Endothelin (ET)-1 and ET-3 promote expression of c-fos and c-jun in human choriocarcinoma via ET(B) receptor-mediated G(i)- and G(q)-pathways and MAP kinase activation.

BACKGROUND AND PURPOSE: Endothelins (ETs) and their G protein-coupled receptors exert key physiological functions during normal and aberrant placental development. Trophoblast cells mediate the contact between the embryo and the mother, by establishing a transient organ, the placenta. Choriocarcinoma cells display many of the biochemical and morphological characteristics of in utero invasive trophoblast cells and may therefore be used as a suitable model to study epithelial tumour progression of foetal-derived cells. EXPERIMENTAL APPROACH: The present study aimed at investigating ET receptor-mediated activation of the mitogen-activated protein kinase (MAPK) pathway in human choriocarcinoma. KEY RESULTS: Both JAR and Jeg-3 choriocarcinoma cell lines expressed ET receptor subtype B (ET(B)) but not ET(A) receptor transcripts. ET(B) receptor engagement by ET-1 and ET-3 resulted in a similar time- and concentration-dependent phosphorylation of p42/44 MAPK, also known as extracellular regulated kinase 1/2. Using specific pharmacological antagonists/inhibitors, we showed that ET-1/-3-mediated signal transduction by the ET(B) receptor is transmitted via G(i)- and G(q)-dependent pathways through activation of the Src (G(i)) and protein kinase C (G(q)) axis that converge at Ras/Raf, leading to downstream activation of p42/44. On a functional level, ET(B) engagement and subsequent phosphorylation of p42/44 resulted in enhanced transcription of the immediate early response genes c-fos and c-jun, a process commonly assumed to be mediated by the ET(A) receptor, and increased cell growth and relative cell area. CONCLUSIONS AND IMPLICATIONS: As human choriocarcinoma cells secrete ETs, pharmacological antagonism of ETs and/or ET(B) receptor-mediated signal transduction could represent a likely target therapy for choriocarcinoma.

Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta.

Indoleamine 2,3-dioxygenase (IDO) has been implicated in regulation of feto-maternal tolerance and protection against intracellular and extracellular pathogens. We have studied the expression of IDO in the human female reproductive tract and the placenta by immunohistochemistry. Endometrial glandular and surface epithelial cells showed increasing IDO expression during the course of the menstrual cycle. In term placenta, IDO was irregularly localized to the mesenchymal core and found in isolated areas of the syncytiotrophoblast. In first trimester pregnancy, IDO was not present in placental villi, but was present in glandular epithelium of the decidua, and there were distinctly positive cells scattered in the connective tissue, sometimes in conjunction with lymphoid aggregates. The endothelium of spiral arteries and of capillaries showed some, albeit no generalized, reactivity. IDO was also present in the epithelium of cervical glands and of Fallopian tubes. Specificity of antibody binding was confirmed by Western blot analysis. IDO mRNA was detected in first trimester decidua as determined by RT-PCR. IDO is secreted, as determined by analysis of cervical mucus by high pressure liquid chromatography for the presence of the tryptophan metabolite L-kynurenine, indicating IDO activity. Our results support the concept of IDO providing a mechanism of innate immunity protecting against ascending infections in the female reproductive tract.

Clinical wear behaviour of ultra-high molecular weight polyethylene cups paired with metal and ceramic ball heads in comparison to metal-on-metal pairings of hip joint replacements.

In the course of 30 years of hip endoprosthetics, a number of material combinations for the cups and balls of total hip prostheses have proven successful under clinical conditions. Favourably priced hip prostheses with polyethylene cups and metal balls are available for older patients with a moderate range of activity. Polyethylene wear of 100-300 microns/year is to be expected with these models. Ceramic balls (aluminium oxide for diameters 32 and 28 mm and zirconium oxide for 22 mm) paired with polyethylene cups are recommended for patients with a life expectancy of 10 to 20 years, because the expected polyethylene wear rate with this material combination is only 50-150 microns/year. In other words, the life cycle of the polyethylene cup is doubled, when it is paired with a ceramic ball. A similar polyethylene wear rate is also to be expected with oxygen-deep-hardened TiAlNb metal balls, which are currently the subject of a clinical field study. Last but not least, CoCrMoC metal-metal and Al2O3 ceramic ceramic pairings, which have the lowest wear rate of 2-20 microns/year, are available for highly active patients with a life expectancy of more than 20 years. As far as the cup-ball pairing is concerned and under the current pressure of costs, the surgeon should be able to select the optimum hip prosthesis model for every patient from these three categories.

Metal-on-metal CoCrMo McKee-Farrar total hip arthroplasty: characteristics from a long-term follow-up study.

A total of 38 cemented metal-on-metal CoCrMo McKee-Farrar total hip arthroplasties (THAs) were clinically and radiographically evaluated over a long-term follow-up. No osteolysis and no granuloma were found more than 20 years after the operation. The main radiological findings were bone erosion and migration of the acetabular component, seen in 17 hips (44.7%). The direction of the migration correlated with the setting position of the acetabular component at operation. At revision surgery, metallosis was observed in unstable THA, and no metallosis was observed in stable THA. Using a micrometer, no wear of the sockets was found. Therefore, the loosening was thought to be due to the equatorial bearing rather than to metallosis. The mean survival of the THA to data was 14.6 years in those patients 60 years old or younger at operation and was significantly less (11.9 years) in those 61 years old or older at operation (P < 0.03). The mean survival time was 13.8 years.

Wear behavior and histopathology of classic cemented metal on metal hip endoprostheses.

The authors reviewed their collection of retrieved all metal hip joints (9 McKee-Farrar, 7 Müller, and 3 Huggler type prostheses) and tissues from the joint capsules and implant beds. The amount of wear was measured, and the total volume was calculated. The tissues were analyzed by atomic absorption spectral analysis or inductively coupled plasma mass spectrometry and examined by light and scanning electron microscopy. The size of particles was measured with a texture analysis system. The articulating surfaces showed many delicate scratches which represent normal wear. The calculated annual wear averaged approximately 5 mm3 per year, which is low compared with polyethylene. The cellular reaction to metal wear particles was regarded as mild. The cellular reaction to scattered and worn bone cement was always more pronounced than to metallic debris. Scanning electron microscopy confirmed the irregular shapes and mostly submicron size of the metal particles. The analytically detected metal content of the periarticular tissue was relatively low and in accordance with the wear measurements from the articulating surfaces. The excess of chromium in the tissues is discussed in the light of the elimination of cobalt as well as the relation between elements representing either corrosion products or elements still bound in wear particles.

Metal-on-metal articulation for artificial hip joints: laboratory study and clinical results.

As wear is inevitable with artificial joint replacement, it has to be minimized to avoid possible aseptic loosening following osteolysis due to particle-initiated foreign body reaction. Co-Cr-Mo-C alloys have a long history with only minimum wear when articulating with themselves. This investigation shows that the choice of the alloy has an effect on the wear rate of this articulation couple. Tribological studies in a screening device, a pendulum apparatus and a hip joint simulator showed a marked influence of the environment as well as the diameter of the implants with metal-on-metal articulation. A wear-resistant combination with low friction characteristics has been developed by using a wrought Co-Cr-Mo-C alloy and reducing the implant diameter to 28 mm. Clinical wear rates are comparable with laboratory data and demonstrate the potential of the metal-on-metal articulation to solve the problem of wear-induced osteolysis of hip joint endoprostheses.

[Clinical Wear Behaviour of UHMW Polyethylene Cups Paired with Metal and Ceramic Ball Heads in Comparison to Metal-on-Metal Pairings of Hip Joint Replacements.]. / Klinisches Verschleissverhalten von UHMW Polyethylen Pfannen in Paarung mit Metall und Keramik Kugeln im Vergleich zur Metallgegen-Metall Paarung beim Hüftgelenkersatz.

In the course of 30 years' hip endoprosthetics, a number of material combinations for the cups and balls of total hip prostheses have proven successful under clinical conditions. Favourably priced hip prostheses with polyethylene cups and metal balls are available for very old patients with a moderate range of activity. Polyethylene wear of 100-300 microm per year is to be expected with these models. Ceramic balls (aluminium oxide for diameters 32 and 28 mm and zirconium oxide for 22 mm) paired with polyethylene cups are recommended for patients with a life expectancy of 10 to 20 years, because the expected polyethylene wear rate with this material combination is only 50-150 microm per annum. In other words, the life cycle of the polyethylene cup is doubled, when it is paired with a ceramic ball. A similar polyethylene wear rate is also to be expected with oxygen-deephardened TiAlNb metal balls, which are currently the subject of a clinical field study. Last but not least, CoCrMoC metal/metal and AI2O3 ceramic/ceramic pairings, which have the lowest wear rate of 2 to 20 microm/year. are available for highly active patients with a life expectancy of more than 20 years. As far as the cup/ball pairing is concerned and under the current pressure of costs, the surgeon should be able to select the optimum hip prosthesis model for every patient from these three categories.

[15 years experience with the Ti-6Al-7Nb alloy for joint prostheses]. / 15 Jahre Erfahrung mit Ti-6AL-7Nb-Legierung für Gelenkprothesen.

The Ti-6Al-7Nb alpha-beta alloy, Protasul-100 was developed between 1978 and 1982, and proved to be highly biocompatible. In 1985 the TiAlNb material was approved for clinical use. Over the last ten years, more than 200 tons of semi-finished bar material has been processed, mainly for the production of cementless femoral stem systems and elastically deformable cup shells. For uncemented femoral components of knee prostheses made of TiAlNb, a special oxygen diffusion hardening process was developed that enables a surface hardness of up to 1200 HV and 600 HV at a depth of 20 microns, as compared with 350 HV in the case of the TiAlNb base material. This ODH-treated, polished surface is extremely scratch and wear resistant, and forms a good articulating surface with UHMW polyethylene. This surface-hardened TiAlNb, Tribosul, has been in clinical use in femoral knee components since 1990, and a multicentric clinical study involving femoral heads for hip prostheses has been ongoing since 1992. These different applications in hip and knee joint prostheses may suffice to demonstrate that the custom-made Ti-6Al-7Nb alpha-beta alloy is a real alternative to the well-known Ti-6Al-4V alloy, which has been used for decades as an implant material. Both national and international standards are available, and the alloy was already approved by the FDA in 1987.

Implant materials for hip endoprostheses: old proofs and new trends.

To judge the significance of a hip joint replacement, the clinical results over 10-20 years must be evaluated. Today, still over half of all hip endoprostheses involves cement fixation. The rest is uncemented, in direct contact with bone. Total hip prostheses with polyethylene cups are equipped either with cobalt-, iron-, surface-hardened titanium-based metal or Al2O3 ceramic ball heads. The pairing Al2O3/Al2O3 and CoCrMoC metal/metal for cups and balls are extremely wear resistant. Most of the cementless cups have spherical or conical cobalt- or titanium-based metal shells with inserts made of polyethylene or CoCrMoC metal. For the fixation stems, high-strength iron-, cobalt- or titanium-based wrought metals are preferred. A taper spigot connection between metallic or ceramic ball heads and stems allows a modular design of hip joint replacements. We have learnt much from the mistakes of the last 40 years in hip endoprosthetics, and there is no excuse to repeat them again.

Total hip joint replacement using a CoCrMo metal-metal sliding pairing.

Late loosening in total hip replacement is explained by a foreign body reaction of the connective tissue along the bone-implant interface due to polyethylene debris. In contrast, metal-metal prostheses of the McKee type implanted in the sixties, may still work perfectly today without any signs of osteolysis along the bone-cement interface, proving that metal-metal pairing is superior to prostheses with polyethylene cups and proving also that cement anchorage may be adequate for fixation. A new metal-metal total hip joint is presented, that has been implanted 90 times between 1988 and 1991.

Joint replacement components made of hot-forged and surface-treated Ti-6Al-7Nb alloy.

We have developed a titanium-aluminium alloy with the inert alloying element niobium. The optimal composition was found to be Ti-6Al-7Nb (Protasul-100). This custom-made alloy designed for implants shows the same alpha/beta structure as Ti-6Al-4V and exhibits equally good mechanical properties. The corrosion resistance of Ti-6Al-7Nb in sodium chloride solution is equivalent to that of pure titanium and Ti-6Al-4V. This is due to a very dense and stable passive layer. Highly stressed anchorage stems of different hip prosthesis designs have been made from hot-forged Ti-6Al-7Nb. The polished surfaces of hip, knee and wrist joints made of Ti-6Al-7Nb and articulating against polyethylene are surface-treated by means of a very hard and 3-5 microns thick titanium nitride coating (Tribosul-TiN) or by oxygen diffusion hardening (Tribosul-ODH) to a depth of 30 microns.

Total Hip Joint Replacement Using a CoCrMo Metal-Metal-Sliding Pairing.

Late loosening in total-hip replacement is explained by a foreign body reaction of the connective tissue along the bone-implant interface due to polyethylene debris. In contrast, metal-metal prostheses of the McKee type implanted in the sixties, may still work perfectly today without any signs of osteolysis along the bone-cement interface, providing that metal-metal pairing is superior to prostheses with polyethylene cups and providing also that cement anchorage may be adequate for fixation. A new metal-metal total hip joint is presented, that has been implanted 62 times between 1988 and 1990. Key words: total hip replacement, metal-metal pairing.

[Joint prostheses components of warm-forged and surface treated Ti-6Al-7Nb alloy]. / Gelenkprothesen-Komponenten aus warmgeschmiedeter und oberflächenbehandelter Ti-6Al-7Nb-Legierung.

In 1978 development of a TiAl alloy with the inert alloying element niobium was initiated. In 1984, the optimal composition was found to be Ti-6Al-7Nb (Protasul-100). This custom-made alloy for implants has the same alpha/beta micro-structure and equally good mechanical properties as Ti-6Al-4V. The corrosion resistance of Ti-6Al-7Nb is better than that of pure titanium and Ti-6Al-4V, due to the very dense and stable passive layer. Since 1985, highly stressed anchoring stems of various hip prosthesis designs have been manufactured from hot-forged Ti-6Al-7Nb/Protasul-100. Polished surfaces of hip, knee or wrist joints made of Ti-6Al-7Nb intended to articulate with polyethylene are surface-treated by the application of a very hard, 3-5 microns thick titanium nitride coating (Tribosul-TiN), or by oxygen diffusion hardening (Tribosul-ODH) to a depth of 30 microns.

New surface modification for Ti-6Al-7Nb alloy: oxygen diffusion hardening (ODH).

PVD-TiN coating and N+ implantation of Ti-6Al-7Nb alloy resulted in surface hardening to a depth of less 3 microns. The new oxygen diffusion hardening (ODH) treatment increased the hardness gradually to 50 microns. PUD-TiN showed an improvement in the tribological properties, while N+ implantation increased the PE wear rate. The wear rate of the ultrahigh-molecular-weight as well as the friction coefficient were reduced to one-half of the values achieved with the combination of CoCrMo-alloy when paired against the ODH-treated surface. In pairing with ZrO2-containing bone cement the ODH-treated surface showed only a minimal reaction.

Long-term results after implantation of McKee-Farrar total hip prostheses.

From 1973 to 1976, McKee-Farrar total hip arthroplasties were performed in the Orthopaedics Department at the Centre of Pulmology. In the present study, only patients with a complete record of radiological changes at the bone/implant or bone/cement interface were evaluated. A series of 81 patients with 100 total hip prostheses in situ according to the Mayo Clinic hip score and 36 patients who had undergone 36 revision operations were studied. The design of the metal cup with metal studs at the outer surface has a favourable effect on the stability of the implant/cement combination: loosening at the implant/cement interface did not occur in any of these cases and there were few cement fractures. In spite of the metal-to-metal combination, abrasion is slight and there is no danger of metallosis.

Massive wear of a steel ball head by ceramic fragments in the polyethylene acetabular cup after revision of a total hip prosthesis with fractured ceramic ball.

The purpose of this case study of severe metallosis is to draw the attention of orthopedic surgeons to extremely serious results of this kind in the event of the fracture of the ceramic ball in a total hip prosthesis. Eleven months after implantation of a KJF hip prosthesis with an aluminum oxide ceramic ball in combination with a polyethylene acetabular cup, fracture of the ceramic ball was observed. After examining the polyethylene cup during the revision operation, the operating orthopedic surgeon merely replaced the fractured ceramic ball with a metal ball head made of stainless steel. Twenty-five months after this procedure, radiography revealed massive wear of the steel ball head with resulting severe metallosis of the surrounding tissues. All prosthetic components therefore had to be removed. Careful examination of the removed prosthetic components clearly showed that sharp-edged ceramic particles originating from the fractured ceramic ball had become embedded in the bearing surface of the polyethylene cup. These tiny ceramic fragments, ranging from 0.05 to 2 mm, were too small to be seen by the operating surgeon's unaided eye. It is these extremely hard ceramic fragments that were responsible for the massive wear of the steel ball head, the hardness of which is approximately ten times less than that of aluminum oxide ceramic. The fracture of the ceramic ball further resulted in damage to the metal taper of the stemmed femoral component. In cases of this kind it is consequently absolutely essential to remove both the polyethylene cup and the ball head, and--if necessary--the femoral component as well.

[The wear behavior of capsules and heads of CoCrMo casts in long-term implanted all-metal hip prostheses]. / Verschleissverhalten von Pfannen und Kugeln aus CoCrMo-Gusslegierung bei langzeitig implantierten Ganzmetall-Hüftprothesen.

We conducted an investigation on total hip prostheses with cups and balls made of cast CoCrMo alloy that were implanted 10-20 years ago; our results showed that this metal/metal alloy showed very low wear and tear. In comparison, the polyethylen/metal alloy showed a 40 times higher wear in the polyethylene part. Based on these promising long-term clinical results, the metal/metal alloy is again of great interest for total hip prostheses.