[Change in concept--from vascular centre to interdisciplinary organ-oriented clinic for vascular medicine]. / Vom Konzept Gefäßzentrum zur interdisziplinären Organklinik für Gefäßmedizin.

Demographic developments have led to an exponential increase of cardiovascular illness. Additionally, the technical development of conservative and invasive treatment modalities has added to an increase of differentiated therapy. The development of vascular centres led to optimised processes in diagnostic and therapy according to their essential requirements. A further development is an increased specialisation and new orientation of vascular specialties through a combination of vascular surgery, endovascular therapy and angiology. The concept of the Hamburg model implements this development by introduction of an organ-orientated clinic for vascular medicine, located within the heart centre of the University of Hamburg's Eppendorf Hospital.

Sonographic and clinical pattern of extracranial and cranial giant cell arteritis.

OBJECTIVES: The aim of our study was to describe the sonographic pattern and clinical manifestations of extracranial (i.e. carotid and proximal arm arteries) and cranial arterial involvement in patients with giant cell arteritis (GCA). METHODS: One hundred and ten consecutive patients with an established diagnosis of GCA between January 2002 and June 2010 were identified retrospectively from a database. All patients underwent colour duplex sonography (CDS) of the superficial temporal, carotid, and proximal arm arteries at the time of diagnosis. Circumferential, homogeneous, hypoechogenic wall thickening was regarded as a typical sign for GCA. Sonographic and clinical characteristics of patients with and without extracranial vessel involvement were compared. RESULTS: Extracranial GCA was observed in 59 of 110 subjects (53.6%). The axillary artery (48.2%) was most frequently affected and bilateral vessel involvement was present in almost all patients (94.8%). Compared to patients with cranial GCA, patients with extracranial GCA were significantly younger, frequently did not meet the American College of Rheumatology (ACR) criteria for classification of cranial GCA, exhibited a lower rate of permanent visual impairment, and were diagnosed later after onset of clinical symptoms (all p < 0.01). With increasing age, a continuous shift from GCA with extracranial arterial involvement to cranial GCA was observed. CONCLUSION: Using CDS, extracranial GCA is a common finding, most frequently observed in the axillary arteries. The clinical pattern of GCA with extracranial arterial involvement differs from that of cranial GCA.

Patterns of extracranial involvement in newly diagnosed giant cell arteritis assessed by physical examination, colour coded duplex sonography and FDG-PET.

BACKGROUND: The clinical spectrum of giant cell arteritis (GCA) varies from classical temporal arteritis (TA) to generalized large vessel GCA (LV-GCA) and fever of unknown origin (FUO). Extent and distribution of extracranial involvement in these different presentations of GCA is not well known, and its detection may depend on the choice of vascular imaging. PATIENTS AND METHODS: In 24 patients with newly diagnosed GCA we systematically evaluated the presence and distribution of extracranial involvement by physical examination, duplex sonography (DS), and FDG-PET. Analysis of FDG-PET results was performed in comparison with 18 age-matched control-subjects scanned for oncological indications. RESULTS: Initial clinical diagnosis was TA in 11 patients, LV-GCA in 8 patients, and FUO in 5 patients. Clinically detectable arterial obstruction was present in 2 patients (18 %) with TA (only upper extremity), all patients with LV-GCA (upper and lower extremities) and no patient with FUO. Upper and/or lower limb large vessel vasculitis was detectable by DS in 45 % of the patients with TA and in 100 % of the patients with LV-GCA or FUO. FDG-PET confirmed upper extremity involvement in all affected patients, but had a very low specificity for lower limb involvement due to concomitant arteriosclerosis in these elderly patients. Aortitis was detectable by FDG-PET in 27 % of patients with TA and 75 - 80 % of patients with LV-GCA or FUO. CONCLUSIONS: The combination of thorough clinical examination and DS is able to detect symptomatic as well as asymptomatic large vessel involvement in a large proportion of patients with newly diagnosed GCA. Distribution and manifestation of large vessel involvement differs between classical TA and LVGCA or FUO. FDG-PET provided only limited additional information and did not change the clinical diagnosis in any patient.

Fever of unknown origin as initial manifestation of large vessel giant cell arteritis: diagnosis by colour-coded sonography and 18-FDG-PET.

OBJECTIVES: To evaluate the clinical characteristics and imaging results (CDS, 18-FDG-PET) of patients with large vessel giant cell arteritis (LV-GCA) presenting as fever of unknown origin (FUO). METHODS: From a series of 82 patients with GCA we identified 8 patients with FUO as initial disease manifestation. Clinical characteristics and results of CDS and 18-FDG-PET were analysed. Patients with FUO and those with other clinical manifestations of GCA were compared. RESULTS: 18-FDG-PET-scans were available for 6/8 patients, revealing enhanced tracer uptake of the thoracic aorta and the aortic branches in all patients. CDS was performed in 8/8 patients, with detection of hypoechogenic wall thickening related to LV-GCA in 7/8 patients. Subjects with FUO were significantly younger (60.9 vs. 69.3 years, p<0.01) and had a stronger humoral inflammatory response (CRP 12.6 vs. 7.1 mg/dl, p<0.01; ESR 110 vs. 71 mm/hour, p<0.01), when compared to the other GCA-patients. CONCLUSIONS: LV-GCA should be considered as important differential diagnosis in patients with FUO. In addition to 18-FDG-PET, which is known to be a valuable method in the diagnostic work-up of FUO, we recommend CDS of the supraaortal and femoropopliteal arteries for the initial diagnostic work-up.

Transformation by myc prevents fusion but not biochemical differentiation of C2C12 myoblasts: mechanisms of phenotypic correction in mixed culture with normal cells.

To study the effects of myc oncogene on muscle differentiation, we infected the murine skeletal muscle cell line C2C12 with retroviral vectors encoding various forms of avian c- or v-myc oncogene. myc expression induced cell transformation but, unlike many other oncogenes, prevented neither biochemical differentiation, nor commitment (irreversible withdrawal from the cell cycle). Yet, myotube formation by fusion of differentiated cells was strongly inhibited. Comparison of uninfected C2C12 myotubes with differentiated myc-expressing C2C12 did not reveal consistent differences in the expression of several muscle regulatory or structural genes. The present results lead us to conclude that transformation by myc is compatible with differentiation in C2C12 cells. myc expression induced cell death under growth restricting conditions. Differentiated cells escaped cell death despite continuing expression of myc, suggesting that the muscle differentiation programme interferes with the mechanism of myc-induced cell death. Cocultivation of v-myc-transformed C2C12 cells with normal fibroblasts or myoblasts restored fusion competence and revealed two distinguishable mechanisms that lead to correction of the fusion defect.

myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts.

The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.

Transcription of muscle-specific genes is repressed by reactivation of pp60v-src in postmitotic quail myotubes.

Quail myogenic cells infected with temperature sensitive (ts) mutants of Rous sarcoma virus (RSV) exhibit a temperature-dependent transformation and block of differentiation. When the cells are allowed to differentiate at the restrictive temperature (41 degrees C) and then shifted back to the permissive temperature (35 degrees C), a sharp reduction in the accumulation of muscle-specific mRNAs is observed, following reactivation of the transforming protein pp60v-src. A kinetic analysis of this down-regulation reveals that the reduction in the accumulation of muscle-specific transcripts occurs fairly rapidly within 6 to 20 h after the shift back, depending on the mRNA analyzed. Studies on transcription of endogenous muscle-specific genes and a transfected chloramphenicol acetyltransferase reporter gene under the control of muscle-specific promoters, at the different temperatures, suggest that the oncogene exerts its control mainly at the transcriptional level. On the contrary, transcription of the CMD1 gene, the avian homolog of the mouse muscle regulatory MyoD gene, is not significantly affected by the oncogene both in proliferating myoblasts and in myotubes shifted back to 35 degrees C. These findings are consistent with the conclusion that v-src blocks myogenesis by controlling transcription of muscle-specific genes independently of cell proliferation. Furthermore, they suggest the existence of an alternative pathway, not requiring the silencing of CMD1 transcription, through which the oncogene exerts its effect.

Stenting of the superficial femoral artery after suboptimal balloon angioplasty: one-year results.

AIM: The aim of this study was to analyze the intermediate results of selective stenting of superficial femoral artery (SFA) lesions after a suboptimal balloon angioplasty result. METHODS: We analyzed 70 consecutive patients with claudication or critical limb ischemia due to peripheral arterial occlusive disease who underwent stent implantation of the SFA after unsuccessful balloon-angioplasty. All patients were followed-up immediately after the procedure and 3, 6 and 12 months thereafter. Restenosis was defined as an increase of peak systolic velocity-index >2 as determined by duplex sonography. RESULTS: Primary patency rates at 3, 6 and 12 months were 83.4%, 66.2% and 59%, respectively. Successful reinterventions were performed for 17 reobstructions, resulting in a secondary patency rate at 3, 6 and 12 months of 91%, 89.3%, and 83.8%, respectively. At 12 months 68.6% of the patients were asymptomatic, 21.6% complained of mild (Fontaine class II a), 5.9% of severe (Fontaine class II b) claudication and 2.9% were in critical limb ischemia. CONCLUSIONS: Our data indicate that selective stenting of the SFA after suboptimal balloon angioplasty results in intermediate patency rates similar to that reported for primarily successful PTA, thereby supporting the widely accepted policy of selective stenting as a rescue procedure after unsuccessful balloon angioplasty.

v-jun oncogene prevents terminal differentiation and suppresses muscle-specific gene expression in ASV-17-infected muscle cells.

Infection of replicating quail myoblasts with avian sarcoma virus 17 (ASV-17) results in the inhibition of terminal differentiation into multinucleated myotubes and in the acquisition of anchorage-independent proliferation. Expression of v-jun, the ASV-17 oncogene, concomitantly leads to the accumulation of the gag-jun polyprotein P65 in the nucleus and to the lack of expression of typical differentiation-specific genes such as myosin heavy chain (MHC) and alpha-actinin. Surprisingly, expression of desmin, the muscle-specific subunit of intermediate filaments, is conserved in ASV-17-transformed myoblasts. Analysis of clonal strains of transformed myoblasts suggests that (i) suppression of morphological and biochemical differentiation depends on the absence of muscle-specific gene transcripts; (ii) inhibition of muscle differentiation by v-jun does not depend on the transcriptional silencing of MyoD, a muscle-specific regulatory gene; (iii) expression of desmin is compatible with proliferation of ASV-17-transformed cells and is independent of v-jun and MyoD levels of expression. The present data suggest that nuclear localization of v-jun prevents terminal differentiation in myoblasts and selectively down-regulates muscle-specific genes in terminally differentiated myotubes. In this respect, the behaviour of v-jun is quite different from that of v-myc, thus suggesting that these two oncogenes, although both encoding nuclear proteins, may have different mechanisms of action.

Transcriptional down-regulation of myogenin expression is associated with v-ras-induced block of differentiation in unestablished quail muscle cells.

Unestablished quail myoblasts were infected with a retroviral vector encoding the oncogenic form of H-Ras in order to investigate the mechanism by which this oncoprotein interferes with terminal differentiation. Primary quail myogenic cells exhibit the simultaneous expression of the muscle regulatory genes myf-5, MyoD and myogenin in proliferative conditions. v-ras-transformed myoblasts displayed an altered growth control and lost the competence for terminal differentiation. When expression of myogenic regulatory genes was analysed, it was immediately apparent that the difference between normal and v-ras-transformed cells was limited to a severely decreased level of myogenin expression. Forced expression of exogenous myogenin in v-ras-transformed quail myoblasts led to a striking recovery of the competence for terminal differentiation. The present data show that: (i) repression of myogenin expression is linked to the differentiation defective phenotype of quail myoblasts transformed by v-ras as well as other retroviral oncogenes; (ii) correction of the differentiation-defective phenotype of v-ras-transformed myoblasts by exogenous myogenin entailed reactivation of endogenous myogenin and of the E-box-dependent transactivating function. These results strongly indicate that myogenin expression plays a central role in regulating the transition into the terminally differentiated state and that its transcriptional down-regulation represents a nodal step in v-ras-induced block of differentiation.

Transformation of NIH3T3 cells by Rous sarcoma virus occurs with high efficiency in the absence of proviral rearrangements or amplification.

NIH3T3 cells could be transformed by a mammaltropic strain of Rous sarcoma virus (RSV) with an efficiency 10(3) times greater than that observed in Balb/c 3T3 cells or other mammalian cell lines and almost identical to that of chick embryo fibroblasts. In infected NIH3T3 cells a single, properly integrated, provirus was sufficient to induce focus formation; moreover, kinase activity of pp60v-src and tyrosine phosphorylation of cellular proteins could be detected very soon after infection in the majority of cells. On the other hand, in transformed foci from RSV-infected Balb/c 3T3 cells both rearrangements and amplification of proviral sequences were frequently detected. Accordingly, expression of pp60v-src and ensuing tyrosine phosphorylation of cellular proteins occurred, at high levels, only in a minority of the infected cells. Furthermore, by using a murine retrovirus carrying the v-src oncogene and an independent selectable marker, we found that Balb/c 3T3 cells were transformed with a 100-fold lower efficiency than NIH3T3 cells, yet the majority of infected untransformed Balb/c 3T3 cells expressed active pp60v-src. These findings are consistent with the existence in most mammalian cell lines of a major restriction to v-src-induced transformation, operating at the level of proviral expression, that is apparently absent in NIH3T3 cells.

Differential influence of adjacent normal cells on the proliferation of mammalian cells transformed by the viral oncogenes myc, ras and src.

We investigated the role of adjacent normal cells in the modulation of focal outgrowth of mammalian fibroblasts transformed by different viral oncogenes (myc, src and ras). NIH3T3 cells transformed by these three oncogenes were derived by transfection or infection and showed comparable cloning efficiencies in semi-solid medium. However, upon replating in liquid medium a small number of transformed cells together with a vast excess of normal mouse embryo fibroblasts C3H10T1/2, ras- and src-transformed cells were able to overgrow the monolayer and formed distinct foci, whereas myc-transformed cells lacked this ability. Conditioned medium from normal cells did not affect the proliferation of myc-transformed cells at clonal density. Addition of phorbol ester tumour promoters, either at the time of plating or as late as after one week, efficiently rescued focus formation by myc-transformed cells. In contrast, when myc-transformed cells were cultivated alone, their clone size and cloning efficiency were slightly reduced by the addition of tumour promoters. These results indicate that cell-cell contacts between transformed cells and adjacent normal cells specifically inhibit the growth of myc- but not of ras- or src-transformed cells. The ability of tumour promoters and phospholipase-C to rescue the focus forming ability of myc-transformed cells is consistent with the possibility that activation of protein-kinase C is involved in the clonal expansion of 'suppressed' myc-bearing cells.

Role of Gas1 down-regulation in mitogenic stimulation of quiescent NIH3T3 cells by v-Src.

Quiescent mammalian fibroblasts can be induced to reenter the cell cycle by growth factors and oncoproteins. We studied the pathway(s) through which v-Src, the oncogenic tyrosine kinase encoded by the v-src oncogene of Rous sarcoma virus, forces serum-starved NIH3T3 cells to enter S-phase. To this purpose, we isolated and characterized a polyclonal population of NIH3T3 cells transformed by the MR31 retroviral vector, encoding G418 resistance and the v-src temperature-sensitive allele from the mutant ts LA31 PR-A. NIH(MR31) cells displayed a temperature-conditional transformed phenotype and could be made quiescent by serum deprivation at the restrictive temperature. Serum stimulation or thermolabile v-Src reactivation induced entry into S-phase to a comparable extent, although with different kinetics. The data suggest that v-Src mitogenic activity involves early activation of the Erk1/Erk2 MAP kinases with very little tyrosine phosphorylation of the Shc adaptor proteins at least during the early stages of v-Src reactivation and that v-Src-induced S-phase entry was strongly inhibited by drugs affecting MEK or PI 3-kinase. Our results also suggest that down-regulation of gas1 gene expression plays an important role in regulating the efficiency of entry into S-phase triggered by reactivated v-Src and that Gas1 down-regulation does not require PI 3-kinase dependent signals.

Effectiveness of low-dose crystalline nicotinic acid in men with low high-density lipoprotein cholesterol levels.

BACKGROUND: Hypoalphalipoproteinemia (low serum concentration of high-density lipoprotein cholesterol [HDL-C]) is a common pattern of dyslipidemia associated with coronary heart disease. High doses of nicotinic acid effectively raise HDL-C levels in this condition, but they are commonly accompanied by side effects. The efficacy of low doses of nicotinic acid that may produce fewer side effects has not been adequately studied. OBJECTIVE: To determine the effects of low-dose nicotinic acid on HDL-C levels in patients with hypoalphalipoproteinemia. METHODS: Forty-four men with low HDL-C levels (< 1.03 mmol/L [< 40 mg/dL]) entered the study. Twenty-four patients otherwise had normal lipid levels, and 20 were moderately hypertriglyceridemic (range of plasma triglyceride levels, 2.82 to 5.64 mmol/L 250 to 500 mg/dL). The trial consisted of 3 phases; each phase lasted 8 weeks. The first phase was diet only (30% fat diet); in the second phase, crystalline nicotinic acid was added at 1.5 g/d; and in the third phase, the dose was increased to 3 g/d. RESULTS: Of the 44 patients who entered the study, 37 completed the low-dose phase (1.5 g/d); the remaining patients were withdrawn because of side effects to nicotinic acid. Four other patients who completed the low-dose phase were excluded from the higher dose phase because of side effects that developed when they were receiving the low dose. Ten other patients withdrew during the high-dose phase because of side effects. In both groups, responses to nicotinic acid therapy tended to be dose-dependent. For both groups, the higher dose generally produced a greater reduction in apolipoprotein B-containing lipoproteins and a greater rise in HDL-C levels. However, for both groups, the low dose of nicotinic acid gave an average 20% increase in HDL-C levels. CONCLUSIONS: A low dose (1.5 g/d) of crystalline nicotinic acid causes an average 20% increase in HDL-C levels and significantly lowers triglyceride levels in both normolipidemic and hyperlipidemic patients with low HDL-C levels. Although the changes induced by this dose are less than those that can be achieved by a higher dose, the lower dose is better tolerated. Nicotinic acid may be useful in combined drug therapy for secondary prevention of coronary heart disease, and if higher doses cannot be tolerated, use of a lower dose should still be useful for producing a moderate rise in HDL-C levels in patients with hypoalphalipoproteinemia.

Refractory Takayasu's arteritis successfully treated with the human, monoclonal anti-tumor necrosis factor antibody adalimumab.

Treatment of Takayasu's arteritis remains a demanding challenge to clinicians. In many patients the course of the disease is characterized by frequent relapses and disease progression under conventional treatment with glucocorticoids and cytotoxic drugs. We present the case of a young woman with severe cerebrovascular and aortic involvement, who experienced disease progression in spite of more than 2 years of treatment with high doses of prednisone, methotrexate and cyclophosphamide. In this patient, treatment with the human, monoclonal anti-tumor necrosis factor-alfa (TNFalfa)-antibody adalimumab achieved clinical remission and allowed tapering of prednisone within a few months. The present case, as well as previous reports on the use of infliximab in giant cell and Takayasu's arteries, suggests that TNFa-blockade may be a new, promising treatment for glucocorticoid-refractory large-vessel vasculitis.

[Behaviour of vancomycin with the new techniques in haemodialysis]. / Comportamiento de la vancomicina con tas nuevas técnicas de diálisis.

UNLABELLED: When using high convection dialysis techniques it arouses the necessity of considering the suitability of the regular protocols when administrating drugs, such as vancomycin. OBJECTIVES: To confirm if the usual guideline of vancomycin is efficient in patients undergoing treatments with acetate free biofiltration (AFB) and haemodiafiltration on-line (on-line). To propose an alternative guideline of administration. MATERIAL AND METHODS: 13 patients treated with AFB or On-line. 10 of them used filters of polysulfone and 3 of them of AN69. First part: 6 patients were administered 1 g iv during the last hour of dialysis. Second part: 7 patients were given a loading dose of 30 mg/kg iv with a reinforcement of 500 mg post-dialysis. The blood levels of the antibiotic were monitorized during the week following the administration. OUTCOMES: During the first phase it was noticed a decrease of 41% in the serum level of vancomycin during dialysis, conditioning subtherapeutic levels in the 83% of the patients until the end of the study. As for the second phase, therapeutic non-toxic levels were maintained during the whole study. The existence of a post-dialysis rebound of the 21 % was confirmed. A bigger clearance of vancomycin was obtained with the On-line technique rather than with AFB (176 vs 135 ml/min). We find a strong correlation between the decrease of the antibiotic and the volume ultrafiltrated with the On-line technique. CONCLUSIONS: The usual guideline of vancomycin may not be enough with the new convective dialysis techniques. A guideline based on a loading dose of 30 mg/kg and a reinforcement of 500 mg at the end of each dialysis could be adequate. The antibiotic clearance with the On-line technique is probably made by convective transport.

Relation of lipoprotein(a) to coronary heart disease and duplexsonographic findings of the carotid arteries in heterozygous familial hypercholesterolemia.

In familial hypercholesterolemia (FH) elevated Lp(a) concentrations are more frequent than in the general Caucasian population, but the clinical relevance of Lp(a) as a risk-factor in this group of patients is controversial. In 91 adult patients with heterozygous FH due to LDL-receptor defect we analyzed the correlation between Lp(a) concentrations, presence of coronary heart disease (CHD) and degree of atherosclerosis of the carotid arteries assessed by duplex scan. Coronary heart disease was present in 32 patients (24 males, 8 females). In the group without CHD the median of the Lp(a) distribution was 23 mg/dl, in the group with CHD 43 mg/dl (P < 0.05). The median of Lp(a) was 8 mg/dl in patients without pathological changes in the duplex scan of the carotids, 13 mg/dl in the group with intimal thickening, 25 mg/dl in patients with non-obstructing plaques, and 45 mg/dl in presence of > 30% luminal obstruction (P < 0.01). The role of Lp(a) as an independent risk factor was analyzed by stepwise logistic regression together with age, sex, LDL-, HDL-cholesterol, serum triglycerides, smoking status and presence of hypertension. For the prediction of CHD only age, HDL cholesterol and gender reached statistical significance. Lp(a) was, however, the lipoprotein parameter with the highest discriminative strength for the presence of a pathological duplex scan (P = 0.016), followed by LDL- (P = 0.03), and HDL-cholesterol (P = 0.03). These results provide direct evidence for a close correlation between Lp(a) and the rate of progression of atherosclerosis in FH, already at early, asymtomatic stages.

Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase.

Marked lowering of plasma total and low-density lipoprotein cholesterol levels that occur during treatment of dyslipidemia with pharmacologic doses of nicotinic acid result from hepatotoxicity. Therefore, a marked reduction in low-density lipoprotein may suggest generalized liver toxicity and drug treatment should be discontinued.