Time filter

Source Type

Paupoo A.A.V.,University of Alabama at Birmingham | Zhu Z.B.,University of Alabama at Birmingham | Wang M.,University of Alabama at Birmingham | Rein D.T.,University of Dusseldorf Medical Center | And 2 more authors.
Human Reproduction | Year: 2010

Background: Novel therapeutic approaches for endometriosis based on molecular strategies may prove to be useful. Conditionally replicative adenoviruses (CRAds) are designed to exploit key differences between target and normal cells. The wild-type adenovirus (Adwt) promoter can be replaced by tissue-specific promoters, allowing viral replication only in target cells. Viral infectivity can be enhanced by altering Ad tropism via fiber modification. We investigated whether CRAds can be used to target endometriosis and determined the most efficient transcriptional-and transductional-targeting strategy. Methods: An in vitro study was carried out using human endometriotic cell lines, 11Z (epithelial) and 22B (stromal), normal human ovarian surface epithelial cell line (NOSE006) and primary human endometriosis cells. A total of 9 promoters and 12 Ad tropism modifications were screened by means of a luciferase reporter assay. From this screening data, three CRAds (CRAd-S-pK7, CRAd-S-RGD, CRAd-S-F5/31, all incorporating the survivin promoter but with different fiber modifications) were selected to perform experiments using Adwt and a replication-deficient virus as controls. CRAds were constructed using a plasmid recombination system. Viral-binding capacity, rates of entry and DNA replication were evaluated by quantitative real-time PCR of viral genome copy. Cell-killing effects were determined by crystal violet staining and a cell viability assay for different concentrations of viral particles per cell. Results: Comparison of promoters demonstrated that the survivin promoter exhibited the highest induction in both endometriotic cell lines. Among the fiber-modified viruses, the polylysine modification (pK7) showed the best infection enhancement. CRAd-S-pK7 was validated as the optimal CRAd to target endometriosis in terms of binding ability, entry kinetics, DNA replication and cell-killing effect. CRAd-S-pK7 also exhibited a high level of DNA replication in primary endometriosis cells. Conclusions: CRAd-S-pK7 has the best infection and cell-killing effect in the context of endometriosis. It could prove to be a useful novel method to target refractory cases of endometriosis. © 2010 The Author. Source

Konig H.-H.,University of Hamburg | Leicht H.,University of Hamburg | Bickel H.,TU Munich | Fuchs A.,University of Dusseldorf Medical Center | And 11 more authors.
BMC Health Services Research | Year: 2013

Background: To analyze the impact of multimorbidity (MM) on health care costs taking into account data heterogeneity. Methods. Data come from a multicenter prospective cohort study of 1,050 randomly selected primary care patients aged 65 to 85 years suffering from MM in Germany. MM was defined as co-occurrence of ≥3 conditions from a list of 29 chronic diseases. A conditional inference tree (CTREE) algorithm was used to detect the underlying structure and most influential variables on costs of inpatient care, outpatient care, medications as well as formal and informal nursing care. Results: Irrespective of the number and combination of co-morbidities, a limited number of factors influential on costs were detected. Parkinson's disease (PD) and cardiac insufficiency (CI) were the most influential variables for total costs. Compared to patients not suffering from any of the two conditions, PD increases predicted mean total costs 3.5-fold to approximately 11,000 per 6 months, and CI two-fold to approximately 6,100. The high total costs of PD are largely due to costs of nursing care. Costs of inpatient care were significantly influenced by cerebral ischemia/chronic stroke, whereas medication costs were associated with COPD, insomnia, PD and Diabetes. Except for costs of nursing care, socio-demographic variables did not significantly influence costs. Conclusions: Irrespective of any combination and number of co-occurring diseases, PD and CI appear to be most influential on total health care costs in elderly patients with MM, and only a limited number of factors significantly influenced cost. Trial registration. Current Controlled Trials ISRCTN89818205. © 2013 König et al.; licensee BioMed Central Ltd. Source

Bock J.-O.,University of Hamburg | Luppa M.,University of Leipzig | Brettschneider C.,University of Hamburg | Riedel-Heller S.,University of Leipzig | And 12 more authors.
PLoS ONE | Year: 2014

Objective: The objective of this study was to describe and analyze the effects of depression on health care utilization and costs in a sample of multimorbid elderly patients. Method: This cross-sectional analysis used data of a prospective cohort study, consisting of 1,050 randomly selected multimorbid primary care patients aged 65 to 85 years. Depression was defined as a score of six points or more on the Geriatric Depression Scale (GDS-15). Subjects passed a geriatric assessment, including a questionnaire for health care utilization. The impact of depression on health care costs was analyzed using multiple linear regression models. A societal perspective was adopted. Results: Prevalence of depression was 10.7%. Mean total costs per six-month period were ∈8,144 (95% CI: ∈6,199-∈10,090) in patients with depression as compared to ∈3,137 (95% CI: ∈2,735-∈3,538; p<0.001) in patients without depression. The positive association between depression and total costs persisted after controlling for socio-economic variables, functional status and level of multimorbidity. In particular, multiple regression analyses showed a significant positive association between depression and pharmaceutical costs. Conclusion: Among multimorbid elderly patients, depression was associated with significantly higher health care utilization and costs. The effect of depression on costs was even greater than reported by previous studies conducted in less morbid patients. Copyright: © 2014 Bock et al. Source

Brettschneider C.,University of Hamburg | Leicht H.,University of Hamburg | Bickel H.,TU Munich | Dahlhaus A.,Goethe University Frankfurt | And 11 more authors.
PLoS ONE | Year: 2013

Background: Multimorbidity has a negative impact on health-related quality of life (HRQL). Previous studies included only a limited number of conditions. In this study, we analyse the impact of a large number of conditions on HRQL in multimorbid patients without preselecting particular diseases. We also explore the effects of these conditions on the specific dimensions of HRQL. Materials and Methods: This analysis is based on a multicenter, prospective cohort study of 3189 multimorbid primary care patients aged 65 to 85. The impact of 45 conditions on HRQL was analysed. The severity of the conditions was rated. The EQ-5D, consisting of 5 dimensions and a visual-analogue-scale (EQ VAS), was employed. Data were analysed using multiple ordinary least squares and multiple logistic regressions. Multimorbidity measured by a weighted count score was significantly associated with lower overall HRQL (EQ VAS), b = -1.02 (SE: 0.06). Parkinson's disease had the most pronounced negative effect on overall HRQL (EQ VAS), b = -12.29 (SE: 2.18), followed by rheumatism, depression, and obesity. With regard to the individual EQ-5D dimensions, depression (OR = 1.39 to 3.3) and obesity (OR = 1.44 to 1.95) affected all five dimensions of the EQ-5D negatively except for the dimension anxiety/depression. Obesity had a positive effect on this dimension, OR = 0.78 (SE: 0.07). The dimensions "self-care", OR = 4.52 (SE: 1.37) and "usual activities", OR = 3.59 (SE: 1.0), were most strongly affected by Parkinson's disease. As a limitation our sample may only represent patients with at most moderate disease severity. Conclusions: The overall HRQL of multimorbid patients decreases with an increasing count and severity of conditions. Parkinson's disease, depression and obesity have the strongest impact on HRQL. Further studies should address the impact of disease combinations which require very large sample sizes as well as advanced statistical methods. © 2013 Brettschneider et al. Source

Rein D.T.,University of Dusseldorf Medical Center | Volkmer A.,University of Dusseldorf Medical Center | Beyer I.M.,University of Dusseldorf Medical Center | Beyer I.M.,University of Washington | And 8 more authors.
Gynecologic Oncology | Year: 2011

Objective: Multidrug resistance gene 1 (MDR1) mediated resistance to chemotherapeutic agents is a major obstacle for the therapy of various cancer types. The use of conditionally replicating adenoviruses (CRAds) is dependent on molecular differences between tumor cells and non tumor cells. Transcriptional targeting of CRAd replication is an effective way to control replication regulation. The aim of this study was to evaluate the effect of a MDR1 targeted fiber-modified CRAd against chemotherapy resistant ovarian cancer. Methods: MDR1 expression was evaluated in chemotherapy naïve and pretreated ovarian cancer cells and various control cells. We constructed 2 variants of a fiber-modified CRAd, Ad5/3MDR1E1 and Ad5/3MDR1E1Δ24 containing the MDR1 promoter to control viral replication via the E1A gene. The MDR promoter activity and cell killing efficacy were evaluated in vitro. Orthotopic murine models of peritoneally disseminated ovarian cancer were utilized to evaluate the preclinical efficacy of MDR targeted CRAds in vivo. To evaluate the liver toxicity of MDR1 targeted CRAds, we compared Ad5/3MDR1E1 with Ad5/3Δ24, a CRAd that replicates in cancer cells inactive in the Rb/p16 pathway by use of an in vivo hepatotoxicity model. Results: We demonstrate efficient oncolysis of Ad5/3MDR1E1 in both chemotherapy resistant ovarian cancer cell lines and in primary tumor cells from pretreated patients as well as therapeutic efficacy in an orthotopic mouse model. Ad5/3MDR1E1 demonstrated significantly decreased liver toxicity compared to other 5/3-fiber modified control vectors examined. Conclusions: In summary, Ad5/3MDR1E1 is an efficient and safe gene therapy approach for specific targeting of chemotherapy resistant cancer cells. © 2011 Elsevier Inc. All rights reserved. Source

Discover hidden collaborations