Arabidopsis species deploy distinct strategies to cope with drought stress.

BACKGROUND AND AIMS: Water limitation is an important determinant of the distribution, abundance and diversity of plant species. Yet, little is known about how the response to limiting water supply changes among closely related plant species with distinct ecological preferences. Comparison of the model annual species Arabidopsis thaliana with its close perennial relatives A. lyrata and A. halleri, can help disentangle the molecular and physiological changes contributing to tolerance and avoidance mechanisms, because these species must maintain tolerance and avoidance mechanisms to increase long-term survival, but they are exposed to different levels of water stress and competition in their natural habitat. METHODS: A dry-down experiment was conducted to mimic a period of missing precipitation. The covariation of a progressive decrease in soil water content (SWC) with various physiological and morphological plant traits across a set of representative genotypes in A. thaliana, A. lyrata and A. halleri was quantified. Transcriptome changes to soil dry-down were further monitored. KEY RESULTS: The analysis of trait covariation demonstrates that the three species differ in the strategies they deploy to respond to drought stress. Arabidopsis thaliana showed a drought avoidance reaction but failed to survive wilting. Arabidopsis lyrata efficiently combined avoidance and tolerance mechanisms. In contrast, A. halleri showed some degree of tolerance to wilting but it did not seem to protect itself from the stress imposed by drought. Transcriptome data collected just before plant wilting and after recovery corroborated the phenotypic analysis, with A. lyrata and A. halleri showing a stronger activation of recovery- and stress-related genes, respectively. CONCLUSIONS: The response of the three Arabidopsis species to soil dry-down reveals that they have evolved distinct strategies to face drought stress. These strategic differences are in agreement with the distinct ecological priorities of the stress-tolerant A. lyrata, the competitive A. halleri and the ruderal A. thaliana.

Plasma fatty acid profile as biomarker of coronary artery disease: a pilot study using fourth generation artificial neural networks.

Many studies, focused on identifying new biomarkers for coronary artery disease (CAD) risk computation and monitoring, suggested a potential diagnostic role for fatty acids (FA). In the present study, we explored the potential diagnostic role of FA by using a data mining approach based on fourth generation artificial neural networks (ANN). Forty-one male subjects were enrolled. According to coronary angiography, 31 displayed CAD and 10 did not (non-CAD, control group). FA analysis was performed on plasma samples using a gas chromatography-mass spectrometry system and analyses were performed by an ANN method. The variables most closely related to CAD were low levels of alpha-linolenic acid, eicosapentaenoic acid, eicosatetraenoic and docosahexaenoic acids. High levels of 1,1-dimethoxyhexadecane, total dimethyl acetals and docosatetraenoic acid were related to non-CAD condition. This subset of variables, which were most closely correlated to the target diagnosis, achieved a consistent predictive rate. The average accuracy obtained was 76.5%, with 93% of sensitivity and 60% of specificity. The area under the ROC curve was equal to 0.79. In conclusion, our study highlighted the association between different plasma FA species, CAD and non-CAD conditions. The specific subset of variables could be of interest as a new diagnostic tool for CAD management.

Interleukin-1ß affects the phospholipid biosynthesis of fibroblast-like synoviocytes from human osteoarthritic knee joints.

OBJECTIVE: Phospholipids (PLs), together with hyaluronan and lubricin, are involved in boundary lubrication within human articular joints. Levels of lubricants in synovial fluid (SF) have been found to be associated with the health status of the joint. However, the biosynthesis and release of PLs within human joints remains poorly understood. This study contributes to our understanding of the effects of cytokines on the biosynthesis of PLs using cultured fibroblast-like synoviocytes (FLS) from human osteoarthritic knee joints. METHODS: Cultured FLS were stimulated with IL-1ß, TNFα, IL-6, or inhibitors of cell signaling pathways such as QNZ, SB203580 and SP600125 in the presence of stable isotope-labeled precursors of PLs. Lipids were extracted and quantified using electrospray ionization tandem mass spectrometry (ESI-MS/MS). RESULTS: Our analyses provide for the first time a detailed overview of PL species being synthesized by FLS. IL-1ß increased the biosynthesis of both phosphatidylethanolamine (PE) and PE-based plasmalogens. We show here that the NF-κB, p38 MAPK and JNK signaling pathways are all involved in IL-1ß-induced PL biosynthesis. IL-6 had no impact on PLs, whereas TNFα increased the biosynthesis of all PL classes. CONCLUSION: The biosynthesis of various PLs is controlled by IL-1ß and TNFα. Our detailed PL species analysis revealed that FLS can partly contribute to the elevated PL levels found in human osteoarthritis (OA) SF. IL-1ß in particular stimulates PE and PE-based plasmalogens which can act as cell-protective antioxidants. These results suggest that during OA progression, FLS undergo alterations in their PL composition to adapt to the new diseased environment.

Comparative lipidomic analysis of synovial fluid in human and canine osteoarthritis.

OBJECTIVE: The lipid profile of synovial fluid (SF) is related to the health status of joints. The early stages of human osteoarthritis (OA) are poorly understood, which larger animals are expected to be able to model closely. This study examined whether the canine groove model of OA represents early OA in humans based on the changes in the lipid species profile in SF. Furthermore, the SF lipidomes of humans and dogs were compared to determine how closely canine lipid species profiles reflect the human lipidome. METHODS: Lipids were extracted from cell- and cellular debris-free knee SF from nine donors with healthy joints, 17 patients with early and 13 patients with late osteoarthritic changes, and nine dogs with knee OA and healthy contralateral joints. Lipid species were quantified by electrospray ionization tandem mass spectrometry (ESI-MS/MS). RESULTS: Compared with control canine SF most lipid species were elevated in canine OA SF. Moreover, the lipid species profiles in the canine OA model resembled early OA profiles in humans. The SF lipidomes between dog and human were generally similar, with differences in certain lipid species in the phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) classes. CONCLUSIONS: Our lipidomic analysis demonstrates that SF in the canine OA model closely mimics the early osteoarthritic changes that occur in humans. Further, the canine SF lipidome often reflects normal human lipid metabolism.

Epicardial adipocyte hypertrophy: Association with M1-polarization and toll-like receptor pathways in coronary artery disease patients.

BACKGROUND AND AIMS: In coronary artery disease (CAD) epicardial adipose tissue (EAT) shows an elevated inflammatory infiltrate. Toll-like receptors (TLRs) are important mediators of adipose tissue inflammation and they are able to recognize endogenous products released by damaged cells. Because adipocyte death may be driven by hypertrophy, our aim was to investigate in CAD and non-CAD patients the association between EAT adipocyte size, macrophage infiltration/polarization and TLR-2 and TLR-4 expression. METHODS AND RESULTS: EAT biopsies were collected from CAD and non-CAD patients. The adipocyte size was determined by morphometric analysis. Microarray technology was used for gene expression analysis; macrophage phenotype and TLRs expression were analyzed by immunofluorescence and immunohistochemical techniques. Inflammatory mediator levels were determined by immunoassays. EAT adipocytes were larger in CAD than non-CAD patients and do not express perilipin A, a marker of lipid droplet integrity. In CAD, EAT is more infiltrated by CD68-positive cells which are polarized toward an M1 state (CD11c positive) and presents an increased pro-inflammatory profile. Both TLR-2 and TLR-4 expression is higher in EAT from CAD and observed on all the CD68-positive cells. CONCLUSIONS: Our findings suggested that EAT hypertrophy in CAD promotes adipocyte degeneration and drives local inflammation through increased infiltration of macrophages which are mainly polarized towards an M1 state and express both TLR-2 and TLR-4.

Epicardial adipose tissue inflammation is related to vitamin D deficiency in patients affected by coronary artery disease.

BACKGROUND AND AIMS: Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti-inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25-hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation-related molecules and EAT thickness. METHODS AND RESULTS: Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFα, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol-metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFα, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness. CONCLUSION: Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation.

[Service productivity in hospital nursing--conceptual framework of a productivity analysis]. / Dienstleistungsproduktivität in der Krankenhauspflege--Konzeptionelle Grundlagen einer Produktivitätsanalyse.

BACKGROUND AND OBJECTIVES: Decreasing staff numbers compounded by an increasing number of cases is regarded as main challenge in German hospital nursing. These input reductions accompanied by output extensions imply that hospital nursing services have had to achieve a continuous productivity growth in the recent years. Appropriately targeted productivity enhancements require approved and effective methods for productivity acquisition and measurement. However, there is a lack of suitable productivity measurement instruments for hospital nursing services. This deficit is addressed in the present study by the development of an integrated productivity model for hospital nursing services. Conceptually, qualitative as well as quantitative aspects of nursing services productivity are equally taken into consideration. METHODS: Based on systematic literature reviews different conceptual frameworks of service productivity and the current state of research in hospital nursing services productivity were analysed. On this basis nursing sensitive inputs, processes and outputs were identified and integrated into a productivity model. RESULTS: As an adequate framework for a hospital nursing services productivity model the conceptual approach by Grönroos/Ojasalo was identified. The basic structure of this model was adapted stepwise to our study purpose by integrating theoretical and empirical findings from the research fields of service productivity, nursing productivity as well as national and international nursing research. Special challenges existed concerning the identification of relevant influencing factors as well as the representation of nursing sensitive outputs. The final result is an integrated productivity model, which can be used as an adequate framework for further research in hospital nursing productivity. CONCLUSIONS: Research on hospital nursing services productivity is rare, especially in Germany. The conceptual framework developed in this study builds on established knowledge in service productivity research. The theoretical findings have been advanced and adapted to the context of German hospital nursing services. The presented productivity model represents a unique combination of services and nursing services research, which did not exist so far. By operationalisation of the model's components it can be used as the basis for further empirical -research.

Potential of gas chromatography-atmospheric pressure chemical ionization-time-of-flight mass spectrometry for the determination of sterols in human plasma.

The application of Gas Chromatography (GC)-Atmospheric Pressure Chemical Ionization (APCI)-Time-of-Flight Mass Spectrometry (TOF-MS) is presented for sterol analysis in human plasma. A commercial APCI interface was modified to ensure a well-defined humidity which is essential for controlled ionization. In the first step, optimization regarding flow rates of auxiliary gases was performed by using a mixture of model analytes. Secondly, the qualitative and quantitative analysis of sterols including oxysterols, cholesterol precursors, and plant sterols as trimethylsilyl-derivatives was successfully carried out. The characteristics of APCI together with the very good mass accuracy of TOF-MS data enable the reliable identification of relevant sterols in complex matrices. Linear calibration lines and plausible results for healthy volunteers and patients could be obtained whereas all mass signals were extracted with an extraction width of 20 ppm from the full mass data set. One advantage of high mass accuracy can be seen in the fact that from one recorded run any search for m/z can be performed.

Neonatal respiratory insufficiency caused by an (homozygous) ABCA3-stop mutation: a systematic evaluation of therapeutic options.

BACKGROUND: Autosomal recessive ABCA3 (ATP-binding cassette protein A3) gene mutations have been associated with neonatal respiratory distress and pediatric interstitial lung disease. The clinical course of the disease depends on the underlying mutations. Therefore, knowledge of course, symptoms and treatment of the disease is important. PATIENT AND METHODS: A term newborn suffered from progressive respiratory insufficiency, which led to death at the age of 4.8 months. The girl developed interstitial lung disease. Infections as well as structural and functional disorders of the lung were systematically excluded. A homozygous c.4681C > T (Arg 1561 Stop) mutation of the ABCA3 gene was identified. A literature review of the pathophysiology and treatment options of the disease was done. Therapeutic approaches with corticosteroids, macrolide, and hydroxychloroquine did not improve the clinical course. RESULTS: Therapeutic strategies for chronic interstitial lung disease have been used successfully in cases of a mild clinical course in juvenile patients with ABCA3 gene mutation. In our patient with homozygous ABCA3 gene mutation,they were not effective. Lung transplantation remains as a therapeutic option, but because of donor organ shortage and associated morbidity and mortality it is rarely feasible. CONCLUSION: More experience in the treatment of newborns with ABCA3 gene mutations is needed. Randomized, prospective evaluation of the different therapeutic approaches in a specific registry may improve prognosis and treatment of affected individuals.

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.

Gas chromatography-tandem mass spectrometry method for the simultaneous determination of oxysterols, plant sterols, and cholesterol precursors.

BACKGROUND: Cholesterol precursors and plant sterols have considerable potential as plasma biomarkers in several disorders of sterol metabolism and intestinal sterol absorption. Oxysterols are associated with atherogenesis, neurodegeneration, and inflammation. We developed a GC-MS method for the simultaneous analysis of these species in human plasma, including 24-, 25-, 27-hydroxycholesterol; 7-ketocholesterol; lanosterol; lathosterol; 7-dehydrocholesterol; desmosterol; stigmasterol; sitosterol; and campesterol. METHODS: Sterols were hydrolyzed with ethanolic potassium hydroxide solution, extracted by liquid/liquid extraction with n-hexane, and derivatized with N-methyl-N-trimethylsilyl-trifluoracetamide. Positive chemical ionization with ammonia, as reagent gas, was applied to generate high abundant precursor ions. RESULTS: The definition of highly sensitive precursor/product ion transitions, especially for coeluting substances, allowed fast gas chromatography run times of under 8.5 min. Using the multiple reaction monitoring mode, detection limits in the picogram per milliliter range could be achieved for most compounds. The method was validated for precision and recovery. Intraassay and interassay CVs were mostly <15% for serum and plasma samples. The recoveries of supplemented plasma samples in different concentrations were 88%-117%. The method was applied to stratification of patients with disorders in cholesterol biosynthesis and/or cholesterol absorption in hypercholesterolemia. The method revealed associations of sterol species with thyroid dysfunction and type 2 diabetes. CONCLUSIONS: This method allows high-throughput sterol profiling in various diseases.

IL-18 level in patients undergoing coronary artery bypass grafting surgery or valve replacement: which link with epicardial fat depot?

Interleukin-18 (IL-18) is a member of the interleukin-1 family of cytokines produced constitutively by different cell types and by adipose tissue. Due to the link between obesity, inflammation and cardiovascular diseases, we aimed to measure IL-18 circulating level in patients undergoing open-heart surgery both for elective coronary artery bypass grafting (CABG) or for valve replacement (VR), and we also evaluated whether epicardial adipose tissue (EAT) depot may be a potential source of IL-18. Circulating IL-18 protein was quantified by enzyme-linked immunosorbent assay. IL-18, IL-18 receptor 1 (IL-18 R1) and IL-18 receptor accessory protein (IL-18-RAP) gene expression in EAT depot were evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. In this study we found that all cardiovascular patients (CABG and VR) have increased circulating IL-18 level compared to healthy control subjects (p < 0.0001), but no statistical significant difference was observed between CABG and VR groups (p = 0.35). A great increase in the gene expression of IL-18 (p < 0.05), IL-18 R1 (p < 0.01) and IL-18 RAP (p < 0.001) was observed in EAT samples obtained from CABG vs VR patients. In conclusion, CABG and VR patients had similar increased level of circulating IL-18 protein, but in EAT depots isolated from CABG gene expression of IL-18, IL-18 R1 and IL-18-RAP resulted higher than in VR patients. Future investigation on local IL-18 protein production, its autocrine-paracrine effect and its correlation with plasmatic IL-18 level could give more information on the relationship between IL-18 and coronary artery disease.

Fifty-kDa hyaluronic acid upregulates some epidermal genes without changing TNF-α expression in reconstituted epidermis.

BACKGROUND: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. METHODS: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-α expression was determined using quantitative PCR. Genomic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. RESULTS: LMWHA of approximately 50 kDa did not significantly alter tumor necrosis factor-α expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. CONCLUSION: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology.

3D sub-nanometer analysis of glucose in an aqueous solution by cryo-atom probe tomography.

Atom Probe Tomography (APT) is currently a well-established technique to analyse the composition of solid materials including metals, semiconductors and ceramics with up to near-atomic resolution. Using an aqueous glucose solution, we now extended the technique to frozen solutions. While the mass signals of the common glucose fragments CxHy and CxOyHz overlap with (H2O)nH from water, we achieved stoichiometrically correct values via signal deconvolution. Density functional theory (DFT) calculations were performed to investigate the stability of the detected pyranose fragments. This paper demonstrates APT's capabilities to achieve sub-nanometre resolution in tracing whole glucose molecules in a frozen solution by using cryogenic workflows. We use a solution of defined concentration to investigate the chemical resolution capabilities as a step toward the measurement of biological molecules. Due to the evaporation of nearly intact glucose molecules, their position within the measured 3D volume of the solution can be determined with sub-nanometre resolution. Our analyses take analytical techniques to a new level, since chemical characterization methods for cryogenically-frozen solutions or biological materials are limited.

Lipid homeostasis in macrophages - implications for atherosclerosis.

In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann-Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism.

Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis.

Niemann-Pick diseases are hereditary neurovisceral lysosomal lipid storage disorders, of which the rare type C2 almost uniformly presents with respiratory distress in early infancy. In the patient presented here, the NPC2 exon 4 frameshift mutation c.408_409delAA caused reduced NPC2 protein levels in serum and lung lavage fluid and the synthesis of an aberrant, larger sized protein of around 28 kDa. Protein expression was strongly reduced also in alveolar macrophages. The infant developed failure to thrive and tachypnea. Lung lavage, computer tomography, and histology showed typical signs of pulmonary alveolar proteinosis with an abnormal intraalveolar accumulation of surfactant as well as macrophages. An NPC2-hypomorph animal model also showed pulmonary alveolar proteinosis and accumulation of macrophages in the lung, liver, and spleen long before the mice died. Due to the elevation of cholesterol, the surfactant had an abnormal composition and function. Despite the removal of large amounts of surfactant from the lungs by therapeutic lung lavages, this treatment was only temporarily successful and the infant died of respiratory failure. Our data indicate that respiratory distress in NPC2 disease is associated with a loss of normal NPC2 protein expression in alveolar macrophages and the accumulation of functionally inactive surfactant rich in cholesterol.

Expression of the lipid transporters ABCA3 and ABCA1 is diminished in human breast cancer tissue.

ATP-binding cassette transporters ABCA3 and ABCA1 are related to a differentiated, lipid-secreting phenotype of type II pneumocytes. Since mammary gland epithelial cells also show pronounced lipid metabolism and secretion, we investigated the expression of these proteins in normal as well as in neoplastic breast tissue. Normal human breast tissue, breast cancer cell lines, and 162 tumor samples of patients with primary unilateral invasive breast cancer were analyzed for ABCA3 and ABCA1 protein expression by immunohistochemistry using tissue microarrays. Strong ABCA3 and ABCA1 expression was found in the inner layer of normal mammary gland epithelium. Concurrent cytoplasmic ABCA3 and ABCA1 immunoreactivity was found in 9 of 11 breast cancer cell lines. ABCA3 and ABCA1 were shown to be differentially expressed in human breast cancer. Loss of ABCA3 staining was significantly associated with positive nodal status and negative progesterone receptor expression. In multivariate analysis, diminished ABCA3 expression proved to be a significant, independent and adverse risk factor for tumor recurrence. ABCA1 expression was associated with positive lymph nodes, but not significantly associated with tumor recurrence or breast cancer-specific survival. ABCA3 and ABCA1 are strongly expressed in normal mammary gland epithelium. Decreased ABCA3 expression in breast cancer seems to be associated with poor prognosis.

[Frontotemporal dementia in association with a family history of dementia and ApoE polymorphism]. / Frontotemporale Demenz im Zusammenhang mit Familienanamnese Demenz und ApoE-Genotyp.

OBJECTIVE: To examine the association between apolipoprotein E (ApoE) and a family history of dementia in 1st- and 2nd-degree relatives of patients with frontotemporal dementia (FTD) with a dementia onset by age 70. METHODS: The study included 494 dementia patients (73 FTD patients) and 82 cognitively normal spousal control subjects. Neuropsychiatric examination, Consortium To Establish a Registry on Alzheimer's Disease (CERAD) testing, the clock-drawing test, and ApoE genotyping were performed in patients and controls. All patients were examined by magnetic resonance imaging. FTD patients fulfilled the Lund-Manchester criteria. RESULTS: All controls had normal Mini Mental State exam (MMSE > or =27). 28 of the 82 spousal controls were excluded because CERAD test results were consistent with the diagnosis of mild cognitive impairment (MCI) or the CERAD was incomplete. The remaining 54 spousal controls had CERAD test results with z-scores >/= -1.5. The number of dementia patients with FTD was 73. Apo epsilon4 homozygosity was found in 13.6% of the FTD patients. None of the spousal controls was homozygous for the Apo epsilon4 genotype (p=0.005). A positive family history of dementia was lowest among cognitively normal spousal controls (9.3%). It rose to 35.6% for FTD patients and was highest among Apo epsilon4 homozygous FTD patients (50.0%). CONCLUSIONS: Apo epsilon4 homozygosity is associated with a family history of dementia and FTD in our cohort if the current clinical criteria are employed. It is likely that autopsy might reveal amyloid beta deposits typical for Alzheimer's disease among the Apo epsilon4 homozygous patients with frontotemporal clinical presentation and neuroimaging consistent with FTD. Apo epsilon4 homozygosity has not yet been defined as an exclusion criterion for the diagnosis of FTD. In the future, a revision of the clinical criteria should consider the ApoE genotype.