[Development of arteriosclerosis]. / Entstehung der Arteriosklerose.

Arteriosclerosis is the general term for a group of arterial vascular diseases characterized by arterial wall thickening and loss of elasticity, which are caused by different biological processes. The most commonly used classification defines four distinct histopathological types: arteriolosclerosis, medial sclerosis, fibromuscular intimal hyperplasia and atherosclerosis. The pathobiological remodeling of the arterial wall essentially represents different repair responses of vascular cells to molecular stress factors and microlesions. This article should contribute to the clarification of the nomenclature and the histopathological classification of the disease symptoms, to elucidate the biological processes underlying the different pathologies during arteriosclerosis and to raise awareness for these differences, because these can decisively contribute to the success of selected treatment modalities.

The expression of glycophorin A and osteoprotegerin is locally increased in carotid atherosclerotic lesions of symptomatic compared to asymptomatic patients.

The aim of this study was to evaluate in detail the histopathological characteristics of endarterectomized carotid atherosclerotic lesions in symptomatic versus asymptomatic patients. Twenty carotid lesions, 10 from asymptomatic and 10 from symptomatic patients who underwent carotid endarterectomy were classified according to histomorphological features. Samples were analyzed for intraplaque localization and for the expression of proteins associated with inflammation, such as CD68, interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), nuclear factor-κB (NF-κB), C-reactive protein (CRP) and transforming growth factor-ß (TGF-ß), as well as for proteins associated with vascular remodelling, such as matrix-metalloproteinase-9 (MMP-9), glycophorin A (GYPA), osteoprotegerin (OPG), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and vascular smooth muscle cell actin (VSMA). Corresponding expression scores were compared between the symptomatic and asymptomatic patients and evaluated statistically. The expression of all 14 evaluated markers was significantly elevated in the border zone adjacent to the mixed plaque compared with the unaffected control area of the same sample (p<0,016). The expression scores of GYPA and OPG were significantly higher in the border zones around the calcified (GYPA, p=0.035; OPG, p=0.043) and mixed (GYPA, p<0.001; OPG, p=0.007) plaque zones of symptomatic patients compared to asymptomatic patients. No difference in expression scores was observed for any of the analyzed inflammatory marker proteins between the border zones of symptomatic and asymptomatic patients. In conclusion, the increased expression of GYPA, indicating intraplaque hemorrhage, and OPG, indicating the transdifferentiation of vascular cells, in carotid atherosclerotic lesions may be associated with an increased risk of plaque instability.

Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers.

Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -ß. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells.

The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling.

Increasing epidemiological and experimental evidence implicates non-steroidal anti-inflammatory drugs (NSAIDs) as anti-tumorigenic agents. The precise mechanisms whereby NSAIDs exert their anti-neoplastic effects remain poorly understood. Studies from hereditary and sporadic colorectal cancer (CRC) patients suggest that NSAIDs may interfere with initiating steps of carcinogenesis, i.e. disturbances within the beta-catenin signaling pathway. We therefore investigated beta-catenin/TCF signaling in response to aspirin or indomethacin, respectively, in four CRC cell lines (SW948, SW480, HCT116, LoVo). Both, aspirin and indomethacin inhibited transcription of a beta-catenin/TCF-responsive reporter gene in a dose dependent manner. In addition, the beta-catenin/TCF transcriptional target cyclin D1 was downregulated by both drugs. Endogenous beta-catenin levels remained unaffected by either drug. Moreover, indirect immunofluorescence studies revealed no significant changes of subcellular beta-catenin localization in either cell line after NSAID treatment. Likewise, binding of the beta-catenin/TCF complex to its specific DNA-binding sites was not altered, as demonstrated by electrophoretic mobility shift assay (EMSA) of nuclear extracts derived from NSAID treated cells. These results strongly suggest that aspirin and indomethacin attenuate the transcription of beta-catenin/TCF-responsive genes, by modulating TCF activity without disrupting beta-catenin/TCF complex formation.

Identification and characterization of novel genes located at the t(1;15)(p36.2;q24) translocation breakpoint in the neuroblastoma cell line NGP.

The distal portion of chromosome 1p is frequently deleted in several human cancers, suggesting the presence of one or more putative tumor suppressor genes on this chromosomal arm. In human neuroblastoma, a consistently deleted region at 1p36.1-p36.2 has been defined by comparison of molecular loss of heterozygosity (LOH) analyses. Recently we described the identification of a yeast artificial chromosome, YAC 927G4, that spans a translocation/duplication breakpoint within the minimally defined LOH region at 1p36.1-p36.2 in the neuroblastoma cell line NGP. Here we describe the identification of two overlapping P1 artificial chromosomes comprising 220 kb at the distal end of YAC 927G4, which we have used as hybridization probes under modified conditions to screen a composite, normalized cDNA library (IMAGE cDNA library). Hybridization screening resulted in the rapid and comprehensive identification of partial cDNAs of which a portion comprised two novel candidate genes, termed DNB1/ARPh and DNB5, which encode putative proteins of 1011 and 447 amino acids, respectively. The DNB1/ARPh gene, which was found to be ubiquitously expressed in human adult and fetal tissues, is highly related to the DRPLA gene, in which expansion of a CAG triplet appears to be causal in the dentatorubral and pallidolysian atrophy disease phenotype. The DNB5 sequence, in contrast, which is predominantly expressed in brain tissues and fetal kidney, failed to show any similarity to sequences in the public domain. A preliminary assessment of transcription and sequence of both genes in several neuroblastoma cell lines does not, thus far, support a causal role in neuroblastoma. However, further analyses are required to confirm these results.

Dominant negative effect of the APC1309 mutation: a possible explanation for genotype-phenotype correlations in familial adenomatous polyposis.

Inactivation of the adenomatous polyposis coli (APC) gene product initiates colorectal tumorigenesis. Patients with familial APC (FAP) carry germ-line mutations in the APC gene and develop multiple colorectal adenomas and subsequent carcinomas early in life. The severity of the disease correlates with the position of the inherited APC mutation (genotype-phenotype correlation). Together with the fact that both germ-line and sporadic APC mutations cluster in the central region of the APC gene, this points to a dominant negative effect of certain APC mutants. Loss of APC function was recently shown to result in enhanced beta-catenin-/Tcf-mediated transcription in colon epithelial cells. Here, we provide experimental evidence for a dominant negative effect of APC gene products associated with severe polyposis. Wild-type APC activity in beta-catenin-/Tcf-mediated transcription was strongly inhibited by a mutant APC that is truncated at codon 1309. In contrast, mutant APC gene products that are associated with attenuated polyposis (codon 386 or 1465) interfered only weakly with wild-type APC activity. These results suggest a molecular explanation for the genotype-phenotype correlation in FAP patients and support the idea that colorectal tumor growth might be, in part, driven by selection for a mutation in the mutation cluster region.

Secretory type II phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa.

There is good evidence now that the secretory type II phospholipase A2 (Pla2g2a) gene represents the Mom1 locus, a genetic modifier of tumor resistance in the multiple intestinal neoplasia (Min) mouse. Previously we have mapped the human homolog PLA2G2A to 1p35-36.1 within a region that is the target of frequent deletions in sporadic colorectal tumors. Here we show 64% loss of heterozygosity (LOH) at the PLA2G2A locus in primary tumors. We studied PLA2G2A expression in both colorectal tumor cell lines and normal mucosa. Most of the lines lacked detectable PLA2G2A transcripts by Northern analysis. Large differences in expression were seen among normal mucosa of different patients with sporadic tumors. We analysed the coding region of PLA2G2A in eight colorectal cancer cell lines with hemizygous deletion at 1p35-36/PLA2G2A, in none we did detect a mutation. Biallelic expression of PLA2G2A was observed in a cell line heterozygous for an exon 3 polymorphism, rendering unlikely that imprinting is a pathway participating in the loss of PLA2G2A function. It remains uncertain if PLA2G2A, in particular its apparent lack of expression in tumor cells, might be a factor in human colorectal tumorigenesis.

Variations in the expression of the adenomatous polyposis coli (APC) tumor suppressor gene in human cancer cell lines of different tissue origin.

The adenomatous polyposis coli (APC) tumor suppressor gene APC is mutated in familial adenomatous polyposis and in most sporadic colorectal tumors. Through its interaction with beta-catenin the APC protein may play a role in a signal transduction pathway regulating cell proliferation. Despite the fact that APC is ubiquitously expressed, mutations leading to truncated proteins are restricted to tumors of the digestive system. To determine further alterations not resulting in protein truncation, but possibly influencing the signaling, we compared the relative expression level of the APC protein and transcripts in 24 human colorectal cancer cell lines and in additional 17 lines of noncolorectal tissue origins, which have not previously been studied. By Western analysis, the highest levels of full-length APC protein were found in a subset of neuroblastoma and retinoblastoma cell lines. In contrast, in five noncolorectal lines it was not detectable. Truncated APC was exclusively found in 18 of the 24 colorectal cancer cell lines, but was never detected in any cell line derived from other tissues. In most colorectal cancer cell lines the protein level of full-length or mutated APC was reduced. By the more sensitive immunoprecipitation analysis, weak expression of full-length APC could be shown even in those noncolorectal cancer cell lines where it was not detectable by Western blotting. In addition, APC transcript expression was found in all cell lines, the level in colorectal cancer cell lines being reduced.

Acquired hyperostosis syndrome--AHYS--(sternocostoclavicular hyperostosis, pustulotic arthro-osteitis, SAPHO-syndrome): bone scintigraphy of the anterior chest wall.

The objective of this report is to provide a description of diagnostically significant scintigraphically recognizable sites and patterns of acquired hyperostosis syndrome (AHYS) on the anterior chest wall (ACW), which is involved in 82% of AHYS patients. In 49/90 of our own AHYS patients, planar bone scans of the ACW were performed with the gamma camera, applying an average of 650 MBq of 99mTc-phosphate complexes. In addition, 53 atraumatic patients with extrathoracic cancer were available for routine whole-body scintigraphy. None of these patients had increased uptake identifiable as metastasis clinically or by imaging modalities in either the ACW or the rest of the skeleton. The scintigraphic involvement of the various morphological ACW structures is described in AHYS. Moreover, attention is called to the diagnostic significance of focal hyperactivities at the anterior end of the 2nd-8th rib of adults, which are in the 5th place with respect to their frequency in AHYS. The diagnostic significance of sternocostal-joint involvement in AHYS can likewise be recognized by bone-scan scintigraphy and will be discussed. Bone scintigraphy is more sensitive than radiomorphological imaging in AHYS. This, however, only applies under three conditions. 1. The increased radiotracer uptake in the upper sternocostoclavicular region must be assessed on both the anterior and the posterior view of the ACW scan. 2. In addition to the anterior view of the routine scintiscan, further anterior scans with reduced scan time of the gamma camera are usually necessary. This ensures better visibility of the involvement of certain morphological structures that are important for AHYS diagnosis. Moreover, a statement can be made about the inflammatory ossifying activity/inactivity of the AHYS on ACW.3. Increased radionuclide uptake in the manubrium sterni and corpus sterni on the anterior scan should be verified by additional lateral or oblique scans of the thorax (sternum).

Endoscopic discectomy in pediatric and juvenile lumbar disc herniations.

Most herniated lumbar discs in children and adolescents respond to conservative treatment, but some young patients with persistent low back and neurological symptoms do not respond to noninvasive treatment and require operative treatment. Because the long-term results of disc surgery depend not only on the disc disease itself but also on the degree of surgical trauma, disc herniations in children and adolescents should be treated with minimally invasive procedures. We report our experience with four young patients aged 8-17 years with contained or small noncontained lumbar disc herniations who were treated by percutaneous endoscopic discectomy (PED). The clinical results were good to excellent in all four cases, with follow-up of 1 to 5 years. There were no complications, and the operation was tolerated well by the young patients. We recommend percutaneous endoscopic lumbar discectomy in patients with contained or small uncontained disc herniations who do not respond to conservative treatment.

[Lumbar epidural lipomatosis]. / Die lumbale epidurale Lipomatose.

Spinal epidural lipomatosis is a pathological accommodation of fat tissue in the spinal canal. It seems to be a disease entity, which, though rare, has recently been diagnosed more frequently and can be accompanied by neurological deficits. The thoracic spinal canal is the preferred localization. Eighteen cases of symptomatic lumbar epidural lipomatosis have been described in the literature. We are reporting on our experience with another 8 patients. Three of these patients presented with the typical signs of spinal nerve irritation. In these cases epidural lipomatosis was associated with a small disk herniation without direct contact to the spinal nerve. Another 5 patients showed the clinical picture of a spinal claudication. In all 5 patients, there was a concentric compression of the thecal sac by epidural fat. In one patient, the cause of the lipomatosis was assumed to be long-term steroid therapy following kidney transplantation. Four patients suffered from extreme obesity. No cause for lipomatosis could be found in 3 patients. A microdiskektomy was performed in the 3 patients with the associated disk herniation; the remaining patients were treated conservatively. In 6/8 patients (3x surgery/3x diet), an "excellent" or "good" clinical result could be achieved after 1 year. Two patients had a "satisfactory" result. Lumbar epidural lipomatosis can be treated conservatively in cases with only mild neurological dysfunctions and known cause (e.g. obesity, steroid therapy). The surgical removal of associated disk herniation proved to be sufficient in cases described in this paper.

[Spondylitis: borderline findings in magnetic resonance tomography]. / Spondylitis: Grenzbefunde im Magnetresonanztomogramm.

MR studies of 41 patients with confirmed spondylitis were evaluated with regard to imaging findings resembling metastases or fracture. 30 patients had MR results considered typical for spondylitis (contiguous changes in two vertebrae and disc, soft tissue tumour). 11 patients had MR studies differing from this pattern. Absence of soft tissue involvement and discontinuous marrow changes may be misdiagnosed as bone marrow metastases.

Impingement symptoms caused by a synovial fold in the glenoid fossa projecting into the sublabral hole.

In this case report, an atypical impingement in a 40-year-old male patient with terminal restrictions in the shoulder joint is used to show the development of an atypical synovial fold through the sublabral hole with protrusion into the glenoid fossa.

[MR tomography in autologous plastic repair of the anterior cruciate ligament: a comparison of 2 surgical methods]. / Die Kernspintomographie bei autologer Plastik des vorderen Kreuzbandes: Vergleich zweier Operationsmethoden.

UNLABELLED: The aim of this prospective MRI study was the analysis of the post-operative signals derived from two techniques for cruciate ligament reconstruction. PATIENTS AND METHODS: Group 1 consisted of 15 patients who had undergone conventional plastic repair by patellar tendon transplant and group 2 was made up of 15 patients with arthroscopic reconstruction with semitendinosus grafts. They were examined at 6 weeks and 6 months post-operatively. RESULTS: Typical appearances of normal transplants were found in 19 patients. After 6 months 8 of the patellar tendon transplants and three of the semitendinosus transplants could not be clearly defined. At this time there was a significant increase in signal intensity in the middle third of the transplant in group 1. CONCLUSION: Bearing in mind the different operative techniques, there was a higher impingement rate in group 1. The post-operative MRI findings at 6 months after surgery allowed differentiation between pathological changes (impingement) and revascularisation (remodelling).

The "mirror image" and "two-thirds" types of hemispherical spondylosclerosis.

Clinical and radiological examination of 167 hemispherical spondylosclerosis (HSS) patients (56 male, 111 female) revealed a total of 186 cases of HSS with multiple incidences occurring in 18 patients. Radiologically these HSS cases were characterized by erosion and new bone formation at the inferior and upper end plate of the vertebra below, periosteal bone apposition or ossification of the anterior longitudinal ligament, spondylophytes, and signs of degenerative alteration of the vertebra and disc. In addition, the size and location (anterior, middle, posterior third) of each HSS in the lateral view was investigated. The cases were also investigated for reflection phenomenon between supra- and infradiscal sclerosis and for kyphotic angulation of the two adjacent vertebrae. The results showed that in 105 cases (56.5%) the HSS filled out the entire vertebral area; 97 cases (52.2%) showed a mirror-image type HSS; while in 8 cases (4.3%), the infradiscal sclerosis was polymorphic. In 81 cases (43.5%), the sclerosis was limited to the anterior two-thirds; this is termed "two-thirds" type. All 81 of these cases of HSS showed a kyphotic angulation of at least 4 degrees. Of these, 61 (32.8% of the total) showed reflection phenomenon while 20 (10.7% of the total) had polymorphic infradiscal sclerosis. Overall, 158 cases of HSS (85%) exhibited the reflection phenomenon between supra- and infradiscal sclerosis, whereas 28 cases (15%) revealed polymorphic sclerosis of the subadjacent vertebra. Kyphotic angulation was completely absent when HSS was visible in the entire vertebra. A dorsal gap of the disc space was seen in 36 cases (19.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

The supercilium acetabuli score: an additional criterion for estimating the biomechanics of the hip joint.

There are significant correlations between the surface of the acetabular roof sclerosis (supercilium acetabuli) in the hip joint on a normal a.p. radiograph and the corresponding surface of cartilage. This correlation can be defined through mathematical formulas and scaled afterwards. These scales are determined on the basis of our clinical experience with the new supercilium acetabuli score. The score is related to the biomechanical situation of the hip joint and describes 3 classes: Class I = optimum, class II = balance, class III = imbalanced correlation between the supercilium acetabuli and the corresponding part of the joint space. For simple measurement of both surfaces, we developed a measuring instrument, the superciliometer, with which it is possible to obtain standardized conclusions describing the functional morphology of the cartilage in the pressure distribution zone of the hip joint, irrespective of whether there are already any visible radiological signs of coxarthrosis or not.

[Analysis of migration of screwed acetabular components following revision arthroplasty of the hip joint. Results of single-image roentgen analysis]. / Wanderungsanalyse verschraubter Hüftpfannen nach Revisionsarthroplastiken am Hüftgelenk. Ergebnisse der Einbildröntgenanalyse (EBRA).

Out of 57 revised acetabular components, which were regularly checked, 47 had been replaced by a cemented Müller's acetabular reinforcement ring resp. a cementless Müller's Sl-shell with flange. Both types of cups are anchored in the acetabular roof with cancellous bone screws (tab. 1). 42 cases with radiograph series permitted a detailed analysis with the EBRA-method, a computer aided method for the evaluation of acetabular spatial migration based on standard radiographs of the pelvis. The clinical results were very satisfying (tab. 6). The screwed acetabular components migrated little, although, some essential displacements of the center of rotation (in relation to the anatomical position) had to be accepted. As was recognizable with today's inaccurate methods of measuring the center of the head, the displacement too far towards cranial influenced the migration tendency less than an excessive lateralisation. Especially satisfying is the fact, that no increased migration was observed after reconstruction bone grafting of severe acetabular defects, provided that at least a partly direct contact between the acetabular component and the original bone stock was obtained. For the first time EBRA shall be introduced here as a method which shows the migration and the spatial inclination of the acetabular cup in a vector chart.

[Whiplash injury of the cervical spine--on the role of pre-existing degenerative diseases]. / Das Schleudertrauma der Halswirbelsäule--über die Rolle degenerativer Vorerkrankungen.

Radiological investigations contribute little in differentiating the problems of patients with whiplash injuries. Nevertheless the more prolonged cases of whiplash injuries must not be attributed to preexisting degenerative disease, despite radiologically-proven medicolegal opinion. In this study, 60 patients who were seen for whiplash injuries in the Department for Trauma and Reconstructive Surgery at the University Hospital Hamburg-Eppendorf for clinical and radiological evaluation, an average of 5.7 years post injury, were divided into two groups (n = 30) depending on radiologically-proven preexisting degenerative changes of the cervical spine. On average the patients with degenerative changes were 11.2 years older than those with healthy vertebral columns and also demonstrated an increase in acute symptoms in the lower cervical spine (cervicobrachial syndrome). The chronicity of individual symptoms such as neck-pain, dizziness, nausea and psychological illness was also observed in both groups. Problems such as paresthesias as well as pain in the shoulder-arm-area appeared to increase in subsequent check-ups, irrespective of the earlier degenerative changes. Patients with typical posterior headaches recovered faster when they had radiologically normal spines. Presenting late, there was a significant accumulation of patients with pre-existing degenerative changes complaining merely of tinnitus. The earlier changes in any individual motion segment do not determine the clinical course of whiplash injuries, but merely represent an area of increased vulnerability to trauma. On the other hand, trauma has not been proven to influence the development or aggravation of degenerative changes in normal or diseased spines. We are not able to differentiate the posttraumatic course from the natural history of the degenerative process, either clinically or radiologically. Considering the involvement of sensitive neurological structures the classical objective organic diagnosis of "whiplash injury" may not be adequate in describing the complaints of patients, and should not be used to justify the rejection of the patients subjective symptoms as mere simulation for financial gains. The evaluation of the patients' X-rays using Arlen's technique sheds no further light on the issue.

Analysis of nucleo-cytoplasmic transport in a thermosensitive mutant of nuclear pore protein NSP1.

NSP1 is related to a group of nuclear pore proteins termed 'nucleoporins'. We observe that in thermosensitive nsp1 mutants lacZ fusion proteins which contain the nuclear targeting sequence of Mat alpha 2 or Pho2 are located inside the nucleus at the permissive temperature (23 degrees C), but are mislocalized in the cytoplasm at the restrictive temperature (37 degrees C). No evidence was obtained that the large lacZ reporter protein leaks out from the nucleus. Another nuclear passenger protein consisting of the NLS of ribosomal protein L25 and cytosolic dihydrofolate reductase (DHFR) is also accumulating in the cytoplasm after shifting ts nsp1 cells to 37 degrees C. In the latter case, this could be attributed to an increased leakage of the reporter protein from the nucleus into the cytoplasm. These data suggest that NSP1 mutation affects nuclear transport and nuclear retention, but the effects depend on the used NLS and the reporter protein.