Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair.

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-ß1 (TGF-ß1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-ß1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-ß1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-ß1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

[A guideline for guidelines--methodological report and use of the guideline women's information]. / Eine Leitlinie für Leitlinien: Die methodische Entwicklung und Anwendung der Leitlinie Fraueninformation.

UNLABELLED: Information and education is needed to empower autonomy and self-determination of patients (informed consent). Furthermore reliable and accurate medical information is necessary for patients who want to take an active part in medical decision-making. The aim of this work is to define the requirements helping to assure the development of good qualified information material relevant for women and female patients as "a guideline on women information". An example of its use is given by embeding this guideline in the guideline for early detection of breast cancer in Germany by defining the specific elements required for developing qualified information on this issue for women. METHODS: A systematic, stepwise methodological process according to a level two guideline of the German Association of the Scientific Medical Societies (AWMF) and the Agency for Quality in Medicine (AZQ) was performed with the following elements: 1. Establishing an expert panel, 2. Generating the guideline statements by a formal, consensus based nominal group process, 3. External review process and finding supportive partners for the guideline on women information, 4. Using the guideline for guidelines: implementing the concept in the guideline of early detection of breast cancer in Germany. RESULTS: The "guideline women information" comprises nine elements of quality assuring requirements for the development of gender-specific information material and eleven specific elements which directly relate to the guideline statements on early detection of breast cancer. After external review 30 organisations gave their written support for future implementation of the guideline. The "guideline women information" was integrated as a tool for quality assurance of lay information into the "guideline for early detection of breast cancer in Germany". CONCLUSION: The "guideline women information" is a systematically developed, consensus-based recommendation to improve the development of qualified lay information at the point of its process by defining gender-specific aspects required for good lay information and its evaluation. As a guideline for guidelines its use is demonstrated by integrating this guideline into the "guideline for early detection of breast cancer in Germany" to ensure the development of qualified guideline compliant information.

Quantitative analysis of epithelial cell aggregation in the simple metazoan Hydra reveals a switch from homotypic to heterotypic cell interactions.

Hydra, a member of the diploblastic phylum Cnidaria, exhibits the most basic type of organized metazoan tissues. Two unicellular sheets of polarized epithelial cells - ectoderm and endoderm - form a double layer throughout the body column. The double layer can be reestablished from single-cell suspensions by tissue-specific cell-sorting processes. However, the underlying pattern of interactions between ectodermal and endodermal epithelial cells responsible for double-layer formation is unclear. By analyzing cell interactions in a quantitative adhesion assay using mechanically dissociated Hydra epithelial cells, we show that aggregation proceeds in two steps. First, homotypic interactions within ectodermal epithelial cells (ecto-ecto) and within endodermal epithelial cells (endo-endo) form homotypic cell clusters. Second, at an aggregate size of about ten epithelial cells/cluster, ectodermal and endodermal clusters start to form heterotypic aggregates. Homotypic ecto-ecto interactions are inhibited by a polyclonal anti-Hydra membrane antiserum, and under these conditions homotypic endo-endo interactions do not proceed beyond a size of about ten epithelial cells/cluster. These data suggest that homotypic cell clusters reduce their initial homotypic affinity and acquire a new heterotypic affinity. A link between cell adhesion and cell signaling in early Hydra aggregates is discussed.

Analysis of the 1998 outbreak of leptospirosis in Missouri in humans exposed to infected swine.

OBJECTIVE: To determine the extent of leptospirosis in persons exposed to infected swine, confirm the source of disease, define risk factors for infection, and identify means for preventing additional infections during an outbreak in Missouri in 1998. DESIGN: Cross-sectional study. SAMPLE POPULATION: 240 people and 1,700 pigs. PROCEDURE: An epidemiologic investigation was conducted of people exposed to infected pigs from the University of Missouri-Columbia swine herd. The investigation included review of health of the pigs, a cross-sectional study of the people handling the pigs, serologic testing of human and porcine sera, and risk-factor analysis for leptospirosis within the human population. RESULTS: Serologic testing of samples collected at the time of the investigation indicated that 59% of the pigs had titers to leptospires, denoting exposure. Of the 240 people in the exposed study population, 163 (68%) were interviewed, and of these, 110 (67%) submitted a blood sample. Nine (8%) cases of leptospirosis were confirmed by serologic testing. Risk factors associated with leptospirosis included smoking (odds ratio [OR], 14.4; 95% confidence interval [CI], 1.39 to 137.74) and drinking beverages (OR, 5.1; 95% CI, 1.04 to 24.30) while working with infected pigs. Washing hands after work was protective (OR, 0.2; 95% CI, 0.03 to 0.81). CONCLUSIONS AND CLINICAL RELEVANCE: Leptospirosis is a risk for swine producers and slaughterhouse workers, and may be prevented through appropriate hygiene, sanitation, and animal husbandry. It is essential to educate people working with animals or animal tissues about measures for reducing the risk of exposure to zoonotic pathogens.

Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

PURPOSE: To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS: No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.

A study of oral etoposide, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small-cell lung cancer. A Mid-Atlantic Oncology Program study.

A combination of oral etoposide, infusional cisplatin (24-hr) and infusional 5-fluorouracil (5-day) was used to treat 87 patients with non-small-cell lung cancer in a Phase II trial. Twenty-six patients were Stage IIIB, and 61 patients were Stage IV (new international classification). The regimen was well tolerated, with 49% grade 3 or 4 toxicities of all types. Response rates, partial and complete, were 40%, (95% confidence interval: 30%, 51%) for Stage IV patients and 20% (95% confidence interval: 10%, 32%), in Stage IIIB. An additional 68% of patients in Stage IIIB and 45% of patients in Stage IV achieved stable disease and had a median survival of 8.8 months, similar to that of patients in partial remission. Median survival was 5.6 months (95% confidence interval: 4.4 months, 10.8 months) for Stage IV patients and 11.0 months (95% confidence interval: 8.8 months, 12.4 months), for Stage IIIB. Of interest was the finding of a higher response rate in patients with a shorter duration of symptoms (less than 6 months versus greater than 6 months).

A study of infusional cisplatin and infusional fluorouracil for locally advanced or metastatic non-small-cell lung cancer: a Mid-Atlantic Oncology Program study.

A combination of cisplatin administered as a 24-hour infusion and fluorouracil administered as a 5-day infusion was used to treat 97 patients with non-small-cell lung (NSCLC) cancer in a phase II trial. Thirty patients had stage IIIB disease; 67 patients, stage IV disease (new international classification). Patients with stage IIIB disease also received thoracic radiation after chemotherapy. The regimen was well tolerated, with 24% or less grade 3 or greater toxicities of all types. One toxic death was attributed to fluid overload. The response rate, partial and complete, was 43% (95% confidence interval, 27% to 63%), and median survival was 13.8 months for patients with stage IIIB disease. Response rates refer to the chemotherapy response. For patients with stage IV disease, the response rate was 34% (95% confidence interval, 24% to 47%), and median survival was 6.2 months. On this regimen, stable-disease patients with stage IV disease had survivals at least equal to responders.

A prospective randomized comparison of protracted infusional 5-fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A Mid-Atlantic Oncology Program study.

One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.