources of occupational data. By contrast, four occupational groups showed a significantly decreased risk of PD using one source of data: construction and extractive workers (e.g., miners, oil well drillers), production workers (e.g., machine operators, fabricators), metal workers, and engineers. These associations with increased or decreased risk did not change noticeably after adjustment for education. CONCLUSION: Subjects with higher education and physicians have an increased risk of Parkinson disease (PD), while subjects with some occupations presumed to involve high physical activity have a decreased risk of PD.

We describe here the Mayo Clinic Family Study of Parkinson’s disease (PD), including the overall study design (historical cohort study of relatives from birth to onset of PD or censoring), the data collection instruments, the strategies implemented to prevent or measure biases, and the sample obtained. These methodological details may provide assistance to other investigators designing studies of the familial aggregation of PD or other aging-related chronic diseases. We investigated the incidence of PD and other neurodegenerative diseases among 1,001 first-degree relatives of 162 patients with PD and 851 relatives of 147 controls representative of the population of Olmsted County, Minn., USA. In addition, we studied 2,713 first-degree relatives of 411 patients with PD referred to the Mayo Clinic. Finally, we studied a group of 625 spouses of either cases or controls. Relatives with PD or other neurodegenerative diseases were ascertained using the family study method.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD − ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis ≥ 66 years; maximum LOD − ZLR = 2.82), with

Objective: To investigate the association of PD with preceding head trauma using a case-control study design. Methods: The medical records-linkage system of the Rochester Epidemiology Project was used to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. The complete medical records of cases and controls in the system were reviewed to detect preceding episodes of head trauma. Results: The frequency of head trauma overall was significantly higher in cases than in controls (odds ratio [OR] = 4.3; 95% CI = 1.2 to 15.2). Compared with subjects who never experienced a trauma, subjects who experienced a mild head trauma with only amnesia had no increased risk; however, subjects who experienced a mild head trauma with loss of consciousness or a more severe trauma had an OR of 11.0 (95% CI = 1.4 to 85.2). Although not significant, head trauma resulting in hospitalization was more frequent in cases than in control subjects (OR = 8.0; 95% CI = 1.0 to 64.0). Whereas the OR was higher for men than women and for patients with later onset of PD than for patients with earlier onset, these differences were not significant. Conclusions: These results suggest an association between head trauma and the later development of PD that varies with severity. Although the OR is high (4.3), the population attributable risk is only 5% because head trauma is a relatively rare event.

Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P

We conducted a population-based case-control study to investigate the association of Parkinson's disease (PD) with preceding nonfatal cancer.We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of PD in Olmsted County, MN (1976-1995). Each case was matched by age and sex to a general population control. We ascertained cancer diagnoses through medical records abstraction.The frequency of any cancer was lower in cases (19.4%) than in controls (23.5%) (OR = 0.79; 95% CI = 0.49-1.27). This pattern was more pronounced in women than in men, and in patients age 71 years or younger at onset of PD than in older patients. We found an interaction between smoking and smoking-related cancers in their association with PD. Bladder cancer (OR = 0.22; 95% CI = 0.03-2.24) and breast cancer (OR = 0.20; 95% CI = 0.02-1.71) were less frequent in PD cases than in controls, whereas prostate cancer was more frequent in PD cases than in controls (OR = 1.80; 95% CI = 0.60-5.37). However, these results are based on small numbers.We did not find a strong association between PD and preceding nonfatal cancer. There were suggestive trends in analyses stratified by sex and age at onset of PD, and for specific cancers related to smoking or hormonal factors.

Recent studies suggest that hereditary prostate cancer is a complex disease involving multiple susceptibility genes and variable phenotypic expression. While conducting a genomewide search on 162 North American families with ⩾3 members affected with prostate cancer (PRCA), we found evidence for linkage to chromosome 20q13 with two-point parametric LOD scores >1 at multiple sites, with the highest two-point LOD score of 2.69 for marker D20S196. The maximum multipoint NPL score for the entire data set was 3.02 (P=.002) at D20S887. On the basis of findings from previous reports, families were stratified by the presence (n=116) or absence (n=46) of male-to-male transmission, average age of diagnosis (

Background: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler‐ Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. Methods: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. Results: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P = .02) and time to recurrence (P = .01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P = .02) and time to recurrence (P = .004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31‐0.82; P = .006) and time to recurrence (HR = 0.42; 95% CI = 0.24‐0.74; P = .003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25‐2.83; P = .002) and time to recurrence (HR = 2.07; 95% CI = 1.32‐3.25; P = .002). Conclusions: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer. [J Natl Cancer Inst 1999; 91:1295‐1303]

To compare survival in incident cases of Parkinson disease (PD) with survival in subjects free of PD from the general population.We used the medical records linkage system of the Rochester Epidemiology Project to identify incident cases of PD in Olmsted County, Minnesota, for the period 1976-1995. Cases were matched by age and sex to referent subjects from the same population. For 196 cases and 185 referent subjects, we studied survival between the date of diagnosis of PD (or index date) and death, loss to follow-up, or end of the study (May 1, 2000).The median length of follow-up was 7.2 years for cases and 8.0 years for referent subjects; 110 patients with PD and 79 referent subjects died during follow-up. The median survival was 10.3 years in cases and 13.4 years in referent subjects. The relative risk (RR) of death was 1.60 (95% confidence interval [CI], 1.20-2.14; P =.002) overall, 1.81 (95% CI, 1.15-2.84; P =.01) in women, and 1.49 (95% CI, 1.01-2.20; P =.04) in men. There was a decreasing trend in the RR of death according to age at onset of PD (in tertiles): younger than 67 years, RR, 2.04 (95% CI, 0.99-4.19; P =.05); 67 to 76 years, RR, 1.76 (95% CI, 1.08-2.86; P =.02); and older than 76 years, RR, 1.48 (95% CI, 0.95-2.29; P =.08). Patients with PD who had both rest tremor and pronounced asymmetry had a better prognosis than patients with neither clinical characteristic. Patients with PD who smoked survived better than expected.Patients with PD face a higher risk of death compared with subjects free of PD from the general population. Certain clinical characteristics and smoking modify survival.

PURPOSE: Men with prostate cancer identified through referral centers tend to be younger on average than those from population-based sources. This could potentially augment the proportion of men with a family history of prostate cancer and therefore bias insights about the role of genetic polymorphisms in case control studies. We sought to examine this hypothesis in the context of an ongoing case control study. METHODS: Cases were identified as the 6,352 consecutive candidates for radical prostatectomy at Mayo Clinic from 1966 to 1995. In 1995, 4,307 of the 5,486 men who were alive (78 percent participation) were queried about family history of prostate cancer and the distance of their home to Rochester, Minnesota was determined on the basis of ZIP code of residence. RESULTS: Among the 4,307 participants, there was a modest shift in age distribution towards younger ages with successively greater distance from Rochester. By contrast, the percentage of men reporting any first degree relatives with prostate cancer shifted very little by distance strata: 30, 30, 27, 27 and 26.5 percent for subjects living 0–100, 101–250, 251–500, 501–1000 and more than 1,000 miles from Rochester, respectively (p for trend = 0.09). The proportion reporting 3 or more first degree relatives differed very little, from 1.2 percent among local subjects to 1.1 percent among those most distant. CONCLUSION: The results from this surgical series provide little evidence of an increased prevalence of family history with increasing referral distance. While they provide some reassurance that referral bias should not overemphasize the contribution of genetic factors in case control studies conducted in referral centers, it would be prudent to investigate this in individual settings.

ICD shocks can lead to costly healthcare utilization. Shock-Less (SL) is a multi-center prospective trial aimed at improving the adoption of evidence-based shock reduction programming schemes, including the use of the Medtronic CareLink® Network, a remote monitoring system (RMS). The objective