Biomedical subjects

M Hahne

Publications and source records attributed to M Hahne.

At least 19 recordsLinked to original sources

PubMed2005

Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation.

APRIL, a proliferation-inducing ligand, is a member of the tumor necrosis factor (TNF) family that is expressed by various types of tumors and influences their growth in vitro and in vivo. Two receptors, transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), bind APRIL, but neither is essential for the tumor-promoting effects, suggesting that a third receptor exists. Here, we report that APRIL specifically binds to heparan sulfate proteoglycans (HSPG) on the surface of tumor cells. This binding is mediated by the heparin sulfate side chains and can be inhibited by heparin. Importantly, BCMA and HSPG do not compete, but can bind APRIL simultaneously, suggesting that different regions in APRIL are critical for either interaction. In agreement, mutation of three lysines in a putative heparin sulfate-binding motif, which is not part of the TNF fold, destroys interaction with HSPG, while binding to BCMA is unaffected. Finally, whereas interaction of APRIL with HSPG does not influence APRIL-induced proliferation of T cells, it is crucial for its tumor growth-promoting activities. We therefore conclude that either HSPG serve as a receptor for APRIL or that HSPG binding allows APRIL to interact with a receptor that promotes tumor growth.

Amino Acid Sequence↗

PubMed2004

Restless legs syndrome--new insights into clinical characteristics, pathophysiology, and treatment options.

We summarize recent advances in the clinical definition of restless legs syndrome (RLS), in understanding the basic mechanisms, and the successful treatments of RLS. New diagnostic instruments and severity scales have been developed for better phenotyping of the individual patient. Iron metabolism related components and the dopaminergic system have been extensively investigated in respect to the pathophysiology of RLS. The presence of mechanical hyperalgesia to pin-prick points towards an involvement of the nociceptive system. Genetic research has reported loci on chromosome 12q and 14q to play a role in the vulnerability to RLS. Placebo-controlled large-scale phase II and III treatment trials have shown that dopamine agonists are safe and efficacious agents for the treatment of this disorder.

Central Nervous System↗

PubMed2003

[Cholangioscopy after successful treatment of complicated choledocholithiasis. Is stone free really stone free?].

BACKGROUND AND OBJECTIVE: After successful percutaneous or endoscopic therapy of complicated choledocholithiasis (requiring more than one therapeutic intervention or lithotripsy), radiological visualization of the bile duct is the standard to determine if any stone fragments are left. It is unknown how often stone fragments, which might be the cause for another period of symptomatic choledocholithiasis, are missed. PATIENTS AND METHODS: We performed cholangioscopy in 31 consecutive patients (age 42 - 85; 14 male, 17 female) with complicated choledocholithiasis after successful therapy when there were no stone fragments left radiographically. RESULTS: Cholangioscopy revealed retained stone fragments in four female patients. Two of these had a benign stricture of the common bile duct. CONCLUSIONS: Cholangioscopy after successful endoscopic or percutaneous therapy of complicated choledocholithiasis seems to be useful, because in bile ducts radiographically free of stones, cholangioscopy detects stone fragments in some patients. Further studies are needed to demonstrate if cholangioscopy can reduce the rate of symptomatic relapse after treatment of complicated choledocholithiasis.

Adult↗

PubMed2003

The uncertain glory of APRIL.

The tumour necrosis factor (TNF) family is intimately connected to the regulation of cellular pathways. A PRoliferation-Inducing Ligand (APRIL) is a rather new member of that family, named for its capacity to stimulate the proliferation of tumour cells in vitro. Subsequent publications also called this ligand TRDL-1 or TALL-2, respectively. APRIL and B-lymphocyte stimulator (BLyS; also termed BAFF, TALL-1, THANK, zTNF4) form a new subfamily of TNF-like ligands that are expressed in haematopoietic cells. Both ligands can bind the two members of the TNF receptor family, namely the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), as well as B-cell maturation antigen (BCMA). BLyS has recently been the subject of several reviews (for an extensive review, see Mackay et al.). The present review will thus focus on APRIL, and discuss BLyS only briefly for the sake of clarity.

Animals↗

PubMed2003

[Diagnosis of a high-grade B-cell lymphoma of the small bowel by means of wireless capsule endoscopy].

Wireless capsule endoscopy is a new diagnostic procedure to detect diseases of the small bowel, in particular in patients with obscure gastrointestinal bleeding. We report on a 76-year-old patient who presented at our hospital with signs of gastrointestinal bleeding and hypochromic anaemia. Bidirectional endoscopy, push enteroscopy, angiography as well as small bowel barium enema rendered no pathologic findings. Wireless capsule endoscopy demonstrated a polypous space in the cantral area of the small bowel. Subsequent intraoperative endoscopy revealed a subtotal stenosing tumour of the upper jejunum which was resected. Based on the histology a high-grade B-Cell lymphoma was diagnosed. The postoperative staging examinations did not indicate any further extranodal involvement.

Aged↗

PubMed2003

Capsule endoscopy versus push enteroscopy in patients with occult gastrointestinal bleeding.

BACKGROUND: Wireless capsule endoscopy is a new method enabling non-invasive diagnostic endoscopy of the entire small intestine. In this study we prospectively examined the diagnostic precision of capsule endoscopy compared with push enteroscopy in patients with occult gastrointestinal bleeding. METHODS: Between July 2001 and October 2002 we examined 48 patients with suspected disorders of the small intestine using capsule endoscopy. 33 patients with obscure bleeding (19 men, 14 women, mean age 58 +/- 23 years) were prospectively examined using capsule endoscopy and push enteroscopy. RESULTS: On average, the patients had been suffering from chronic gastrointestinal bleeding for 30 +/- 36 (1-120) months. The lowest haemoglobin level was 6.5 +/- 1.6 g/dl (2.3-9.6) and on average 9 +/- 10 (0-50) blood units were transfused. Each patient underwent 4 +/- 2 (1-10) hospitalisations, with a mean 9 +/- 4 (5-17) diagnostic procedures before capsule endoscopy was used. Definitive bleeding sites were diagnosed by push enteroscopy in 7 patients (angiodysplasia [n = 5], ulcers [n = 1], multiple jejunal diverticula [n = 1]). Capsule endoscopy showed a bleeding source in 25 cases (76 %) (angiodysplasias [n = 15], Meckel's diverticulum [n = 1], ulcers [n = 7], ileum diverticulosis [n = 1], B-cell lymphoma [n = 1]). Push enteroscopy localised an additional bleeding source in comparison with capsule endoscopy (multiple jejunal diverticula) in one patient. Both methods of examination were safe and showed no complications. DISCUSSION: The present study shows that capsule endoscopy had the highest diagnostic yield and was superior to push enteroscopy in patients with chronic gastrointestinal bleeding. By using the capsule at an early stage the subsequent therapeutic procedure could be considerably shortened and diagnostic processes could possibly be optimised.

Adolescent↗

PubMed2002

[Endoscopy of the small intestine without tube or enema? A video capsule makes it possible].

The diagnosis of unclear bleeding in the small bowel remains a gastroenterological problem. To date, the diagnostic approach routinely employed has been roentgen Sellink. With such newer techniques as magnetic resonance tomography (MRT) substantially more diagnostic information can now be obtained. A recent new development is capsule endoscopy, which is intended for use when conventional endoscopic examinations fail to identify the source of bleeding. Using this new option in the Ludwigshafen Klinikum the small bowel lesions were discovered in 81% of the 26 patients in whom they had been previously remained undetected. At present, the patients have to bear the cost of this examination themselves.

Capsules↗

PubMed2002

[Inflammatory bowel diseases: diagnosis (including new procedures for small intestine examination)].

Medical history, clinical examination, general laboratory data and microbial stool examinations are basic diagnostics in inflammatory bowel diseases. Specific immunologic parameters can make classification easier in indefinite disease, their use is still in an experimental state. Ultrasound and endoscopic examinations have largely replaced conventional radiological procedures. For the experienced examiner, ultrasound allows assessment of small bowel and colon as well as other organs. Ileo-colonoscopy with biopsies remains the gold standard in the diagnosis of inflammatory bowel diseases. For small bowel examination, modern methods like push-enteroscopy, capsule endoscopy or the Hydro-MRI can be employed. At the moment, their usage is limited to specialized centers. Because of its broad availability small bowel follow through is still the standard in small bowel examination. After 8 years of colitis ulcerosa, ileo-colonoscopy with biopsy should be performed every year according to the guidelines. If these recommendations also apply to Crohn's disease is not sure yet.

Biomarkers↗

PubMed2002

An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein.

TWEAK and APRIL are two recently identified tumour necrosis factor (TNF) ligand family members, implicated in angiogenesis and immune regulation, respectively. TWEAK is a transmembrane protein expressed on the cell surface, whereas APRIL acts solely as a secreted factor. In this report, using RACE, RT-PCR, cDNA library screening and an RNase protection assay, we characterize a hybrid transcript between TWEAK and APRIL mRNAs. The encoded TWE-PRIL protein is composed of TWEAK cytoplasmic and transmembrane domains fused to the APRIL C-terminal domain. TWE-PRIL mRNA is expressed and translated in human primary T cells and monocytes, and endogenous TWE-PRIL protein was detected in primary human T lymphocytes and monocytic cell lines. TWE-PRIL is membrane anchored and presents the APRIL receptor-binding domain at the cell surface. It is a biologically active ligand, as it stimulates cycling in T- and B-lymphoma cell lines. Much like membrane-bound and secreted TNF-alpha, the different cellular localizations of TWE-PRIL and APRIL suggest that they exert distinct biological roles.

Amino Acid Sequence↗

PubMed2002

Deep-brain stimulation for Parkinson's disease.

Deep brain simulation (DBS) is a powerful new therapeutic approach for patients with Parkinson's disease. However, patient selection is critical for a valuable therapeutic result. Dopa sensitivity of the target symptoms, severe disability and low neurosurgical risks are among the major criteria for this indication. Other criteria like age or cognition must still be addressed in future prospective studies. The preferred target for DBS in PD is the subthalamic nucleus for various good reasons. However, prospective studies for this procedure are lacking and some clinical problems may be more easily solved with targeting the internal pallidum or the thalamus. Despite major progress in this field, much work remains to be done.

Electric Stimulation Therapy↗

PubMed2002

Wireless capsule endoscopy in a patient with obscure occult bleeding.

A case of obscure/occult bleeding in a 39-year old man with a 7-year history of chronic fatigue and iron-deficiency anemia is presented here. Esophagogastroduodenoscopy, push enteroscopy, ileocolonoscopies, and a magnetic resonance imaging small-bowel follow-through did not reveal any abnormalities. Multiple inflammatory lesions with fibrin-covered ulcers and petechial bleeding in the area of the lower jejunum and ileum were diagnosed only with capsule endoscopy. One ulcer located near the ileocecal valve was then biopsied during a repeat ileocolonoscopy, and the histology showed signs of Crohn's enteritis. The further treatment approach was changed, with medical treatment being initiated and intraoperative enteroscopy being averted. Wireless capsule endoscopy clarified the cause of the obscure/occult bleeding in this patient and contributed to the diagnosis and endoscopic imaging of an isolated Crohn's enteritis, which is the cause of bleeding in approximately 10 - 20 % of cases of occult bleeding.

Adult↗

PubMed2001

Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase.

Tumor necrosis factor (TNF) ligand family members are synthesized as transmembrane proteins, and cleavage of the membrane-anchored proteins from the cell surface is frequently observed. The TNF-related ligands APRIL and BLyS and their cognate receptors BCMA/TACI form a two ligand/two receptor system that has been shown to participate in B- and T-cell stimulation. In contrast to BLyS, which is known to be cleaved from the cell surface, we found that APRIL is processed intracellularly by furin convertase. Blockage of protein transport from the endoplasmic reticulum to the Golgi apparatus by Brefeldin A treatment abrogated APRIL processing, whereas monensin, an inhibitor of post-Golgi transport, did not interfere with cleavage of APRIL, but blocked secretion of processed APRIL. Thus, APRIL shows a unique maturation pathway among the TNF ligand family members, as it not detectable as a membrane-anchored protein at the cell surface, but is processed in the Golgi apparatus prior to its secretion.

Antibodies, Monoclonal↗

PubMed2001

Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors.

The concept for cellular immunotherapy of solid tumors relies heavily on the capacity of class I MHC-restricted cytotoxic T lymphocytes (CTLs) to eliminate tumor cells. However, tumors often have managed to escape from the cytolytic machinery of these effector cells. Therefore, it is very important to chart the mechanisms through which this escape can occur. Target-cell killing by CTLs involves the induction of apoptosis by two major mechanisms: through death receptors and the perforin/granzyme B (GrB) pathway. Whereas tumors previously were shown to exhibit mechanisms for blocking the death receptor pathway, we now demonstrate that they also can resist CTL-mediated killing through interference with the perforin/GrB pathway. This escape mechanism involves expression of the serine protease inhibitor PI-9/SPI-6, which inactivates the apoptotic effector molecule GrB. Expression of PI-9 was observed in a variety of human and murine tumors. Moreover, we show that, indeed, expression results in the resistance of tumor cells to CTL-mediated killing both in vitro and in vivo. Our data reveal that PI-9/SPI-6 is an important parameter determining the success of T cell-based immunotherapeutic modalities against cancer.

Animals↗

PubMed2001

APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis.

APRIL (a proliferation-inducing ligand) is a newly identified member of the tumor necrosis factor (TNF) family. Tumor growth-promoting as well as apoptosis-inducing effects of APRIL have been described. Here, we report that five of 12 human malignant glioma cell lines express APRIL. APRIL gene transfer experiments revealed that malignant glioma cells are refractory to growth-promoting activity of APRIL in vitro and in vivo. Interestingly, ectopic expression of APRIL confers minor protection from apoptotic cell death induced by the death ligands, CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L). This antiapoptotic activity is specific for death ligand/receptor-mediated apoptosis since APRIL does not protect glioma cells from the cytotoxicity of the drugs, teniposide, vincristine, lomustine or cisplatin. Ectopic expression of APRIL is associated with the upregulation of X-linked inhibitor of apoptosis protein (XIAP), providing a possible explanation for the antiapoptotic activity observed here. In contrast, APRIL does not regulate the expression levels of the antiapoptotic proteins FLICE-inhibitory protein (FLIP), Bcl-2 or Bcl-X(L). These findings suggest that APRIL is involved in the regulation of death ligand-induced apoptotic signaling in malignant glioma cells.

Animals↗

PubMed2001

Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke.

Stroke is the third most common cause of death in the Western world. The mechanisms of brain damage in the affected areas are largely unknown. Hence, rational treatment strategies are limited. Previous experimental evidence suggested that cerebral lesions were less prominent in CD95 (APO-1/Fas)-deficient (lpr) than in wild-type mice. Additional results strongly suggested that the CD95-ligand (CD95L) was a major cause of neuronal autocrine suicide in the penumbra. These data and the assumption that death-receptor systems might determine stroke-related damage in the brain prompted us to examine these systems in in vitro and in vivo models of ischemia. We showed that hybrids of TNF-deficient and gld mice were strongly resistant towards stroke-induced damage. To determine the mechanism of action of TNF and CD95L, we separately investigated their influence on primary ischemic death and secondary inflammatory injury. Inhibition of both TNF and CD95L in vitro prevented death of primary neurons induced by oxygen-glucose deprivation and reperfusion. The recruitment of inflammatory cells to the ischemic hemisphere was abrogated in the absence of both TNF and CD95L. Significantly, mice injected with a mixture of neutralizing anti-TNF and anti-CD95L antibodies 30 min after induction of stroke showed a marked decrease in both infarct volumes and mortality. Accordingly, the locomotor performance of these animals was not significantly impaired in comparison to sham-operated animals. These data reveal that inhibition of TNF and CD95L blocks stroke-related damage at two levels, the primary ischemic and the secondary inflammatory injury. These results offer new approaches in stroke treatment.

Animals↗

PubMed2001

[Bleeding in the lower intestinal tract: indications and results of endoscopic therapy].

Colonoscopy is the method of choice in clarifying an intestinal bleeding if upper gastrointestinal bleeding is excluded. It allows identification of the bleeding source and immediate therapy by thermal, mechanical and injection procedures. Depending on the origin of the bleeding, the applied method and the examiner's abilities, hemostasis can be achieved in up to 100% of the cases with low rebleeding and complication rates. Because there are only few prospective randomized trials comparing different endoscopical hemostasis methods, the examiner's competence and the local availabilities of endoscopic procedures are decisive for the results of endoscopic therapy.

Colonoscopy↗

PubMed2000

The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.

BACKGROUND: Activation of Fas (CD95) by its ligand (FasL) rapidly induces cell death through recruitment and activation of caspase-8 via the adaptor protein Fas-associated death domain protein (FADD). However, Fas signals do not always result in apoptosis but can also trigger a pathway that leads to proliferation. We investigated the level at which the two conflicting Fas signals diverge and the protein(s) that are implicated in switching the response. RESULTS: Under conditions in which proliferation of CD3-activated human T lymphocytes is increased by recombinant FasL, there was activation of the transcription factors NF-kappaB and AP-1 and recruitment of the caspase-8 inhibitor and FADD-interacting protein FLIP (FLICE-like inhibitory protein). Fas-recruited FLIP interacts with TNF-receptor associated factors 1 and 2, as well as with the kinases RIP and Raf-1, resulting in the activation of the NF-kappaB and extracellular signal regulated kinase (Erk) signaling pathways. In T cells these two signal pathways are critical for interleukin-2 production. Increased expression of FLIP in T cells resulted in increased production of interleukin-2. CONCLUSIONS: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.

Apoptosis↗

PubMed2000

Fas-dependent tissue turnover is implicated in tumor cell clearance.

The apoptosis-inducing Fas receptor has been shown to be down-regulated in various types of tumors, while its ligand (FasL) appears to be frequently up-regulated. Here we provide evidence that there is a strong selective pressure in vivo against Fas-expressing, tumorigenic NIH3T3 cells, favoring survival, proliferation and eventually tumor formation by Fas-negative cells. Importantly, re-expression of Fas in these cells results in either the complete abolishment of tumor development, or in a significant extenuation of the latency period of tumor outgrowth. In addition, we found that environmental conditions which prevail during tumorigenesis, such as limiting amounts of survival factors and the lack of cell adhesion, are markedly sensitizing tumor cells to Fas-mediated suicide. Our data suggest that in addition to T cell-mediated immune responses, mechanisms of Fas-dependent tissue turnover are also centrally implicated in tumor cell clearance.

3T3 Cells↗