Optimizing remote ischemic conditioning (RIC) of cutaneous microcirculation in humans: Number of cycles and duration of acute effects.

OBJECTIVE: Non-invasive Remote Ischemic Conditioning (RIC) offers an approach to reduce tissue damage in various organs/tissues. Besides attenuation of Ischemia-Reperfusion injury (I/R), beneficial effects on cutaneous microcirculation of free microsurgical flaps have been reported. Given the recency of this technique, there are considerable gaps in the current understanding of its mechanism of action. As a result, clinical transfer of RIC is prolongated in several fields. We aimed to optimize the RIC protocol by examination of different RIC-cycle numbers and its effect on changes of cutaneous microcirculation and duration. METHODS: 80 subjects were divided into groups (1, 3, 5, 7 RIC cycles). RIC was applied via an inflatable tourniquet. Cutaneous microcirculation was continuously assessed at the contralateral anterior lateral thigh utilizing a ©O2C-device continuously. RESULTS: RIC caused significant and sustained changes in microcirculation. Four hours after completion of RIC, a maximum increase of +80.8% (CI 1.395-2.221) in blood flow and +23.5% (CI 1.098-1.372) in tissue oxygen saturation was measured (three-cycle group). A higher number of applied cycles was accompanied with significant higher mean pain. CONCLUSION: Acute improvement of cutaneous microcirculation due to RIC lasted for at least 4 h after completion of the RIC-protocol. Dose-dependent effects of RIC are likely. With regard to the increase in pain, we recommend a RIC protocol of 3 cycles for future clinical application.

[Regulation of bone metabolism by the Wnt signaling pathway]. / Regulation des Knochenstoffwechsels durch den Wnt-Signalweg.

The development and homeostasis of multicellular organisms depends on a complex cellular interaction between proliferation, migration, differentiation, adhesion, and cell death. Wnt signaling pathways coordinate these different cellular responses. Wnt signaling plays a role as a regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. The Wnt signaling pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for the regeneration of skeletal tissue. Recent studies indicate that Wnt ligands are capable of promoting bone growth, suggesting that Wnt factors could be used to stimulate bone healing in osteogenic disorders.

[Soft tissue sarcomas: limb salvage using reconstructive plastic surgery techniques]. / Weichgewebssarkome: Extremitätenerhalt durch plastisch-rekonstruktive Verfahren.

The treatment of choice for soft tissue sarcomas with local involvement is still the complete surgical removal into healthy tissue. The aim of surgery is to achieve tumor-free resection margins in the sense of a R0 resection. No other treatment option can equally replace this important oncological condition. The enormous development in the field of reconstructive plastic surgery and in particular the advances in flap techniques and microsurgery enable limb salvage and the functional reconstruction even in the case of extensive tumors.

Myostatin serum concentration as an indicator for deviated muscle metabolism in severe burn injuries.

INTRODUCTION: Patients experiencing thermal injuries with an extent of over 20% of total body surface area suffer from systemic catabolic disease. The thermal trauma-induced loss of muscle mass causes a higher incidence for comorbidities and subsequently a higher mortality. In this study, we aimed to investigate the role of myostatin in the interplay with follistatin during muscle cachexia. METHODS: Patients with burn injuries (>10% total body surface area) between the ages of 18 and 75 were prospectively included within the first 48 h after trauma to determine deviations of parameters connected to muscle catabolism. In the chronic state of burn injury (9-12 months after trauma), we re-evaluated myostatin and follistatin concentrations as well as muscle strength of the non-dominant forearm. RESULTS: We were able to show a time-dependent alteration (9-12 months after burn injury) of myostatin with an initial decrease (p < 0.001) and long-term increase (p < 0.001) after thermal injury in blood serum. For follistatin, a reciprocal correlation was observed (r = -0.707, p = 0.001). Accordingly, muscle strength of the non-dominant hand and forearm was significantly decreased 9-12 months after injury in post-burn patients compared with healthy patients with a significant correlation to myostatin levels (r = -0.899, p < 0.001). In addition, initial myostatin serum concentration was predictive for long-term muscle strength impairment. CONCLUSION: With regard to the muscle metabolism after thermal trauma, our data suggest an acute anabolic response, presumably to spare muscle mass, which is converted to catabolic conditions accompanied by muscle strength reduction in the chronic phase. Myostatin plays a crucial role in this orchestration and initial myostatin concentration may predict the long-term muscle strength.

Curcumin and Viscum album Extract Decrease Proliferation and Cell Viability of Soft-Tissue Sarcoma Cells: An In Vitro Analysis of Eight Cell Lines Using Real-Time Monitoring and Colorimetric Assays.

BACKGROUND: The cytostatic effects of the polyphenol curcumin and Viscum album extract (VAE) were assessed in soft-tissue sarcoma (STS) cells. METHODS: Eight human STS cell lines were used: fibrosarcoma (HT1080), liposarcoma (SW872, T778, MLS-402), synovial sarcoma (SW982, SYO1, 1273), and malignant fibrous histiocytoma (U2197). Primary human fibroblasts served as control cells. Cell proliferation, viability, and cell index (CI) were analyzed by BrdU assay, MTT assay, and real-time cell analysis (RTCA). RESULTS: As indicated by BrdU and MTT, curcumin significantly decreased the cell proliferation of five cell lines (HT1080, SW872, SYO1, 1273, and U2197) and the viability of two cell lines (SW872 and SW982). VAE led to significant decreases of proliferation in eight cell lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, 1293, and U2197) and reduced viability in seven STS lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, and 1273). As indicated by RTCA for 160 h, curcumin decreased the CI of all synovial sarcoma cell lines as well as T778 and HT1080. VAE diminished the CI in most of the synovial sarcoma (SW982, SYO1) and liposarcoma (SW872, T778) cell lines as well as HT1080. Primary fibroblasts were not affected adversely by the two compounds in RTCA. CONCLUSION: Curcumin and VAE can inhibit the proliferation and viability of STS cells.

[Reconstructive methods after Fournier gangrene]. / Rekonstruktive Möglichkeiten nach Fournier-Gangrän.

BACKGROUND: Fournier's gangrene is a variant of the necrotizing fasciitis restricted to the perineal and genital region. It presents as an acute life-threatening disease and demands rapid surgical debridement, resulting in large soft tissue defects. Various reconstructive methods have to be applied to reconstitute functionality and aesthetics. The objective of this work is to identify different reconstructive methods in the literature and compare them to our current concepts for reconstructing defects caused by Fournier gangrene. METHODS: Analysis of the current literature and our reconstructive methods on Fournier gangrene. RESULTS: The Fournier gangrene is an emergency requiring rapid, calculated antibiotic treatment and radical surgical debridement. After the acute phase of the disease, appropriate reconstructive methods are indicated. The planning of the reconstruction of the defect depends on many factors, especially functional and aesthetic demands. Scrotal reconstruction requires a higher aesthetic and functional reconstructive degree than perineal cutaneous wounds. In general, thorough wound hygiene, proper pre-operative planning, and careful consideration of the patient's demands are essential for successful reconstruction. CONCLUSIONS: In the literature, various methods for reconstruction after Fournier gangrene are described. Reconstruction with a flap is required for a good functional result in complex regions as the scrotum and penis, while cutaneous wounds can be managed through skin grafting. Patient compliance and tissue demand are crucial factors in the decision-making process.

Toward a highly-detailed 3D pelvic model: approaching an ultra-specific level for surgical simulation and anatomical education.

The surgical anatomy of the pelvis is highly complex. Anorectal and urogenital dysfunctions occur frequently after pelvic oncological surgery and are mainly caused by surgical damage of the autonomic nerves. A highly-detailed 3D pelvic model could increase the anatomical knowledge and form a solid basis for a surgical simulation system. Currently, pelvic surgeons still rely on the preoperative interpretation of 2D diagnostic images. With a 3D simulation system, pelvic surgeons could simulate and train different scenes to enhance their preoperative knowledge and improve surgical outcome. To substantially enrich pelvic surgery and anatomical education, such a system must provide insight into the relation between the autonomic network, the lymphatic system, and endopelvic fasciae. Besides CT and MR images, Visible Human Datasets (VHDs) are widely used for 3D modeling, due to the high degree of anatomical detail represented in the cryosectional images. However, key surgical structures cannot be fully identified using VHDs and radiologic imaging techniques alone. Several unsolved anatomical problems must be elucidated as well. Therefore, adequate analysis on a microscopic level is inevitable. The development of a comprehensive anatomical atlas of the pelvis is no straightforward task. Such an endeavor involves several anatomical and technical challenges. This article surveys all existing 3D pelvic models, focusing on the level of anatomical detail. The use of VHDs in the 3D reconstruction of a highly-detailed pelvic model and the accompanying anatomical challenges will be discussed.

Origin of presacral local recurrence after rectal cancer treatment.

BACKGROUND: The objective of this study was to obtain detailed anatomical information about the lateral lymph nodes, in order to determine whether they might play a role in presacral local recurrence of rectal cancer after total mesorectal excision without lateral lymph node dissection. METHODS: Ten serially sectioned human fetal pelvises were studied at high magnification and a three-dimensional reconstruction of the fetal pelvis was made. RESULTS: Examination of the histological sections and the three-dimensional reconstruction showed that lateral lymph node tissue comprises a major proportion of the pelvic tissue volume. There were no lymph nodes located in the presacral area. Connections between the mesorectal and extramesorectal lymph node system were found in all fetal pelvises, located below the peritoneal reflection on the anterolateral side of the fetal rectum. At this site middle rectal vessels passed to and from the mesorectum, and branches of the autonomic nervous system bridge to innervate the rectal wall. CONCLUSION: The findings of this study support the hypothesis that tumour recurrence might arise from lateral lymph nodes.

Neutron-induced 63Ni in copper samples from Hiroshima and Nagasaki: a comprehensive presentation of results obtained at the Munich Maier-Leibnitz Laboratory.

Those inhabitants of Hiroshima and Nagasaki who were affected by the A-bomb explosions, were exposed to a mixed neutron and gamma radiation field. Few years later about 120,000 survivors of both cities were selected, and since then radiation-induced late effects such as leukemia and solid tumors are being investigated in this cohort. When the present study was initiated, the fast neutron fluences that caused the neutron doses of these survivors had never been determined experimentally. In principle, this would have been possible if radioisotopes produced by fast neutrons from the A-bomb explosions had been detected in samples from Hiroshima and Nagasaki at distances where the inhabitants survived. However, no suitable radioisotope had so far been identified. As a contribution to a large international effort to re-evaluate the A-bomb dosimetry, the concentration of the radionuclide (63)Ni (half-life 100.1 years) has been measured in copper samples from Hiroshima and Nagasaki. These measurements were mainly performed at the Maier-Leibnitz-Laboratory in Munich, Germany, by means of accelerator mass spectrometry. Because the (63)Ni had been produced in these samples by fast A-bomb neutrons via the reaction (63)Cu(n,p)(63)Ni, these measurements allow direct experimental validation of calculated neutron doses to the members of the LSS cohort, for the first time. The results of these efforts have already been published in a compact form. A more detailed discussion of the methodical aspects of these measurements and their results are given in the present paper. Eight copper samples that had been significantly exposed to fast neutrons from the Hiroshima A-bomb explosion were investigated. In general, measured (63)Ni concentrations decreased in these samples with increasing distance to the hypocenter, from 4 x 10(6 ) (63)Ni nuclei per gram copper at 391 m, to about 1 x 10(5 ) (63)Ni nuclei per gram copper at about 1,400 m. Additional measurements performed on three large-distant copper samples from Hiroshima (distance to the hypocenter 1,880-7,500 m) and on three large-distant copper samples from Nagasaki (distance to the hypocenter 3,931-4,428 m) that were not exposed significantly to A-bomb neutrons, suggest a typical background concentration of about 8 x 10(4 ) (63)Ni nuclei per gram copper. If the observed background is accounted for, the results are consistent with state-of-the-art neutron transport calculations for Hiroshima, in particular for those distances where the victims survived and were included in the life span study cohort.

Ureterocystoneostomy (UCN) and subureteral collagen injection (SCIN): combined one-stage correction of high-grade bilateral vesicoureteral reflux (VUR) in children.

The treatment of vesicoureteral reflux (VUR) is still a controversial issue. The efficacy of medical treatment appears to be equal to that of operative procedures in avoiding new formation of renal scars. However, there are generally accepted indications for operative procedures including bilateral high-grade VUR, especially in young patients. Ureteral reimplantation (UCN) is the operative treatment of choice in cases with high-grade VUR. Alternatively in cases with lower-grade VUR, injection of bulking agents under the refluxive orifice can be performed. It is also generally accepted that UCN with extravesical preparation of the ureter and the bladder should not be done bilaterally in a one-stage procedure. Postoperative bladder dysfunction may result due to detrimental neurogenic effects. In this study we report on our operative procedure in cases with bilateral high-grade VUR, during which we perform intra/extravesical UCN (mod. Leadbetter-Politano) of the higher-grade refluxive ureter, and (open) subureteral collagen injection (SCIN) of the lower-grade refluxive orifice as a combined one-stage procedure. In this study 50% of the patients had no VUR on either side after the first combined procedure. 15% of the patients showed significant down-grading of VUR of the injected side. These patients underwent a 2nd endoscopic SCIN. 35% of the patients showed no change of VUR of the injected side after the first procedure; these patients underwent reimplantation of this side in another operation. Accordingly, 50% of patients with bilateral high-grade VUR required a 2nd operative procedure under full anesthesia to achieve loss of VUR on both sides. None of the patients showed bladder dysfunction postoperatively. Mean follow-up after the last operative correction was 29.9 months (6 - 84 months).

Measuring fast neutrons in Hiroshima at distances relevant to atomic-bomb survivors.

Data from the survivors of the atomic bombs serve as the major basis for risk calculations of radiation-induced cancer in humans. A controversy has existed for almost two decades, however, concerning the possibility that neutron doses in Hiroshima may have been much larger than estimated. This controversy was based on measurements of radioisotopes activated by thermal neutrons that suggested much higher fluences at larger distances than expected. For fast neutrons, which contributed almost all the neutron dose, clear measurement validation has so far proved impossible at the large distances (900 to 1,500 m) most relevant to survivor locations. Here, the first results are reported for the detection of 63Ni produced predominantly by fast neutrons (above about 1 MeV) in copper samples from Hiroshima. This breakthrough was made possible by the development of chemical extraction methods and major improvements in the sensitivity of accelerator mass spectrometry for detection of 63Ni atoms (refs 8-11). When results are compared with 63Ni activation predicted by neutron doses for Hiroshima survivors, good agreement is observed at the distances most relevant to survivor data. These findings provide, for the first time, clear measurement validation of the neutron doses to survivors in Hiroshima.

Effect of cell growth and cell differentiation on 1-beta-D-arabinofuranosylcytosine metabolism in myeloid cells.

Resistance of leukaemic blasts to 1-beta-D-arabinofuranosylcytosine (ara-C) has been shown to be associated with changes in the metabolism of this drug. However, effects of cell growth and maturation stage on ara-C metabolizing enzymes have to be excluded as a possible cause of different enzyme activities in leukaemic blasts between nonresponders and patients achieving complete remission. We evaluated the effects of cell cycle phase and cell differentiation on the activity of cytidine deaminase, deoxycytidylate deaminase and deoxycytidine kinase in myeloid cell lines. Our data indicate that different enzyme profiles in nonresponders might not only be caused by the emergence of mutator phenotypes but may also reflect the growth and maturation stage of leukaemic blasts.

S-adenosylmethionine metabolism in HL-60 cells: effect of cell cycle and differentiation.

The effect of the cell cycle and differentiation on S-adenosylmethionine (SAM) metabolism in HL-60 cells has been investigated. Synthesis and pool sizes of SAM and S-adenosylhomocysteine (SAH) were cell-cycle-independent (SAM, 315 microM; SAH, 4.6 microM). The SAM-synthase (ATP: L-methionine S-adenosyltransferase) of HL-60 cells has a Km for methionine of 12.8 +/- 2.0 microM and thus appears to be of the intermediate Km type found in other malignant tissues. The enzyme does not show cell-cycle regulation. Treatment of cells with DMSO resulted in a rapid and marked decrease of SAM and SAH levels without affecting pool turnover or the SAM/SAH ratio. A decrease in SAM concentration could also be observed in a variant cell line resistant to differentiation with DMSO. DMSO inhibited SAM-synthase in cell-free extracts. This inhibition was noncompetitive with respect to L-methionine. Inhibition of SAM-synthase by cycloleucine lowered SAM levels in intact cells, but resulted in differentiation of only a minor percentage of cells. These data indicate that changes in SAM and SAH levels in HL-60 cells seem to be a consequence rather than a cause of differentiation.