Presentation and Management of Metastatic Periacetabular Disease: A Case Report.

Multiple myeloma is a malignancy of blood cells that commonly metastasizes to bone. Metastasis to the acetabulum can cause significant patient distress due to pathological fractures that can be extremely painful and affects patients' ability to ambulate. The lytic lesions are unique and often require surgical management in order to restore normal anatomy to allow for weight bearing. A multidisciplinary approach is necessary to establish patient goals and optimize treatment plans. This report describes the presentation and treatment of an elderly patient with multiple myeloma and an unstable acetabular fracture with a large lytic lesion of the pelvis.

Microfabricated bioelectrodes on self-expandable NiTi thin film devices for implants and diagnostic instruments.

State of the art minimally invasive treatments and diagnostics of neurological and cardiovascular diseases demand for flexible instruments and implants that enable sensing and stimulation of bioelectric signals. Besides medical applications, implantable bioelectronic brain-computer interfaces are envisioned as the next step in communication and data transfer. Conventional microelectrode arrays used for these types of applications are based on polymer substrates that are not suitable for biostable, rigid and self-expanding devices. Here, we present fully integrated bioelectrodes on superelastic NiTi carriers fabricated by microsystem technology processes. The insulation between the metallic NiTi structure and the Pt electrode layer is realized by different oxide layers (SiOx, TaOx and Yttrium stabilized Zirconia YSZ). Key properties of bioelectronic implants such as dissolution in body fluids, biocompatibility, mechanical properties and bioelectrical sensing/stimulation capabilities have been investigated by in vitro methods. Particular devices with YSZ are biostable and biocompatible, enabling sensing and stimulation. The major advantage of this system is the combination of medically approved materials and novel fabrication technology that enables miniaturization and integration beyond the state-of-the-art processes. The results demonstrate that this functionalization of superelastic NiTi is an enabling technology for the development of new kinds of bioelectronic devices.

Effect of crystallographic compatibility and grain size on the functional fatigue of sputtered TiNiCuCo thin films.

The positive influence of crystallographic compatibility on the thermal transformation stability has been already investigated extensively in the literature. However, its influence on the stability of the shape memory effect or superelasticity used in actual applications is still unresolved. In this investigation sputtered films of a highly compatible TiNiCuCo composition with a transformation matrix middle eigenvalue of 1±0.01 are exposed to thermal as well as to superelastic cycling. In agreement with previous results the thermal transformation of this alloy is with a temperature shift of less than 0.1 K for 40 cycles very stable; on the other hand, superelastic degradation behaviour was found to depend strongly on heat treatment parameters. To reveal the transformation dissimilarities between the differently heat-treated samples, the microstructure has been analysed by transmission electron microscopy, in situ stress polarization microscopy and synchrotron analysis. It is found that good crystallographic stability is not a sufficient criterion to avoid defect generation which guarantees high superelastic stability. For the investigated alloy, a small grain size was identified as the determining factor which increases the yield strength of the composition and decreases the functional degradation during superelastic cycling.This article is part of the themed issue 'Taking the temperature of phase transitions in cool materials'.

Failed metal-on-metal hip arthroplasties: a spectrum of clinical presentations and operative findings.

BACKGROUND: A number of recent reports have described novel failure mechanisms of metal-on-metal bearings in total and resurfacing hip arthroplasty. Hip arthroplasties with metal-on-metal articulations are also subject to the traditional methods of failure seen with different bearing couples. There is currently little information in the literature to help guide timely clinical evaluation and management of these patients. QUESTIONS/PURPOSES: We therefore describe the (1) clinical presentations; (2) reasons for failure; (3) operative findings; and (4) histologic findings in patients with failed metal-on-metal hip arthroplasties. METHODS: We retrospectively identified all 37 patients (37 hips) with metal on metal total hip or resurfacing arthroplasties who underwent revision over the past 3 years at our institution. Relevant clinical, radiographic, laboratory, intraoperative, and histopathologic findings were analyzed for all patients. RESULTS: Of the 37 patients, 10 were revised for presumed hypersensitivity specific to the metal-on-metal articulation. This group included eight patients with tissue histology confirming chronic inflammation with lymphocytic infiltration, eight with aseptic loosening of a monoblock screwless uncemented acetabular component, two with iliopsoas impingement associated with a large-diameter femoral head, and three with femoral neck fracture after resurfacing arthroplasty; the remainder of the patients were revised for infection, instability, component malposition, and periprosthetic fracture. CONCLUSIONS: Increased awareness of the modes of failure will bring to light the potential complications particular to metal-on-metal articulations while placing these complications into the context of failures associated with all hip arthroplasties. This novel clinical information should be valuable for the practicing surgeon faced with this patient population. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Magnetic moment investigation by frequency mixing techniques.

Gas turbines and other large industrial equipment are subjected to high-temperature oxidation and corrosion. Research and development of efficient protective coatings is the main task in the field. Also, knowledge about the depletion state of the coating during the operation time is important. To date, practical nondestructive methods for the measurement of the depletion state do not exist. By integrating magnetic phases into the coating, the condition of the coating can be determined by measuring its magnetic properties. In this paper, a new technique using frequency mixing is proposed to investigate the thickness of the coatings based on their magnetic properties. A sensor system is designed and tested on specific magnetic coatings. New approaches are proposed to overcome the dependency of the measurement on the distance between coil and sample that all noncontact techniques face. The novelty is a low cost sensor with high sensibility and selectivity which can provide very high signal-to-noise ratios. Prospects and limitations are discussed for future use of the sensor in industrial applications.

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(3); p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti- and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001).

Alteration of radiation-induced hematotoxicity by amifostine.

PURPOSE: To investigate whether amifostine can reduce radiation hematotoxicity. PATIENTS AND METHODS: Seventy-three patients undergoing radiotherapy for squamous cell carcinoma of the head and neck at the university clinics of Freiburg, Heidelberg, and Erlangen were evaluated. All received 60 Gy (50-70 Gy) at 5 x 2 Gy fractions per week employing standard techniques. Thirty-five were randomized to receive 200 mg/m(2) amifostine i.v. 30 min before radiation; 38 served as control patients. Blood counts (total n = 501) were determined before, during, and while completing radiotherapy. Changes of leukocyte, platelet, and hemoglobin levels were determined and compared using the t test. RESULTS: The blood hemoglobin level and the platelet count were not affected by irradiation, for either the amifostine-treated or control patients. Similarly, the leukocyte counts of amifostine-treated patients did not change during irradiation. However, control patients experienced a decrease in leukocyte count from 8.1 x 10(3)/mm(3) to 5.8 x 10(3)/mm(3) (difference: 2.3 x 10(3)/mm(3)). This seems to be line specific: Whereas amifostine does not affect lymphocyte count, a radiation-induced decrease of neutrophil granulocytes seems to be prevented. CONCLUSION: Amifostine protects from radiation hematotoxicity, particularly affecting the granulocytopoiesis. These data confirm results from our former study.

Blood hemoglobin level may affect radiosensitivity-preliminary results on acutely reacting normal tissues.

PURPOSE: To evaluate the influence of blood hemoglobin concentration on the radiosensitivity of acutely reacting normal tissues. METHODS AND MATERIALS: Weekly scores (EORTC/RTOG criteria) for acute reactions of skin and mucosa are available for 60 patients with cancer of the head and neck undergoing a standard conventional radiotherapy. The prognostic significance of blood hemoglobin levels on the development of acute reactions is studied by multivariate analysis (Cox Proportional Hazards Model). Further, the incidence and the time to development of these reactions is looked at in cohorts of patients with different mean blood hemoglobin concentrations during radiotherapy. Patients are therefore classified into a "severely anemic group" (hemoglobin < 11.0 g/100 mL), and into a cohort with a blood hemoglobin value equal or above 11.0 g/100 mL. RESULTS: Normal tissue scoring and monitoring of blood hemoglobin levels allows for a detailed analysis of possible correlations. A decrease in the mean blood hemoglobin value of 1 g/100 mL predicts a reduced risk to develop a skin reaction of Grade 2 or 3 (RR = 0.9; p = 0.08; RR = 0.8; p = 0.26, respectively) or a mucosa reaction of Grade 3 (RR = 0.8; p = 0.16), independent from the radiation dose, the treatment time and from previous surgery within the radiation volume (multivariate analysis). Likewise, patients with severe anemia develop grade 3 mucositis or dermatitis less often (0%; 13%) as compared to those with blood hemoglobin concentrations equal or above 11.0 g/100 mL (21%; 19%). Skin and mucosa reactions further tend to occur later in the course of radiation. The observations are not statistically significant and possible reasons will be discussed. CONCLUSIONS: A decreased blood hemoglobin concentration may-perhaps by an impaired tissue oxygenation-reduce the radiosensitivity of normal tissue such as skin and mucosa. However, the data is preliminary and needs further confirmation.

[Alteration of radiation-induced hematotoxicity by amifostine (ethyol)]. / Veränderte bestrahlungsinduzierte Hämatotoxizität durch Amifostin (Ethyol).

BACKGROUND: Radiotherapy--even of small volumes--can decrease leukocyte counts. We examined whether the radio-protector amifostine can reduce this hematotoxicity. PATIENTS AND METHODS: Twenty-six patients (Table 1) undergoing radiotherapy for squamous cell carcinoma of the head and neck were evaluated. All were given 60 (to 70) Gy 5 x 2 Gy per week in standard radiation techniques. Thirteen patients are randomized to receive 200 mg/m2 amifostine i.v., 30 minutes before radiation. Blood counts and differentials were determined before, during and following radiotherapy. Differences of these parameters are calculated and compared by t-test. RESULTS: The blood hemoglobin and the thrombocyte levels did not change during the radiotherapy course, neither for the amifostine treated, nor the control patients. Similarly the leukocyte counts of amifostine treated patients did not change during irradiation. The control patients, however, had a decrease of leukocytes from 8.4 to 6.0 x 10(3)/microliter, p = 0.03 (Table 2), and the reduction of the neutrophilic granulocyte count was more impressive for these patients. CONCLUSION: In this explorative study amifostine diminished radiation induced leukocyte toxicity.

Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors.

The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise.

Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor.

The human immunodeficiency virus (HIV) fusion inhibitor siamycin I, a 21-residue tricyclic peptide, was identified from a Streptomyces culture by using a cell fusion assay involving cocultivation of HeLa-CD4+ cells and monkey kidney (BSC-1) cells expressing the HIV envelope gp160. Siamycin I is effective against acute HIV type 1 (HIV-1) and HIV-2 infections, with 50% effective doses ranging from 0.05 to 5.7 microM, and the concentration resulting in a 50% decrease in cell viability in the absence of viral infection is 150 microM in CEM-SS cells. Siamycin I inhibits fusion between C8166 cells and CEM-SS cells chronically infected with HIV (50% effective dose of 0.08 microM) but has no effect on Sendai virus-induced fusion or murine myoblast fusion. Siamycin I does not inhibit gp120 binding to CD4 in either gp120- or CD4-based capture enzyme-linked immunosorbent assays. Inhibition of HIV-induced fusion by this compound is reversible, suggesting that siamycin I binds noncovalently. An HIV-1 resistant variant was selected by in vitro passage of virus in the presence of increasing concentrations of siamycin I. Drug susceptibility studies on a chimeric virus containing the envelope gene from the siamycin I-resistant variant indicate that resistance maps to the gp160 gene. Envelope-deficient HIV complemented with gp160 from siamycin I-resistant HIV also displayed a resistant phenotype upon infection of HeLa-CD4-LTR-beta-gal cells. A comparison of the DNA sequences of the envelope genes from the resistant and parent viruses revealed a total of six amino acid changes. Together these results indicate that siamycin I interacts with the HIV envelope protein.

Characterization of a human immunodeficiency virus type 1 variant with reduced sensitivity to an aminodiol protease inhibitor.

Development of viral resistance to the aminodiol human immunodeficiency virus (HIV) protease inhibitor BMS 186,318 was studied by serial passage of HIV type 1 RF in MT-2 cells in the presence of increasing concentrations of compound. After 11 passages, an HIV variant that showed a 15-fold increase in 50% effective dose emerged. This HIV variant displays low-level cross-resistance to the C2 symmetric inhibitor A-77003 but remains sensitive to the protease inhibitors Ro 31-8959 and SC52151. Genetic analysis of the protease gene from a drug-resistant variant revealed an Ala-to-Thr change at amino acid residue 71 (A71T) and a Val-to-Ala change at residue 82 (V82A). To determine the effects of these mutations on protease and virus drug susceptibility, recombinant protease and proviral HIV type 1 clones containing the single mutations A71T and V82A or double mutation A71T/V82A were constructed. Subsequent drug sensitivity assays on the mutant proteases and viruses indicated that the V82A substitution was responsible for most of the resistance observed. Further genotypic analysis of the protease genes from earlier passages of virus indicated that the A71T mutation emerged prior to the V82A change. Finally, the level of resistance did not increase following continued passage in increasing concentrations of drug, and the resistant virus retained its drug susceptibility phenotype 34 days after drug withdrawal.

Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease.

A series of aminodiol inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were identified by using an in vitro peptide cleavage assay. BMS 182,193, BMS 186,318, and BMS 187,071 protected cells against HIV-1, HIV-2, and simian immunodeficiency virus infections, with 50% effective doses ranging from 0.05 to 0.33 microM, while having no inhibitory effect on cells infected with unrelated viruses. These compounds were also effective in inhibiting p24 production in peripheral blood mononuclear cells infected with HIV-1 IIIB and against the zidovudine-resistant HIV-1 strain A018C. Time-of-addition studies indicated that BMS 182,193 could be added as late as 27 h after infection and still retain its antiviral activity. To directly show that the activity of these compounds in culture was due to inhibition of proteolytic cleavage, the levels of HIV-1 gag processing in chronically infected cells were monitored by Western blot (immunoblot) analysis. All compounds blocked the processing of p55 in a dose-dependent manner, with 50% effective doses of 0.4 to 2.4 microM. To examine the reversibility of BMS 186,318, chronically infected CEM-SS cells were treated with drug and virions purified from the culture medium. Incubation of HIV-1 particles in drug-free medium indicated that inhibition of p55 proteolysis was slowly reversible. The potent inhibition of HIV-1 during both acute and chronic infections indicates that these aminodiol compounds are effective anti-HIV-1 compounds.

Genotypic and phenotypic analysis of human immunodeficiency virus type 1 isolates from patients on prolonged stavudine therapy.

Development of stavudine resistance was studied using human immunodeficiency virus type 1 isolates from 13 patients treated with stavudine for 18-22 months. Drug sensitivity testing on 11 of these pre- and posttherapy isolates identified only 2 posttreatment isolates with decreased stavudine sensitivity (ED50s < 4-fold higher than the average pretreatment ED50). Genotypic analysis of all 13 pairs of isolates identified multiple mutations in the reverse transcriptase (RT) gene. However, no genetic basis was identified to account for the observed changes in stavudine susceptibility. A recombinant virus containing the entire RT gene of the posttherapy isolate displaying the greatest resistance remained sensitive to stavudine. Five of the stavudine posttreatment isolates developed resistance (9- to 176-fold) to zidovudine, although the relationship between stavudine treatment and the appearance of zidovudine resistance remains unexplained. Analysis of 10 additional pairs of isolates did not confirm this relationship. The low frequency and modest degree of change in stavudine sensitivity following prolonged treatment is very encouraging.

Substituted naphthalenones as a new structural class of HIV-1 reverse transcriptase inhibitors.

A novel substituted naphthalenone (TGG-II-23A) has been found that inhibits HIV-1 infection of CEM-SS cells at concentrations that are not cytotoxic. Time of addition experiments indicate that TGG-II-23A functions at a stage of the HIV-1 life cycle at or near reverse transcription. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse transcriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A was specific for HIV-1 and failed to inhibit the replication of HIV-2. The binding site of TGG-II-23A appears to be in close proximity to that of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also resistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitive inhibitor that exhibits the same template:primer selectivity as other non-nucleoside inhibitors. TGG-II-23A therefore represents a new structural entry into the TIBO/Nevirapine class of inhibitors of HIV-1 reverse transcriptase.