Orthopädische Universitätsklinik

Abstract Various scoring systems have been proposed to quantify the disability caused by knee ligament injuries and to evaluate the results of treatment. None of these systems has found worldwide acceptance, mainly because all scoring systems attribute numerical values to factors that are not quantifiable, and then the arbitrary scores are added together for parameters not comparable with each other. For these reasons a group of knee surgeons from Europe and America met in 1987 and founded the International Knee Documentation Committee (1KDC). A common terminology and an evaluation form was created. This form is the standard form for all publications on results of treatment of knee ligament injuries. It is a concise one‐page form. It includes a documentation section, a qualification section and a evaluation section. For evaluation there are four problem areas (subjective assessment, symptoms, range of motion and ligament examination). These are supplemented with four additional areas that are only documented but not included in the evaluation (compartmental findings, donor site pathology, X‐ray findings and functional tests). The form can be used pre‐ and postoperatively and at follow‐up. It has been specified that in any publication the minimum follow‐up time for shortterm results should be 2 years, for medium‐term results 5 years and for long‐term results 10 years. The largest part of the sheet is the qualification section. It is called “qualification” section rather than “scoring” section because no scores are given. Each parameter is qualified as “normal”, “nearly normal”, “abnormal” or “severely abnormal”. This qualification is less subjective and emotional than “very good”, “good”, “fair” and “poor”. No knee and no knee function can be better than normal, and it is rather doubtful whether any knee, once operated on, can ever be “normal” again. For evaluation, the parameters of the four problem ares “subjective assessment”, “symptoms”, “range of motion” and “ligament examination”, are qualified for the group qualification. The worst qualification within the group gives the group qualification. The worst group qualification gives the final evaluation. If the knee is abnormal in any of the problem areas, it cannot be a “normal” knee. For chronic knee conditions there is also the possibility of evaluating the sum of levels of improvement or deterioration of all groups compared with the preoperative evaluation. The committee also recommends that terms describing knee ligament problems should be used according to the definitions of Noyes et al. [32]. The use of the IKDC evaluation form will reveal less favourable results than those evaluated with other current evaluation forms, because a still existing knee problem cannot be hidden with a high numerical score that is added up from other, unrelated parameters. It is to be hoped, however, that the use of this new form will enable us to compare treatment methods in various publications with each other.

Microsomes from rat liver form hydrogen peroxide in the presence of an NADPH‐generating system in proportion to protein concentrations as determined by three independent methods: ferrithiocyanate, cytochrome c peroxidase, and scopoletin fluorescence. Maximal rates observed were about 15 μmol H 2 O 2 /g microsomal protein per minute. The oxygen concentration for half‐maximal rates was 50 μM. It is suggested that NADPH‐dependent hydrogen peroxide formation in microsomes is mainly due to NADPH oxidase; however, partial inhibition by carbon monoxide suggests that about one third arises from the autoxidation of cytochrome P‐450. Similarities exist between microsomal acetaldehyde production from ethanol ( i.e. the microsomal ethanol‐oxidizing system of Lieber and DeCarli [4]) and hydrogen peroxide formation: viz. requirement for NADPH and oxygen, identical oxygen concentrations for halfmaximal rates, and sensitivity to carbon monoxide. Microsomal acetaldehyde production in the presence of either an NADPH‐ or an H 2 O 2 ‐generating system exhibits identical characteristics as follows: (a) ethanol concentration for half‐maximal rates ( i.e. 12 mM); (b) dependency of maximal rates on rates of hydrogen peroxide formation; (c) competitive inhibition by peroxidatic substrates for catalase, e.g. formate (half‐maximal effect: 150 μM); (d) inhibition by catalase inhibitors, e.g. azide (half‐maximal effect: 50 μM), with identical azide insensitive rates; (e) diminished acetaldehyde production in microsomes from rats pretreated with aminotriazole or pyrazole with identical residual rates. Moreover, NADPH‐dependent acetaldehyde production is suppressed in the presence of an active H 2 O 2 ‐utilizing system. Thus, it is concluded that the NADPH‐dependent microsomal ethanol‐oxidizing system of Lieber and DeCarli [4] is due to a hydrogen peroxide formation from NADPH and a subsequent peroxidation of ethanol by contaminating catalase. The data indicate that the existence of a unique system in addition to the peroxidatic reaction of catalase as postulated recently [4] is highly doubtful.

Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H 2 O 2 produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins. (Endocrine Reviews 26: 944 -984, 2005) I. Historical Aspects II. Biosynthesis and Degradation of Eukaryotic Selenoproteins III. Recently Discovered Eukaryotic Selenoproteins A. Selenoenzymes and new selenoproteins with unknown functions B. Preferential selenium supply of the vital endocrine organs during deficiency and repletion IV. Hormonal Regulation of the Thioredoxin/Thioredoxin Reductase System A. Expression and secretion of thioredoxin and thioredoxin reductase B. Biochemistry and structure of thioredoxin reductase C. Thioredoxin reductase and thioredoxin are involved in signal transduction and regulation of gene expression V. Selenium, Cell Defense, and Thyroid Pathology A. Selenium and thyroid pathology in humans: endemic cretinism B. Experimental thyroid model C. Selenium deficiency and neurological cretinism VI. Selenoproteins and the Thyroid Axis A. Deiodinase enzymes-selenoproteins activating and inactivating thyroid hormones B. Selenium and thyroid function-the role of selenium in thyroid hormone synthesis C. Selenium status and supplementation in the "low-T 3 syndrome," nonthyroidal illness, sepsis, and related pathophysiological conditions D. Selenium, the thyroid axis, and chronic hemodialysis VII. Selenium and the Endocrine System A. Selenium and the pituitary hormones B. Selenium accumulation in the pineal gland C. Selenium and selenoproteins during lactation and in the mammary gland D. Selenium and the adrenals E. Selenium, pancreas, and diabetes F. Selenium and selenoproteins in the female reproductive tract G. Selenium and male reproduction H. Selenoproteins in bone I. Selenium, the hormonal system of the skin, and selenoproteins in muscle J. Selenoproteins and the hormonal regulation of endothelial function I. Historical Aspects

A complex network of mediator molecules constitutes a communication system coordinating different cells and tissues within the body, thus maintaining or restoring physiological homeostasis.In the past few years, progress in molecular immunobiology has led to the characterization of a still growing number of hormonelike proteins that, besides the classical hormones, mediate the interaction between different cells and tissues.These hormonelike proteins are called cytokines or peptide regulatory factors (1-5).Most of these cytokines are glycoproteins with a molecular mass below 80,000 Da.Cells involved in cytokine synthesis include blood cells such as monocytes, lymphocytes, neutrophils and platelets; stromal cells such as fibroblasts, endothelial cells and smooth muscle cells; and epithelial cells such as keratinocytes and hepatocytes.Cytokines usually act in picomolar concentrations through specific high-affinity cell surface receptors.In contrast to the classical hormones, they act mainly in a paracrine and autocrine manner on neighboring cells and themselves, but they can also act in an endocrine manner on distant cells.A single cytokine may not only be produced by a variety of cell types in response to different stimuli but may also have multiple biological effects on different target cells (Table 1).Most cytokines have been identified by analyzing mediator molecules responsible for the dramatic changes occurring during inflammation.Cytokines represent the signal substances causing the changes during the inflammatory response such as fever, leukocytosis and thrombocytosis, immune responses and the hepatic acute-phase response.Most of what we know about the effects of cytokines is related to inflammatory events.Therefore little is known about cytokine functions under normal physiological conditions.Until now these could only be deduced from the knowledge of their action during inflammation.Molecular cloning of cytokines has allowed the study of the effects of pure cytokines i n vitro and in viuo, and such an approach will help us learn more about their functions.Not only does the liver play a pivotal role as a major organ of intermediary metabolism, but it also partici-

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

We have recently reported that nicotine has angiogenic effects, which appear to be mediated through non-neuronal nicotinic acetylcholine receptors (nAChRs). Here, we describe the endogenous cholinergic pathway for angiogenesis. In an in vitro angiogenesis model, increasing concentrations of the nonselective nAChR antagonist mecamylamine completely and reversibly inhibited endothelial network formation. Although several nAChR isoforms are expressed on endothelial cells (ECs), a similar inhibition was only obtained with the selective alpha7-nAChR antagonist alpha-bungarotoxin, whereas other selective antagonists did not result in significant inhibition of network formation. alpha7-nAChR was upregulated during proliferation, by hypoxia in vitro, and by ischemia in vivo. The nAChR-induced network formation was partially dependent on VEGF, was completely dependent on the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, and finally resulted in NF-kappaB activation. In vivo, pharmacological inhibition of nAChR as well as genetic disruption of alpha7-nAChR expression significantly inhibited inflammatory angiogenesis and reduced ischemia-induced angiogenesis and tumor growth. Our results suggest that nAChRs may play an important role in physiological and pathological angiogenesis. To our knowledge, this is the first description of a cholinergic angiogenic pathway, and it suggests a novel avenue for therapeutic modulation of angiogenesis.

STUDY DESIGN: Intradiscal pressure and intersegmental rotation of human lumbar spines were measured in vitro. OBJECTIVES: To determine the effect of a follower load on mechanical behavior at all levels of the lumbar spine. SUMMARY OF BACKGROUND DATA: Different loads have been proposed for studying the mechanical behavior of the lumbar spine. The influence of a follower load on intradiscal pressure at the different levels is unknown. METHODS: Ten human cadaveric lumbar spines were loaded in the three main anatomic planes with pure moments of 3.75, 7.5, and 7.5 Nm plus a follower load of 280 N. Intradiscal pressure and intersegmental rotation were measured at all levels. RESULTS: An additional follower load increased the intradiscal pressure, slightly reduced the intersegmental rotation for axial rotation, and hardly affected intersegmental rotation for lateral bending and flexion-extension. CONCLUSIONS: A superimposed follower load renders spinal loading with pure moments more physiologic.

Integrins and other adhesion receptors are essential components for outside-in and inside-out signaling through the cell membrane. The platelet glycoprotein IIb-IIIa (also known as fibrinogen receptor or integrin alpha IIb beta 3) is activated by platelet agonists, inhibited by cyclic-nucleotide-elevating agents, and is involved in the activation of protein tyrosine kinases including the 125-kDa focal adhesion kinase (pp125FAK). However, the molecular details of glycoprotein IIb-IIIa regulation are not well understood. Here we report that in ADP-activated human platelets cAMP- and cGMP-dependent protein-kinase-mediated phosphorylation of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) at Ser157 correlates well with glycoprotein IIb-IIIa inhibition. Human platelets contain similar concentrations of glycoprotein IIb-IIIa complexes (fibrinogen binding sites) and VASP. Using gel-filtered platelets, cAMP-elevating agents [e.g. prostaglandin E1 and the forskolin analog 6-(3-dimethylaminopropionyl)forskolin (NKH 477)] caused VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to 70-100%. NO-generating, cGMP-elevating agents [e.g. 3-morpholinosydnonimine hydrochloride (SIN1) and sodium nitroprusside] stimulated VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to a maximal extent of 30-50%. The effects of cAMP- and cGMP-elevating agents on VASP phosphorylation and fibrinogen binding were reversible and could be mimicked by membrane-permeant selective activators of platelet cAMP- or cGMP-dependent protein kinase, respectively. Using threshold concentrations, the nitrovasodilator SIN 1 potentiated the effects of the forskolin analog NKH 477 with respect to inhibition of platelet aggregation, VASP phosphorylation and glycoprotein IIb-IIIa inhibition. It is proposed that the inhibition of glycoprotein IIb-IIIa induced by cyclic nucleotide involves cAMP-and cGMP-dependent protein-kinase-mediated VASP phosphorylation at Ser157.

OBJECTIVE: To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. DESIGN: Randomised, blinded, multicentre trial with parallel group design. SETTING: Nine hospitals and one outpatient clinic in Germany. PARTICIPANTS: 272 patients with chronic plantar fasciitis recalcitrant to conservative therapy for at least six months: 135 patients were allocated extracorporeal shock wave therapy and 137 were allocated placebo. MAIN OUTCOME MEASURES: Primary end point was the success rate 12 weeks after intervention based on the Roles and Maudsley score. Secondary end points encompassed subjective pain ratings and walking ability up to a year after the last intervention. RESULTS: The primary end point could be assessed in 94% (n=256) of patients. The success rate 12 weeks after intervention was 34% (n=43) in the extracorporeal shock wave therapy group and 30% (n=39) in the placebo group (95% confidence interval - 8.0% to 15.1%). No difference was found in the secondary end points. Few side effects were reported. CONCLUSIONS: Extracorporeal shock wave therapy is ineffective in the treatment of chronic plantar fasciitis.

BACKGROUND: Autologous chondrocyte implantation (ACI) is frequently used to treat symptomatic defects of the articular cartilage. PURPOSE: To test whether matrix-associated autologous chondrocyte implantation or the original periosteal flap technique provides superior outcomes in terms of clinical efficacy and safety. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Twenty-one patients (mean age, 29.3 +/- 9.1 years) with symptomatic isolated full-thickness cartilage defects (mean 4.1 +/- 09 cm2) at the femoral condyle were randomized to matrix-associated autologous chondrocyte implantation or the original periosteal flap technique. The primary outcome parameter was the postoperative change in knee function as assessed by the International Knee Documentation Committee (IKDC) score at 12 months after ACI. In addition, the IKDC score was assessed at 3, 6, 12, and 24 months after surgery. Secondary outcome parameters were postoperative changes in health related quality of life (Short Form-36 Health Survey), knee functionality (Lysholm and Gillquist score), and physical activity (Tegner Activity Score) at 3, 6, 12, and 24 months after ACI. Magnetic resonance imaging was performed to evaluate the cartilage 6, 12, and 24 months after ACI and rated using the Magnetic Resonance Observation of Cartilage Repair Tissue score. Adverse events were recorded to assess safety. RESULTS: The primary outcome parameter showed improvement of patients 1 year after autologous chondrocyte implantation, but there was no difference between the periosteal flap technique and matrix-associated ACI (P = .5573); 2 years after ACI, a similar result was found (P = .4994). The study groups did not show differences in the Short Form-36 categories and in knee functionality as assessed by Tegner Activity Score 12 months (P = .4063) and 24 months (P = .1043) after ACI. There was a significant difference in the Lysholm and Gillquist score at 12 months (P = .0449) and 24 months (P = .0487) favoring the periosteal flap technique group. At 6 months after surgery, a significantly lower Magnetic Resonance Observation of Cartilage Repair score was obtained in the matrix-associated ACI group (P = .0123), corresponding to more normal magnetic resonance imaging diagnostic findings. Twelve and 24 months after ACI, the differences between the 2 groups were not significant (12 months, P = .2065; 24 months, P = .6926). Adverse events were related to knee problems such as transplant delamination, development of an osseous spur, osteochondral dissection, and transplant hypertrophy. Systemic (allergic, toxic, or autoimmune) reactions did not occur. CONCLUSION: There was no difference in the efficacy between the original and the advanced ACI technique 12 and 24 months after surgery regarding International Knee Documentation Committee, Tegner Activity Score, and Short Form-36; however, with respect to the Lysholm and Gillquist score, better efficacy was observed in the periosteal flap technique group.

We evaluated 29 knees with a minimum follow-up of 2 years after anterior cruciate ligament (ACL) reconstruction using doubled autogenous semitendinosus tendons. On the femoral side, a 5-mm Mersilene tape (Ethicon, Norderstedt, Germany) with an Endobutton (Acufex Microsurgical, Mansfield, MA) was used. The tendon was fixed on the tibial side with two staples. Regarding the IKDC score, 66% of the patients were graded as normal or nearly normal. The anterior laxity side-to-side difference (KT 1000, man-max-drawer) was under 3 mm in 55% and under 5 mm in 90%. Radiographs taken in the lateral and anteroposterior projections of the knee showed sclerotic bone tunnel margins. The diameter of the bone tunnels were measured, corrected for magnification, then compared with the original reamed diameter to determine any change in size. Enlargement of at least 2 mm was identified in 72% of the femoral tunnels and 38% of the tibial tunnels. No correlation was found concerning the enlargement of the tunnel and the IKDC score or the residual joint laxity. We conclude that using an Endobutton-Mersilene construct in ACL reconstruction leads to femoral and tibial bone tunnel enlargement at follow-up of 2 years.

The skeleton is the most common site to be affected by metastatic cancer. The place of surgical treatment and of different techniques of reconstruction has not been clearly defined. We have studied the rate of survival of 94 patients and the results of the surgical treatment of 91 metastases of the limbs and pelvis, and 18 of the spine. Variables included the different primary tumours, the metastatic load at the time of operation, the surgical margin, and the different techniques of reconstruction. The survival rate was 0.54 at one year and 0.27 at three years. Absence of visceral metastases and of a pathological fracture, a time interval of more than three years between the diagnosis of cancer and that of the first skeletal metastasis, thyroid carcinoma, prostate carcinoma, renal-cell carcinoma, breast cancer, and plasmacytoma were positive variables with regard to survival. The metastatic load of the skeleton and the surgical margin were not of significant influence. In tumours of the limbs and pelvis, the local failure rate was 0% after biological reconstruction (10), 3.6% after cemented or uncemented osteosynthesis (28) and 1.8% after prosthetic replacement (53). The local failure rate after stabilisation of the spine (18) was 16.6%. There was local recurrence in seven patients (6.4%), and in four of these the primary tumour was a renal-cell carcinoma. The local recurrence rate was 0% after extralesional (24) and 8.2% after intralesional resection (85). Improvements in the oncological management of patients with primary and metastatic disease have resulted in an increased survival rate. In order to avoid additional surgery, it is essential to consider the expected time of survival of the reconstruction and, in bony metastases with a potentially poor response to radiotherapy, the surgical margin.

PURPOSE: The inability to fully activate the quadriceps femoris muscle voluntarily is known to accompany several different knee-joint pathologies. The extent of a voluntary-activation deficit in patients after isolated rupture of the anterior cruciate ligament (ACL), however, has been reported to be small or nonexistent, making it questionable if a voluntary-activation deficit is a relevant factor for these patients at all. METHODS: In this study the ability to voluntarily activate the quadriceps femoris muscles was quantified in 22 male patients with arthroscopically-proven isolated ACL ruptures using an established highly sensitive twitch-interpolation technique. Furthermore, the maximal voluntary contraction force of the quadriceps muscle was obtained by isometric knee-joint torque measurements. The results were compared with an age-, gender-, and activity-matched control group. RESULTS: There was a moderate but significant mean reduction in maximal voluntary activation (VA) in both the injured (VA: 83.9 +/- 2.3%, mean +/- SEM) and uninjured side (VA: 84.7 +/- 2.2%) in comparison with controls (VA: 91.1 +/- 0.8%). However, of the patients the 23% who presented a considerably reduced voluntary-activation of less than 80% were mainly responsible for the significant mean deficit. CONCLUSIONS: The deficit of isometric muscle strength on the injured side compared with that of controls was explained by the voluntary-activation deficit and a true muscle weakness. On the other hand, the diminished muscle strength of the uninjured side was explained sufficiently by the voluntary-activation deficit alone. Considering the bilateral voluntary-activation deficit, functional muscle tests might not be valid when the uninjured extremity serves as reference.

When the published data on the radial disc bulge in relation to the axial compression of the motion segment are compared to a simple mechanical model, it follows that an axial inward bulge of the vertebral endplates should occur during compression. The model predicts that the disc height at its center should remain practically constant under compression. The axial endplate bulge has been measured in specimens of the human lumbar spine by stereoroentgen-photogrammetric methods. The results confirm the prediction that the axial endplate bulge is comparable in magnitude to the linear compression of the motion segment. Axial endplate bulge and deformation of the underlying trabecular bone are thus important determinants for the compression characteristics of the human spine.

Background: It is difficult to achieve a successful revision total hip replacement when a patient has severe proximal femoral bone loss. The Wagner SL revision stem has some theoretical advantages, but the durability of this prosthesis is not known. Methods: We reviewed the results of 129 revisions of the femoral component with a Wagner SL revision stem in 123 patients. The indication for revision was aseptic loosening in ninety-seven hips, periprosthetic fracture in thirteen (one of which also had an infection), and septic loosening in sixteen. In the three remaining hips, a Wagner revision stem was inserted during a second-stage reimplantation after the performance of a Girdlestone resection arthroplasty to treat chronic deep infection. The prerevision defects were classified with the system described by Pak et al. as well as with our system. A functional evaluation of the patients and a survival analysis of the revision stems were performed. Results: The mean duration of follow-up was 4.8 years (range, two months to 11.1 years). Six revision stems required repeat revision. With removal of the stem for any cause or the worst case (removal of the stem for any cause and/or lost to follow-up) as the end point, cumulative survival at 11.1 years was 93.9% and 92.8%, respectively. The mean Merle d’Aubigné score improved from 7.7 points preoperatively to 14.8 points at the latest follow-up examination. The most recent radiographs showed good or excellent restoration of the proximal part of the femur in 113 hips (88%). Conclusions: Because of the encouraging results of implantation of this femoral component with distal fixation, we will continue to use it in the majority of femoral revisions. However, the need for regular follow-up remains, since the rate of complications such as osteolysis of the femur, aseptic loosening, periprosthetic fracture, and late infection may increase in the future.

Most platelet agonists activate and elevate the cytosolic free calcium concentration in human platelets through receptor-dependent mechanisms that are antagonized by cAMP- and cGMP-elevating agents. Nitrovasodilators such as nitroprusside and endothelium-derived relaxing factor are potent cGMP-elevating platelet inhibitors. In the present study, the role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of ADP- and thrombin-evoked calcium elevation and activation of human platelets was investigated. Preincubation of platelets with 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-pCPT-cGMP; a membrane-permeant selective activator of the cGMP-dependent protein kinase that does not significantly affect cGMP-regulated phosphodiesterases) inhibited the thrombin-induced phosphorylation mediated by myosin light chain kinase and protein kinase C. Nitrovasodilator-induced protein phosphorylation in human platelets was distinct from that induced by cAMP-elevating prostaglandins and could be mimicked by 8-pCPT-cGMP. Preincubation of human platelets with nitrovasodilators or 8-pCPT-cGMP inhibited the ADP- and thrombin-evoked calcium elevation in the presence and absence of external calcium. Nitrovasodilators and 8-pCPT-cGMP also inhibited the agonist-induced Mn2+ influx, but stopped-flow experiments indicated that the ADP receptor-operated cation channel was not significantly inhibited. These results suggest that in human platelets nitrovasodilators inhibit the agonist-induced calcium mobilization from intracellular stores and the secondary store-related calcium influx but not the ADP receptor-operated cation channel. The results also suggest that these nitrovasodilator effects are mediated by cGMP and the cGMP-dependent protein kinase.

The syndrome of diminished femoral antetorsion, evaluated in 111 joints of 59 children and adults, is described. Internal rotation of the femur was significantly decreased, and external rotation was increased. Femoral antetorsion was diminished in biplane radiographs to an 8.5 degrees mean value [1.0 degree in computed tomography (CT) scans]. Antetorsion values are higher in children, even in this syndrome. Pain was mainly experienced between the ages of 12 and 30 years. Ten patients had signs of beginning osteoarthritis. Rotational osteotomies performed to increase antetorsion were successful.

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.

STUDY DESIGN: This investigation was aimed at characterizing anomalies and syndromes associated with Klippel-Feil syndrome in a large group of patients. The authors evaluated the clinical and radiographic features, documented the associated anomalies, and registered the type of treatment. OBJECTIVE: The anomalies or syndromes and the development of scoliosis were correlated to the type of Klippel-Feil syndrome. MATERIAL AND METHODS: In a cross-sectional study, the authors reviewed data from 57 patients with Klippel-Feil syndrome treated over 25 years at the Department for Orthopedics of the University of Heidelberg. The patients (17 males and 40 females; average age of the first contact, 12 years) were classified into three types according to the description of Feil in 1919. RESULTS: Klippel-Feil syndrome Type I (fusion of cervical and upper thoracic vertebra with synostosis) and Type II (isolated cervical spine) corresponded to 40% and 47% of patients, respectively. Type III (cervical vertebra associated with lower thoracic or upper lumbar fusion) was displayed in 13% of the patients only. The authors found a variety of combinations of Klippel-Feil syndrome and other anomalies in the patients examined in this study, with 67% of the patients characterized by an association with other disorders or syndromes. Of the patients, 70% showed scoliosis. Its degree depended on the type of Klippel-Feil syndrome. Scoliosis in Type I correlated with 31 degrees (Cobb angle), in Type III with 23 degrees, and in Type II with 9 degrees only. Thus, Type II, with isolated cervical fusion, shows a low risk for scoliosis. CONCLUSION: This study increases knowledge of a wide range of anomalies and syndromes identified in association with Klippel-Feil syndrome. A special finding of the study was a correlation between the degree of scoliosis and Klippel-Feil syndrome Types I, II, and III.