Statin withdrawal and health-related quality of life in a primary cardiovascular prevention cohort.

PURPOSE: While some work has been done on Health-Related Quality of Life (HRQoL) in statin users, none has focused specifically on statin-associated muscle symptoms (SAMS) sufferers. The objective was to assess self-reported HRQoL, before and after statin withdrawal, in patients reporting SAMS. We hypothesized that the presence of SAMS associated with decreased self-reported physical and mental well-being. METHODS: Patients (50 men/28 women [M/W], aged 49 ± 9 years [Mean ± SD]) in primary cardiovascular prevention were recruited into three cohorts: statin users with (SAMS, 29 M/18W) or without symptoms (No SAMS, 10 M/5W) and controls (11 M/5W). The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. All variables were measured before and after 2 months of statin withdrawal, and repeated measures analyses were used to verify withdrawal and group effects as well as their interaction. RESULTS: SF-36 physical and mental component scores (respectively, PCS and MCS) were lower in the SAMS group compared with other groups (both p < 0.01). Statin withdrawal led to an increase in LDL cholesterol for statin users (+69.0%, p < 0.01) and an improvement in well-being in the SAMS group, other groups showing no change. A time x category interaction (p = 0.02) was seen for PCS and post hoc analyses showed that statin withdrawal improved PCS and MCS (respectively, +12.5% [ES 0.77] and +5.1% [ES 0.27], both p < 0.05) in the SAMS group. CONCLUSION: Patients self-reporting SAMS showed improved HRQoL following drug withdrawal, but this was mirrored by a rise in LDL cholesterol. These findings should be considered by clinicians in the evaluation and follow-up of treatment with statins.

Prediabetes is associated with microalbuminuria, reduced kidney function and chronic kidney disease in the general population: The KORA (Cooperative Health Research in the Augsburg Region) F4-Study.

BACKGROUND AND AIMS: We investigated the associations of serum fasting (FG) and 2-h postload (2HG) glucose from an oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), fasting insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) with urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). METHODS AND RESULTS: We performed cross-sectional analyses of 2713 subjects (1429 women; 52.7%) without known type 2 diabetes, aged 31-82 years, from the KORA (Cooperative Health Research in the Augsburg Region) F4-Study. FG, 2HG, HbA1c, fasting insulin, HOMA-IR and glucose tolerance categories were analyzed for association with ACR and eGFR in multivariable adjusted linear and median regression models, and with isolated microalbuminuria (i-MA), isolated reduced kidney function (i-RKF) and chronic kidney disease (CKD, defined as MA and/or RKF) in multivariable adjusted logistic regression models. Among the 2713 study participants, 28% revealed prediabetes (isolated impaired fasting glucose [i-IFG], isolated glucose tolerance [i-IGT] or both by American Diabetes Association definition), 4.2% had unknown type 2 diabetes, 6.5% had i-MA, 3.1% i-RKF and 10.9% CKD. In multivariable adjusted analysis, all continuous variables (FG, 2HG, HbA1c, fasting insulin and HOMA-IR) were associated with i-MA, i-RKF and CKD. The odds ratios (ORs) for i-MA and CKD were 1.54 (95% confidence interval: 1.02-2.33) and 1.58 (1.10-2.25) for individuals with i-IFG. Moreover, the OR for i-RKF was 2.57 (1.31-5.06) for individuals with IFG + IGT. CONCLUSION: Our findings suggest that prediabetes might have harmful effects on the kidney.

Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies.

BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and antioxidative glycoprotein. Plasma apoA-IV levels are elevated in patients with primary chronic kidney disease (CKD) or renal failure. The association between apoA-IV and kidney function has not been investigated in the general population; therefore, we analysed this relationship in two large population-based cohorts. METHODS: Plasma apoA-IV concentrations were measured in the Cooperative Health Research in the Region of Augsburg (KORA) F3 (n = 3159) and KORA F4 (n = 3061) studies. CKD was defined by the serum creatinine-estimated glomerular filtration rate (eGFR) and/or urine albumin-to-creatinine ratio. RESULTS: Mean (±SD) apoA-IV concentration was 17.3 ± 4.7 mg dL(-1) in KORA F3 and 15.3 ± 4.3 mg dL(-1) in KORA F4. Fully adjusted linear mixed models revealed a significant association between apoA-IV concentration and lower eGFR in the third and fourth versus the first quartile of apoA-IV (ß = -1.78 mL min(-1) /1.73 m², P = 0.0003 and ß = -5.09 mL min(-1) /1.73 m², P = 2.83 × 10(-23) , respectively). ApoA-IV was significantly associated with an eGFR of <60 mL min(-1) /1.73 m², which was observed in 601 of the 6220 study participants [odds ratio (OR) 1.46, P = 0.03 and OR 3.47, P = 6.84 × 10(-15) for the third and fourth vs. the first quartile of apoA-IV, respectively]. Adding apoA-IV (fourth vs. first quartile) to the fully adjusted model significantly improved discrimination of eGFR <60 mL min(-1) /1.73 m² in KORA F3 [integrated discrimination improvement (IDI) 0.03, P = 1.30 × 10(-7) ] and KORA F4 (IDI 0.04, P = 1.32 × 10(-9) ) beyond classical risk factors for CKD. CONCLUSION: The present analysis in two population-based cohorts revealed that high plasma apoA-IV concentrations are strongly associated with low kidney function defined by eGFR independent of major CKD risk factors. ApoA-IV appears to be an early marker of impaired kidney function.

Serum potassium is associated with prediabetes and newly diagnosed diabetes in hypertensive adults from the general population: the KORA F4-study.

AIMS/HYPOTHESIS: Evidence suggests that low serum potassium concentrations or hypokalaemia induced by the intake of diuretics are associated with incident diabetes and increased risk for diabetes in persons with hypertension. We examined a possible association between serum potassium and prediabetes (defined as isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT] or combined IFG/IGT), as well as known and newly diagnosed diabetes (NDD), in 32- to 81-year-old men and women with and without hypertension. METHODS: This cross-sectional analysis was based on 2,948 participants in the Cooperative Health Research in the Region of Augsburg (KORA) F4 study conducted in 2006-2008 in southern Germany. Serum concentrations of potassium were measured by indirect potentiometry. RESULTS: In the total sample there was no association between serum potassium concentrations and prediabetes. In hypertensive persons however serum potassium levels in the first and second quartile compared with the highest quartile were independently significantly associated with prediabetes after multivariable adjustment (OR for prediabetes, 2.02 [95% CI 1.27, 3.21] for quartile 2 and 2.00 [95% CI 1.27, 3.15] for quartile 1), while in persons without hypertension no association was found. In multinomial logistic regression analysis these findings could be confirmed. In hypertensive participants after multivariable adjustment the associations were statistically significant for i-IGT and NDD (i-IGT OR 1.23; NDD OR 1.41). However, in non-hypertensive persons, all associations between serum potassium levels and each of the categories of impaired glucose regulation were non-significant. CONCLUSIONS/INTERPRETATION: Serum potassium levels were independently associated with prediabetes and NDD in hypertensive adults from the general population.

Genetic variation in the vaspin gene affects circulating serum vaspin concentrations.

OBJECTIVE: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine potentially linking obesity, insulin resistance and type 2 diabetes. Here, we searched for genetic determinants that could explain the variability in serum vaspin concentrations. RESEARCH DESIGN AND METHODS: First, we conducted a genome-wide association study (GWAS) for serum vaspin in the Sorbs cohort (N=826). Subsequently, 26 single-nucleotide polymorphisms (SNPs) covering genetic variation in the vaspin locus were genotyped in the Sorbs. In addition, we measured serum vaspin concentrations in 1806 samples from Augsburg/the Cooperative Health Research in the Region of Augsburg (KORA) for replication of the association signals. Finally, we conducted association analyses of vaspin SNPs with metabolic traits in the Sorbs (N=1013), KORA (N=1813) and a further cohort from Germany (Leipzig: N=1857). RESULTS: Six SNPs mapping between serpinA1 and serpinA4, including the vaspin locus, on chromosome 14 reached P-values < or = 10(-8) in the GWAS in the Sorbs. The fine mapping of variants within the vaspin locus in the Sorbs and subsequent replication in the KORA sample revealed several SNPs significantly associated with serum vaspin concentrations reaching P-values of up to 10(-35). However, no significant association with type 2 diabetes or related traits was found in either cohort after the Bonferroni correction for multiple comparisons. CONCLUSION: Our data show that the variability in serum vaspin concentrations might be explained by its genetic variants.

Patient time costs attributable to healthcare use in diabetes: results from the population-based KORA survey in Germany.

AIMS: Patient time costs have been described to be substantial; however, data are highly limited. We estimated patient time costs attributable to outpatient and inpatient care in study participants with diagnosed diabetes, previously undetected diabetes, impaired glucose regulation and normal glucose tolerance. METHODS: Using data of the population-based KORA S4 study (55-74 years, random sample of n = 350), we identified participants' stage of glucose tolerance by oral glucose tolerance test. To estimate mean patient time costs per year (crude and standardized with respect to age and sex), we used data regarding time spent with ambulatory visits including travel and waiting time and with hospital stays (time valued at a 2011 net wage rate of €20.63/h). The observation period was 24 weeks and data were extrapolated to 1 year. RESULTS: Eighty-nine to 97% of participants in the four groups (diagnosed diabetes, undetected diabetes, impaired glucose regulation and normal glucose tolerance.) had at least one physician contact and 4-14% at least one hospital admission during the observation period. Patient time [h/year (95% CI)] was 102.0 (33.7-254.8), 53.8 (15.0-236.7), 59.3 (25.1-146.8) and 28.6 (21.1-43.7), respectively. Age-sex standardized patient time costs per year (95% CI) were €2447.1 (804.5-6143.6), €880.4 (259.1-3606.7), €1151.6 (454.6-2957.6) and €589.2 (435.8-904.8). CONCLUSIONS: Patient time costs were substantial--even higher than medication costs in the same study population. They are higher in participants with diagnosed diabetes, but also in those with undetected diabetes and impaired glucose regulation compared with those with normal glucose tolerance. Research is needed in larger populations to receive more precise and certain estimates that can be used in health economic evaluation.

Age at menarche is associated with prediabetes and diabetes in women (aged 32-81 years) from the general population: the KORA F4 Study.

AIMS/HYPOTHESIS: The aim of this study was to examine the association between age at menarche and prediabetes as well as diabetes, considering confounding factors and the possible mediating role of adult obesity. METHODS: This cross-sectional study analysed data on 1,503 women aged 32-81 years from the German population-based KORA (Cooperative Health Research in the Region of Augsburg, South Germany) F4 Study (2006-2008). Data were collected by standardised interviews, physical examinations, and whole blood and serum measurements, including administration of an OGTT in non-diabetic participants. RESULTS: Of the 1,503 women, 226 showed a prediabetic state (impaired fasting glucose and/or impaired glucose tolerance) and 140 persons had diabetes (45 participants with previously undiagnosed diabetes and 95 with known diabetes). In Poisson regression analysis, age at menarche was significantly inversely associated with prediabetes or diabetes after adjustment for year of birth (RR 0.88; 95% CI 0.82, 0.94, p < 0.0001 per additional year of menarche) and after additional adjustment for a number of confounding factors (RR 0.88; 95% CI 0.83, 0.94, p = 0.0001). Further adjustment for current BMI slightly attenuated the association with prediabetes or diabetes (RR 0.89; 95% CI 0.83, 0.95, p = 0.0009), but the association remained clearly significant. CONCLUSIONS/INTERPRETATION: Age at menarche seems to be inversely associated with prediabetes and diabetes independent of confounding factors including current BMI. Women at risk for diabetes might be identified by a history of young age at menarche.

Light quality and dormancy overcoming in seed germination of Echium plantagineum L. (Boraginaceae).

Light is considered a factor that influences the seed germination of many weed species, and it can signal whether the environmental conditions are favorable or are not favorable for germination. We aimed to study if there is an influence of light quality and dormancy overcoming in seed germination of Echium plantagineum L. We carried out a 2 x 6 factorial experiment, with and without dormancy overcoming with potassium nitrate followed by immersion in gibberellic acid; six light qualities, obtained through the light filters: blue, green, red, far-red, white light and absence of light. The evaluations performed were germination speed index (GSI), average germination time (AGT), germination at the four and 14 days after seeding (DAS), accumulated germination and relative frequency of germination. We observed significant interaction among the light qualities and seed dormancy overcoming or not for the studied variables. There was no significant effect of light qualities, in the evaluated variables, when performing dormancy overcoming, presenting germination above 90% in all the light qualities. However, without dormancy overcoming, we observed greater GSI, germination at four and 14 DAS for the red light filter with 5, 4, 29 and 45%, respectively. When the seeds were submitted to the absence of light, and without dormancy overcoming, there was only 7% of germination at 14 DAS. The seeds of E. plantagineum presented greater germination under incidence of red light, without dormancy overcoming, being classified as preferably positively photoblastics, provided that the dormancy is not overcome.

Genes and lifestyle factors in obesity: results from 12,462 subjects from MONICA/KORA.

BACKGROUND: Data from meta-analyses of genome-wide association studies provided evidence for an association of polymorphisms with body mass index (BMI), and gene expression results indicated a role of these variants in the hypothalamus. It was consecutively hypothesized that these associations might be evoked by a modulation of nutritional intake or energy expenditure. OBJECTIVE: It was our aim to investigate the association of these genetic factors with BMI in a large homogenous population-based sample to explore the association of these polymorphisms with lifestyle factors related to nutritional intake or energy expenditure, and whether such lifestyle factors could be mediators of the detected single-nucleotide polymorphism (SNP)-association with BMI. It was a further aim to compare the proportion of BMI explained by genetic factors with the one explained by lifestyle factors. DESIGN: The association of seven polymorphisms in or near the genes NEGR1, TMEM18, MTCH2, FTO, MC4R, SH2B1 and KCTD15 was analyzed in 12,462 subjects from the population-based MONICA/KORA Augsburg study. Information on lifestyle factors was based on standardized questionnaires. For statistical analysis, regression-based models were used. RESULTS: The minor allele of polymorphism rs6548238 C>T (TMEM18) was associated with lower BMI (-0.418 kg m(-2), P=1.22 × 10(-8)), and of polymorphisms rs9935401 G>A (FTO) and rs7498665 A>G (SH2B1) with increased BMI (0.290 kg m(-2), P=2.85 × 10(-7) and 0.145 kg m(-2), P=9.83 × 10(-3)). The other polymorphisms were not significantly associated. Lifestyle factors were correlated with BMI and explained 0.037% of the BMI variance as compared with 0.006% of explained variance by the associated genetic factors. The genetic variants associated with BMI were not significantly associated with lifestyle factors and there was no evidence of lifestyle factors mediating the SNP-BMI association. CONCLUSIONS: Our data first confirm the findings for TMEM18 with BMI in a single study on adults and also confirm the findings for FTO and SH2B1. There was no evidence for a direct SNP-lifestyle association.

Surgery of inferior vena cava associated malignant tumor lesions.

BACKGROUND: Tumor lesions of the inferior vena cava (IVC) can originate from the vein or can develop by malignant tumor infiltration from the surrounding tissue. In this context, particular attention should be paid to tumor lesions with pegs into or within the IVC. The aim of this series of a single surgical center was to analyze the perioperative management, the individual-specific and -adapted surgical technique, as well as the outcome including prognostic considerations in IVC-associated malignant tumor lesions. PATIENTS AND METHODS: Over a 6-year time period, all consecutive patients with IVC-associated malignant tumor lesions and their patient- and finding-specific characteristics were registered, data and parameters of the diagnostic and therapeutic management were documented, and both the short- and long-term outcomes (complication rate, perioperative morbidity/mortality, tumor recurrence rate, survival) were assessed with periodic follow-up investigations. RESULTS: Overall, 12 patients were enrolled in the study from 1/1/2001-31/12/2006:6 primary IVC-tumors (leiomyosarcomas, 50%) and 6 secondary IVC-tumors (2 retroperitoneal tumor lesions, 16.7%, 3 renal cell carcinomas 25% and 1 carcinoma of the adrenal gland, 8.3%). 4 of the secondary tumors had pegs into the IVC. The RO resection rate was 83%. The perioperative morbidity was 33%; whereas, the hospital mortality was 8.3% (n = 1). Surgical reconstruction of IVC was achieved in each case (100%). There was a mean postoperative observation period of 20 months (range, 1-58 months). Complete follow-up documentation was obtained for all of the patients (100%). Three patients experienced recurrent tumor growth (27.5% out of n = 11). While the overall mortality through the follow up observation period was 27.5%, the tumor-specific mortality was 16%. CONCLUSIONS: The primary surgical aim is RO resection to provide a long-term outcome with no tumor recurrence including the reconstruction of the IVC based on a reasonable risk-to-benefit ratio. The favorable outcome of this case series demonstrates that IVC-associated tumor lesions can be approached if there is an appropriate expertise of the surgical team, a sufficient perioperative management and an adequate financial background with a reasonable survival rate. The variable prognosis of the various tumor lesions depends on tumor entity, stage, resection status and individual risk factors.

Genetic variants in the leukemia-associated Rho guanine nucleotide exchange factor (ARHGEF12) gene are not associated with T2DM and related parameters in Caucasians (KORA study).

OBJECTIVE: The aim of our study was to determine the variant pattern of the leukemia-associated Rho guanine nucleotide exchange factor (LARG, or ARHGEF12) gene and investigate whether LARG variants are associated with diabetes mellitus type 2 (T2DM), the metabolic syndrome (MetS), or related parameters such as insulin sensitivity in German Caucasians. DESIGN: We analyzed single nucleotide polymorphisms (SNPs) in the LARG gene in the 55-74-year-old individuals of the population-based German Caucasian Cooperative Health Research in the region of Augsberg (KORA) survey 4 (S4). METHODS: Sequencing of Tyr1306Cys, which was of functional relevance in Pima Indians, in 48 randomly selected individuals and genotyping of 11 additional LARG SNPs in 1653 subjects were performed. Four linkage disequilibrium (LD) blocks (r(2)> or =0.8) were established and each block was statistically analyzed for association with metabolic traits. The association with T2DM and the MetS was analyzed by logistic regression in 1462 subjects, and HOMA-IR (homeostasis model assessment of insulin resistance) as a measure of insulin sensitivity was analyzed by the Kruskal-Wallis test in 1346 fasting subjects. RESULTS: The polymorphism Tyr1306Cys, which was significantly associated with insulin sensitivity in Pima Indians, was not found in the KORA S4 population. Statistical analysis yielded no significant associations (P>0.05) between the analyzed LARG variants and T2DM, the MetS, or related parameters such as insulin sensitivity. CONCLUSIONS: Caucasian individuals and Pima Indians differ in their genetic variance pattern in the LARG gene region. There is no evidence in the Caucasian KORA study that variants of the LARG gene confer susceptibility for T2DM, insulin sensitivity, or the MetS.

Light quality and dormancy overcoming in seed germination of Echium plantagineum L. (Boraginaceae) / Qualidade da luz e superação de dormência na germinação de sementes de Echium plantagineum L. (Boraginaceae)

Abstract Light is considered a factor that influences the seed germination of many weed species, and it can signal whether the environmental conditions are favorable or are not favorable for germination. We aimed to study if there is an influence of light quality and dormancy overcoming in seed germination of Echium plantagineum L. We carried out a 2 x 6 factorial experiment, with and without dormancy overcoming with potassium nitrate followed by immersion in gibberellic acid; six light qualities, obtained through the light filters: blue, green, red, far-red, white light and absence of light. The evaluations performed were germination speed index (GSI), average germination time (AGT), germination at the four and 14 days after seeding (DAS), accumulated germination and relative frequency of germination. We observed significant interaction among the light qualities and seed dormancy overcoming or not for the studied variables. There was no significant effect of light qualities, in the evaluated variables, when performing dormancy overcoming, presenting germination above 90% in all the light qualities. However, without dormancy overcoming, we observed greater GSI, germination at four and 14 DAS for the red light filter with 5, 4, 29 and 45%, respectively. When the seeds were submitted to the absence of light, and without dormancy overcoming, there was only 7% of germination at 14 DAS. The seeds of E. plantagineum presented greater germination under incidence of red light, without dormancy overcoming, being classified as preferably positively photoblastics, provided that the dormancy is not overcome.

Resumo A luz é considerada um fator que influencia a germinação das sementes de muitas espécies de plantas daninhas, podendo sinalizar se as condições ambientais são favoráveis ou não para a germinação. Objetivou-se estudar se há influência da qualidade da luz e superação de dormência na germinação de sementes de Echium plantagineum L. Realizou-se um experimento fatorial 2 x 6, com e sem superação de dormência com nitrato de potássio seguido pela imersão em ácido giberélico; seis qualidades de luz, obtidas através de filtros de luz: azul, verde, vermelho, vermelho-distante, luz branca e ausência de luz. As avaliações realizadas foram índice de velocidade de germinação (IVG), tempo médio de germinação (TMG), germinação aos quatro e 14 dias após a semeadura (DAS), germinação acumulada e frequência relativa de germinação. Observou-se interação significativa entre as qualidades de luz e a superação ou não de dormência das sementes para as variáveis estudadas. Não houve efeito significativo das qualidades de luz, nas variáveis avaliadas, ao realizar superação de dormência, apresentando germinação acima de 90% em todas as qualidades de luz. Todavia, sem superação de dormência, observou-se maior IVG, germinação aos quatro e 14 DAS para o filtro de luz vermelha com 5,4, 29 e 45%, respectivamente. Quando as sementes foram submetidas à ausência de luz, e sem superação de dormência, houve apenas 7% de germinação aos 14 DAS. As sementes de E. plantagineum apresentam maior germinação sob incidência de luz vermelha, sem superação de dormência, sendo classificadas como fotoblásticas positivas preferenciais, desde que não seja superada a dormência.

Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans.

BACKGROUND: Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT(1)-R and AT(2)-R) in patients with AF. METHODS AND RESULTS: Atrial tissue samples from 30 patients undergoing open heart surgery were examined. Eleven patients had chronic persistent AF (> or =6 months; cAF), 8 patients had paroxysmal AF (pAF), and 11 patients were in sinus rhythm. AT(1)-R and AT(2)-R were localized in the atrial tissue by immunohistochemistry and quantified at the protein and mRNA level by Western blotting and quantitative polymerase chain reaction. Both types of AT-R were predominantly expressed in atrial myocytes in all groups. The amount of AT(1)-R was reduced to 34.9% during cAF (P<0.01) and to 51.7% during pAF (P<0.05) compared with patients in sinus rhythm. In contrast, AT(2)-R was increased during cAF (246%; P=NS) and pAF (505%; P<0.01). AT(1)-R/AT(2)-R mRNA content was similar in all groups. CONCLUSIONS: AF is associated with the down-regulation of atrial AT(1)-R and the up-regulation of AT(2)-R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.

Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation.

OBJECTIVES: The purpose of this study was to determine whether atrial expression of the extracellular signal-regulated kinases Erk1/Erk2 and of the angiotensin-converting enzyme (ACE) is altered in patients with atrial fibrillation (AF). BACKGROUND: Recent studies have demonstrated that atrial fibrosis can provide a pathophysiologic substrate for AF. However, the molecular mechanisms responsible for the development of atrial fibrosis are unclear. METHODS: Atrial tissue samples of 43 patients undergoing open heart surgery were examined. Seventeen patients had chronic persistent AF (> or =6 months; CAF), 8 patients had paroxysmal AF (PAF) and 18 patients had no history of AF. Erk expression was analyzed at the mRNA (quantitative reverse transcription polymerase chain reaction), the protein (immunoblot techniques) and atrial tissue (immunohistochemistry) levels. Erk-activating kinases (MEK1/2) and ACE were analyzed by immunoblot techniques. RESULTS: Increased amounts of Erk2-mRNA were found in patients with CAF (75 +/- 20 U vs. sinus rhythm: 31 +/- 25 U; p < 0.05). Activated Erk1/Erk2 and MEK1/2 were increased to more than 150% in patients with AF compared to patients with sinus rhythm. No differences between CAF and PAF were found. The expression of ACE was three-fold increased during CAF. Amounts of activated Erk1/Erk2 were reduced in patients treated with ACE inhibitors. Patients with AF showed an increased expression of Erk1/Erk2 in interstitial cells and marked atrial fibrosis. CONCLUSIONS: An ACE-dependent increase in the amounts of activated Erk1/Erk2 in atrial interstitial cells may contribute as a molecular mechanism for the development of atrial fibrosis in patients with AF. These findings may have important impact on the treatment of AF.

Association of low 25-hydroxyvitamin D levels with the frailty syndrome in an aged population: results from the KORA-age Augsburg study.

OBJECTIVES: Older adults often suffer from vitamin D deficiency and from the frailty syndrome charac-terized by different physical limitations, complicating independent everyday life. Previous studies have suggested a relationship between vitamin D status and the frailty syndrome, but results have been partly inconsistent, particularly regarding the shape of the association. Therefore, our aim was to further assess the association of 25-hydroxyvitamin D (25(OH)D) serum levels and frailty in older participants. DESIGN: Cross-sectional population-based study. PARTICIPANTS: The study population included 478 men and 462 women of the KORA (COoperative health research in the Region of Augsburg)-Age study born before 1944 examined in 2009. MEASUREMENTS: Classification of participants into different frailty states was performed according to the following criteria: weight loss, exhaustion, physical inactivity, slowness, and weakness. PARTICIPANTS who met 1-2 or ≥ 3 of the 5 criteria were classified as prefrail or frail, respectively. Total 25(OH)D was measured in non-fasting serum samples with an enhanced chemiluminescence immunoassay. Sequential logistic regression models adjusted for age, sex, season, lifestyle factors, diseases and biomarkers including parathyroid hormone (PTH) were calculated. RESULTS: High levels of 25(OH)D were inversely associated with being prefrail (N=351) or frail (N=38) in the model adjusted for age, sex, season and lifestyle factors. Compared to levels <15 ng/ml, odds ratios (ORs) (95% confidence intervals (CIs) were 0.52 (0.34-0.78) for levels of 15-<20 ng/ml, 0.55 (0.37-0.81) for levels of 20-<30 ng/ml and 0.32 (0.21-0.51) for levels ≥ 30 ng/ml. Additional adjustment for potential mediators including PTH only slightly attenuated these associations. For single frailty-components, significantly decreased ORs were found for exhaustion, physical inactivity and slowness comparing 25(OH)D levels ≥ 30 ng/ml with levels <15 ng/ml. CONCLUSION: Subjects with 25(OH)D serum levels ≥ 15 ng/ml were less frequently prefrail or frail.

Diagnosis of segmental necrosis in a pancreas transplant by thallium-201 perfusion scintigraphy.

Thallium-201 was used to image a patient with a pancreatic transplant. Incomplete visualization of the graft on the 201Tl scan, compared to CT, led to the diagnosis of segmental necrosis of the tail of the graft. Due to the low background and favorable target-to-non-target ratio, 201Tl pancreas scintigraphy may be useful in the follow-up of pancreatic transplants.

Antioxidant and antiprotease status in peripheral blood and BAL fluid after cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass (CPB) triggers systemic inflammation. Recent evidence suggests that metabolic and oxygenation management can affect the outcome of patients after cardiac surgery. We investigated the influence of oxidant/antioxidant and protease/antiprotease imbalance during the course of systemic and pulmonary inflammation. METHODS: In a study of 61 patients, we measured the intracellular thiol concentration, the intracellular activity of cathepsins and elastase, and the concentrations of secreted elastase, soluble alpha(1)-proteinase inhibitor (alpha(1)-PI), and secretory leukoprotease inhibitor (SLPI). Peripheral blood and BAL fluid (BALF) were obtained preoperatively and 2 h after CPB. RESULTS: A post-CPB depletion of thiol was found in blood granulocytes, lymphocytes, and monocytes, as well as BALF lymphocytes and macrophages. The degree of postoperative depletion correlated with PO(2) and blood glucose levels during CPB. Concomitant reduction of FEV(1) showed positive correlation with thiol depletion of blood monocytes and granulocytes. Elastase and cathepsin activities were increased in blood cells but not in lymphocytes or macrophages from BALF. The concentrations of secreted elastase were significantly increased in blood plasma but not in BALF. Enhanced antiprotease (alpha(1)-PI, SLPI) concentrations were measured in BALF but not in peripheral blood. CONCLUSIONS: The inflammatory response of the intra-alveolar compartment is clearly distinguishable from systemic inflammation. CPB causes a differentiated impairment of the antioxidant defense system as well as a protease/antiprotease imbalance in blood and BALF. Oxygenation under circumstances of CPB and concomitant pulmonary disease, as well as blood glucose metabolism, influence the antioxidative defense. Individual perioperative management of blood glucose and oxygenation could improve cellular defense systems in the peripheral blood and BALF and therefore result in a more favorable patient outcome.

Myocardial kinetics of 99m technetium-Q agents: studies in isolated cardiac myocyte, isolated perfused rat heart, and canine regional myocardial ischemia models.

OBJECTIVE: Based on reports of high cellular uptake and low plasma binding of nonreducible mixed ligand Tc(III) cations (Q complexes) and high linear uptake versus blood flow of 99mTc-Q3 in canine hearts, the authors hypothesized that the two Q complexes, 99mTc-Q63 and 99mTc-Q64, would have high cell uptake and better differentiation between ischemic and nonischemic myocardium compared with other 99mTc-based compounds. METHODS: Uptake and retention kinetics of 99mTc-Q63 and 99mTc-Q64 were measured in isolated rat cardiac myocytes, isolated perfused rat hearts, and intact canines and compared with previously reported Q-based compounds, a clinically available 99mTc perfusion agent (sestamibi), and 201Tl. RESULTS: Uptake of Q63, Q64, and sestamibi by isolated cardiac myocytes was similar. Maximum extraction (Emax) of Q64 by isolated perfused rat hearts was greatest among the 99mTc agents (P < 0.02), but net extraction (Enet) of Q64 was not different from Q63 or sestamibi 3 minutes after tracer injection. By 15 minutes, 201Tl Enet was lower than Q63, Q64, and sestamibi (P < 0.05). Among 99mTc agents, the uptake versus flow of Q3, Q63, and Q64 by canine heart was superior to Q12 and sestamibi (P < 0.05). CONCLUSIONS: The activity of Q63 and Q64 in the myocardium is related to actual myocardial blood flow over a broad, clinically relevant range of flows. The ischemic-to-normal zone activity distributions of Q63 and Q64 approximate actual flow in a manner more like that of 201Tl than sestamibi or Q12. These results provide a rational foundation in support of further evaluation of Q63 and Q64 in humans.

Myocardial capillaries and autonomic nerves in diabetes: Morphometric study of auricles from bypass surgery biopsies.

Patients with diabetes mellitus are excessively vulnerable to myocardial ischemia and often suffer from autonomic cardiac dysfunction. They are also known to have specific capillary pathology and abnormalities of substances essential for the neoangiogenic cascade. These background data led us to the hypothesis that the severity of ischemic heart disease in diabetes is attributable (at least in part) to microcirculatory and autonomic inadequacy caused by microangiopathy and failure of postischemic adaptive neoangiogenesis. To test this hypothesis we compared myocardial capillaries, autonomic nerve endings of 19 diabetics, 30 normoglycemics with ischemic heart disease, and 9 valve replacements serving as nonischemic controls. Right atrial appendages obtained during coronary bypass surgery were utilized for light, fluorescent, and electron microscopic morphometry. Although in this series there were no significant differences in the clinical and laboratory hemodynamic values between the ischemic normoglycemic and diabetic patients, the latter showed marked capillary and nerve terminal pathology, and their capillary density as well as capillary to myofiber ratios were significantly lower. In addition, the mean capillary area, volume fraction, and intercapillary distance were higher in diabetics. The mean area of the nerve varicosities was also smaller, and this was correlated with capillary density. We concluded that the findings support the hypothesis that cardiac vulnerability in diabetes is connected with inadequate adaptive neoangiogenesis and that this seems to be associated with atrophic changes in the nerve terminals.

A contrastive analysis of release patterns of biochemical markers of brain damage after coronary artery bypass grafting and valve replacement and their association with the neurobehavioral outcome after cardiac surgery.

OBJECTIVE: The present study aimed at a comparative analysis of neurobiochemical markers of brain damage and the neurobehavioral outcome in patients undergoing either valve replacement (VR) or isolated coronary artery bypass surgery (CABG). In order to control for well known risk factors both samples were strictly matched according to age, sex and preoperative neuropsychological performance. METHODS: We analysed neurone-specific enolase (NSE) and protein S-100B (S-100B) concentrations in serial venous blood samples taken preoperatively and 1, 6, 20 and 30 h postoperatively in 36 patients undergoing VR (N = 18) or isolated CABG surgery (N = 18). Mini Mental State Examination (MMS) was performed preoperatively, 3 and 7 days after surgery and 0.5 years later. Neuropsychiatric assessments were based on the diagnosis of postoperative delirium according to DMS-IIIR criteria and the Brief Psychiatric and the Delirium Rating Scale. RESULTS: VR and CABG patients, respectively, showed an increase of both S-100B (exact two-tailed Wilcoxon signed ranks test: P = 0.0001) and NSE (P = 0.0001) concentrations followed by a decrease during the next 30 h. Whereas S-100B values did not differ between patients groups subjects undergoing VR surgery exhibited higher NSE values during the postoperative course. Furthermore, VR patients showed a higher decline in cognitive performance which was also detectable 0.5 years after surgery. We found a weak association between the degree of individual postoperative decline of cognitive performance and S-100B area under curve values. CONCLUSIONS: Our data indicate that--apart from patients' age and preoperative neuropsychological performance--type of surgery remains a risk factor for postoperative neurobehavioral disorders. The different vulnerability of neurobehavioral disorders might be mirrored in different postoperative release patterns of NSE. We assume that both, NSE release and neurobehavioral disorders might be caused by a higher amount of intraoperative cerebral embolic events in VR patients.