Treatment of an infected total hip replacement with the PROSTALAC system: Part 1: Infection resolution

INTRODUCTION: Infection after total hip replacement (THR) is a serious medical complication with significant negative ramifications for both the patient and the health care system. The prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) was designed to treat the joint infection while maintaining functional movement in the hip. METHODS: We identified 28 patients treated for infected THR with the PROSTALAC system, by retrospective chart review. Preoperative and intraoperative cultures were taken to identify the causative organism. After PROSTALAC insertion, patients underwent at least 6 weeks of intravenous (IV) antibiotics. Prior to undergoing posttreatment cultures, patients were required to be antibiotic-free for a minimum of 6 weeks, with normal laboratory values. We defined resolution infection as retention of a joint prosthesis for a minimum of 2 years. RESULTS: Infection was identified in 28 patients in either the joint aspirate or intraoperative cultures. Of these patients, 2 failed to clear infection, requiring repeat PROSTALAC insertion. Two additional patients had positive 48-hour cultures post-second stage, treated with additional IV antibiotics. Retention of the post-PROSTALAC prosthesis is 100% at 2 years. CONCLUSION: PROSTALAC has acceptable infection resolution outcomes and appears effective for treating infected THR.     

Postamputation Pain and Sensory Changes in Treatment-naive Patients: Characteristics and Responses to Treatment with Tramadol, Amitriptyline, and Placebo

Background: Pain after amputation is common but difficult to treat, and few controlled treatment studies exist.

Methods: In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0-100], 40 [95% confidence interval, 38-41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment.

Results: After 1 month, phantom pain intensity was 1 (0-2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391-505 mg]), 0 (0-0) in the 40 amitriptyline responders (55 [50-59] mg), and 0 (0-0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol.     

Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor.

(111)In-DTPA-human epidermal growth factor ((111)In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of (111)In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. METHODS: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 x 10(6) EGFRs/cell) in the presence or absence of 1 microM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with (111)In-DTPA-hEGF for 24 h at 37 degrees C in the presence or absence of 1 microM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by (111)In were quantified using the gamma-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of (111)In-DTPA-hEGF alone or in combination with gefitinib. RESULTS: Gefitinib (1 microM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized (111)In that localized in the nucleus was statistically significantly greater when (111)In-DTPA-hEGF was combined with gefitinib compared with (111)In-DTPA-hEGF alone (mean +/- SD: 26.0% +/- 5.5% vs. 14.6% +/- 4.0%, respectively; P < 0.05). Induction of gamma-H2AX foci was greater in MDA-MB-468 cells that were treated with (111)In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 microM ) compared with those treated with (111)In-DTPA-hEGF alone (mean +/- SD: 35 +/- 4 vs. 24 +/- 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when (111)In-DTPA-hEGF (5 ng/mL, 6 MBq/microg) was combined with gefitinib (1 microM ) compared with (111)In-DTPA-hEGF alone (42.9% +/- 5.7% vs. 22.9% +/- 3.6%, respectively; P < 0.01). CONCLUSION: The efficacy of (111)In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when (111)In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.     

Analysis of radionuclide arthrograms, radiographic arthrograms, and sequential plain radiographs in the assessment of painful hip arthroplasty

An analysis of sequential plain radiographs (XR), radionuclide arthrography, (RNA), and radiographic arthrography (RGA) was performed to determine the efficacy and usefulness of each study in the diagnosis of loosening of prosthetic hip components. Over a 2-year-period, 65 hip prostheses were assessed before operation using each type of study; these results were compared to the intraoperative assessment of the status of the components. Of the three studies, sequential plain radiographs were overall the most accurate, sensitive, and specific. Radionuclide arthrography was of no use on the acetabular side but quite useful on the femoral side, especially in cases with only minimal femoral component loosening. Radiographic arthrography was overall the least accurate or sensitive of the three studies performed.     

Effect of propranolol on nitrogen and energy metabolism in sepsis

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.     

Analysis of Various Creatinine Clearance Formulas in Predicting Gentamicin Elimination in Patients With Low Serum Creatinine

Predicted gentamicin elimination rate constants (k_els) using creatinine clearance (C1_cr) estimates from seven equations were compared with k_els calculated from steady-state serum gentamicin concentrations in 186 hospitalized patients. In predicting k_el, the equations varied significantly in precision (mean absolute percentage error), and were particularly imprecise among patients with serum creatinine values of 71 μmol/L or less. Significant differences in bias (mean prediction error) were also observed. All equations using serum creatinine as an element showed improved precision, and most showed reduced bias when a minimum value of 71 μmol/L was used. The Cockcroft-Gault normalized to 72 kg and the Hull equations are among the simplest to calculate and, when using a minimum serum creatinine of 71 μmol/L, had significantly greater precision and less bias than several of the equations. We recommend one of these two methods for predicting gentamicin k_el in patients with low serum creatinine values.     

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.     

Fine mapping of the spatial relationship between acute ischemia and dendritic structure indicates selective vulnerability of layer V neuron dendritic tufts within single neurons in vivo.

We have evaluated the spatial relationship between clotted vasculature and the structural integrity of layer V cortical neurons in YFP (yellow fluorescent protein)-H transgenic mice 2 to 10 h after photothrombotic stroke. Fortuitously, ischemic zones could be finely mapped about dysmorphic YFP labeled axons and dendrites using histology since Texas-red dextran used to assess blood flow in vivo was trapped within fixed clotted vessels. Ischemic damage to layer V neurons located at the border of ischemia was contained within apical tuft spiny dendritic structures and did not propagate to spines on the more proximal region of the apical dendrite. The lateral spread of dendritic damage decayed sharply with distance from the edge of ischemia (50% reduction in beaded dendrites within approximately 100 microm) and increased with time up to 6 h after stroke but not thereafter. Axonal damage also increased with time but extended further laterally than dendritic damage, up to 500 microm from the stroke core. Apoptotic and necrotic cell death cascades were activated 6 h after stroke; however, only within 300 microm of the ischemic core. These data suggest that the axonal and dendritic circuitry of neurons located 300 microm outside of an ischemic zone can be relatively free of damage or commitment to cell death suggesting that they may be in an ideal position to contribute to functional recovery. Given that ischemic damage may have a larger effect on circuitry involving superficial dendrites and projecting axons, it is conceivable that surviving peri-infarct neurons may have unique structural and functional properties.