In vivo compatibility of Dynesys(®) spinal implants: a case series of five retrieved periprosthetic tissue samples and corresponding implants.

PURPOSE: To determine whether particulate debris is present in periprosthetic tissue from revised Dynesys(®) devices, and if present, elicits a biological tissue reaction. METHODS: Five Dynesys(®) dynamic stabilization systems consisting of pedicle screws (Ti alloy), polycarbonate-urethane (PCU) spacers and a polyethylene-terephthalate (PET) cord were explanted for pain and screw loosening after a mean of 2.86 years (1.9-5.3 years). Optical microscopy and scanning electron microscopy were used to evaluate wear, deformation and surface damage, and attenuated total reflectance Fourier transform infrared spectroscopy to assess surface chemical composition of the spacers. Periprosthetic tissue morphology and wear debris were determined using light microscopy, and PCU and PET wear debris by polarized light microscopy. RESULTS: All implants had surface damage on the PCU spacers consistent with scratches and plastic deformation; 3 of 5 exhibited abrasive wear zones. In addition to fraying of the outer fibers of the PET cords in five implants, one case also evidenced cord fracture. The pedicle screws were unremarkable. Patient periprosthetic tissues around the three implants with visible PCU damage contained wear debris and a corresponding macrophage infiltration. For the patient revised for cord fracture, the tissues also contained large wear particles (>10 µm) and giant cells. Tissues from the other two patients showed comparable morphologies consisting of dense fibrous tissue with no inflammation or wear debris. CONCLUSIONS: This is the first study to evaluate wear accumulation and local tissue responses for explanted Dynesys(®) devices. Polymer wear debris and an associated foreign-body macrophage response were observed in three of five cases.

[LiLa classification for paediatric long bone fractures. Intraobserver and interobserver reliability]. / LiLa-Klassifikation für Frakturen der langen Röhrenknochen im Wachstumsalter. Intra- und Interobserverreliabilität.

BACKGROUND: There are two child-specific fracture classification systems for long bone fractures: the AO classification of pediatric long-bone fractures (PCCF) and the LiLa classification of pediatric fractures of long bones (LiLa classification). Both are still not widely established in comparison to the adult AO classification for long bone fractures. METHODS: During a period of 12 months all long bone fractures in children were documented and classified according to the LiLa classification by experts and non-experts. Intraobserver and interobserver reliability were calculated according to Cohen (kappa). RESULTS: A total of 408 fractures were classified. The intraobserver reliability for location in the skeletal and bone segment showed an almost perfect agreement (K = 0.91-0.95) and also the morphology (joint/shaft fracture) (K = 0.87-0.93). Due to different judgment of the fracture displacement in the second classification round, the intraobserver reliability of the whole classification revealed moderate agreement (K = 0.53-0.58). Interobserver reliability showed moderate agreement (K = 0.55) often due to the low quality of the X-rays. Further differences occurred due to difficulties in assigning the precise transition from metaphysis to diaphysis. CONCLUSIONS: The LiLa classification is suitable and in most cases user-friendly for classifying long bone fractures in children. Reliability is higher than in established fracture specific classifications and comparable to the AO classification of pediatric long bone fractures. Some mistakes were due to a low quality of the X-rays and some due to difficulties to classify the fractures themselves. Improvements include a more precise definition of the metaphysis and the kind of displacement. Overall the LiLa classification should still be considered as an alternative for classifying pediatric long bone fractures.

[Influencing factors on the length of stay in lumbar spine surgery : analysis of the German spine registry]. / Einflussfaktoren auf die Verweildauer in der Wirbelsäulenchirurgie : Eine Datenanalyse des Deutschen Wirbelsäulenregisters.

INTRODUCTION: Spinal disc herniation, lumbar spinal stenosis and spondylolisthesis are known to be leading causes of lumbar back pain. The cost of low back pain management and related operations are continuously increasing in the healthcare sector. There are many studies regarding complications after spine surgery but little is known about the factors predicting the length of stay in hospital. The purpose of this study was to identify these factors in lumbar spine surgery in order to adapt the postoperative treatment. MATERIAL AND METHODS: The current study was carried out as a post hoc analysis on the basis of the German spine registry. Patients who underwent lumbar spine surgery by posterior surgical access and with posterior fusion and/or rigid stabilization, whereby procedures with dynamic stabilization were excluded. Patient characteristics were tested for association with length of stay (LOS) using bivariate and multivariate analyses. RESULTS: A total of 356 patients met the inclusion criteria. The average age of all patients was 64.6 years and the mean LOS was 11.9 ± 6.0 days with a range of 2-44 days. Independent factors that were influencing LOS were increased age at the time of surgery, higher body mass index, male gender, blood transfusion of 1-2 erythrocyte concentrates and the presence of surgical complications. CONCLUSION: Identification of predictive factors for prolonged LOS may allow for estimation of patient hospitalization time and for optimization of postoperative care. In individual cases this may result of a reduction in the LOS.

Evaluation of costs associated with fertility treatment leading to a live birth after one fresh transfer: A global perspective.

Considerable costs are associated with infertility treatment, but little evidence is available on the main drivers of treatment costs. This cost analysis investigated key costs for treatment with assisted reproductive technology (ART) and the proportion of costs attributed to the acquisition of recombinant human follicle-stimulating hormone (r-hFSH) alfa originator for one fresh embryo transfer (ET) leading to a live birth in Spain, Norway, the UK, Germany, Denmark, South Korea, Australia, and New Zealand. The total costs for one ART cycle with a fresh ET leading to a live birth varied between countries (€4108-€12,314). Costs for pregnancy and live birth were the major contributors in European countries, and the costs of oocyte retrieval, monitoring during ovarian stimulation, pregnancy, and live birth were the top contributors in the Asia-Pacific countries, included in this analysis. Acquisition costs for r-hFSH alfa originator contributed to only 5%-17% of the total costs of one ART cycle with one fresh ET leading to a live birth.

Neurological outcome, working capacity and prognostic factors of patients with SCIWORA.

STUDY DESIGN: Retrospective case review. OBJECTIVES: In the present study, the neurological outcome, retirement and prognostic factors of patients with spinal cord injury without radiographic abnormality (SCIWORA) were evaluated. SETTING: Swiss national work accident insurance database. METHODS: The medical histories of 32 patients who were insured by the Swiss Accident Insurance Fund (SUVA) and had SCIWORA between 1995 and 2004 were evaluated thoroughly. Moreover, all available magnetic resonance imaging (MRI) scans were evaluated. RESULTS: At the last follow-up, none of the patients had complete spinal cord injury, only 4 patients had severe deficits and 12 patients had normal motor and sensory function in the neurological examination. However, only 7 out of 32 patients had returned to full-time work and 10 out of 32 patients were fully retired. Both the presence of spinal cord change (ρ=0.51) and higher maximum spinal cord compression (ρ=0.57) in MRI scan correlated with the likelihood for retirement; older age (ρ=0.38) and physical load of work (ρ=0.4) correlated with retirement to a lesser extent. CONCLUSION: Although the neurological outcome of SCIWORA is mostly good, the retirement rate is high. Presence of spinal cord change and severity of cord compression are the best predictors for the degree of retirement.

Identification of prognostic factors for chronicity in patients with low back pain: a review of screening instruments.

Low back pain (LBP) is currently the most prevalent and costly musculoskeletal problem in modern societies. Screening instruments for the identification of prognostic factors in LBP may help to identify patients with an unfavourable outcome. In this systematic review screening instruments published between 1970 and 2007 were identified by a literature search. Nine different instruments were analysed and their different items grouped into ten structures. Finally, the predictive effectiveness of these structures was examined for the dependent variables including "work status", "functional limitation", and "pain". The strongest predictors for "work status" were psychosocial and occupational structures, whereas for "functional limitation" and "pain" psychological structures were dominating. Psychological and occupational factors show a high reliability for the prognosis of patients with LBP. Screening instruments for the identification of prognostic factors in patients with LBP should include these factors as a minimum core set.

Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis.

The Fas system, comprising the Fas receptor (Fas, CD95, APO-1) and its ligand, Fas ligand (FasL), is a central mediator of programmed cell death in various physiological and pathological processes. Recent evidence indicated that tumor cells can exploit this system to their benefit in the dialogue with the host immune system. We have shown that all human pancreatic adenocarcinoma cell lines tested by fluorescence-activated cell sorting analysis (6 of 6) and immunocytochemistry (12 of 12) were positive for Fas expression, as were normal and malignant duct cells in pancreatic tissue sections. However, despite Fas expression, pancreatic tumor cells have become largely resistant toward recombinant FasL- or anti-APO-1 agonistic antibody-induced apoptosis. This resistance correlated with high levels in pancreatic tumor cells of mRNA for FAP-1, a Fas-associated phosphatase that can block the apoptotic function of Fas. Using a variety of methodological approaches, we also present evidence for the production of FasL by pancreatic tumor cells because 6 of 6 pancreatic tumor cell lines were found to contain FasL mRNA as well as the Mr 40,000 and Mr 26,000 forms of the FasL protein. Likewise, pancreatic tissue revealed FasL-specific immunostaining in pancreatic tumor cells but not in the surrounding stroma. In coculture experiments, pancreatic tumor cells displayed a cytotoxic effect toward the Fas-sensitive Jurkat T-cell line, which could be inhibited by a FasL-specific neutralizing antibody. Together, these results support the recently proposed "counterattack model" for local deletion of tumor-reactive T-cells by tumor cell-derived FasL.

Modulation of platelet-derived growth factor A- and B-chain/c-sis mRNA by tumor necrosis factor and other agents in adenocarcinoma cells.

Human Platelet Derived Growth Factors (PDGF) are potent mitogens for mesenchymal cells and encoded by two related genes, the A- (or 1-) and B- (or 2-) chain. The latter is known as the human homolog (c-sis) of the v-sis oncogene. We investigated the expression and cytokine-mediated regulation of PDGF A- and B-chain mRNA in endoderm-derived cells, i.e. cultured human pancreatic adenocarcinoma cells. Northern blot analysis revealed that out of 14 cells lines 11 were positive for the A-chain and 10 for the B-chain. Tumor Necrosis Factor (TNF) -alpha and -beta, but not Interferon (IFN) -gamma, drastically upregulate the mRNA levels for PDGF B-chain and for the A-chain in a dose-dependent manner in nearly every pancreatic tumor cell line investigated (n = 6). With respect to the signal pathway stimulated by TNF, no evidence emerged for an activation of protein kinase A. The inhibition of protein kinase C by staurosporine (in the absence or presence of TNF) as well as its stimulation by PMA resulted in an increased mRNA level for the B-chain, indicating a functional role of PKC in this system. Furthermore, time course experiments and Cycloheximide treatment showed that the A- and B-chain mRNA are regulated by different mechanisms in transformed epithelial cells. Irrespective of these differences, the sum of their biological functions may contribute to the phenomenon of desmoplasia in pancreatic tumors by epithelial/mesenchymal interactions.

p53 and K-RAS alterations in pancreatic epithelial cell lesions.

We have analysed the expression of p53 at the mRNA level, and extensively at the protein level by immunostaining, Western blotting, and ELISA measurements revealing a p53 increase in 8 out of 14 cell lines established from human pancreatic carcinomas. The mRNA levels closely paralleled the protein levels in most of the cell lines. Overexpression of p53 in tumor cells correlated with mutations in the p53 gene. Immunocytochemistry was also performed with tissue cryosections showing a nuclear p53 staining in 8 out of 12 exocrine, and 2 out of 2 endocrine tumors. In addition, nonmalignant peri-tumoral tissue specimens and cells derived from pancreatic juice of acute pancreatic patients were also positively stained. These findings may suggest functions of p53 in stress situations induced by acute inflammation or tissue regeneration. Genomic mutations in the tumor suppressor gene were associated with point mutations in either codon 12, 13 or 61 in the c-K-RAS oncogene in about two-thirds of cell lines. The frequent activations of a RAS oncogene in combination with mutations of a tumor suppressor gene are likely to contribute to the malignant phenotype of pancreatic adenocarcinomas.

Circulating APRIL levels are correlated with advanced disease and prognosis in rectal cancer patients.

We have previously shown that the tumor necrosis factor family member a proliferation-inducing ligand (APRIL) enhances intestinal tumor growth in various preclinical tumor models. Here, we have investigated whether APRIL serum levels at time of surgery predict survival in a large cohort of colorectal cancer (CRC) patients. We measured circulating APRIL levels in a cohort of CRC patients (n=432) using a novel validated monoclonal APRIL antibody (hAPRIL.133) in an enzyme-linked immunosorbent assay (ELISA) setup. APRIL levels were correlated with clinicopathological features and outcome. Overall survival was examined with Kaplan-Meier survival analysis, and Cox proportional hazards ratios were calculated. We observed that circulating APRIL levels were normally distributed among CRC patients. High APRIL expression correlated significantly with poor outcome measures, such as higher stage at presentation and development of lymphatic and distant metastases. Within the group of rectal cancer patients, higher circulating APRIL levels at time of surgery were correlated with poor survival (log-rank analysis P-value 0.008). Univariate Cox regression analysis for overall survival in rectal cancer patients showed that patients with elevated circulating APRIL levels had an increased risk of poor outcome (hazard ratio (HR) 1.79; 95% confidence interval (CI) 1.16-2.76; P-value 0.009). Multivariate analysis in rectal cancer patients showed that APRIL as a prognostic factor was dependent on stage of disease (HR 1.25; 95% CI 0.79-1.99; P-value 0.340), which was related to the fact that stage IV rectal cancer patients had significantly higher levels of APRIL. Our results revealed that APRIL serum levels at time of surgery were associated with features of advanced disease and prognosis in rectal cancer patients, which strengthens the previously reported preclinical observation of increased APRIL levels correlating with disease progression.

Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.

Besides its pharmacological effect on cholesterol biosynthesis, lovastatin inhibits p21ras proteins by substrate depletion for post-translational protein farnesylation and geranylation. This inhibition has previously been used to reverse cell proliferation after cellular transformation by the mutant p21ras oncogene. We investigated the biological effects of lovastatin on two pancreatic carcinoma cell lines. The SW-850 cell line contained the k-ras wild-type gene and the A818-4 cell line contained the mutant gene with a point mutation at codon 12 (GGTZCGT; glyZarg). Lovastatin inhibited the proliferation of pancreatic carcinoma cells dose-dependently showing an IC20-30 at 5 microM and IC40-50 at 10 microM. Proliferation of both cancer cell lines, A818-4 (p21ras-M) and SW-850 (p21ras-WT) were inhibited to a very similar extent. After 24 h of drug exposure, cell cycle arrest in G1 and G2/M-phase occurred in a large proportion of cells. At this time, neither cell line showed alteration of protein phosphorylation and did not undergo apoptosis. However, after 72 h of drug exposure, lovastatin significantly decreased protein phosphorylation on tyrosine, serine and threonine residues in A818-4 (p21ras-M) cells. Only a minute reduction of protein phosphorylation was detected in SW-850 (p21ras-WT) cells. Apoptosis occurred in both cell lines, but the SW-850 (p21ras-WT) showed a higher percentage of apoptotic cells than the A818-4 (p21ras-M). In conclusion, there is further evidence for a growth inhibitory effect on cancer cells regardless of the ras mutation status. However, as the effects on protein phosphorylation and induction of apoptosis differed between the mutant and wild-type cell lines, the mechanism of action of lovastatin may depend on partially different mechanisms.

Psoriatic erythroderma and bullous pemphigoid treated successfully with acitretin and azathioprine.

We present the case of a 59-year-old male patient who developed lesions of a bullous pemphigoid during the course of a long-lasting severe psoriasis which had been treated for years with different topical treatments as well as with PUVA and UV-B radiations. Our patient was successfully treated with a combination of acitretin and azathioprine (follow up 28 months). Our case shows that it is possible to avoid systemic corticosteroid treatment in this difficult therapeutic situation.

The relationship between cup design and the radiological signs of aseptic loosening in total hip arthroplasty.

We assessed differences in the incidence and appearance of the radiological signs of loosening of the cup for various types of design. This was an observational study based on hip registry data of 15,340 patients with 17,951 total hip arthroplasties collected over a period of 33 years in 49 hospitals in Central Europe. The threaded and the press-fit titanium cups showed significantly less aseptic loosening than the other systems. The direction of migration and the frequency of the radiological signs of loosening differed between the cup systems and were time-dependent. Our findings indicate the superiority of uncemented threaded cups and press-fit titanium cups over other designs of cup.

Risk factors for early dislocation after total hip arthroplasty: a matched case-control study.

PURPOSE: To evaluate risk factors for early dislocation after primary total hip arthroplasty (THA). METHODS: Records of 175 cases with dislocation during hospitalisation after THA and 651 controls without dislocation were reviewed. Cases and controls were matched for age, gender, body mass index classification, primary diagnosis, cup design, hospital, and year of intervention. Version and inclination of the acetabular component and version of the femoral component were assessed intra- and post-operatively. Various risk factors were analysed, including surgical approach, cup positioning, combined cup and stem positioning, and femoral head size. RESULTS: The posterior approach was 6 fold more prone to dislocation (odds ratio [OR]=6.3, p<0.018) than the anterolateral or straight lateral approach. With regard to combined cup and stem positioning, the acceptable position was at significantly higher risk of dislocation than the ideal position (OR=2.59, p=0.033). Larger femoral head sizes were associated with significantly lower risk of dislocation (OR=0.84, p=0.02). CONCLUSION: Surgical approach, combined cup and stem positioning, and femoral head size were significant risk factors for dislocation during hospitalisation.

Reappearance in vivo of neuraminidase-sensitive sialic acid in L 5222 rat leukemia cells.

Cell electrophoretic data and quantitative sialic acid determination show that, 16 to 20 h after i.p. implantation of neuraminidase-treated L 5222 rat leukemia cells, the original sialic acid content at the cell periphery is reconstituted.

Tumor necrosis factor (TNF) up-regulates the expression of p75 but not p55 TNF receptors, and both receptors mediate, independently of each other, up-regulation of transforming growth factor alpha and epidermal growth factor receptor mRNA.

The expression and cytokine-mediated regulation of the two different receptors for tumor necrosis factor, TNF-R-75 and TNF-R-55, was investigated in human malignant epithelial cell lines. Here we show that cells treated with TNF-alpha up-regulate the TNF-R-75 mRNA and protein levels. No changes were seen regarding the level of TNF-R-55 transcripts. Phospholipase and protein kinase C inhibitors abrogated the signal transduction pathway of TNF-mediated TNF-R-75 mRNA up-regulation which proceeded in the absence of transcriptional activation. This process was also elicited by an agonistic antibody binding specifically to TNF-R-55. Ligand binding assays using specific inhibitory antibodies showed a marked shift in active binding sites from p55 to p75 without significant changes in the total binding for TNF-alpha after up-regulation of p75 TNF-R. This ligand-induced regulation of one of the corresponding receptors has so far only been detected in malignant epithelial cells and not in hematopoietic cell lines. In our search for a specific function we were able to show that p75 is the specific receptor for TNF-mediated up-regulation of transforming growth factor alpha mRNA, whereas p55 is the signal transducer for TNF-induced up-regulation of epidermal growth factor receptor mRNA. This is the first demonstration of an exclusive function of TNF-R-75 in cells of epithelial origin.

Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.

Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells.

Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells.

Recombinant human tumor necrosis factor (TNF)-alpha increased the expression of epidermal growth factor receptor (EGFR) mRNA and protein in all of six human pancreatic carcinoma cell lines tested. In addition, TNF-alpha increased the expression of an EGFR ligand, transforming growth factor (TGF)-alpha, at the mRNA and protein level in all cell lines. Increased expression of EGFR protein was associated with elevated steady-state EGFR mRNA levels. Nuclear run-on analysis showed that increase in EGFR mRNA was due to an increased rate of transcription. Induction of EGFR mRNA expression by TNF-alpha was abrogated by cycloheximide but occurred independently of TNF-alpha-induced production of TGF-alpha protein. Protein kinase A or Gi-type guanine nucleotide-binding proteins were not involved in this process as assessed by using appropriate stimulators and inhibitors of these signal transduction pathways. By contrast, staurosporine, an inhibitor of protein kinase C, partially inhibited, and 4-bromophenacyl bromide, a phospholipase inhibitor, completely inhibited TNF-alpha-dependent EGFR mRNA expression. The phospholipase C-specific inhibitor tricyclodecan-9-yl xanthogenate did not alter TNF-alpha-dependent EGFR mRNA expression, suggesting that phospholipase A2 is involved in the modulation of EGFR expression by TNF-alpha. The simultaneous induction of a ligand/receptor system by TNF-alpha suggests that this cytokine modulates autocrine growth-regulatory pathways in pancreatic cancer cells.

Condition-specific outcome measures for low back pain. Part I: validation.

A literature review of the nine most widely used, condition-specific, self-administered assessment questionnaires for low back pain has been undertaken. General and historic aspects, reliability, responsiveness and minimum clinically important difference, external validity, floor and ceiling effects and available languages were analysed for the nine most-used outcome tools. When considering which condition-specific measure to employ, the present overview on assessment tools should provide the necessary information to define the technical aspects of the nine questionnaires. These criteria, however, are only part of the consideration. In part II the construction of these scales in relationship to the measurement domains will be evaluated.