A rapid point-of-care assay accurately measures vitamin D.

PURPOSE: Vitamin D (VitD) is a pleiotropic hormone with effects on a multitude of systems and metabolic pathways. Consequently, the relevance of a sufficiently high VitD serum level becomes self-evident. METHODS: A rapid immunofluorescence assay designed for the point-of-care measurement of serum VitD3 solely was tested. Inter- and intra-assay validation, double testing and result comparison with a standardized laboratory method were performed. RESULTS: An overall linear correlation of r = 0.89 (Pearson, 95% CI 0.88-0.92, p < 0.01) between the point of care and the conventional reference assay was registered. Accuracy and precision were of special interest at cut-points (10 ng/ml [mean deviation 1.7 ng/ml, SD 1.98 ng/ml, SE 0.16 ng/ml], 12 ng/ml [MD 0.41, SD 1.89, SE 0.19] and 30 ng/ml [MD - 1.11, SD 3.89, SE 0.35]). Only a slight deviation was detected between the two assays when using fresh (r = 0.91, 95% CI 0.86-0.94, p < 0.01) and frozen serum samples (r = 0.86, 0.82-0.89, p < 0.01). Results remained steady when samples were frozen several times. Inter- and intra-assay validation according to the CLSI protocol as well as multiuser testing showed stable results. CONCLUSION: This novel, innovative, and controlled study indicates that the evaluated rapid point of care VitD assay is reliable, accurate, and suited for clinical practice.

Frequency of cataract surgery and its impact on visual function-results from the German Gutenberg Health Study.

PURPOSE: To determine the frequency of cataract surgery in Germany and to evaluate its impact on visual function in an adult population. METHODS: The population-based Gutenberg Health Study was conducted in Germany with its baseline examination between 2007 and 2012 and a 5-year follow-up examiantion. An ophthalmological examination including slit-lamp examination, ocular biometry, and Scheimpflug imaging was carried out. Overall and age-specific frequencies of unilateral and bilateral cataract surgery within 5 years were computed including the 95% confidential intervals [95%-CI]. Association analyses were conducted to determine social and ocular associated factors using multivariable logistic regression analysis. Vision-related quality of life was assessed using NEI VFQ-25. RESULTS: A total of 10,544 people aged 35 to 74 years were bilateral phakic at baseline and had information on lens status at the 5-year examination. Of these, 168 had unilateral cataract surgery (1.6% [1.4-1.9%]), and 448 had bilateral cataract surgery (4.2% [3.9-4.7%]) in the following 5 years. The frequency of cataract surgery increased with age: 45-54-year-old subjects had twice as often cataract surgery (in at least on eye: OR = 2.32) than at age 35-44 years. The frequency further strongly increases with age (55-64 years: OR = 10.5; 65-74 years: OR = 43.8, p < 0.001). Subjects with glaucoma were more likely to have cataract surgery (OR = 2.52, p < 0.001). Visual function increased when undergoing bilateral cataract surgery. CONCLUSIONS: The frequency of cataract surgery is low at younger ages and increases up to 26% at age 70-74 years. Persons with glaucoma are more likely to undergo cataract surgery at population-based level in Germany.

Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study.

Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4-11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049.

Subclinical levels of anxiety but not depression are associated with planning performance in a large population-based sample.

BACKGROUND: Major depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range. METHODS: Planning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40-80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis. RESULTS: Higher anxiety ratings were associated with lower planning performance (ß = -0.20; p < 0.0001) independent of age (ß = 0.03; p = 0.47). When directly comparing the predictive value of depression and anxiety on cognition, only anxiety attained significance (ß = -0.19; p = 0.0047), whereas depression did not (ß = -0.01; p = 0.71). CONCLUSIONS: Subclinical levels of anxiety but not of depression showed negative associations with cognitive functioning independent of age. Our results demonstrate that associations observed in clinical groups might differ from those in population-based samples, also with regard to the trajectory across the life span. Further studies are needed to uncover causal interrelations of anxiety and cognition, which have been proposed in the literature, in order to develop interventions aimed at reducing this negative affective state and to improve executive functioning.

[Abnormal laboratory results : Plausibility, reliability, and implications]. / Auffällige Laborwerte : Plausibilität, Aussagekraft und Konsequenzen.

In outpatient care or the emergency room laboratory tests oftentimes provide the first clues to the medical condition that made the patient seek medical help. Quite commonly, rapid medical decisions are required in these situations. Therefore, laboratory results must be evaluated immediately and interpreted within the broader context of the patient's presentation. During this process test results must be checked for plausibility, their positive and/or negative predictive values for the individual patient must be considered, and finally, the potential clinical implications need to be assessed. The latter in particular is of the utmost importance. This article discusses several laboratory tests commonly ordered for emergency patients and provides some guidance on their relevance in the decision to refer an outpatient to an emergency room or for inpatient care, or whether a patient can be safely diagnosed in the outpatient setting.

Current and cumulative night shift work and subclinical atherosclerosis: results of the Gutenberg Health Study.

PURPOSE: The study examines the association between exposure to current and cumulative night shift work and subclinical parameters of atherosclerosis. METHODS: Participants of a population-based cohort study (the Gutenberg Health Study, N = 15,010) aged 35-64 years were examined at baseline (2007-2012). Investigations included measurements of arterial stiffness, vascular function [reactive hyperaemia (RH) index], and intima media thickness (IMT). Also, a complete job history (including up to 15 periods), occupational exposures, a variety of lifestyle, and dispositional variables were enquired. RESULTS: Night shift work was performed by 1071 out of 8065 currently employed individuals. The strongest association after adjustment for age, sex, job complexity level, being a manager, overtime work, and noise appeared for more than 660 night shifts within the last 10 years and a significantly increased arterial stiffness of 0.33 m/s. This reflects a 4 % flow velocity increase for individuals with more than 660 night shifts compared to non-night workers. Regarding the entire professional life, night shift workers showed a significantly decreased vascular function by -0.054 RH index points by using the same adjustment. IMT values did not differ statistically from non-night workers. Lifestyle and dispositional factors showed an influence on all used subclinical atherosclerosis parameters. CONCLUSIONS: The cross-sectional results demonstrate an association between night work and detrimental changes in the atherosclerotic process. The association is more pronounced with more years in night shift and is partly explained by lifestyle and dispositional factors. Longitudinal analyses are necessary to confirm the results.

Inflammatory bowel disease (IBD) locus 12: is glutathione peroxidase-1 (GPX1) the relevant gene?

Genome-wide association studies have identified and repeatedly confirmed the association of rs3197999 in MST1 with inflammatory bowel disease (IBD). However, the underlying pathophysiology remains unclear. rs3197999 is a non-synonymous single-nucleotide polymorphism which modifies the function of macrophage stimulating protein-1 (MST1). We show by haplotyping that rs3197999 is in linkage disequilibrium with rs1050450 in GPX1, with almost complete cosegregation of the minor alleles. As shown by immunoassay, rs3197999 influences the MST-1 level in serum. But also rs1050450 causes an amino acid exchange in glutathione peroxidase 1 (GPx-1) and reduced activity of this antioxidant enzyme. The association of GPx deficiency and IBD in mice was already shown. We propose that GPx-1 is a better candidate than MST1 for the pathophysiologic link between IBD locus 12 and IBD.

Transport of lipids from golgi to plasma membrane is defective in tangier disease patients and Abc1-deficient mice.

Mutations in the gene encoding ATP-binding cassette transporter 1 ( ABC1) have been reported in Tangier disease (TD), an autosomal recessive disorder that is characterized by almost complete absence of plasma high-density lipoprotein (HDL), deposition of cholesteryl esters in the reticulo-endothelial system (RES) and aberrant cellular lipid trafficking. We demonstrate here that mice with a targeted inactivation of Abc1 display morphologic abnormalities and perturbations in their lipoprotein metabolism concordant with TD. ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux. Structural and functional abnormalities in caveolar processing and the trans-Golgi secretory pathway of cells lacking functional ABC1 indicate that lipid export processes involving vesicular budding between the Golgi and the plasma membrane are severely disturbed.

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease.

Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg(689) (MSP(wt)) and Cys(689) (MSP(mut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP(mut) significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.

[The Gutenberg Health Study]. / Die Gutenberg Gesundheitsstudie.

The Gutenberg Health Study is a population-based, prospective, single-center cohort study that started in 2007 at the University Medical Center Mainz. The project focuses on cardiovascular diseases, cancer, eye diseases, metabolic diseases, diseases of the immune system and mental diseases. The study aims at improving the individual risk prediction for diseases. Therefore, lifestyle, psychosocial factors, environment, laboratory parameters as well as the extent of the subclinical disease are investigated. A comprehensive biobank enables biomolecular examinations including a systems biological approach. During the baseline visit 15,000 individuals aged 35-74 years were invited to a 5 h examination program in the study center. This will be followed by a computer-assisted telephone interview with a standardized interview and assessment of endpoints after 2.5 years. After 5 years a detailed follow-up examination comparable to the visit at study inclusion will be performed in the study center. Further follow-up visits of the cohort are envisaged.

The association of depression and all-cause mortality: Explanatory factors and the influence of gender.

BACKGROUND: The association of depression with mortality and the significance of explanatory factors, in particularly gender, have remained an issue of debate. We therefore aimed to estimate the effect of depression on all-cause mortality, to examine potential explanatory factors and to assess effect modification by gender. METHODS: We used Cox regression models to estimate the effect of depression on mortality based on data from the Gutenberg Health Study, which is a prospective cohort study of the adult population in the districts of Mainz and Mainz-Bingen, Germany. Baseline assessment was between 2007 and 2012. Effect modification by gender was measured on both additive and multiplicative scales. RESULTS: Out of 14,653 participants, 7.7% were depressed according to Patient Health Questionnaire 9 (PHQ-9), and 1,059 (7.2%) died during a median follow-up of 10.7 years. Depression elevated the risk of mortality in men and women in age-adjusted models (HR: 1.41, 95%-CI: 1.03-1.92; resp. HR: 1.96, 95%-CI: 1.43-2.69). Adjustment for social status, physical health and lifestyle covariates attenuated the effect and in the fully-adjusted model the hazard ratio was 0.96 (95%-CI: 0.69-1.33) in men and 1.53 (95%-CI: 1.10-2.12) in women. For effect modification by gender, the measure on multiplicative interaction was 0.68 (95%-CI 0.44-1.07) and on additive interaction was RERI=-0.47 (95%-CI -1.24-0.30). LIMITATIONS: The PHQ-9 is a single self-report measure of depression reflecting symptoms of the past two weeks, limiting a more detailed assessment of depression and course of symptoms, which likely affects the association with mortality. CONCLUSIONS: Depression elevates mortality by multifactorial pathways, which should be taken into account in the biopsychosocially informed treatment of depression. Effect modification by gender was not statistically significant.

[Occlusion of the left portal vein in newborns]. / Der linksseitige Pfortaderastverschluss des Neugeborenen.

PURPOSE: The occlusion of the left portal vein in newborn infants is shown and discussed in 14 cases. MATERIALS AND METHODS: The occlusion of the left portal vein in ten male and in four female newborn infants was diagnosed using ultrasound. Only one of the newborn infants was treated with an umbilical vessel catheter. In one case the occlusion of the left portal vein was suspected in an MRI. In the remaining 12 patients, the diagnosis was an incidental finding. RESULTS: Real-time ultrasound showed a hyperechogenic left portal vein without receiving a signal in duplex sonography in thirteen patients. A partly obstructive thrombus was only seen in one patient. Seven patients had enlarged and increased liver arteries already during the primary examination. Recanalization was achieved in two patients who received anticoagulative treatment and in one patient spontaneously. In the other eleven patients the liver arteries increased in caliber and number. DISCUSSION: The origin of the occlusion of the left portal vein is based on the adjustment to the postnatal hemodynamic situation in the umbilical recess. So far there is no evidence of the development of a permanent defect. For this reason and because of the possibility of spontaneous recanalization, treatment with anticoagulative drugs is hardly questioned. CONCLUSION: Occlusion of the left portal vein is mostly an incidental finding. It may appear without catheterizing the umbilical vessel and might be a reason for the "idiopathic lack" of the left portal vein.

TSH receptor antibody (TRAb) assays based on the human monoclonal autoantibody M22 are more sensitive than bovine TSH based assays.

Measurements of TSH receptor autoantibodies (TRAb) using assays based on the human monoclonal TSH receptor autoantibody M22 or bovine TSH have been compared in 136 adult patients. They suffered from Graves' disease (GD, n=62), Hashimoto's thyroiditis (HT, n=26), or non-autoimmune hyperthyroidism (NAH, n=48) and were selected on the basis of undetectable, borderline or low TRAb levels (0.6-3 IU/l) as measured by TSH based TRAb assay (Dynotest TRAKhuman from BRAHMS). The time interval between initial diagnosis of GD and TRAb determination was high and ranged from 1 month to 3.5 years (median: 2.3 years). Using the kit manufacturer's cutoff values, 53/62 (85.5%) of the selected group of GD patients were TRAb positive (>0.4 IU/l) by M22 based TRAb ELISA (Medizym TRAb clone, Medipan) and 45/62 (72.6%) were TRAb positive (>1.5 IU/l) by TSH based TRAb assay. In the HT group, 9/26 (34.6%) sera were positive in the M22 based ELISA and all but one of these 9 were positive or borderline in the TSH based assay. ROC plot analysis of the GD group using the NAH group as reference showed that at 95% specificity, the bovine TSH based TRAb assay had a sensitivity of 62.9% (cutoff for positivity=1.64 IU/l) and the M22 based TRAb ELISA a sensitivity of 90.3% (cutoff for positivity=0.32 IU/l). Overall therefore, the M22 based Medizym TRAb clone assay is more sensitive than the bovine TSH based Dynotest TRAK human assay.

Electro-physiological parameters of hepatic radiofrequency ablation--a comparison of an in vitro versus an in vivo porcine liver model.

BACKGROUND: Radiofrequency ablation (RFA) is an inherent part of curative treatment within a multimodal therapy concept of malignant liver tumors. The biggest problem is the high rate of local recurrences in tumors with a diameter of more than 3 cm because of the high variability and poor reproducibility of the zone of ablation. No imaging modality facilitates monitoring during neither intraoperativ nor percutaneous RFA. This experimental study describes and compares an in vitro and in vivo porcine model by its electro-physiological parameters with the aim of monitoring RFA procedures. MATERIALS AND METHODS: RFA was performed in a perfused in vitro porcine (one RFA per liver) and in vivo porcine model (24 animals) with three different RFA systems (Rita XL 5 cm, Rita XLi 7 cm, LeVeen 5 cm). In the in vivo model, percutaneous placement of the RFA device was guided by native and contrast-enhanced CT scan. The electro-physical parameters during RFA were online (in real time) recorded by a dedicated software. After the RFA, the livers were explanted, sliced, and measured according to the consensus technique. RESULTS: The delivered energy was in vivo versus in vitro: Rita XL 238 +/- 135 kJ versus 135 +/- 53 kJ (p = 0.247); Rita XLi 711 +/- 180 kJ versus 159 +/- 54 (p = 0.016) and with LeVeen 212 +/- 71 kJ (in vivo). The LeVeen system was inconsistent in the in vitro model. This correlates to an energy consumption per ml of necrosis in vivo versus in vitro Rita XL of 8 +/- 3 kJ/ml versus 6.4 +/- 3.9 kJ/ml (p = 0.537), Rita XLi of 10 +/- 6 kJ/ml versus 1.8 +/- 0.2 kJ/ml (p = 0.016), and LeVeen of 14.0 +/- 12 kJ/ml (in vivo). The volume of ablation was in vivo versus in vitro Rita XL 30 +/- 10 ml versus 26 +/- 17 ml (p = 0.329), Rita XLi 90 +/- 58 ml versus 88 +/- 21 ml (p = 0.905), and LeVeen 22 +/- 11 ml versus 50 +/- 12 ml (p = 0.04). The impedance during RFA were in vivo versus in vitro Rita XL 39 +/- 4 Omega versus 50 +/- 14 Omega (p < 0.247), Rita XLi 33 +/- 5 Omega versus 61 +/- 16 Omega (p = 0.016) and LeVeen 31 +/- 2 Omega (in vivo). CONCLUSION: The volume of ablation showed analogue data in vivo and in vitro. The delivered energy and energy consumption was in vivo up to five times (Rita XLi) higher than in vitro and the impedance in vivo was always lower than in vitro. These differences observed between in vivo and in vitro were more pronounced than previously described. Thus the use of an in vitro model for research of the RFA technique must be challenged. The large deployment of the Rita XLi was a problem for percutaneous positioning of the device without direct contact to liver surface or major vessels in 80-kg pigs and to a lesser extent in in vitro liver originating from 130- to 140-kg pigs. Modern RFA systems which generate large volume of tissue necrosis can therefore only be adequately tested in a porcine model with a liver weight of at least 1.5-2 kg. Alternatively, a bovine liver model (with a liver weight up to 10 kg) should be developed in the future.

Transthyretin and complex protein pattern in aqueous humor of patients with primary open-angle glaucoma.

PURPOSE: To analyze protein patterns in the aqueous humor of glaucoma patients in comparison to control subject using two different methods. METHODS: Aqueous humor was collected from 52 patients with primary open-angle glaucoma (POAG) and from 55 control subjects (CO). Twenty-two POAG samples and 24 CO samples were used for protein profiling through surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) ProteinChip arrays. The data were analyzed by multivariate statistical methods and artificial neural networks. One highly significant biomarker was identified through matrix assisted laser desorption/ionisation time of flight-mass spectrometry (MALDI-TOF). Thirty samples from patients with POAG and 31 control samples were analyzed through two-dimensional electrophoresis. Subsequently, the protein spots of all gels were detected, and the two groups were compared. One spot group exhibiting clear differential abundance was identified by mass spectrometry (electrospray ionization mass spectrometry). RESULTS: In the samples analyzed by SELDI-TOF-MS, about 250 protein peaks could be consistently clustered in both groups. The analyses revealed eight biomarkers, which discriminated glaucoma from non-glaucoma controls with a sensitivity of 90% and a specificity of 87%. These biomarkers were purified further, and one marker, which was upregulated in glaucoma patients (p=0.006), was identified as transthyretin. The upregulation of transthyretin in POAG patients was also confirmed by enzyme linked immunosorbent assay (ELISA; p=0.03). In all samples analyzed by two-dimensional electrophoresis, complex protein patterns were detected in a total of 177 spot groups. The aqueous humor of all glaucoma patients revealed some regions that were clearly different from the controls. Several spots were significantly increased in the aqueous humor of glaucoma patients. One of the proteins that is highly abundant in the aqueous of glaucoma patients was identified as transthyretin. CONCLUSIONS: The aqueous humor of glaucoma patients revealed characteristic differences in protein/peptide profiles from control patients using two different analytical methods, SELDI-TOF-MS and two-dimensional electrophoresis. Interestingly, we could detect elevated transthyretin concentrations in glaucoma samples. Transthyretin might play a role in the onset of glaucoma since it has been shown to form amyloid deposits. These particles could cause outflow obstructions thereby increasing intraocular pressure as a possible onset mechanism.

Balloon occlusion of the celiac artery: a test for evaluation of collateral circulation prior endovascular coverage.

INTRODUCTION: Visceral ischemia is a possible complication after endovascular coverage of the celiac artery (CA). A selective mesenteric angiography during simultaneous balloon occlusion of the CA imitates endovascular coverage and might therefore be suited for evaluation of collateral circulation. We report the feasibility of a balloon occlusion test (BOT) of the CA for this purpose. REPORT: We performed a BOT in 5 patients selected for endovascular surgery with intended coverage of the CA. The BOT could demonstrate sufficient collateral circulation in all cases, which was not evident without occlusion of the CA. The most important collateral vessels were the pancreaticoduodenal arcades and the dorsal pancreatic artery. All patients tolerated the BOT well without abdominal symptoms or pathological laboratory findings. DISCUSSION: Our report suggests that a BOT of the CA is a feasible and safe procedure. It can demonstrate collateral pathways before definite coverage is performed. This test might be useful for selection of patients prior intended coverage of the CA.

Coagulation and inflammation in long-term cancer survivors: results from the adult population.

Essentials The increase of cancer survival remains curtailed by cardiovascular mortality. We studied a large range of inflammatory and coagulation biomarkers in long-term cancer survivors. Cancer history has an important impact on mortality independent of cardiovascular risk factors. Fibrinogen and von Willebrand factor are potential biomarkers in survivors of increased mortality. SUMMARY: Background The advances in cancer treatment and detection of early cancer have resulted in a steady increase in the number of of cancer survivors over the years. However, because of the long-term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular disease (CVD) is increasing in survivors. Objectives To investigate traditional cardiovascular risk factors (CVRFs), inflammation and the coagulation profile in long-term cancer survivors (cancer diagnosis ≥ 5 years) from a large adult population-based study sample. Methods The presence of cardiovascular risk factors (CVRFs) and laboratory markers were compared in individuals with (n = 723) and without (n = 13626) a long-term history of cancer from the Gutenberg Health Study. Data on coagulation factors, D-dimer and von Willebrand factor (VWF) activity were available for 4974 individuals (n = 244 cancer survivors). Results In multivariable regression models, a history of cancer was, independently of CVRFs and CVD, associated with higher fibrinogen levels (ß 6.99, 95% confidence interval [CI] 1.16-12.8), VWF activity (ß 5.08, 95% CI 0.02-10.1), and antithrombin activity (ß 1.85, 95% CI 0.44-3.27). Cancer survivors with CVD showed notably higher VWF activity than individuals with CVD without a history of cancer, with a difference in the means of 23.0 (7.9-38.1). Multivariate Cox regression analysis, adjusted for CVRFs, confirmed that a long-term history of cancer is associated with a 72% higher mortality. Increased mortality in cancer survivors was dependent on fibrinogen level and VWF activity level. Conclusion Cancer survivors showed a worse inflammation and coagulation profile than individuals without a history of cancer. Overall mortality in long-term cancer survivors was increased independently of traditional CVRFs. These results underline the need to further investigate plasma biomarkers as complementary cardiovascular risk predictors in cancer survivors.

High density lipoprotein deficiency with xanthomas. A defect in reverse cholesterol transport caused by a point mutation in the apolipoprotein A-I gene.

A 7-yr-old girl with high density lipoprotein (HDL) deficiency and xanthomas has been identified in a Turkish kindred with repetitive consanguinity. She has severely reduced HDL-cholesterol and no apolipoprotein (apo) A-I. ApoA-II is reduced, whereas apoA-IV and apoC-III are normal. ApoB and low density lipoprotein (LDL)-cholesterol are increased. This is reflected in hypercholesterolemia. VLDL and IDL particles are low, and serum triglycerides are normal. The genetic defect could be identified as a base insertion into the third exon of the apoA-I gene. This leads to a nonsense peptide sequence beginning at amino acid 5 of the mature plasma protein and early termination of translation. The patient is homozygous for this mutation. Pedigree analysis indicated an autosomal dominant inheritance with no evidence of another genetic defect of lipoprotein metabolism in the kindred. In HDL deficiency, HDL binding to leukocytes was increased compared to normal. In the postprandial state, binding of labeled HDL3 to leukocytes is unchanged. This is in contrast to results with postprandially isolated leukocytes from controls or Tangier patients, which have a reduced binding capacity for HDL3. These results indicate that postprandial HDL precursors may compete the binding of labeled HDL3. The metabolic consequences of HDL deficiency were analyzed. There is only a small number of HDL-like particles containing apoA-II, apoA-IV, apoE, and lecithin/cholesteryl acyl transferase. The C-apolipoproteins were normal in the proband. Due to the lack of HDL they can only associate with apoB-containing particles, where they may interfere with cellular uptake. Thus, pure apoA-I deficiency leads to a complex metabolic derangement.

A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.

The genetic defect leading to cholesteryl ester storage disease (CESD) has been determined in a 12-yr-old patient. Lysosomal acid lipase (LAL) activity in cultured skin fibroblasts was reduced to approximately 9% of control fibroblasts. Plasma cholesterol (255 mg/dl) and LDL-cholesterol (215 mg/dl) were elevated whereas HDL-cholesterol was reduced (19 mg/dl). Triglycerides were moderately elevated (141 mg/dl). There were no clinical abnormalities with the exception of hepatosplenomegaly. Both parents have reduced LAL activity in white blood cells. PCR analysis of the LAL mRNA from the propositus revealed a single slightly smaller mRNA species in skin fibroblasts as well as in leukocytes. The mother of the patient and his older brother had two mRNA species: one of normal size and one of the same size as the propositus. The father has a LAL mRNA of normal size only. Sequence analysis of a PCR-amplified cDNA fragment showed a 72-bp in-frame deletion resulting in the loss of the codons for amino acids 254-277. Analysis of genomic DNA revealed that the 72 bp represent an exon, indicating that the deletion in the mRNA is caused by defective splicing. Sequence analysis of the patient's genomic DNA revealed a G-->A substitution in the last nucleotide of the 72-bp exon in one of his alleles. The mutant allele was shown to cosegregate with the truncated mRNA in the pedigree, providing further evidence that the G-->A substitution causes aberrant splicing and exon skipping. No normal-sized mRNA is detectable in the propositus even though he is not homozygous for the splice site mutation. This can be only accounted for by assuming that he is a compound heterozygote with a null allele inherited from his father. In summary, the data presented provide evidence that deletion of the codons for amino acids 254-277 in the LAL mRNA in combination with a null allele cause the clinical expression of CESD in our patient.