Measurement of non-isothermal transport coefficients in a near-eutectic succinonitrile/(d)camphor mixture.

We have determined nonisothermal diffusive transport coefficients of a succinonitrile-(d)camphor mixture with a composition of c = 0.239 wt.-frac. (d)camphor at a temperature of 318.2 K, which is close to the eutectic point. The employed experimental techniques are optical beam deflection in a Soret cell and photon correlation spectroscopy. The diffusion coefficient is D = (1.43 ± 0.04) × 10-10 m2 s-1, the thermodiffusion coefficient is DT = (2.00 ± 0.06) × 10-12 m2 s-1 K-1, and the Soret coefficient is ST = (1.40 ± 0.02) × 10-2 K-1. Camphor migrates toward the lower and succinonitrile migrates toward the higher temperatures. While the diffusion coefficient is in good agreement with the literature, the Soret coefficient has been determined for the first time. Our analysis shows that a significant concentration shift can be established in the liquid mixture in the presence of a temperature gradient. The mixture has a negative separation ratio, which leads to convective instabilities if heated from above.

Posaconazole liquid vs tablet formulation in lung transplant recipients.

Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx-recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were ≥700 ng/mL (prophylaxis) and ≥1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS-Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched.

[The Ludwigshafen Osteoporosis Screening Questionnaire (LOS Questionnaire): result of the evaluation of anamnestic risk factors in osteoporosis diagnostics]. / Ludwigshafener Osteoporosescreeningbogen (LOS-Bogen) : Resultat aus der Evaluation anamnestischer Risikofaktoren in der Osteoporosediagnostik.

BACKGROUND: Osteoporosis is a major health problem worldwide and is included in the WHO list of the top ten major diseases. However, it is often undiagnosed until the first fracture occurs, due to inadequate patient education and lack of insurance coverage for screening tests. METHODS AND MATERIAL: In our study of 78 patients with metaphyseal long bone fractures, we searched for a correlation between anamnestic risk factors, bone-specific laboratory values, and the bone morphogenic density (BMD). Each indicator was examined as a possible diagnostic instrument for osteoporosis. The secondary aim of this study was to demonstrate the high prevalence of osteoporosis in patients with metaphyseal fractures. RESULTS: Of our fracture patients 76.9% had decreased bone density and 43.6% showed manifest osteoporosis in DXA (densitometry) measurements. Our modified LOS Questionnaire, identifying anamnestic risk factors, correlated highly significantly (p=0.01) with reduced BMD, whereas seven bone-specific laboratory values (p=0.046) correlated significantly. CONCLUSION: Anamnestic risk factors correlate with pathological BMD more than bone-specific laboratory values. The LOS Questionnaire used in this study would therefore function as a cost-effective primary diagnostic instrument for identification of osteoporosis patients.

[French translation, validation and adaptation of the Stigma Scale]. / Mesurer la stigmatisation perçue chez les personnes souffrant de troubles psychiques: traduction française, validation et adaptation de la Stigma Scale.

AIM: People suffering from mental illness are exposed to stigma. However, only few tools are available to assess stigmatization as perceived from the patient's perspective. The aim of this study is to adapt and validate a French version of the Stigma Scale (King et al., 2007 [8]). This self-report questionnaire has a three-factor structure: discrimination, disclosure and positive aspects of mental illness. Discrimination subscale refers to perceived negative reactions of others. Disclosure subscale refers mainly to managing disclosure to avoid discrimination and finally positive aspects subscale taps into how patients are becoming more accepting, more understanding toward their illness. METHOD: In the first step, internal consistency, convergent validity and test-retest reliability of the French adaptation of the 28-item scale were assessed in a sample of 183 patients. Results of confirmatory factor analyses (CFA) did not confirm the hypothesized structure. In the light of the failed attempts to validate the original version, an alternative 9-item short-form version of the Stigma Scale, maintaining the integrity of the original model, was developed based on results of exploratory factor analyses in the first sample and cross-validated in a new sample of 234 patients. RESULTS: Results of CFA did not confirm that the data fitted well to the three-factor model of the 28-item Stigma Scale (χ(2)/df=2.02, GFI=0.77, AGFI=0.73, RMSEA=0.07, CFI=0.77 and NNFI=0.75). Cronbach's α was excellent for discrimination (0.84) and disclosure (0.83) subscales but poor for potential positive aspects (0.46). External validity was satisfactory. Overall Stigma Scale total score was negatively correlated with the score on Rosenberg's Self-Esteem Scale (r=-0.49), and each subscale was significantly correlated with a visual analogue scale that referred to the specific aspect of stigma (0.43≤|r|≤0.60). Intraclass correlation coefficients between 0.68 and 0.89 indicated good test-retest reliability. The results of the CFA demonstrated that the items chosen for the short version of the Stigma Scale have the expected fit properties (χ(2)/df=1.02, GFI=0.98, AGFI=0.98, RMSEA=0.01, CFI=1.0 and NNFI=1.0). Considering the small number (three) of items in each subscale of the short version of the Stigma Scale, α coefficients for discrimination (0.57), disclosure (0.80) and potential positive aspects subscales (0.62) are considered as good. CONCLUSION: Our results suggest that the 9-item French short version of the Stigma Scale is a useful, reliable and valid self-report questionnaire to assess perceived stigmatization in people suffering from mental illness. The time of completion is really short and questions are well understood and accepted by the patients.

Microgravity studies of solidification patterns in model transparent alloys onboard the International Space Station.

We review recent in situ solidification experiments using nonfaceted model transparent alloys in science-in-microgravity facilities onboard the International Space Station (ISS), namely the Transparent Alloys (TA) apparatus and the Directional Solidification Insert of the DEvice for the study of Critical Liquids and Crystallization (DECLIC-DSI). These directional-solidification devices use innovative optical videomicroscopy imaging techniques to observe the spatiotemporal dynamics of solidification patterns in real time in large samples. In contrast to laboratory conditions on ground, microgravity guarantees the absence or a reduction of convective motion in the liquid, thus ensuring a purely diffusion-controlled growth of the crystalline solid(s). This makes it possible to perform a direct theoretical analysis of the formation process of solidification microstructures with comparisons to quantitative numerical simulations. Important questions that concern multiphase growth patterns in eutectic and peritectic alloys on the one hand and single-phased, cellular and dendritic structures on the other hand have been addressed, and unprecedented results have been obtained. Complex self-organizing phenomena during steady-state and transient coupled growth in eutectics and peritectics, interfacial-anisotropy effects in cellular arrays, and promising insights into the columnar-to-equiaxed transition are highlighted.

In-situ X-ray monitoring of solidification and related processes of metal alloys.

X-ray radioscopy enables the in-situ monitoring of metal alloy processes and then gives access to crucial information on the dynamics of the underlying phenomena. In the last decade, the utilisation of this powerful imaging technique has been adapted to microgravity platforms such as sounding rockets and parabolic flights. The combination of microgravity experimentation with X-ray radioscopy has resulted in a leap in the understanding of fundamental science and has opened new paths in the fields of materials science. The present review focuses on the short history of this research, which includes facility developments, microgravity experiments and results obtained by partners of the XRMON (In-situ X-Ray MONitoring of advanced metallurgical processes under microgravity and terrestrial conditions) research project in the framework of the MAP (Microgravity Application Promotion) programme of the European Space Agency. Three illustrative research topics that were advanced significantly through the use of X-ray radioscopy will be detailed: solidification of metal alloys, metallic foam formation and diffusion in melts.

[Results of nonunion treatment with bone morphogenetic protein 7 (BMP-7)]. / Ergebnisse der Pseudarthrosenbehandlung mit "bone morphogenetic protein 7" (BMP-7).

BACKGROUND: Complex patterns of impaired bone healing can result in a severe economic and social burden for the patient. Herein we describe the local application of recombinant human bone morphogenetic protein 7 (BMP-7). The goal of this prospective study is to review the indications, application and validation of this therapy. MATERIAL AND METHOD: From June 2002 to June 2008, we applied 101 BMP-7 treatments in 101 nonunions of 98 patients. The average age of the patients was 50 years (18-88 years). The gender composition was 29 women (30%) and 69 men (70%). Before BMP-7 application, patients had already underwent surgical treatement an average of 3.3 times (median 3, 1- to 13-times). We used BMP-7 "off-label" in all long bones. RESULTS: In 93 cases (92%), we observed proper bone healing. The average healing time was 4.8 months (range 1.5-11 months). The average time from injury to BMP-7 application was 18.4 months (3-84 months). In 65 cases, BMP-7 application was combined with re-osteosynthesis and autologous bone grafting. Serious side effects were not observed. CONCLUSIONS: BMP-7 should not be used as general treatment of nonunion in all patients, but appears to be effective for the treatment of complex cases. In clinical practice, the decision to proceed with off-label use of BMP-7 should be made on a case-by-case basis.

Usefulness of exhaled nitric oxide to guide risk stratification for bronchiolitis obliterans syndrome after lung transplantation.

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow-up of 3 months: (1) stable non-BOS, (2) unstable non-BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non-BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non-BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

Zinc oxide nanorod based photonic devices: recent progress in growth, light emitting diodes and lasers.

Zinc oxide (ZnO), with its excellent luminescent properties and the ease of growth of its nanostructures, holds promise for the development of photonic devices. The recent advances in growth of ZnO nanorods are discussed. Results from both low temperature and high temperature growth approaches are presented. The techniques which are presented include metal-organic chemical vapour deposition (MOCVD), vapour phase epitaxy (VPE), pulse laser deposition (PLD), vapour-liquid-solid (VLS), aqueous chemical growth (ACG) and finally the electrodeposition technique as an example of a selective growth approach. Results from structural as well as optical properties of a variety of ZnO nanorods are shown and analysed using different techniques, including high resolution transmission electron microscopy (HR-TEM), scanning electron microscopy (SEM), photoluminescence (PL) and cathodoluminescence (CL), for both room temperature and for low temperature performance. These results indicate that the grown ZnO nanorods possess reproducible and interesting optical properties. Results on obtaining p-type doping in ZnO micro- and nanorods are also demonstrated using PLD. Three independent indications were found for p-type conducting, phosphorus-doped ZnO nanorods: first, acceptor-related CL peaks, second, opposite transfer characteristics of back-gate field effect transistors using undoped and phosphorus doped wire channels, and finally, rectifying I-V characteristics of ZnO:P nanowire/ZnO:Ga p-n junctions. Then light emitting diodes (LEDs) based on n-ZnO nanorods combined with different technologies (hybrid technologies) are suggested and the recent electrical, as well as electro-optical, characteristics of these LEDs are shown and discussed. The hybrid LEDs reviewed and discussed here are mainly presented for two groups: those based on n-ZnO nanorods and p-type crystalline substrates, and those based on n-ZnO nanorods and p-type amorphous substrates. Promising electroluminescence characteristics aimed at the development of white LEDs are demonstrated. Although some of the presented LEDs show visible emission for applied biases in excess of 10 V, optimized structures are expected to provide the same emission at much lower voltage. Finally, lasing from ZnO nanorods is briefly reviewed. An example of a recent whispering gallery mode (WGM) lasing from ZnO is demonstrated as a way to enhance the stimulated emission from small size structures.

A non-invasive probe for online-monitoring of turgor pressure changes under field conditions.

An advanced non-invasive, field-suitable and inexpensive leaf patch clamp pressure probe for online-monitoring of the water relations of intact leaves is described. The probe measures the attenuated output patch clamp pressure, P(p), of a clamped leaf in response to an externally applied input pressure, P(clamp). P(clamp) is generated magnetically. P(p) is sensed by a pressure sensor integrated into the magnetic clamp. The magnitude of P(p) depends on the transfer function, T(f), of the leaf cells. T(f) consists of a turgor pressure-independent (related to the compression of the cuticle, cell walls and other structural elements) and a turgor pressure-dependent term. T(f) is dimensionless and assumes values between 0 and 1. Theory shows that T(f) is a power function of cell turgor pressure P(c). Concomitant P(p) and P(c) measurements on grapevines confirmed the relationship between T(f) and P(c). P(p) peaked if P(c) approached zero and assumed low values if P(c) reached maximum values. The novel probe was successfully tested on leaves of irrigated and non-irrigated grapevines under field conditions. Data show that slight changes in the microclimate and/or water supply (by irrigation or rain) are reflected very sensitively in P(p).

[Presentation of the french adaptation of McHale's coparenting scale for families with young children.] / Présentation de l'adaptation française de << l'échelle de coparentage >> de McHale pour familles avec jeunes enfants.

The aim of this paper is to present McHale's coparenting scale,a self-administered questionnaire enabling assessment of the quality of coparenting, and first steps in structural and construct validation of the French version. A total of 41 French speaking Swiss families and 84 US families completed this questionnaire and the Dyadic Adjustment Scale, a measure of marital satisfaction. The results of the Swiss families correspond to those of US families: first, items distributed into four factors (family integrity, conflict, affection and disparagement) and second, a partial link was found between quality of coparenting and marital adjustment. This finding supports the construct validity of the questionnaire, reflecting the established link between these two family sub-systems. Given that coparenting quality has a major influence on children's socio-affective development, the questionnaire will find great use in assessing not just negative features of coparenting, such as conflicts and disparagement, but also positive components such as warmth and support. This will be an important asset for research as well as clinical purposes.

Instant stem cell therapy: characterization and concentration of human mesenchymal stem cells in vitro.

In regenerative medicine, there is an approach to avoid expansion of the mesenchymal stem cell (MSC) before implantation. The aim of this study was to compare methods for instant MSC therapy by use of a portable, automatic and closed system centrifuge that allows for the concentration of MSCs. The main outcome measures were the amount of MSCs per millilitre of bone marrow (BM), clusters of differentiation (CD), proliferation and differentiation capacities of the MSC. A volume reduction protocol was compared to the traditional laboratory methods of isolation using a Ficoll gradient and native BM. Fifty millilitres of BM were obtained from haematologically healthy male Caucasians (n=10, age 8 to 49 years). The number of colony forming units-fibroblast (CFU-F)/ml BM was highest in the centrifuge volume reduction protocol, followed by the native BM (not significant), the centrifuge Ficoll (p=0.042) and the manual Ficoll procedure (p=0.001). The MSC of all groups could differentiate into the mesenchymal lineages without significant differences between the groups. The CD pattern was identical for all groups: CD13+; CD 44+; CD73 +; CD90+; CD105+; HLA-A,B,C+; CD14-; CD34-; CD45-; CD271-; HLA-DR-. In a further clinical pilot study (n=5) with 297 ml BM (SD 18.6), the volume reduction protocol concentrated the MSC by a factor of 14: there were 1.08 x 10(2) MSC/ml BM (standard deviation (SD) 1.02 x 10(2)) before concentration, 14.8 x 10(2) MSC/ ml BM (SD 12.4 x 10(2)) after concentration, and on average 296 x 10(2) MSC (SD 248.9 x 10(2), range 86.4-691.5 x 10(2)) were available for MSC therapy. The volume reduction protocol of the closed centrifuge allows for the highest concentration of the MSC, and therefore, is a promising candidate for instant stem cell therapy.

Efficacy of a single session protocol for endodontic treatment in primary teeth: in vivo study.

AIMS: To determine the efficacy of a single session protocol (SSP) in the reduction of septic content of primary teeth root canals and identify the persistence of bacterial species associated with unsuccessful treatment. METHODS: Primary teeth root canals (16) with pulp necrosis and peri-radicular lesions were treated. Samples were collected at baseline (T1), and after chemo-mechanical preparation, before filling (T2). Identification of the microorganisms was determined using checkerboard DNA-DNA hybridisation. STATISTICAL ANALYSIS: Wilcoxon test was applied for comparison of mean number of species, proportion and mean count of each species between the evaluation times. RESULTS: Significant reductions were found in the mean number of bacteria species between T1 and T2 (p < 0.05), but not for the reduction in proportion (p > 0.05). There was a reduction (6.0-4.6) of the mean number of species associated with failure, without statistical significance. CONCLUSION: The SSP was capable of significantly reducing the septic content, even though, many of the bacteria associated with failure persisted at the time of root canal filling.

Intra-cultivar variability of the soil-to-grain transfer of fallout 137Cs and 90Sr for winter wheat.

Differences between the root uptake of fallout radionuclides by different cultivars ('inter-cultivar' variability) growing on the same field may be influenced not only by genetic differences of the cultivars, but also by the spatial variability of the soil-to-grain transfer within the cultivation area of each cultivar. This 'intra-cultivar' variability was investigated in 2001 and 2002 for 137Cs and 90Sr using three winter wheat cultivars with four replicates for each cultivar at three different sites in Bavaria, Germany. The intra-cultivar variability proved to be in the same range as the inter-cultivar variability which was determined earlier at the same sites for both radionuclides. An ANOVA of the 137Cs data set revealed that the variability of the 137Cs soil-to-grain transfer was caused by the soil and climate (year) at the field sites and the interaction of cultivar and field. A significant contribution of the factor 'cultivar' alone to the variability could not be detected. This may be due to the complex environmental conditions to which plants are exposed in field experiments. To find wheat cultivars with minimal uptake of fallout radionuclides it may be better to examine the molecular mechanisms of their root uptake in order to identify targets for breeding "safer" plants.

[The 20-item Toronto alexithymia scale: structural validity, internal consistency and prevalence of alexithymia in a Swiss adolescent sample]. / Qualités psychométriques de la version française de la TAS-20 et prévalence de l'alexithymie chez 264 adolescents tout-venant.

BACKGROUND: The alexithymia construct is mainly characterized by a difficulty in identifying and expressing feelings that is thought to reflect a deficit in cognitive processing and regulation of emotional states. During the last decade, alexithymia has been associated with a large variety of medical and psychiatric disorders in the adult population. Although adolescence is probably an opportune time to explore processes of emotion regulation, alexithymia has been rarely examined during this period. The 20-item Toronto alexithymia scale (TAS-20) is the most widely used self-report measure of alexithymia. For this scale, a three-factor structure was proposed: difficulty identifying feelings (DIF), difficulty describing feelings (DDF) and externally oriented thinking (EOT). Research has yielded considerable evidence that the TAS-20 is a reliable and valid measure of alexithymia in normal and clinical adult samples. To date, no psychometric data concerning the use of the TAS-20 with adolescent samples are available. OBJECTIVES: The aim of the study is to provide psychometric data concerning the TAS-20 when administered to healthy adolescents. Furthermore, in a developmental perspective, this study explores the evolution of alexithymia across age groups in adolescence. METHOD: The TAS-20 was administered to a sample of 264 adolescents aged from 14 to 19 years. In order to compare alexithymia across age groups, the sample was divided into three groups: group 1 (<16 years old), group 2 (16-17 years old) and group 3 (>17 years old). RESULTS: Results of a confirmatory factor analysis (CFA) confirmed that the data fitted well to the three-factor model of the TAS-20 (chi(2)/df=2.22, GFI=0.88, AGFI=0.84 and RMSEA=0.068). The internal reliability coefficients and mean interitem correlations are acceptable for DIF (alpha>0.60; mean interitem correlation=0.22) and good for DDF (alpha>0.70, mean interitem correlation=0.33). As often reported in most translations of the TAS-20, the internal reliability of EOT is poor. Results of a one-way Anova showed a significant linear trend indicating that, with age, the level of alexithymia (TAS-20 total score), the difficulty in identifying feelings and the externally oriented thinking decreased. DISCUSSION: This study demonstrated that the TAS-20 has sufficient construct validity in a non-clinical sample of adolescents. Our results support the idea that adolescence period is associated with the development of the ability to regulate emotions.

Opioid antagonist detoxification under anaesthesia versus traditional clonidine detoxification combined with an additional week of psychosocial support: a randomised clinical trial.

BACKGROUND: While detoxification under anaesthesia accelerates the detoxification procedure, there is a lack of randomised clinical trials evaluating its effectiveness compared to traditional detoxification procedures, and a lack of data on long-term abstinence. METHODS: Prospective randomised clinical trial. Analysis by intention to treat and per protocol. SETTING: Specialised substance abuse unit in a psychiatric teaching hospital and an intensive care unit of a general hospital. PARTICIPANTS: Seventy patients with opiate mono-dependence requesting detoxification: 36 randomised to RODA (treatment as allocated received by 26) and 34 randomised to classical clonidine detoxification (treatment as allocated received by 21). MAIN OUTCOME MEASURES: Successful detoxification, safety and self-reported abstinence at 3, 6 and 12 months after detoxification. RESULTS: Socio-demographics were similar in both groups at baseline. No complications were reported during or after anaesthesia. According to the intention to treat analysis, 28/36 (78%) RODA patients and 21/34 (62%) of the clonidine group successfully completed the detoxification process (p=0.14). In the intention to treat analysis, 30% of RODA patients were abstinent after 3 months compared to 14% in the clonidine group (p=0.11). No difference was found at 6 and 12 months (both groups showed less than 5% abstinence after 12 months). The per-protocol analysis showed similar results with no statistical differences either for ASI mean scores or for the SF36 questionnaire. CONCLUSION: Although the detoxification success rate and abstinence after 3 months were slightly better for the RODA procedure compared to clonidine treatment, these differences were not statistically significant and disappeared completely after 6 and 12 months.

The breast mucin MUCI as a novel adhesion ligand for endothelial intercellular adhesion molecule 1 in breast cancer.

The MUC 1 mucin is expressed on normal breast epithelium and in 90% of breast cancers. We report here that tumor-associated MUC1 is a ligand for intercellular adhesion molecule 1 (ICAM-1). Antibodies to ICAM-1 and to MUC1 inhibited adhesion of human and transfected mouse MUC1-positive cell lines to human umbilical vein endothelial cell monolayers and immobilized recombinant human ICAM-1-immunoglobulin fusion protein. Purified MUC1 pretreatment of recombinant human ICAM-1 was an equally effective inhibitor of adhesion. The interaction between MUC1 and ICAM-1 may be critical to the process of bloodborne metastases in breast cancer.

Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer.

The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.

Systemic regulation of angiogenesis and matrix degradation in bone regeneration--distraction osteogenesis compared to rigid fracture healing.

Aim of this study was the investigation of systemic biochemical regulation mechanisms of bone regeneration by angiogenic and matrix-degrading enzymes during distraction osteogenesis compared to rigid osteotomy bone healing. Serum samples of 10 otherwise healthy patients with callus distraction for lower limb-lengthening and 10 osteotomy patients undergoing elective axis correction have been collected prospectively in a standardized time schedule before and up to 6 months after the procedure. At the end of the individual investigation period, concentrations of metalloproteinases (MMP-9, -13), tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2) and the angiogenic factors angiogenin and VEGF have been detected by use of commercially available enzyme immunoassays. Results have been compared to our preliminary study on proMMP-1-3. In distraction osteogenesis, significantly elevated serum concentrations compared to baseline could be detected postoperatively for proMMP-1, MMP-9, TIMP-1, angiogenin and VEGF but not for proMMP-2, proMMP-3 or TIMP-2. In patients with rigid osteotomy healing, MMP-9, TIMP-1, TIMP-2, angiogenin and VEGF were significantly increased respectively. Comparison of both patient collectives revealed significantly higher increases of serum proMMP-1, VEGF and TIMP-1 in distraction patients during the lengthening period and significantly higher serum concentrations of TIMP-2 in late fracture healing period in osteotomy patients. Serum levels of MMP-13 were below the lowest standards, and therefore quantitative analysis was not possible. Bone regeneration in distraction osteogenesis and rigid osteotomy healing is accompanied by systemic increase of matrix-degrading and angiogenic factors in a certain time course and quantity. This might reflect biochemical regulation of local bone healing in the circulation. ProMMP-1, VEGF and TIMP-1 seem to be key regulatory factors during distraction osteogenesis.

TGF-beta1 as a marker of delayed fracture healing.

Mitogens of the TGF-beta superfamily have been shown to be crucial local and systemic regulatory molecules involved in fracture healing. However, there exists only little information about systemic regulation of bone regeneration by growth factors and no reports comparing serum levels of bone growth factors between normal and failed fracture healing have been published so far. We hypothesized that quality of fracture healing might be reflected by systemic alterations of key regulatory growth factors involved in bone formation and remodeling. Therefore, the aim of this study was to evaluate possible differences in serum levels of BMP-2, BMP-4, and TGF-beta1 in patients with normal and delayed fracture healing. 103 patients with diaphyseal fractures of long bones were recruited prospectively. Peripheral blood samples were collected over a period of 6 months following a standardized time schedule. At the end of the individual investigation period, growth factor serum levels were measured using commercially available enzyme immunoassays. For the elimination of disturbing influences, patients in both groups were matched by gender, age, fracture type, and localization as well as applied technique of osteosynthesis. During a study period of 1 year, 10 patients with an atrophic type of delayed union could be retrieved and matched to 10 patients with normal fracture healing. The diagnosis of delayed union was assumed in case of failed consolidation 4 months after trauma. We found an increase of TGF-beta1 serum levels up to 2 weeks after fracture in both groups with a following return to the reference value within 6 weeks after trauma. However, decline of serum concentration occurred earlier in patients with delayed fracture healing. At 4 weeks after trauma, serum levels of TGF-beta1 were significantly lower in patients of the delayed union group. Serum levels of BMP-2 and BMP-4 were below detection level in all patients, respectively. These findings support the critical role of TGF-beta1 in fracture healing. Events during the consolidation phase seem to be dependent on sufficient availability of TGF-beta1.