Use or Misuse of Albumin in Critical Ill Patients.

Since 1940 albumin has been used worldwide and is widely available commercially since this time. However, a meta-analysis in 1998 challenged the use of albumin and identified a trend toward higher mortality in critically ill patients who had received albumin. Since then, many studies including multicenter randomized controlled trials have been carried out investigating the safety and efficacy of albumin treatment in different patient cohorts. In this context, patient cohorts that benefit from albumin were identified. However, particularly in non-liver patients, the use of albumin remains controversial. In our comprehensive review, we would like to highlight the most important studies in the recent 20 years and therefore offer an evidence-based outlook for the use of albumin for patients treated in the ICU.

Fibrillin-1 Regulates Arteriole Integrity in the Retina.

Fibrillin-1 is an extracellular matrix protein that assembles into microfibrils that provide critical functions in large blood vessels and other tissues. Mutations in the fibrillin-1 gene are associated with cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Fibrillin-1 is a component of the wall of large arteries but has been poorly described in other vessels. We examined the microvasculature in the retina using wild type mice and two models of Marfan syndrome, Fbn1C1041G/+ and Fbn1mgR/mgR. In the mouse retina, fibrillin-1 was detected around arterioles, in close contact with the basement membrane, where it colocalized with MAGP1. Both a mutation in fibrillin-1 or fibrillin-1 underexpression characteristically altered the microvasculature. In Fbn1C1041G/+ and Fbn1mgR/mgR mice, arterioles were enlarged with reduced MAGP1 deposition and focal loss of smooth muscle cell coverage. Losartan, which prevents aortic enlargement in Fbn1C1041G/+ mice, prevented smooth muscle cell loss and vessel leakiness when administrated in a preventive mode. Moreover, losartan also partially rescued the defects in a curative mode. Thus, fibrillin-1/MAGP1 performs essential functions in arteriolar integrity and mutant fibrillin-1-induced defects can be prevented or partially rescued pharmacologically. These new findings could have implications for people with Marfan syndrome.

FBN2 Silencing Recapitulates Hypoxic Conditions and Induces Elastic Fiber Impairment in Human Dermal Fibroblasts.

Most chronic wounds are characterized by varying degrees of hypoxia and low partial pressures of O2 that may favor the development of the wound and/or delay healing. However, most studies regarding extracellular matrix remodeling in wound healing are conducted under normoxic conditions. Here, we investigated the consequences of hypoxia on elastic network formation, both in a mouse model of pressure-induced hypoxic ulcer and in human primary fibroblasts cultured under hypoxic conditions. In vitro, hypoxia inhibited elastic fiber synthesis with a reduction in fibrillin-2 expression at the mRNA and protein levels. Lysyl oxidase maturation was reduced, concomitant with lower enzymatic activity. Fibrillin-2 and lysyl oxidase could interact directly, whereas the downregulation of fibrillin-2 was associated with deficient lysyl oxidase maturation. Elastic fibers were not synthesized in the hypoxic inflammatory tissues resulting from in vivo pressure-induced ulcer. Tropoelastin and fibrillin-2 were expressed sparsely in hypoxic tissues stained with carbonic anhydrase IX. Different hypoxic conditions in culture resulted in the arrest of elastic fiber synthesis. The present study demonstrated the involvement of FBN2 in regulating elastin deposition in adult skin models and described the specific impact of hypoxia on the elastin network without consequences on collagen and fibronectin networks.

A supplement-free osteoclast-osteoblast co-culture for pre-clinical application.

There is increasing demand for efficient and physiological in vitro cell culture systems suitable for testing new pharmaceutical drugs or for evaluating materials for tissue regeneration. In particular, co-cultures of two or more tissue-relevant cell types have the advantage to study the response of cells on diverse parameters in a more natural environment with respect to physiological complexity. We developed a direct bone cell co-culture system using human peripheral blood monocytes (hPBMC) and human bone marrow stromal cells (hBMSC) as osteoclast/osteoblast precursor cells, respectively, strictly avoiding external supplements for the induction of differentiation. The sophisticated direct hPBMC/hBMSC co-culture was characterized focusing on osteoclast function and was compared with two indirect approaches. Only in the direct co-culture, hPBMC were triggered by hBMSC into osteoclastogenesis and became active resorbing osteoclasts. Bisphosphonates and sulfated glycosaminoglycans were used to examine the suitability of the co-culture system for evaluating the influence of certain effectors on bone healing and bone regeneration and the contribution of each cell type thereby. The results show that the investigated substances had more pronounced effects on both osteoblasts and osteoclasts in the co-culture system than in respective monocultures.

Biphasic influence of PGE2 on the resorption activity of osteoclast-like cells derived from human peripheral blood monocytes and mouse RAW264.7 cells.

Osteoclasts are large bone-resorbing cells of hematopoietic origin. Their main function is to dissolve the inorganic component hydroxyapatite and to degrade the organic bone matrix. Prostaglandin E2 (PGE2) indirectly affects osteoclasts by stimulating osteoblasts to release factors that influence osteoclast activity. The direct effect of PGE2 on osteoclasts is still controversial. To study the influence of PGE2 on osteoclast activity, human peripheral blood monocytes (hPBMC) and mouse RAW264.7 cells were cultured on osteoblast-derived extracellular matrix. hPBMC and RAW264.7 cells were differentiated by the addition of macrophage colony-stimulation factor and receptor activator of NFκB ligand and treated with PGE2 before and after differentiation induction. The pit area, an indicator of resorption activity, and the activity of tartrate-resistant acid phosphatase were dose-dependently inhibited when PGE2 was present ab initio, whereas the resorption activity remained unchanged when the cells were exposed to PGE2 from day 4 of culture. These results lead to the conclusion that PGE2 treatment inhibits only the differentiation of precursor osteoclasts whereas differentiated osteoclasts are not affected.

Human Bone Marrow Stromal Cells: A Reliable, Challenging Tool for In Vitro Osteogenesis and Bone Tissue Engineering Approaches.

Adult human bone marrow stromal cells (hBMSC) are important for many scientific purposes because of their multipotency, availability, and relatively easy handling. They are frequently used to study osteogenesis in vitro. Most commonly, hBMSC are isolated from bone marrow aspirates collected in clinical routine and cultured under the "aspect plastic adherence" without any further selection. Owing to the random donor population, they show a broad heterogeneity. Here, the osteogenic differentiation potential of 531 hBMSC was analyzed. The data were supplied to correlation analysis involving donor age, gender, and body mass index. hBMSC preparations were characterized as follows: (a) how many passages the osteogenic characteristics are stable in and (b) the influence of supplements and culture duration on osteogenic parameters (tissue nonspecific alkaline phosphatase (TNAP), octamer binding transcription factor 4, core-binding factor alpha-1, parathyroid hormone receptor, bone gla protein, and peroxisome proliferator-activated protein γ). The results show that no strong prediction could be made from donor data to the osteogenic differentiation potential; only the ratio of induced TNAP to endogenous TNAP could be a reliable criterion. The results give evidence that hBMSC cultures are stable until passage 7 without substantial loss of differentiation potential and that established differentiation protocols lead to osteoblast-like cells but not to fully authentic osteoblasts.

Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells.

The synthetic glucocorticoid dexamethasone (dex) is a mandatory additive to induce osteogenic differentiation of bone marrow stromal cell (BMSC) in vitro; however it is also known to promote the pathogenesis of osteoporotic bone disease in vivo. In this study human (h)BMSC were cultured in osteogenic medium containing ß-glycerophosphate and ascorbate (OM) and in OM containing dex (OM/D). It was seen that dex induced in human (h)BMSC both, osteogenic and adipogenic differentiation markers. Dex reveals its anti-inflammatory effect by reducing endogenous prostaglandin E2 (PGE2) formation and by suppressing the inducible enzymes cyclooxygenase 2 and microsomal PGE2 synthase 1. It was further seen that dex enhanced the expression of prostaglandin receptors, mainly EP2 and EP4 receptor subtypes. We thus hypothesized that dex enforces the susceptibility of hBMSC to respond to exogenous PGE2. Permanent exposure of hBMSC which were cultured in OM/D to PGE2, decreased osteogenic and increased adipogenic differentiation markers. The effects of PGE2 were preferentially mediated by receptor subtypes EP2 and EP4; EP1 was partially involved in pro-adipogenic effects, and EP3 was partially involved in anti-osteogenic effects. These results suggest that dex suppresses the formation of endogenous PGE2 but also enables hBMSC to respond to PGE2 due to the induction of PGE2 receptors EP2 and EP4. PGE2 then shifts in hBMSC the balance from osteogenic to adipogenic differentiation.

Artificial extracellular matrices with oversulfated glycosaminoglycan derivatives promote the differentiation of osteoblast-precursor cells and premature osteoblasts.

Sulfated glycosaminoglycans (GAG) are components of the bone marrow stem cell niche and to a minor extent of mature bone tissue with important functions in regulating stem cell lineage commitment and differentiation. We anticipated that artificial extracellular matrices (aECM) composed of collagen I and synthetically oversulfated GAG derivatives affect preferentially the differentiation of osteoblast-precursor cells and early osteoblasts. A set of gradually sulfated chondroitin sulfate and hyaluronan derivatives was used for the preparation of aECM. All these matrices were analysed with human bone marrow stromal cells to identify the most potent aECM and to determine the influence of the degree and position of sulfate groups and the kind of disaccharide units on the osteogenic differentiation. Oversulfated GAG derivatives with a sulfate group at the C-6 position of the N-acetylglycosamine revealed the most pronounced proosteogenic effect as determined by tissue nonspecific alkaline phosphatase activity and calcium deposition. A subset of the aECM was further analysed with different primary osteoblasts and cell lines reflecting different maturation stages to test whether the effect of sulfated GAG derivatives depends on the maturation status of the cells. It was shown that the proosteogenic effect of aECM was most prominent in early osteoblasts.

Artificial matrices with high-sulfated glycosaminoglycans and collagen are anti-inflammatory and pro-osteogenic for human mesenchymal stromal cells.

Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro-inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)-1ß-induced pro-inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high-sulfated glycosaminoglycan (GAG) derivatives did not secrete IL-6, IL-8, monocyte chemoattractant protein-1, and prostaglandin E2 in response to IL-1ß. The activation and nuclear translocation of nuclear factor κBp65 induced by IL-1ß, tumor necrosis factor-α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non-specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL-1ß-induced TNAP activity. These data suggest that aECM with high-sulfated GAG derivatives suppress the formation of pro-inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process.

Over-sulfated chondroitin sulfate derivatives induce osteogenic differentiation of hMSC independent of BMP-2 and TGF-ß1 signalling.

Natural glycosaminoglycans (GAGs) and chemically modified GAG derivatives are known to support osteogenic differentiation of mesenchymal stromal cells (MSC). This effect has mainly been described to be mediated by increasing the effectiveness of bone anabolic growth factors such as bone morphogenetic proteins (BMPs) due to the binding and presentation of the growth factor or by modulating its signal transduction pathway. In the present study, the influence of chondroitin sulfate (CS) and two chemically over-sulfated CS derivatives on osteogenic differentiation of human mesenchymal stromal cells (hMSC) and on BMP-2 and transforming growth factor ß1 (TGF-ß1) signalling was investigated. Over-sulfated CS derivatives induced an increase of tissue non-specific alkaline phosphatase (TNAP) activity and calcium deposition, whereas collagen synthesis was slightly decreased. The BMP-2-induced Smad1/5 activation was inhibited in the presence of over-sulfated CS derivatives leading to a loss of BMP-2-induced TNAP activity and calcium deposition. In contrast, the TGF-ß1-induced activation of Smad2/3 and collagen synthesis were not affected by the over-sulfated CS derivatives. BMP-2 and TGF-ß1 did not activate the extracellular signal-regulated kinase 1/2 or mitogen-activated protein kinase p38 in hMSC. These data suggest that over-sulfated CS derivatives themselves are able to induce osteogenic differentiation, probably independent of BMP-2 and TGF-ß1 signalling, and offer therefore an interesting approach for the improvement of bone healing.

Response of human bone marrow stromal cells, MG-63, and SaOS-2 to titanium-based dental implant surfaces with different topography and surface energy.

OBJECTIVES: Osseointegration is dependent on different parameters of the implant surface like surface roughness and physicochemical properties. In vitro studies using a wide variety of surface parameters and cell lines make it difficult to address the influence of a single parameter. With this study the influence of surface topography and energy on different osteoblast derived cell lines, namely MG-63 and SaOS-2 and of human mesenchymal stromal cells (hMSC) were investigated. MATERIAL AND METHODS: Cells were cultured on polished (POL) and sandblasted/hot acid etched (SBA) titanium surfaces which were partly alkaline treated (SBA NaOH). Cell morphology, metabolic activity, tissue non-specific alkaline phosphatase (TNAP) activity and prostaglandin E(2) (PGE(2) ) formation were determined. RESULTS: Impaired spreading was found on both SBA surfaces. Proliferation after 4 and 7 days increased on POL compared to both SBA surfaces. TNAP activity of hMSC and MG-63 was increased on POL compared to both SBA surfaces whereas SaOS-2 did not discriminate between the three surfaces. PGE(2) formation of hMSC and MG-63 was on both SBA surfaces after 2 days significantly higher than on POL. CONCLUSIONS: The results of this study show that surface roughness has a distinct influence on proliferation and differentiation of osteoblasts. However, variations in physicochemical properties seem to have little influence under the used experimental conditions. It is suggested that more sever and long-lasting modifications of surface chemistry would have an influence on osteoblastic cells.

Artificial extracellular matrices composed of collagen I and sulfated hyaluronan with adsorbed transforming growth factor ß1 promote collagen synthesis of human mesenchymal stromal cells.

Sulfated glycosaminoglycans (GAG) are multifunctional components of the extracellular matrix and are involved in the regulation of adhesion, proliferation and differentiation of cells. The effects of GAG are mediated in general by their interactions with cations and water, and in particular by their binding to growth factors. The aim of this study was to generate artificial extracellular matrices (aECM) containing collagen I and hyaluronan sulfate (HyaS), which are capable of adsorbing and releasing transforming growth factor ß1 (TGF-ß1), and to promote collagen synthesis of cultured human mesenchymal stromal cells (hMSC). For the preparation of aECM, monosulfated Hya (HyaS1) or trisulfated Hya (HyaS3) were used; the natural chondroitin-4-sulfate was used as a control. As applied for the in vitro experiments, the resulting matrices were composed of 93-98% collagen I and 2-7% GAG derivative. Adsorption of TGF-ß1 to the aECM and release from the aECM was dependent on the degree of sulfation of hyaluronan. Collagen synthesis of hMSC was promoted only by aECM with adsorbed TGF-ß1; the bare aECM had a slightly inhibitory effect on collagen synthesis. The promoting effect did not correlate either to the amount of adsorbed TGF-ß1 nor to the release of TGF-ß1, indicating that the correct presentation of TGF-ß1 to the cells might be critical. The results indicate that sulfated hyaluronan-containing aECM have the potential to control both the adsorption and release of TGF-ß1, and thereby promote collagen synthesis of hMSC. Thus, these aECM might be a useful tool for different tissue-engineering applications to enhance bone formation when used for biomaterial coating.

Bihemispheric cerebral FDG PET correlates of cognitive dysfunction as assessed by the CERAD in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a variety of cognitive deficits which can be reliably assessed by the neuropsychological test battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), but the cerebral changes underlying the respective cognitive deficits are only partly understood. Measures of severity of dementia in AD as well as delayed episodic memory performance in mild cognitive impairment significantly correlated with bihemispheric cerebral glucose hypometabolism. We therefore hypothesized that the CERAD cognitive battery may represent cerebral dysfunction of both hemispheres in patients with AD. In 32 patients with AD, cerebral glucose metabolism was investigated using positron-emission-tomography with 18Fluorodeoxyglucose (FDG PET) and associated with the test scores of the CERAD cognitive battery by statistical parametric mapping. Episodic memory scores significantly correlated with temporopari etal glucose metabolism of both hemispheres while delayed episodic memory significantly was correlated with the right frontotemporal cortices. Verbal fluency and naming scores significantly correlated with glucose metabolism in left temporoparietal and right frontal cortices, whereas constructional praxis predominantly correlated significantly with the bilateral precuneus. In conclusion, the results of our study demonstrate that not only memory function but also functions of language and constructional praxis in AD are associated with glucose metabolism as revealed by FDG PET in subsets of uni- and bilateral brain areas. The findings of our study for the first time demonstrate that in AD neuropsychological deficits as assessed by the CERAD refer to different cerebral sites of both hemispheres.

Differential effect of chondroitin-4-sulfate on the immediate and delayed prostaglandin E2 release from osteoblasts.

The present study examines the effect of chondroitin-4-sulfate (C4S) on the immediate (non-inflammatory conditions) and the delayed (inflammatory conditions) prostaglandin E(2) (PGE(2)) release from rat calvarial osteoblasts. An immediate low release of PGE(2) was induced by PAF, phorbol ester and arachidonic acid but not by IL1beta, TNF-alpha and LPS whereas a delayed high release of PGE(2) was induced by the inflammatory agents IL1beta, TNF-alpha and LPS but not by PAF, phorbol ester and arachidonic acid. C4S had no effect on the immediate PGE(2) release but inhibited the delayed release of PGE(2). IL1beta, TNF-alpha and LPS enhanced the expression of COX-2 and mPGES1 whereas phorbol ester enhanced COX-2 expression only. PAF and arachidonic acid had no effect on the expression of COX-2 and mPGES1. C4S inhibited the enhanced expression of COX-2 and mPGES1 but had no effect on the IL1beta-induced decrease of I-kappaBalpha and nuclear translocation of NF-kappaB. These results indicate that the beneficial effects of C4S in bone inflammatory diseases might be due to a specific inhibition of the delayed high PGE(2) release from osteoblasts.

A novel resorption assay for osteoclast functionality based on an osteoblast-derived native extracellular matrix.

Osteoclasts are large, mobile, bone-resorbing cells and play a critical role in bone remodeling and catabolic bone diseases. The major function of osteoclasts is to hydrolyze inorganic hydroxyapatite and degrade organic bone matrix, mainly collagen. For evaluation of differentiation to fully functional osteoclasts in vitro, a quantitative functional resorption assay is essential. Currently available commercial test systems are either based on the organic or the inorganic part of the bone matrix. The novel resorption assay presented here is based on decellularized osteoblast-derived matrix. SaOS-2 cells were used for the synthesis of a densely mineralized extracellular bone matrix (ECM) in alpha-MEM medium, which strongly accelerates their matrix synthesis. After removal of the SaOS-2 cells, osteoclast precursors are plated on the osteoblast-derived matrix and stained by von Kossa. Subsequently, resorption pits were quantified by densitometry using an imaging program. Using this novel assay, we show that (i) RAW 264.7 cells resorbed the osteoblast-derived matrix continuously from day 6 until day 9 of culture, a process that is dose dependent on the macrophage colony-stimulating factor (M-CSF) concentration, (ii) the resorption performance of RAW 264.7 was dose-dependently inhibited by IFN-gamma, and (iii) the assay is working with primary human and mouse osteoclast precursors as well. In conclusion, this quantitative, functional, easy-to-use, inexpensive assay will advance analysis of osteoclast biology.

Response of osteoblast-like SAOS-2 cells to zirconia ceramics with different surface topographies.

OBJECTIVES: Zirconia is a suitable biomaterial for use in medicine (stomatology, orthopaedics) due to its good biocompatibility and outstanding mechanical properties. This study compares the effect of (i) zirconia to the widely used titanium and (ii) zirconia with two different surface topographies (sandblasted and sandblasted/etched) on the adhesion, proliferation and differentiation of SAOS-2 osteoblasts. METHODS: SAOS-2 cells were cultured on either sandblasted or sandblasted/etched zirconia and compared with sandblasted/etched titanium. 2 and 24 h after plating, cell morphology was investigated by scanning electron microscope (SEM) and fluorescence imaging. At 24 and 48 h, cell number-relevant parameters were determined. Alkaline phosphatase (ALP) activity and mineral accumulation were measured at days 8, 11, 15 and day 22 of culture, respectively. RESULTS: SEM and fluorescence images revealed a faster spreading as well as higher number of adherent cells after 24 h incubation on zirconia compared with titanium. Also, the cellular metabolic activity after 24 h and the proliferation rate after 48 h is higher with zirconia compared with titanium. Zirconia had a more pronounced effect compared with titanium on the differentiation of SAOS-2 cells: ALP activity, an early differentiation marker increased earlier and mineralization, a late differentiation marker was increased. Only minor differences were found between zirconia with two different surface topographies; etched zirconia promoted slightly greater the differentiation of SAOS-2 cells. CONCLUSIONS: These data indicate that zirconia mediates a pronounced stronger effect on the adhesion, proliferation and differentiation compared with titanium; and that topographical differences of zirconia have minor effects on osteoblast biology.

Sulfated hyaluronan derivatives reduce the proliferation rate of primary rat calvarial osteoblasts.

Glycosaminoglycans (GAG) and proteoglycans, which are components of the extracellular bone matrix, are also localized in and at the membrane of osteoblasts and in the pericellular matrix. Due to their interaction with several growth factors, water and cations these molecules play an important role in regulating proliferation and differentiation of osteoblasts and bone development. The aim of this study was to assess in vitro the effects of two chemically sulfated hyaluronan (HyaS) derivatives on the proliferation of rat calvarial osteoblasts and to compare with those of native hyaluronan (Hya) and natural sulfated GAG such as chondroitin-4-sulfate (C4S), chondroitin-6-sulfate (C6S), dermatan sulfate (DS) and heparan sulfate (HS). Moderately and highly sulfated HyaS derivatives caused a time-dependent reduction of osteoblast proliferation. The anti-proliferative effect of HyaS was accompanied by a cell cycle arrest in the G1 phase, but was not associated with cell death. Whereas non-sulfated high molecular weight (HMW)- and low molecular weight (LMW)-Hya as well as C4S, C6S, DS and HS showed no effect on the cell proliferation.

Dresden Faculty selection procedure for medical students: what impact does it have, what is the outcome?

Since 2004 German universities have been able to use a selection procedure to admit up to 60 percent of new students. In 2005, the Carl Gustav Carus Faculty of Medicine at Dresden introduced a new admission procedure. In order to take account of cognitive as well as non-cognitive competencies the Faculty used the following selection criteria based on the legal regulations for university-admissions:the grade point average of the school-leaving exam (SSC, Abitur), marks in relevant school subjects; profession and work experience; premedical education; and a structured interview. In order to evaluate the effects of the Faculty admission procedures applied in the years 2005, 2006 and 2007, the results on the First National Medical Examination (FNME) were compared between the candidates selected by the Faculty procedures (CSF-group) and the group of candidates admitted by the Central Office for the Allocation of Places in Higher Education (the ZVS group, comprising the subgroups: ZVS best, ZVS rest and ZVS total). The rates of participation in the FNME within the required minimum time of 2 years of medical studies were higher in the CSF group compared to the ZVS-total group. The FNME pass rates were lowest in the ZVS rest group and highest in the ZVS best group. The ZVS best group and the ZVS total group showed the best FMNE results, whereas the results of the CSF-group were equal or worse compared to the ZVS rest group. No correlation was found between the interview results and the FNME results. According to studies of the prognostic value of various selection instruments, the school leaving grade point average seems the best predictor of success on the FNME. In order to validate the non-cognitive selection instruments of the Faculty procedure, complementary instruments are needed to measure non-cognitive aspects that are not captured by the FNME-results.

Neural correlates of delayed episodic memory in patients with mild cognitive impairment--a FDG PET study.

Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer's disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with (18)Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7+/-7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.

A Faculty Development Program can result in an improvement of the quality and output in medical education, basic sciences and clinical research and patient care.

The Carl Gustav Carus Faculty of Medicine, University of Technology Dresden, Germany, was founded in 1993 after the reunification of Germany. In 1999, a reform process of medical education was started together with Harvard Medical International.The traditional teacher- and discipline-centred curriculum was displaced by a student-centred, interdisciplinary and integrative curriculum, which has been named Dresden Integrative Patient/Problem-Oriented Learning (DIPOL). The reform process was accompanied and supported by a parallel-ongoing Faculty Development Program. In 2004, a Quality Management Program in medical education was implemented, and in 2005 medical education received DIN EN ISO 9001:2000 certification. Quality Management Program and DIN EN ISO 9001:2000 certification were/are unique for the 34 medical schools in Germany.The students play a very important strategic role in all processes. They are members in all committees like the Faculty Board, the Board of Study Affairs (with equal representation) and the ongoing audits in the Quality Management Program. The Faculty Development program, including a reform in medical education, the establishment of the Quality Management program and the certification, resulted in an improvement of the quality and output of medical education and was accompanied in an improvement of the quality and output of basic sciences and clinical research and interdisciplinary patient care.