These

These PD 0332991 results encourage us to apply combination therapy of therapeutic mAbs with IL-21. Although the effect of IL-21 on murine NK cells has been extensively elucidated, there is still limited information about the effect of IL-21 on human NK cells (Skak et al, 2008b). IL-21 had only moderate effects on surface levels of inhibitory (CD158a and CD158b) and activating NK-cell receptors (NKG2D) in human NK cells (Skak et al, 2008a). Moreover, IL-21 was able to increase both mRNA and protein levels of the effector molecules perforin and granzyme-B, as well as enhance NK cytotoxicity against K562 (Skak et al, 2008a). In this study, we provided novel findings that IL-21 induced the significant upregulation of CD247 molecules on NK cells, important molecules for Fc receptor (CD16)-dependent NK killing (Whiteside, 2004).

These results suggested that the upregulation of CD247 molecules was one of the mechanisms behind IL-21-enhanced ADCC in patients with ESCC. However, we did not detect the upregulation of perforin and granzyme-B in response to IL-21 treatment in this study. Although the reason for this discrepancy is currently unknown, it may be due to the difference in in vitro culture condition, for example, unfractionated PBMCs vs purified NK cells, or incubation time. In this study, we showed that IL-21 could directly act on NK cells, as one of the mechanisms behind IL-21 enhances ADCC activity, as it was shown that purified NK cells treated with IL-21 could enhance ADCC activity.

In addition, it was previously shown that IL-21 indirectly enhanced NK cell function through cytokine production such as IFN-��, when PBMCs were treated with IL-21 (Roda et al, 2007). Thus, it is likely that IL-21 has pleiotrophic roles in a wide variety of cells, leading to the enhancement of ADCC activity (Roda et al, 2006). In this study, we showed that the highest dose of IL-21 was sometimes less effective for the enhancement of ADCC than Carfilzomib IL-21 at lower levels. It is likely that there might be some plateau effect of IL-21 at the highest dose in some patients, although further experiments are needed to clarify the mechanisms. A phase I study involving IL-21 monotherapy for metastatic melanoma or renal cell carcinoma reported that monotherapy was well tolerated and exhibited anti-tumour activity in some patients (Davis et al, 2007; Thompson et al, 2008), thereby suggesting that IL-21 may have an anti-tumour effect as a monotherapy. However, this study clearly showed that IL-21 could efficiently enhance impaired ADCC activity in ESCC patients, suggesting that combination therapy of Trastuzumab or Cetuximab with IL-21 might result in the enhancement of the anti-tumour effect.

To our knowledge, there has been no study assessing

To our knowledge, there has been no study assessing definitely prognostic values of EGFR in a large cohort of GISTs. However, no significant association was found between the EGFR expression and prognostic analysis of GISTs in our study. Increased COX-2 expression has been observed in colorectal adenoma and carcinoma[27]. The induction of COX-2 has been shown to promote cell growth, inhibit apoptosis and enhance cell motility and adhesion[28]. Over-expression of COX-2 has tumorigenic effects in animal models[29]. Expression levels of COX-2 and vascular endothelial growth factor were found to be significantly higher in malignant GISTs than those in benign and intermediate GISTs[30].

A study reported a correlation between the COX-2 expression and tumor cell proliferation in GISTs, but no association was found between COX-2 expression and mortality, metastasis, tumor size, the risk of stages, the dose of tyrosine kinase inhibitors, or the rate of complete resection[31]. Our results demonstrated that levels of COX-2 expression were significantly different between gastric tumors and nongastric tumors (P < 0.001), but no significant relationship was found between the COX-2 expression and risk factors, or survival. Imatinib therapy reduces rates of recurrence in GISTs. Nevertheless, it remains unclear how to screen patients who would be more likely to benefit from the adjuvant therapy. In our study, we found that imatinib treatment could significantly improve 3-year DSS rates in the intermediate and high risk categories of patients after a complete tumor resection.

In conclusion, Ki-67 expression is significantly associated with GIST malignancy and can be used as a putative prognostic marker in GISTs. p53 and COX-2 also provide additional valuable information in the evaluation of malignancy and types of GISTs. COMMENTS Background Gastrointestinal stromal tumors (GISTs) are known to have a wide variability in malignancy and prognosis. Risk grading based on tumor size, location and mitotic counts has been proposed to predict adverse outcomes of GIST in the literature. Research frontiers Recent molecular studies have found that the deregulations of Ki-67, cyclin A, B1, D1, E, cdc2 and other cell-cycle regulators were significantly associated with a shorter disease-free survival in GISTs.

Innovations and breakthroughs In this study, expressions of Ki-67, p53, epidermal growth factor receptor (EGFR) and COX-2 were investigated in a large cohort of GIST patients and their roles as prognostic values for GISTs were also evaluated. To our knowledge, this is the first assessment of the prognostic value of EGFR in patients with GISTs. Applications The immunohistochemical staining of these tumorigenetic and cell proliferative proteins provides an alternative approach for follow-up and clinical Carfilzomib decisions regarding the treatment for GISTs.

The cells were then washed 3 times with PBS, re-plated with compl

The cells were then washed 3 times with PBS, re-plated with complete medium, and allowed to rest overnight. For the coculture of BMDCs with syngeneic splenocytes in a mixed leukocyte reaction, the spleens were harvested, crushed, and filtered through 100 ��m filters and the red blood cells were lysed with ammonium-chloride-potassium (ACK) lysing solution. selleck Tipifarnib The mixed leukocyte reaction was performed with a splenocyte-to-BMDC ratio of 10 to 1. Supernatants were collected for cytokine analysis at 72 h. Animal studies C57BL/6 and TLR2KO mice were orally gavaged with H. pylori SS1 (3 times over 1 week). After 2 months, the mice were analyzed. The stomach was cut along the greater curvature and removed. Strips (2 mm) composed of fundus and antrum were embedded in Tissue-Tek optimum cutting temperature (OCT) compound (Sakura Finetek, Torrance, CA) and immersed in liquid nitrogen.

Paraffin sections were also prepared for H&E staining. Meanwhile, splenocytes from C57BL/6 and TLR2KO mice were cocultured for 18 h with BMDCs infected with H. pylori. The splenocyte-to-BMDC ratio was 10 to 1. After 72 h, splenocytes were collected and the percentages of IFN-��, IL-17A, and Foxp3 were measured by flow cytometry (i.e., FACS, fluorescence-activated cell sorting). Measurement of cytokine production by BMDCs and splenocytes The supernatant from the coculture of BMDCs and splenocytes was collected and the concentrations of IL-12p70, IL-23p19, IL-6, TNF-��, IFN-��, IL-10, and IL-17A were measured using Quantikine ELISA Kits (eBioscience, San Diego, CA, or BD Biosciences, San Jose, CA).

Determination of the expression of intracellular markers on splenocytes and surface markers on BMDCs by flow cytometry Splenocytes were labelled with fluorescence-conjugated antibodies to Foxp3, IFN-��, and IL-17A (eBioscience). Stimulated BMDCs were dual-labelled with fluorescence-conjugated antibodies to CD11c and TLR2 or TLR4. For cytokine profiles, the cells were stimulated, stained, and analyzed, as previously published [20], with a Coulter XL Flow Cytometer (Beckman Coulter, Miami, FL). Histological analysis After H. pylori infection of 2 months duration, the stomachs of WT and TLR2KO mice were removed and measured. Two adjacent full-thickness longitudinal strips were removed from the greater curvature and fixed in formalin for histological analysis.

The specimens were scored separately for the presence Cilengitide or absence of each of the following histologic criteria: neutrophil infiltration (polymorphonuclear neutrophils), gastritis, and epithelial metaplasia. The results were reported as the percentage of fields affected each slide [21]. Immunohistochemistry Paraffin sections (8��m) were de-waxed in xylene twice, incubated in 100%, 95%, and 70% ethanol for 1 minute each, and hydrated in water for 5 minutes.

e , 30% vs 40%) in the current design using logistic regression

e., 30% vs. 40%) in the current design using logistic regression was .25 with alpha of .05. Randomization and Masking Participants were randomly assigned to the intervention or control arm using a computerized full read adaptive randomization program (Taves, 1974) that minimized the likelihood of imbalance between the study arms with respect to biological sex and intensity of smoking (i.e., heavy smoker [��20 cigarettes per day]) while maintaining a ratio of 2:1 in the intervention:control groups. Participants were assigned at a higher ratio to the intervention to increase the amount of information obtained about the intervention experience. Participants, but not researchers, were blind to arm allocation. Ongoing monitoring of the arm allocations revealed an imbalance in the minimum number of participants intended for each study arm within each subgroup (e.

g., male heavy smokers). As a result, allocation concealment was broken for the last eight participants enrolled. To rectify the imbalance, these participants were manually assigned to the arm subgroup that required additional participants to become balanced. For example, the control group had fewer male light smokers than it should have; as such, all seven male light smokers in the queue were assigned to the control group. The proportion of participants in each subgroup designed to balance the study arms were maintained for both arms. Procedures Smokers expressed their interest by completing an online screener form, which was then e-mailed to the project coordinator.

Eligible candidates were contacted by the project coordinator, who scheduled an appointment over the phone to confirm eligibility, explain study details, obtain verbal consent, and complete the registration process. All participants, irrespective of study arm, identified a quit day that was at least 15 days but no more than 30 days from their registration date. Those who smoked 10 cigarettes or more per day were counseled to consider pharmacotherapy to assist in their quitting (Agency for Healthcare Research and Quality, 2009). After registration, participants were e-mailed an online survey link and instructed to complete the survey as soon as possible. The baseline survey had to be completed in order to receive text messages. Both control and intervention messages began 14 days prior to one��s quit date.

Participants received incentives of $10 and $20 after completing the 4-week and 3-month postquit follow-ups, respectively. A third of participants received an additional $10 if they responded within 48hr, another third of participants received $10 GSK-3 if they completed the online survey within 48hr of receiving a second reminder text, and a different third received $10 if they completed a minisurvey via text messaging at 3 months. Participants could opt-out of the study at any time by texting ��end�� to the program or by contacting project staff.

Russell et al suggested that the relative reduction of plasma ni

Russell et al. suggested that the relative reduction of plasma nicotine spikes in heavy smokers http://www.selleckchem.com/products/AP24534.html is to avoid any drop in nicotine, which will cause discomfort or other negative effects. In contrast, the rapid peaks (boosts) in nicotine in regular smokers are positively reinforcing. They also concluded that a venous blood nicotine boost of 10 ng/ml per tobacco cigarette is sufficient for positive subjective effects. A similar boost in venous plasma nicotine produces electroencephalographic changes consistent with increased arousal (Kadoya, Domino, & Matsuoka, 1994). Such a nicotine boost can also be obtained from oral and nasal snuff or nasal spray but as rapidly as other forms, such as nicotine gum and patches. Russell et al.

(1980) suggested in very heavy smokers reinforcement through withdrawal relief, in contrast to light smokers where positive reinforcement to nicotine boost occurs. In light tobacco smokers, there is a positive correlation between the number of cigarettes smoked and plasma nicotine, whereas there is little correlation in heavy tobacco smokers. Similar findings were reported by Gori and Lynch (1985) using a much larger sample. Besides nicotine, the major pharmacologically active ingredient, there are many other chemicals in tobacco smoke (Bernhard, 2011; Layten-Davis & Nielson, 1999; Rodgman & Perfetti, 2008; Schmeltz, 1995). Fowler, Volkow, Wang, Pappas, Logan, MacGregor, et al. (1996) and Fowler, Volkow, Wang, Pappas, Logan, Shea, et al. (1996) reported that tobacco smoke inhibits brain monoamine oxidase A and B, but exactly what chemical is responsible is still unclear.

Clemens et al. (2009) found five minor tobacco alkaloids that increase rat nicotine locomotor activity and nicotine self-administration. Rodd-Henricks et al. (2002) described the reinforcing effects of acetaldehyde (also in tobacco smoke) in the posterior tegmental area of alcohol preferring rats. Presumably, all of these substances are present equally in the smoke of the denic as well as nic cigarettes used and could be one explanation of the effects of denic tobacco smoking. Another could be the psychological cues surrounding cigarettes and other addictive substances that acquire value. This is central to many theories of addiction, most notably the incentive sensitization theory of addiction of Robinson and Berridge (1993). In real world situations, Cilengitide there are cues that surround and pervade the life of smokers such as time breaks, advertisements, etc. Cues are strongly linked to the maladaptive behavior of addicts to many different substances including tobacco (Berridge, 2000, 2007; Flagel, Akil, & Robinson, 2009; Jansen, 1998).

, 1993; Ziedonis et al , 2008; Schroeder

, 1993; Ziedonis et al., 2008; Schroeder Perifosine Phase 3 & Morris, 2010). There have been relatively few population-based research investigations that have compared the smoking behaviors of persons with and without mental illness across the spectrum of psychiatric disorders. The first of such population-based studies was conducted by Lasser et al. (2000) analyzing data from the 1991�C1992 National Comorbidity Survey. Their results showed that persons with alcohol, drug, or mental problems (ADM) in the past month comprised 28.3% of the U.S. population, were twice as likely to be current smokers as those without ADM disorders (41.0% vs. 22.5%), and accounted for 40.6% of all current smokers and 44.4% of total cigarettes sold in the United States.

Using the same data, another study found that persons with nonsubstance-related mental illness in the past twelve months constituted 24% of the U.S. population but consumed about 40% of all cigarettes in the United States (Saffer & Dave, 2005). Using data from the 2001�C2002 National Epidemiologic Survey on Alcohol and Related Conditions, Grant, Hasin, Chou, Stinson, and Dawson (2004) found that individuals with ADM disorders in the past twelve months made up 30.3% of the population but consumed 46.3% of all cigarettes in the United States. These three studies defined mental illness based on the Diagnostic and Statistical Manual of Mental Disorders, Revised third edition DSM-III-R or fourth edition DSM-IV (American Psychiatric Association, 1987, 1994), and they reached a strikingly similar conclusion that more than 40% of all cigarettes sold in the United States are consumed by individuals with mental illness.

However, a recent Brefeldin_A study, which also defined mental illness according to the DSM-IV but focused on a nationally representative sample of Black Americans in 2001�C2003, derived much lower estimates, reporting that those with mental illness in the past twelve months represented 18.1% of the sample but consumed 23.9% of all cigarettes by Blacks (Hickman, Delucchim & Prochaskam, 2010), perhaps due to the fact that Blacks have a lower prevalence of mental disorders than Whites (J. Breslau et al., 2006; Kessler et al., 1994). Instead of using the diagnostic criteria such as those in the DSM-IV, Hagman, Delnevo, Hrywna, and Williams (2008) defined mental illness with a clinically validated brief psychological screening instrument, the K6 scale (Kessler et al., 2002, 2003), designed to screen populations for serious psychological distress (SPD). Using the 2002 National Survey of Drug Use and Health data, they found that 8.3% of U.S. adults had SPD in the past twelve months, and those with SPD had higher rates of current cigarette smoking than those without SPD (44.9% vs. 26.0%).

(Basel, Switzerland) for supplying PKF115-584 We thank Dr Manue

(Basel, Switzerland) for supplying PKF115-584. We thank Dr. Manuela Gariboldi (IFOM, Milan, Italy) for providing the SW837 cell line. Funding Statement This work was supported by the Italian Association for Cancer Research (AIRC), Cariplo Foundation, the click here Italian Ministry of Health and Lombardy Regional Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Dyslipidemia, with low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), is a well established risk factor for coronary artery disease (CAD) and a significant cause of mortality in individuals with type 2 diabetes (T2D) [1].

The risk of developing CAD is 2�C3 times higher in diabetic males and 4�C5 times higher in diabetic females compared to male and female non-diabetics [2]. There is considerable ethnic difference in the prevalence and progression of T2D and CAD; the incidences of these diseases are about 3�C5 times higher in Asian Indians compared to Euro-Caucasians [3]. Lipid levels are widely measured in clinical practice and are used as therapeutic targets for prevention and treatment of CAD especially in patients with diabetes [4]. Recent genome-wide association scans (GWAS) and meta-analysis studies in European populations have identified common variants in many genes, including previously known loci that are potentially involved in lipid regulation [5]�C[8].

High heritability (40% to 60%) of lipid traits and strong association signals among common variants in these genes involved in lipid metabolism provide a strong rationale to search for causal variants that may uncover novel pathways crucial for lipid regulation and eventually lead to treatment or prevention of CAD [9], [10]. Replication of GWAS signals in different ethnic groups is important as the frequency of the susceptible alleles at these loci may vary significantly between world populations [11]. Also, these studies can help identify population-specific environmental factors controlling disease risk or protection associated with specific demographic and cultural histories [11]. In particular, replication of GWAS loci associations will have more relevance in population groups with high disease burdens such as Asian Indians [12].

A few studies have reported associations of these novel loci with lipid traits in Asian Indian immigrants living in the UK [6], [13], [14]. The present investigation was carried out to examine the role of six of the most strongly associated and extensively replicated GWAS loci (CELSR2-PSRC1-SORT1 AV-951 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) (summarized in Table 1) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) [15].

Supporting Information Figure S1 T cell responses to individual p

Supporting Information Figure S1 T cell responses to individual peptides from acute HBV patients. Acute HBV patients were stimulated in vitro with 15mer overlapping peptides covering the entire HBV proteome for http://www.selleckchem.com/products/ganetespib-sta-9090.html 10 d and screened for HBV specific T cell responses using 2 dimensional IFN-�� Elispot. Short-term lines were stimulated with 5 ��g/ml of each individual peptide identified from the IFN-�� elispot for 5 h and screened using intracellular cytokine staining or CD107a degranulation assay to confirm individual peptide responses. Remaining cells from the 10 d culture were stimulated overnight with confirmed peptides and supernatants were harvested to screen for CXCL-8 production in figure 3B. (TIF) Click here for additional data file.(158K, tif) Footnotes Competing Interests: The authors have declared that no competing interests exist.

Funding: Work was funded by the Agency for Science Technology and Research (A*STAR; http://www.a-star.edu.sg/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Hepatitis B virus (HBV) infection remains a major public health problem worldwide with approximately 2 billion people having been infected and 350 million of these patients becoming chronic carriers [1]. HBV infection is endemic in Taiwan and the carrier rate of HBsAg in general population has been as high as 15�C20% before initiation of the vaccination program. Infection of HBV is associated with a wide spectrum of clinical manifestations, ranging from acute or fulminant hepatitis to various forms of chronic diseases, including asymptomatic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) [1], [2].

Since the first successful human liver transplantation (LT) in 1963 by Starzl et al [3], LT has become the treatment of choice in eligible patients with hepatic failure or early HCC in many medical centers. However, the results of early experience with LT for HBV related diseases were unsatisfactory in the 1980s, as majority of patients developed recurrent HBV infection in the early post-LT period, leading to loss of the allograft with reduced patient survival [4], [5]. Patients with active viral replication prior to transplantation are particularly at risk of hepatitis B relapse. On the other hand, in patients harboring a lower viral load prior to LT, a favorable long-term outcome is generally expected.

This observation led to an effective strategy to improve LT outcome through reduction of pre-transplantation HBV viral load [6]. The clinical outcomes of patients as well as graft survivals in HBV LT recipients have been dramatically improved with the Entinostat introduction of long-term hepatitis B immune globulin (HBIG) therapy and the availability of highly effective antiviral agents such as lamivudine (LAM) and adefovir dipivoxil [7].

The most commonly used classification defines a level of 10 mg/g

The most commonly used classification defines a level of 10 mg/g and 15 mg/g as the upper normal limit for men and women, respectively [4]. Higher levels are classified as high selleckchem Lenalidomide normal, micro- and macroalbuminuria [4]. Albuminuria is associated with an increased risk of renal function loss, cardiovascular and end stage renal disease, cardiovascular and all-cause mortality [3]�C[8]. Albuminuria independently predicted cardiovascular events among normoalbuminuric patients with type 2 diabetes in a study by Ruggenenti et al [9]. It is an independent predictor of stroke, possibly even better than other markers of renal function such as glomerular filtration rate (GFR) and cystatin C [10]. Besides, albuminuria is in observational studies associated with other disorders such as cognitive impairment and chronic obstructive pulmonary disease (COPD) [11], [12].

Since a decrease in urine albumin excretion is associated with a lower risk of cardiovascular and renal disease [13], [14], microalbuminuria is an important therapeutic target. We aimed to investigate whether other causes of death beside cardiovascular disease and diabetes contribute to the association between UACR and risk of dying. We investigated the prospective association between UACR and cause-specific mortality according to The International Classification of Disease (ICD) in two cohorts from a general Danish population. Methods Ethics Statement Participants gave their written informed consent, and the studies were approved by the local ethics committee of Copenhagen County and the Danish Data Protection Agency.

The recommendations of the Declaration of Helsinki were followed. Study populations We used the two population based studies, Monica10 and Inter99. The Monica10 study carried out in 1993�C1994 was a 10 year follow-up study of the MonicaI study conducted in 1982�C1984. The MonicaI population was recruited from the Danish Central Personal Register as an age- and sex-stratified random sample of the population. The Monica10 study included 2,656 individuals between the ages 40�C71 years, and the participation rate was 64.3% [15]. A total of 2,654 participants from the Monica10 study with measurements of UACR were included in the study. The Inter99 study that was carried out in 1999�C2001 included 13,016 individuals aged 30�C60 years drawn from an age- and sex-stratified random sample of the population in the same area as MonicaI [16].

A total of 6,784 persons participated yielding Carfilzomib a baseline participation rate of 52.5%. The Inter99 study was a population-based randomized controlled trial (CT00289237, ClinicalTrials.gov) set to investigate the effects of lifestyle intervention on cardiovascular disease (CVD) [16]. A total of 6,471 participants from Inter99 with measurements of UACR were included in the present study. Inter99 data were considered observational, and analyses were adjusted for study group.

Genotyping for the KORA F3/500K Study which included the lung fun

Genotyping for the KORA F3/500K Study which included the lung function characterized KORA C sample selleck chem inhibitor was partly funded by UBS Wealth Foundation Grant BA29s8Q7-DZZ. Korcula: The Korcula study (Croatia) was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (Vis) (108-1080315-0302). NFBC1966: Financial support was received from the Academy of Finland (project grants 104781, 1114194, 120315 and Center of Excellence in Complex Disease Genetics), Oulu University Hospital, Biocenter Oulu, University of Oulu, Finland, the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council (studentship grant G0500539).

The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Institute for Health and Welfare, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. A.R. was supported by the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community) contract number 018996 under the Integrated Program LSH-2004-1.2.5-1 Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control. NSPHS: EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 01947 (LSHG-CT-2006-01947).

The Northern Swedish Population Health Study (NSPHS) was funded by the Swedish Medical Research Council (project number K2007-66X-20270-01-3). The computations were performed on UPPMAX (http://www.uppmax.uu.se) resources under Project p2008027. ORCADES: The ORCADES study was funded by the Chief Scientist Office of the Scottish Government, the Royal Society and the MRC Human Genetics Unit. DNA extraction was performed at the Wellcome Trust Clinical Research Facility in Edinburgh. Genotyping was funded by the European Union Framework Programme 6 EUROSPAN project. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no.

01ZZ9603, 01ZZ0103, and 01ZZ0403), the German Asthma and COPD Network (COSYCONET; BMBF grant 01GI0883), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a Batimastat member of the ��Center of Knowledge Interchange�� program of the Siemens AG.