[Stem cell-induced liver regeneration]. / Stammzell-induzierte Leberregeneration.

BACKGROUND: The liver has an excellent regenerative capacity after resection. However, below a critical level of future liver remnant volume (FLRV), partial hepatectomy is accompanied by a significant increase of postoperative liver failure. There is accumulating evidence for the contribution of bone marrow stem cells (BMSC) to participate in liver regeneration. Here we report our experience with portal vein embolisation (PVE) and CD133+ BMSC administration to the liver, compared with PVE alone, to augment hepatic regeneration in patients with critically low FLRV or impaired liver function. PATIENTS AND METHODS: Eleven patients underwent PVE of liver segments I and IV-VIII to stimulate hepatic regeneration prior to extended right hepatectomy. In these 11 patients with a FLRV below 25% and/or limited quality of hepatic parenchyma, PVE alone did not promise adequate proliferation. These patients underwent additional BMSC administration to segments II and III. Two radiologists blinded to patients' identity and each other's results measured liver and tumour volumes with helical computed tomography. Absolute, relative and daily FLRV gains were compared with a group of patients that underwent PVE alone. RESULTS: The increase of the mean absolute FLRV after PVE with BMSC application from 239.3 mL±103.5 (standard deviation) to 417.1 mL±150.4 was significantly higher than that from 286.3 mL±77.1 to 395.9 mL±94.1 after PVE alone (p<0.05). Also the relative gain of FLRV in this group (77.3%±38.2%) was significantly higher than that after PVE alone (39.1%±20.4%) (P=0.039). In addition, the daily hepatic growth rate after PVE and BMSC application (9.5±4.3 mL/d) was significantly superior to that after PVE alone (4.1±1.9 mL/d) (p=0.03). Time to surgery was 27 days±11 in this group and 45 days±21 after PVE alone (p=0.02). Short- and long-term survival were not negatively influenced by the shorter waiting period. CONCLUSION: In patients with malignant liver lesions, the combination of PVE with CD133+ BMSC administration substantially increased hepatic regeneration compared with PVE alone. This procedure bears the potential to allow the safe resection of patients with a curative intention that would otherwise carry the risk post-operative liver failure.

PTH-receptors regulate norepinephrine release in human heart and kidney.

Recent data suggests that chronic renal failure and hyperparathyroidism are associated with sympathetic overactivity. Since peptide hormones are known to modulate norepinephrine (NE) release by activating prejunctional receptors, this study investigates whether parathyroid hormone fragment (1-34) (hPTH(1-34)) increases neuronal NE release in human heart and kidney. Using specific PTH-receptor agonists and antagonists, this study furthermore highlights functional differences between PTH1 and PTH2 receptors. Human atrial and renal tissues were incubated with [(3)H]-NE and superfused. Three electrical stimulations (5Hz, 1min) induced a stable [(3)H]-NE release which was taken as an index of endogenous NE release. RT-PCR with specific primers for PTH1- and PTH2-receptor was performed in heart and kidney. hPTH(1-34) (0.01-0.1µmol/L) and a stable analog of its second messenger cAMP (8-bromo-cAMP) increased [(3)H]-NE release in human atria. This facilitatory effect of PTH was also observed in human renal cortex. The PTH1-receptor antagonist (D-Trp(12), Tyr(34))-pTH-(7-34) (0.5µmol/L) abolished the effect of hPTH(1-34). This data was verified using isolated perfused mouse kidneys. Tuberoinfundibular peptide of 39 residues (TIP-39) (0.1nmol/L-0.1µmol/L) decreased [(3)H]-NE release in atria. PTH1- and PTH2-receptor expressions were demonstrated in human heart and kidney. Moreover, a splice variant of the PTH2-receptor was detected in human kidney. In conclusion, PTH is able to facilitate NE release in human atria and renal cortex by activation of PTH1-receptors. The highly increased PTH levels that can be observed in chronic renal failure might be one contributor for the elevated sympathetic nerve activity and the associated cardiovascular mortality in patients with end stage renal disease.

Transmyocardial laser revascularization combined with intramyocardial endothelial progenitor cell transplantation in patients with intractable ischemic heart disease ineligible for conventional revascularization: preliminary results in a highly selected small patient cohort.

OBJECTIVE: Transmyocardial laser revascularization for angina relief and intramyocardial autologous endothelial progenitor cell injection for neoangiogenesis may offer a new treatment strategy for patients with intractable ischemic heart disease. METHODS: Transmyocardial laser revascularization and intramyocardial injection of bone marrow-derived CD133+ cells was performed in six highly symptomatic patients. Transmyocardial laser channels were created and isolated CD133+ cells were injected intramyocardially. All patients were followed up for a minimum of 6 months postoperatively. RESULTS: One patient died shortly after the operation due to refractory heart failure. In the five survivors, CCS class improved as well as left ventricular ejection fraction. Left ventricular end-diastolic volume and myocardial perfusion varied between the patients. All patients described a considerable improvement in quality of life postoperatively. Repeated 24-hour Holter monitoring revealed no significant arrhythmias. CONCLUSIONS: In this small patient cohort, intramyocardial CD 133+ cell injection combined with transmyocardial laser revascularization led to an improvement in clinical symptomatology in all patients and in left ventricular function in 4 out of 5 patients, with an unclear effect on myocardial perfusion. Caution is advised when employing this therapy in patients with severely depressed left ventricular function.

Transplanted human cord blood-derived unrestricted somatic stem cells improve left-ventricular function and prevent left-ventricular dilation and scar formation after acute myocardial infarction.

OBJECTIVE: Functional improvement after acute myocardial ischaemia (MI) has been achieved by transplantation of different adult stem and progenitor cell types. It is controversial whether these cell types are able to form novel functional myocardium. Alternatively, graft-related or immune-related paracrine mechanisms may preserve existing myocardium, improve neovascularisation, affect tissue remodelling or induce endogenous de novo formation of functional myocardium. We have applied an alternative somatic cell type, human cord-blood-derived unrestricted somatic stem cells (USSCs) in a porcine model of acute MI. METHODS: USSCs were transplanted into the acutely ischaemic lateral wall of the left ventricle (LV). LV dimension and function were assessed by transoesophageal echocardiography (TEE) pre-MI, immediately post-MI, 48 hours and 8 weeks after USSC injection. Additionally, apoptosis, mitosis and recruitment of macrophages were examined 48 hours post-engraftment. RESULTS: Gender-specific and species-specific FISH/immunostaining failed to detect engrafted donor cells 8 weeks post-MI. Nevertheless, cell treatment effectively preserved natural myocardial architecture. Global left ventricular ejection fraction (LVEF) before MI was 60% (7%). Post-MI, LVEF decreased to 34% (8%). After 8 weeks, LVEF had further decreased to 27% (6%) in the control group and recovered to 52% (2%) in the USSC group (p<0.01). Left-ventricular end-diastolic volume (LVEDV) before MI was 28 (2) ml. 8 weeks post-MI, LVEDV had increased to 77 (4) ml in the control group. No LV dilation was detected in the USSC group (LVEDV: 26 (2) ml, p<0.01). Neither apoptosis nor recruitment of macrophages and mitosis were different in either groups. CONCLUSIONS: Transplantation of USSCs significantly improved LV function and prevented scar formation as well as LV dilation. Since differentiation, apoptosis and macrophage mobilisation at infarct site were excluded as underlying mechanisms, paracrine effects are most likely to account for the observed effects of USSC treatment.

Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery.

INTRODUCTION: Cell transplantation for myocardial regeneration has been shown to have beneficial effects on cardiac function after myocardial infarction. Most clinical studies of intramyocardial cell transplantation were performed in combination with coronary artery bypass grafting (CABG). The contribution of implanted stem cells could yet not be clearly distinguished from the effect of the CABG surgery. Our current phase 1 clinical study has focused on the safety and feasibility of CD133+-enriched stem cell transplantation without CABG and its potential beneficial effect on cardiac function. METHOD AND RESULTS: Ten patients with end-stage chronic ischemic cardiomyopathy (ejection fraction <22%) were enrolled in the study. Bone marrow (up to 380 mL) was harvested from the iliac crest. CD133+ cells were purified from bone marrow cells using the CliniMACS device with purities up to 99%. Autologous bone marrow CD133+ cells (1.5-9.7 X 106 cells) were injected into predefined regions. Cardiac functions prior to and 3, 6, and 9 months after cell transplantation were assessed by cardiac magnetic resonance imaging. Stem cell transplantation typically improved the heart function stage from New York Heart Association/Canadian Cardiovascular Society class III-IV to I-II. The mean preoperative and postoperative ventricular ejection fractions were 15.8 +/- 5% and 24.8 +/- 5%, respectively. CONCLUSION: CD133+ injection into ischemic myocardium was feasible and safe. Stem cell transplantation alone improved cardiac function in all patients. This technique might hold promise as an alternative to medical management in patients with severe ischemic heart failure who are ineligible for conventional revascularization.

Autologous transplantation of CD133+ BM-derived stem cells as a therapeutic option for dilatative cardiomyopathy.

We report the case of a 58-year-old man with end-stage non-ischemic cardiomyopathy. Baseline transthoracic echocardiography (TTE) and cardiac magnetic resonance (cMRI) revealed a markedly depressed left ventricle systolic function. He underwent autologous CD133+ BM-derived cell transplantation through a minimally invasive approach. During surgery 19 x 10(6) BM-derived stem cells were injected by the transepimyocardial route. Six months after the operation TTE and cMRI showed a clear improvement in left ventricular contractility.

Intraoperative isolation and processing of BM-derived stem cells.

To improve tissue regeneration of ischemic myocardium, autologous bone marrow-derived stem cells have been injected intramyocardially in five patients undergoing coronary artery bypass grafting and transmyocardial laser revascularization. An innovative method for the intraoperative isolation of CD133(+)-stem cells in less than 3 hours has been established. After induction of general anesthesia, approx. 60-240 ml of bone marrow were harvested from the posterior iliac crest and processed in the operating room under GMP conditions using the automated cell selection device Clini-MACS. Following standard CABG surgery, LASER channels were shot in predefined areas within the hibernating myocardium. Subsequently, autologous CD133(+)-stem cells (1.9-9.7 x 10(6) cells; purity up to 97%) were injected in a predefined pattern around the laser channels. Through the intraoperative isolation of CD133(+)-cells, this effective treatment of ischemic myocardium can be applied to patients scheduled both for elective and for emergency revascularisation procedures.

Autologous bone marrow-derived stem cell therapy in combination with TMLR. A novel therapeutic option for endstage coronary heart disease: report on 2 cases.

We report 2 cases in which patients with coronary heart disease not amenable for conventional revascularization underwent transmyocardial laser revascularization (TMLR) and implantation of AC133+ bone-marrow stem cells. The reason for using TMLR in combination with stem cell application is to take advantage of the synergistic angiogenic effect. The local inflammatory reaction induced by TMLR should serve as an informational platform for stem cells and may trigger their angiogenic differentiation. Functional analysis of myocardial performance after treatment in these 2 cases revealed dramatic improvement of the wall motion at the site of the TMLR and stem cell application. Because TMLR does not enhance myocardial contractility and there was no angiographic evidence of major collaterals to the ischemic region in either patient, we assume that the synergistic effect of stem cells and TMLR-induced angiogenesis occurred; however, our assumption is of a speculative nature. We think that TMLR in combination with stem cell transplantation might become a novel revascularization therapy for ischemic myocardium.

[Sprengel deformity in a nine-year-old boy: diagnosis and therapy]. / Sprengel-Deformität bei einem neunjährigen Jungen: Diagnostik und Therapie.

Sprengel deformity is a congenital malformation with usually unilateral elevation and medial rotation of the scapula. An omovertebral bone is generally present. Associated skeletal malformations are frequently present. Though functional impairment is mild, the cosmetic and psycho-social impairment can be considerable. The prognosis of early surgical therapy is good. The presented case also justifies surgical correction in the older child.

[Imaging diagnostics of the wrist: MRI and Arthrography/Arthro-CT]. / Bildgebende Diagnostik des Handgelenkes: MRT und Arthrographie/Arthro-CT.

PURPOSE: To evaluate the use of magnetic resonance imaging (MRI) compared with arthrography and arthro-CT (AG/ACT) in patients with wrist pain. METHODS: MRI and arthrography/arthro-CT (AG/ACT) of the wrist joint were retrospectively evaluated in 346 patients over a three-year period. Imaging findings were correlated to surgical results (n = 78) or clinical course in an at least 6-month follow-up. RESULTS: For tears of the triangular fibrocartilage, arthrography, arthro-CT, and MRI demonstrated a sensitivity and specificity of more than 0.96. Only the positive predictive value was superior for arthrography/arthro-CT (0.99 and 0.98, respectively) compared with MRI (0.94). Arthrography was superior for functional diagnosis of scapho-lunate ligament tears (n = 25). Ulno-lunate and ulno-triquetral ligament defects were demonstrated more exactly by arthrography. Traumatic osseous defects, particularly scaphoid fractures (n = 33) and avascular necrosis (n = 17), were better diagnosed using MRI. CONCLUSION: For suspected lesions of the triangular fibrocartilage complex, AG/ACT is slightly more reliable than MRI. However, MRI was found to be highly accurate in diagnosing TFC tears, and is superior to AG/ACT in detecting traumatic and vascular lesions of the wrist.

The moon and madness reconsidered.

Belief that the full moon is associated with psychiatric disturbance persists despite 50 years research showing no association. This article traces the historical roots of belief in the power of the moon to cause disorders the mind, especially insanity and epilepsy. Putative mechanisms of lunar action are critiqued. It is proposed that modern findings showing lack of lunar effect can be reconciled with pre-modern beliefs in the moon's power through a mechanism of sleep deprivation. Prior to the advent of modern lighting the moon was a significant source of nocturnal illumination that affected sleep-wake cycle, tending to cause sleep deprivation around the time of full moon. This partial sleep deprivation would have been sufficient to induce mania/hypomania in susceptible bipolar patients and seizures in patients with seizure disorders. The advent of modern lighting attenuated this lunar effect, especially in modern urban areas, where most 20th century studies of lunar effects on the mind have been conducted. The hypothesis presented in this article is open to empirical validation or falsification. Potential tests for the sleep-deprivation hypothesis of lunar action are discussed.

Clinical significance of three-dimensional helical CT in neurosurgery.

The authors report about a 3-years experience with helical CT and 3-D surface reconstruction applied in neurosurgical patients. All examinations were performed in addition to preexisting diagnostic CT, MRI, or angiography. The aim of this study was to assess the clinical value of this method with regard to planning of the surgical approach to anterior, middle, and posterior skull base and spinal lesions. 75 examinations of 55 patients were analysed and ranked as follows: A = examination with significant additional information for neurosurgical planning of skull base or spinal procedures or for postoperative evaluation of the neurosurgical approach, B = examination with some useful information for the neurosurgical planning or postoperative control, however, without significant advantage as compared to established diagnostic methods, C = examination without significant additional information. Classification was performed independently by two experienced surgeons. Examinations of anterior, middle, and posterior skull base lesions including cerebral aneurysms were in the majority rated as helpful and significantly informative, (A = 21, B = 24, C = 9, n = 54). Three-dimensional imaging of the spine was of clinical value only in specific cases (A = 6, B = 6, C = 9, n = 21). The authors conclude that three-dimensional imaging is a valuable diagnostic tool for pre- and postoperative imaging of tumorous and vascular lesions adjacent to the skull base, allowing for optimal surgical approaches with minimal invasiveness.

[Preoperative spiral CT cholangiography with 3-dimensional surface reconstruction: the anatomical imaging potentials, limits and application strategies]. / Präoperative Spiral-CT-Cholangiographie mit dreidimensionaler Oberflächenrekonstruktion: anatomische Darstellungsmöglichkeiten, Grenzen und Einsatzstrategien.

PURPOSE: Evaluation of CT cholangiography compared to i.v. cholangiography concerning its diagnostic value before laparoscopic cholecystectomy and optimisation of CT cholangiography. METHOD: I.v. and CT cholangiographies of 54 patients were retrospectively evaluated by two radiologists. The time interval between contrast infusion and CT was correlated with the assessment of CT cholangiographies to detect the optimal timing for CT scanning. RESULTS: CT cholangiography was judged to be generally better than i.v. cholangiography. The optimal time interval for CT scanning is between 30 min and 60 min post contrast infusion. CONCLUSION: CT cholangiography should replace the conventional tomograms if i.v. cholangiography does not yield sufficient depiction of the biliary tree. It should be performed within 60 min post contrast infusion. Complete abolishment of i.v. cholangiography is not warranted. This is due to the fact that conventional cholangiography can sufficiently delineate the biliary tree and thereby reduce x-ray exposure and cost compared to initial performance of CT cholangiography.

Induction of heat shock protein 70 (HSP70) by zinc bis (DL-hydrogen aspartate) reduces ischemic small-bowel tissue damage in rats.

The aim of the study was to determine whether the induction of HSP70 by Zn2+ is able to protect the small bowel of rats against ischemia. Twenty-four male Wistar rats (weight 200-300 g) were divided into four groups: (1) saline treatment for 24 h (n = 4); (2) Zn2+ treatment for 24 h (n = 4); (3) Saline pretreatment for 24 h and ischemia (n = 8); (4) Zn2+ pretreatment for 24 h and ischemia (n = 8). Pretreatment with Zn2+ was carried out by intraperitoneal administration of 50 mg/kg zinc bis (DL-hydrogen aspartate) = 10 mg/kg Zn2+. Ischemia in a defined segment of the small bowel was produced by ligation of the mesenteric vein and artery and ligation of both ends of the segment. Tissue samples were collected before and 2, 4 and 6 h after ligation and investigated by histology, immunohistochemistry and Western blotting. Twenty-four h after i.p. Zn2+ injection, the small bowel expressed increased HSP70 tissue levels. Histology with subsequent grading of ischemic tissue injury showed significantly decreased tissue necrosis after Zn2+ pretreatment and HSP70 induction compared with saline pretreated controls. In conclusion, this study proves that Zn2+ is inducing HSP70 in the small bowel in vivo and hereby able to protect the small bowel against ischemia.

CT and MRI of experimentally induced mesenteric ischemia in a porcine model.

OBJECTIVE: Our goal was to assess the value of CT and MRI for the detection of bowel wall changes in experimentally induced mesenteric ischemia. METHODS: in 18 female pigs, a percutaneous embolization of the superior mesenteric artery was performed with buthyl-2-cyanoacrylate and Lipiodol (1:1) (experimental group). In six animals, only diagnostic imaging and histologic evaluation were performed (control group). CT was carried out 3, 6, and 12 h after occlusion. Incremental CT (1 s scan time, 5 mm slice thickness, 7 mm increment, 120 kV/290 mAs) and spiral CT (slice thickness 5 mm, pitch 1.5, 120 kV/165 mA) were performed pre and post contrast injection (Somatom Plus/Siemens). Serial CT was carried out after intravenous contrast injection (1 ml/kg, 2 ml/s). MRI (Magnetom 1.5 T; Siemens) was performed with T1 (pre and post 0.01 mmol/kg Gd-DTPA; Magnevist; Schering, Germany), T2, and proton density images in axial orientation. Slice thickness was 3 mm and slice gap 1 mm. Additionally, a T1-weighted GE sequence (multislice FLASH 2D) was obtained in dynamic technique (before and 30, 60, and 90 s after contrast agent injection) with a slice thickness of 5 mm. Biometrical monitoring included blood pressure, heart frequency, blood cell count, electrolyte status, blood gas analysis, and determination of serum lactate. Image evaluation included morphological analysis and determination of the enhancement pattern. Histological specimens were obtained and analyzed according to the Chiu classification. RESULTS: The histologic workup of the specimen 3, 6, and 12 h after vascular occlusion revealed an average Chiu state 3, 4, and 5. On CT, the bowel wall had a thickness of 4.7 mm on average in the ischemic segments. There was a significant difference from the control group (average 3 mm). Free intraperitoneal fluid and intramural gas were seen after 12 h of ischemia in 80%. In ischemic bowel segments, no mural enhancement was seen. Normal segments and the bowel of the control animals showed an enhancement of 34 HU on average (SD = 3.1 HU; p.<0.01). In MRI, S/N and C/N differed significantly between experimental and control groups in T1 and proton density images. In ischemic segments of all phases, the bowel wall did not show contrast enhancement. Healthy segments and bowel of control animals showed a significant enhancement (p<0.01). CONCLUSION: Cross-sectional imaging has a high sensitivity for delineation of ischemic bowel wall segments. The enhancement pattern of the bowel wall enables detection of location, extent, and cause of a acute arterial mesenteric ischemia with high accuracy in an early phase.

Microsurgical management of ventral and ventrolateral foramen magnum meningiomas.

The authors report their experiences gained from 19 patients with ventral or ventrolateral foramen magnum meningiomas operated on via the dorsolateral, suboccipital transcondylar access route. It is emphasized that the microsurgical management of these lesions includes two important aspects which increase the safety of the procedure: a meticulous preoperative planning based on the microanatomical details of each patient, as well as an individualized tailoring of the surgical approach. There were no deaths, and, in the past 5 years, no neurological complications in this series. Gross total removal of the tumour was achieved in each case. It is concluded that microsurgical removal of ventral or ventrolateral foramen magnum meningiomas with this technique constitutes a safe and recommendable procedure.

Pattern recognition system for focal liver lesions using "crisp" and "fuzzy" classifiers.

RATIONALE AND OBJECTIVES: To determine the diagnostic performance of an artificial intelligence system for classification of focal liver lesions, in comparison to human observers. METHODS: One hundred forty-three focal hepatic lesions were evaluated with dynamic computed tomography. The study comprised 59 hemangiomas, 24 other benign lesions (focal nodular hyperplasia, adenoma), and 60 malignant liver lesions (18 primary, 42 secondary). All lesions but the hemangiomas were histologically examined by needle biopsy. For delineation of the lesion, a region of interest was defined interactively. The pattern recognition was performed in two steps with initial extraction of textural features: training of a classifier and classification of the lesions. The accuracy of classification of hepatic lesions into three groups (hemangioma, other benign processes, malignant lesions) was tested. The results were compared with those achieved by human observers using receiver operating characteristic statistical analysis. RESULTS: The accuracy (total rate of correct diagnoses) was 90.2%. False classifications were found owing to small size, weak contrast enhancement after bolus injection, respiratory movement, and atypical morphology of the lesion. The area under the receiver operating characteristic curve was not significantly different for computer and human observers. CONCLUSIONS: The system demonstrated a diagnostic accuracy comparable to human observers. Further improvement with increasing numbers of typical computed tomographic series for training of the classifier can be expected.