Hans-Joachim Wagner

Generation of pluripotent stem cells from adult human testis

Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis. Cellular and molecular characterization of these cells revealed many similarities to human embryonic stem cells, and the germline stem cells produced teratomas after transplantation into immunodeficient mice. The human adult germline stem cells differentiated into various types of somatic cells of all three germ layers when grown under conditions used to induce the differentiation of human embryonic stem cells. We conclude that the generation of human adult germline stem cells from testicular biopsies may provide simple and non-controversial access to individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells.

Transarterial Chemoembolization of Advanced Liver Metastases of Neuroendocrine Tumors – A Retrospective Single-Center Analysis

Background: In neuroendocrine tumors, metastases are a negative prognostic factor for survival and quality of life. Transcatheter arterial chemoembolization (TACE) is thought to be an effective symptomatic and antiproliferative treatment in patients with otherwise progressive disease. Methods: 62 chemoembolization procedures in 26 patients with progressive neuroendocrine tumors were reviewed. The underlying disease was carcinoid syndrome in 10, non-functional midgut tumor in 2, non-functional pancreatic tumor in 7, malignant insulinoma in 2 patients, non-functional tumor of the stomach in 1 and of unknown origin in 4 patients. Tumor burden of the liver was <25% in 3, 25–50% in 11, 50–75% in 6 and >75% in 6 patients. Results: TACE was technically successful in 57 cases. Four patients developed minor and 5 major complications. The 30-day mortality rate was 7.7%. According to WHO criteria, 14 patients had no change in tumor burden, 2 had regression and 5 progress after chemoembolization. Patients with a tumor burden >75% of the liver did not benefit from TACE due to the development of major complications, whereas patients with low (<50%) tumor burden and high (>50%) lipiodol uptake showed a trend towards longer survival. Five-year survival time after diagnosis was 48%. Patients treated with octreotide and/or α-interferon had no benefit from chemoembolization with regard to their carcinoid syndrome. Conclusions: In this retrospective study, patients with low (<50%) tumor burden and high (>50%) lipiodol uptake responded better to TACE than end-stage patients.

Glutamate and dopamine modulate synaptic plasticity in horizontal cell dendrites of fish retina

Horizontal cell dendrites protruding into the cone pedicles in fish retina exhibit a light-dependent plasticity. In a light-adapted retina they form numerous spinules having membrane densities at their tips. These spinules disappear during dark adaptation. Experiments with light- or dark-adapted retinas which were incubated in glutamate or its agonists and antagonists, respectively, revealed that this putative cone transmitter is able to reduce the expression of spinules in a light-adapted retina. Dopamine, on the other hand, induces the formation of spinules in a dark-adapted retina and haloperidol reduces the expression in a light-adapted retina. These data suggest a control of spinules plasticity through two retinal neurotransmitter systems.

K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas.

OBJECTIVE To evaluate clinical parameters, presurgical diagnostic tests, histologic findings, and the presence of K-ras oncogene mutations in cystic tumors of the pancreas to determine which best predict malignancy. SUMMARY BACKGROUND DATA Because presurgical, intraoperative, and final pathologic differentiation is difficult in cystic tumors of the pancreas, it would be a major benefit to identify markers that accurately predict malignancy in these rare tumors. The role of K-ras oncogene mutations as an indicator of malignancy has not been determined in these tumors. METHODS Nineteen patients with cystic tumors of the pancreas were evaluated, including K-ras mutation analysis based on polymerase chain reaction and restriction digestion assays and direct DNA sequencing, to screen for parameters that accurately predict malignancy. RESULTS All malignant cystic pancreatic tumors (five cystadenocarcinomas and three mucin-producing adenocarcinomas) harbored K-ras mutations at codon 12 or 13. K-ras mutations were also detected in the percutaneous fine-needle aspirates of two of these patients. In contrast, none of nine benign cystadenomas or the solid-papillary neoplasm had K-ras mutations. None of the patients with a benign tumor carrying K-ras wild-type sequences developed recurrent disease after a mean follow-up of 50 months. Seven of the 8 malignant cystic pancreatic tumors, but none of the 11 benign tumors, showed dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography. CONCLUSIONS K-ras mutation analysis seems to be a powerful tool to determine the malignant potential of cystic pancreatic tumors before and after surgery. Dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography is highly suggestive for malignancy in these rare tumors.

Selective Internal Radiotherapy with Yttrium-90 Microspheres for Hepatic Metastatic Neuroendocrine Tumors: A Prospective Single Center Study

Background: To assess prospectively the safety and efficacy of Yttrium-90 microspheres in patients with unresectable liver metastases from neuroendocrine tumors. Materials and Methods: Microspheres were administered via a temporarily placed hepatic catheter. Patients were monitored prospectively. All patients were followed with laboratory and imaging studies at regular intervals to determine response rates. Toxicity and quality of life scores were measured. Results: Nine patients (7 female) with a mean age of 58.8 years were enrolled in this prospective trial. The mean tumor load was 58.8%. The estimated percentage shunting to the lungs on MAA scans was 5.04 ± 2.4%. Visceral artery embolization of extrahepatic arteries before treatment was performed in 6 patients. The median dose of microspheres was 2.1 ± 0.4 GBq. A total of 12 therapy sessions was performed. The mean follow-up was 21.7 months. Technical success was 100%. No major complications occurred. Survival rates were 100, 57 and 57% for 1, 2 and 3 years, respectively. Three months after SIRT therapy partial response (PR) was seen in 6 patients (66%). Calculated reduction of liver metastasis volume was 49%. In 3 patients (33%) stable disease was seen with a calculated tumor reduction of 13%. The estimated time to progression was 11.1 months. Conclusion: Radioembolization with 90Y microspheres is safe and produces high response rates even with extensive tumor replacement for up to 1 year. Acute and late toxicity was very low. Further investigations compared with other local ablative techniques is warranted.

The eyes of deep-sea fish II. Functional morphology of the retina

Three different aspects of the morphological organisation of deep-sea fish retinae are reviewed: First, questions of general cell biological relevance are addressed with respect to the development and proliferation patterns of photoreceptors, and problems associated with the growth of multibank retinae, and with outer segment renewal are discussed in situations where there is no direct contact between the retinal pigment epithelium and the tips of rod outer segments. The second part deals with the neural portion of the deep-sea fish retina. Cell densities are greatly reduced, yet neurohistochemistry demonstrates that all major neurotransmitters and neuropeptides found in other vertebrate retinae are also present in deep-sea fish. Quantitatively, convergence rates in unspecialised parts of the retina are similar to those in nocturnal mammals. The differentiation of horizontal cells makes it unlikely that species with more than a single visual pigment are capable of colour vision. In the third part, the diversity of deep-sea fish retinae is highlighted. Based on the topography of ganglion cells, species are identified with areae or foveae located in various parts of the retina, giving them a greatly improved spatial resolving power in specific parts of their visual fields. The highest degree of specialisation is found in tubular eyes. This is demonstrated in a case study of the scopelarchid retina, where as many as seven regions with different degrees of differentiation can be distinguished, ranging from an area giganto cellularis, regions with grouped rods to retinal diverticulum.

Communication in troubled waters: responses of fish communication systems to changing environments

Fish populations are increasingly being subjected to anthropogenic changes to their sensory environments. The impact of these changes on inter- and intra-specific communication, and its evolutionary consequences, has only recently started to receive research attention. A disruption of the sensory environment is likely to impact communication, especially with respect to reproductive interactions that help to maintain species boundaries. Aquatic ecosystems around the world are being threatened by a variety of environmental stressors, causing dramatic losses of biodiversity and bringing urgency to the need to understand how fish respond to rapid environmental changes. Here, we discuss current research on different communication systems (visual, chemical, acoustic, electric) and explore the state of our knowledge of how complex systems respond to environmental stressors using fish as a model. By far the bulk of our understanding comes from research on visual communication in the context of mate selection and competition for mates, while work on other communication systems is accumulating. In particular, it is increasingly acknowledged that environmental effects on one mode of communication may trigger compensation through other modalities. The strength and direction of selection on communication traits may vary if such compensation occurs. However, we find a dearth of studies that have taken a multimodal approach to investigating the evolutionary impact of environmental change on communication in fish. Future research should focus on the interaction between different modes of communication, especially under changing environmental conditions. Further, we see an urgent need for a better understanding of the evolutionary consequences of changes in communication systems on fish diversity.

Management of nonfunctioning islet cell carcinomas.

Tumors arising from the pancreatic islet cells are rare and represent a heterogeneous group of benign or malignant lesions. Most tumors present with well characterized syndromes, whereas others appear to be nonfunctioning. The clinical features of 11 men and 7 women with nonfunctioning islet cell carcinomas operated on between 1983 and 1998 were reviewed. The median patient age was 53.5 years (range 26–74 years). The most frequent presenting symptoms were abdominal pain (13 patients), weight loss (7 patients), and obstructive jaundice (4 patients). Gut hormone profiles were normal in all patients. Abdominal sonography and computed tomography localized the tumor in 17 patients, and correct prediction of an endocrine tumor was achieved in 12 patients. Six of seven patients showed a hypervascular tumor upon angiograpy, and seven of eight patients preoperatively had positive somatostatin receptor scintigraphy. At operation, regional or distant metastases were present in 15 (83%) and 6 (33%) patients, respectively. Eleven patients underwent potentially curative resections, and the remaining seven patients were managed palliatively by resection (four patients) or bypass procedures (three patients). Three patients had up to three more resection for metastases. Eight patients received postoperative octreotide, interferon α therapy, or both. The overall cumulative 5- and 10-year survival rates were 65.4% and 49.1%, respectively. Of the 11 patients who underwent curative resection, 10 were alive after a median follow-up of 63 months (range 7–180 months), but only 5 are free from disease. Although surgical cure is rare in nonfunctioning islet cell carcinomas, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach and, when indicated, additional medical therapy.

Plasticity of cone horizontal cell functioning in cyprinid fish retina: effects of background illumination of moderate intensity

SummaryIn electrophysiological experiments involving intracellular recording from horizontal cells in the isolated retina of the roach, light adaptation of the retina has been shown to result in potentiation both of (1) the depolarizing component of biphasic chromaticity type S-potentials, and (2) the temporal frequency transfer functions of photopic luminosity type horizontal cells. Under identical light adaptation conditions, the number of spinules on horizontal cell dendrites positioned laterally at cone pedicle ribbon synapses, increase by some threefold. The latter effect occurs equally in pedicles of red- and green-sensitive cones. Thus, horizontal cells are ‘plastic’ in both structural and electrophysiological respects. Furthermore, since the two electrophysiological parameters studied depend on negative feedback from horizontal cells onto cones, the results suggest that it is the inhibitory synapses that are plastic and that spinules may be sites of the negative feedback interaction. Physiological and behavioural aspects of light-dependent horizontal cell plasticity are also discussed.

Morphological changes in the retina of Aequidens pulcher (Cichlidae) after rearing in monochromatic light

We investigate the processing of chromatic information in the outer retina of a cichlid fish, Aequidens pulcher. The colour opponent response characteristics of some classes of cone-specific horizontal cells in the fish retina are the result of feedforward-feedback loops with cone photoreceptors. To interfere with the reciprocal transmissions of signals, animals were reared in monochromatic lights which preferentially stimulated the spectrally different cone types. Here we report the effects on the cones. Their absorbance spectra were largely unaffected, indicating no change in photopigment gene expression. Significant changes were observed in the cone outer segment lengths and the frequencies of spectral cone types. Quantum catch efficiency and survival of cones appear to be controlled in a spectrally selective way. Our results suggest that the retina responds to spectral deprivation in a compensatory fashion aimed at balancing the input from the different cone types to second order neurons.