AIM OF THE STUDY: Since MRI-studies had begun to establish the diagnosis of transitory bone marrow edema syndrome of the hip orthopedic surgeons have tried to integrate this new syndrome into the internationally accepted system of musculoskeletal diseases. Particularly, the relation to non-traumatic osteonecrosis of the femoral head and the possibilities in therapy were investigated in our clinical trial. METHODS: Our clinical trial encompassed 106 patients suffering from the transitory bone marrow edema syndrome diagnosed in our department between the years 1985 and 2000. In order to confirm this diagnosis we used the patients' histories, their clinical courses, MRI studies, scintigraphic bone scans, intraosseal pressure measurements, phlebographies, laboratory data, and histologic specimens. One half of our collective positive for transient bone marrow edema of the hip underwent core-decompression surgery (50 patients), the other half (56 patients) was treated conservatively by analgesic medication combined with restriction of weight-bearing in the affected extremity. RESULTS: Patients positive for transitory bone marrow edema syndrome of the hip are middle-aged individuals with a male to female predominance of 60 : 40. This group has no or only few risk factors usually associated with osteonecrosis of the femoral head. Thus, the missing alcoholic abuse is striking. All patients suffering from transitory bone marrow edema syndrome of the hip recovered completely independent of the therapy we initiated and none of them showed any signs of osteonecrosis. The one half undergoing surgical decompression of the edema by using a 4.5 mm drill experienced an markedly accelerated relief of their clinical symptoms as well as their signal changes on MRI studies. Conventional X-ray pictures and scintigraphic bone scans are not useful for early differentiation between early stages of osteonecrosis and bone marrow edemas. This also accounts for the historical measurements of intraosseal pressure determinations and phlebographies. In contrast to that, MRI studies are effective in early differentiation between osteonecrosis and bone marrow edema syndrome of the hip, especially when contrast medium (gadolinium) is administrated intravenously and fat-suppressed MRI-sequences find use. Beginning osteonecrosis of the femoral head shows a segmental loss of contrast medium, a "double line sign" interface to the intact bone marrow, and only in a few cases they are associated with a huge symptomatic edema. The histologic examination of specimens obtained from 43 patients with transitory bone marrow edema syndrome of the hip revealed no signs of osteonecrosis. CONCLUSION: MRI studies are useful in differentiation between bone marrow edema syndrome of the hip and non-traumatic osteonecrosis of the femoral head in each stage of these two diseases. The thorough differentiation between these two diseases is of extraordinary importance for the clinical work-up of the patients as well as for scientific reasons. The course of primary bone marrow edema is benign as it results in entire recovery. The core decompression surgery offers the chance to shorten the course of the disease.

Adult↗

PubMedDate not supplied

[Liposomal daunorubicine combined with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children].

BACKGROUND: First-line treatment in AML commonly included high cumulative doses of anthracyclines with an increasing risk of cardiotoxicity. Liposomal daunorubicin (L-DNR) is thought to be less cardiotoxic without impairment of efficacy. METHODS: The AML-BFM REZ 97 study included two reinduction blocks with L-DNR (2 x 60 mg/m (2) n = 38, since 2/1999 3 x 60 mg/m (2) n = 31) combined with cytarabine (500 mg/m (2) 4 d). Children who achieved a second blast clearance were allocated to allogeneic stem cell transplantation either from a matched related (MRD) or a matched unrelated donor (MUD). Lack of a donor justified haploidentical SCT in early relapse (1st remission < 1 year) and autologous SCT in late relapse. PATIENTS: Between 1/1997 and 9/2001, 69 children were enrolled in the AML-BFM 97 relapse study. The median duration of first remission was 0.9 years. Forty-one patients had a remission of less than one year, 28 of more than a year. RESULTS: 46 children (67 %) achieved a second remission, defined as clearance of blasts in bone marrow and at least a partial hematological reconstitution. Seventeen of these children are alive (12 of 25 children receiving allogeneic SCT (MFD/MUD); 1 of 8 children after haploidentical SCT; 1 of 4 patients after autologous SCT and 3 of 9 patients treated with chemotherapy only). Further three children without 2nd remission survived after MFD-SCT (n = 2) or chemotherapy (n = 1; follow-up 0.3 to 0.7 years). Duration of first remission remains a significant prognostic factor. The pharmacokinetic investigation showed a high overall AUC of 234.6 mg/l h at a dose of 60 mg/m (2), and a volume of distribution of 1.98 l/m (2), which is much lower in comparison to conventional Daunorubicin. Regarding toxicity, the combination of L-DNR and cytarabine followed by SCT was feasible in experienced centers, however, acute complications like infection or septicemia in aplasia, mucositis and GvHD were common. By contrast, no clinical relevant cardiotoxicity was seen so far, but definitive results in long-term cardiotoxicity await a longer follow-up. In conclusion, L-DNR/cytarabine treatment induced a 2nd remission in most of the children with relapsed or refractory AML. It has to be followed by allogeneic SCT which enables long-term survival.

Adolescent↗

PubMedDate not supplied

Insulin-like growth factor I (IGF-I) stimulates proliferation but also increases caspase-3 activity, Annexin-V binding, and DNA-fragmentation in human MG63 osteosarcoma cells: co-activation of pro- and anti-apoptotic pathways by IGF-I.

Insulin-like growth factor-I (IGF-I) was found to promote proliferation, cell survival, and inhibition of apoptosis. But in some instances, IGF-I was found to mildly induce apoptosis, i. e. Fas-mediated apoptosis in human MG63 osteosarcoma cells. In the present study, we intended to further investigate IGF-I dependent pathways leading either to proliferation and cell survival or to cell death. MG63 osteosarcoma cells were treated with serum free medium alone or in combination with IGF-I, a neutralizing antibody against the human IGF-I receptor (alphaIR-3) or non-immune control IgG (1) for two to six days. We investigated cell survival (cell count), proliferation (CD71-FACS), apoptosis (Annexin-V-FACS, Caspase-3 activity, PCD) and anti-apoptosis (112-Ser Bad phosphorylation), and regulation of IGF-I receptor surface expression (IGF-I receptor-FACS). We found that IGF-I treatment (48 h) stimulated cell growth and proliferation, but also mildly induced apoptosis. IGF-I activated specific apoptotic pathways (Caspase-3 activation, Annexin-V binding and DNA degradation), as well as anti-apoptotic signals (Bad phosphorylation at serine 112). alphaIR-3 blocked cell proliferation, strongly induced apoptosis, and inhibited Bad-phosphorylation. Thus, IGF-I treatment overall resulted in increased tumour cell mass, despite a detectable stimulation of apoptosis; in other words proliferation exceeded cell death. If IGF-I was first added on day 0, 2, or 4 of serum free culture, we found decreasing IGF-I specific effects on proliferation and apoptosis. In parallel, we found a down-regulation of IGF-I receptors (FACS) by serum withdrawal, which was partly reversed if IGF-I was added. Therefore receptor number might have an impact on IGF-I function in MG63 cells. In conclusion, co-activation of apoptosis and proliferation by IGF-I might result in higher cell turnover in MG63 osteosarcoma cells. Furthermore, in sarcomas or carcinomas showing clinical association to IGF-I levels and malignancy, IGF-I dependent apoptosis and proliferation could be a significant mechanism of malignant tumour growth.

Annexin A5↗

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Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group.

Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.

Adolescent↗

PubMedDate not supplied

Fluorescence studies on lung tumors.

Illumination of unstained 9 microns cryosections of lung tissue with 365 nm results in visible fluorescence light with a maximum intensity at about 460 nm. These fluorescence tomographical studies can be used for detecting carcinoma of the lung. The fluorescence pattern obtained can be matched nicely with histological findings. Since it takes less than 5 min for getting the fluorescence images, the fluorescence tomographical technique might be used in addition to established methods for determining the histology of a biopsy sample.

Adult↗

PubMedDate not supplied

Elastosis and cancer.

Recently we have shown that the autofluorescence within or just outside of a malignant tumor is rather small or large resp. in comparison to healthy tissue when excited at 365 nm. Studies with unfixed, unstained cryosections of skin with melanomas have revealed bulky fiber-like structures with a high fluorescence intensity just outside of a malignant tumor. Using polarized light, the structures could be identified as elastic fibers. This was also confirmed by studies on arterial walls.

Aged↗

PubMedDate not supplied

Aerosol bolus dispersion in the respiratory tract of children.

To investigate mechanisms of intrapulmonary convective gas transport, aerosol bolus dispersion was measured in 16 healthy children aged 7-11 years. Subjects inhaled 50-mL aerosol boluses consisting of 0.4-micron droplets of di(2-ethylhexyl) sebacate suspended in air into volumetric lung depths between 95 and 540 mL. Bolus dispersion was quantified by volumetric bolus half-width and by volumetric standard deviation of particle concentrations. Bolus half-width increased from a mean of 160 mL to 360 mL with increasing lung depth, the regression being a power law with an average exponent of 0.48. Standard deviation increased from 68 to 136 mL with the 0.42th power of volumetric penetration. There was no correlation of bolus dispersion with age, body height, or lung function parameters, except for boluses penetrating very deep into the lung where dispersion was weakly related to lung volume. The results obtained in children did not differ from those found in an adult population in an earlier study. It was concluded that airway size per se does not have a strong influence on bolus dispersion. Rather, parameters of airway geometry may be among the dominating factors influencing the fate of inhaled particles.

Aerosols↗

PubMedDate not supplied

Accuracy and resolution power of aerosol-derived airway morphometry in a simple lung model.

Aerosol-derived airway morphometry (ADAM) uses sedimentational deposition of monodisperse aerosol particles during breathhold to estimate intrapulmonary air-space dimensions. To determine the accuracy and resolution power of this technique a simple physical lung model comprised of uniform glass beads was investigated. Using the chordlength model, aerosol recovery from this porous medium was calculated by computer simulation of the geometrical structure of air-spaces between glass beads. The results of this calculation were then compared with experimental data: Calculated and measured air-space dimensions differ less than 2% for particles with diameters above about 1 micron. The measured air-space dimension can be described geometrically by the mean chordlength of the porous medium. To estimate the resolution power of ADAM, a defined change in air-space dimensions represented by a horizontal air slit was introduced into the porous medium. This air slit induces a marked increase of measured air-space dimensions. The volumetric width of this increase is the higher the deeper the slit is situated within the medium. Intercomparison of these data with the results of aerosol bolus dispersion measurements suggests that the resolution power of ADAM is decreased by the same mechanisms that increase dispersion of aerosol boluses, demonstrating the close relationship between both methods.

Aerosols↗

PubMedDate not supplied

Influence of gas composition on convective and diffusive intrapulmonary gas transport.

The influence of gas composition on convective and diffusive gas transport in the lungs was assessed by studying the dispersion of combined particle and argon (Ar) boluses induced by the passage through the lungs filled with three different gas mixtures. Particles, as a "nondiffusing gas," served as a tracer for convective gas transport, while the significance of diffusive gas transport was inferred from the difference in the behavior of Ar and particles. The lungs of six anesthetized and mechanically ventilated beagle dogs were equilibrated with air or either of the test atmospheres, He-O2 or SF6-O2, where nitrogen was replaced by helium (He) or sulfur hexafluoride (SF6). Due to differences in gas density and gas viscosity Reynolds numbers varied by a factor of twelve and Ar diffusivity by a factor of four between He-O2 and SF6-O2, suggesting that both kinds of intrapulmonary gas transport, convection and diffusion, should be affected. Combined particle and Ar boluses were inhaled into various lung depths and the extent of gas transport was inferred from changes in bolus shape induced by the passage through the lungs. In air, convective bulk gas transport generally followed the symmetric first-in, last-out principle and acted at all tested lung depths. Within the conducting airways, gas transport to the lung periphery was primarily due to convection but beyond these airways diffusion became rapidly significant. Breathing test atmospheres affects intrapulmonary gas transport only slightly. The extent of convective mixing was increased by 4% in SF6-O2 (p < .01) and reduced by 5% in He-O2 (p < .01) as compared to air. The symmetry of convective lung filling and emptying was slightly disturbed. In SF6-O2 the mean of the exhaled bolus was shifted by 8% toward the lung periphery. In He-O2 it was shifted by 4% toward the airway opening. In both test atmospheres exhaled Ar boluses were similar, suggesting that diffusive gas transport overwhelms the small changes in convective gas transport. Hence, factors other than gas composition-related flow characteristics, e.g., nonreversibility of in- and expiratory flow profiles or features of lung geometry, are the major determinants of gas transport in the lungs.

Animals↗

PubMedDate not supplied

Influence of intrinsic particle properties on the assessment of convective gas transport by aerosol bolus technique.

Aerosol bolus measurements are increasingly being used in patients and healthy subjects to assess convective gas transport and mixing in the lungs. To investigate the extent to which intrinsic particle properties confound parameters derived for the assessment of intrapulmonary transport, bolus inhalation experiments were performed in six anesthetized, intubated, and mechanically ventilated beagle dogs using DEHS particles of 0.5, 1, or 2 microns diameter. Therefore, particle displacement by diffusion varied by a factor of two, settling velocity by a factor of 13, and particle inertia as inferred from the stopping distance by a factor of 16. By using a standardized breathing maneuver 6-mL boluses were inhaled into lung depths between 75 and 475 mL. Mode, half-width, and intrapulmonary particle deposition along with mean, standard deviation, and skewness of the particle concentration distributions in the expired air were determined. For all particle sizes studied particle deposition increased with increasing lung depth not exceeding 25% for 0.5-micron particles, but being 80% in deep lung regions for 2-micron particles. Whereas half-width and standard deviation exhibited only small differences between particle sizes (less than 20%), mode and mean of the exhaled bolus were clearly dependent on particle size, in particular for particles inhaled deep into the lung. No significant effects were detectable for the skewness. Hence, convective mixing assessed by half-width or standard deviation is only slightly dependent on particle size, but the estimate of convective bulk transport as inferred from the mean volume from which the bolus is exhaled is highly dependent on particle size. Yet, the intrinsic mobility of unit-density 0.5-micron particles was found to be small enough to consider these particles as ideal tracers for probing convective gas transport in the lungs.

Administration, Inhalation↗