Biologic failures of hip arthroplasty have emerged as an increasing threat to the longevity of the prosthesis. While wear of modern-day bearings has been greatly reduced with the advent of ...cross-linked polyethylene, local reaction to metal particles either from the bearing itself or to any of the modular tapers appears to be on the rise. Monitoring of these reactions by the use of plain radiographs or serum markers appears to be insufficient to gauge the gravity of the response.
Over the past decade, the use of magnetic resonance imaging (MRI) techniques has emerged as the superior noninvasive instrument to assess the extent of soft tissue reaction around hip implants. The use of MRI around implants was initially challenging due to the presence of relatively high ferrous metals especially cobalt which causes local distortion of the magnetic fields. Novel changes in pulse sequencing have greatly improved the sensitivity and specificity of MRI so that at this time, MR is the most predictive diagnostic tool in evaluating the extent of tissue destruction. We feel strongly that modern MRI techniques are the most important tool in the workup of the patient suspected of having an adverse tissue reaction after hip arthroplasty.
Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with ...newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.
We compared bolus flavopiridol (50 mg/m(2)/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m(2) over 30 min followed by 40 mg/m(2) over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.
Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.
Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.
Abstract The aims of this study were to assess damage on the surface of retrieved oxidized zirconium (OxZr) metal femoral heads, to measure surface roughness of scratches, and to evaluate the extent ...of surface effacement using scanning electron microscopy (SEM). Ceramic zirconia-toughened alumina heads were analyzed for comparison. OxZr femoral heads explanted for recurrent dislocation had the most severe damage ( P < 0.001). The median surface roughness of damaged OxZr femoral heads was 1.49 μm, compared to 0.084 μm for damaged ceramic heads and 0.052 μm for undamaged OxZr ( P < 0.001). This may be of clinical concern because increased surface roughness has the potential to increase the wear of polyethylene liners articulating against these OxZr heads in THA.
Large-fiber diabetic polyneuropathy (DPN) leads to balance and gait abnormalities, placing patients at risk for falls. Large sensory axons innervating muscle spindles provide feedback for balance and ...gait and, when damaged, can cause altered sensorimotor function. This study aimed to determine whether symptoms of large-fiber DPN in type 1 and type 2 diabetic mouse models are related to alterations in muscle spindle innervation. In addition, diabetic mice were treated with insulin to assess whether sensorimotor and spindle deficits were reversible.
Behavioral assessments were performed in untreated and treated streptozotocin (STZ)-injected C57BL/6 mice to quantitate diabetes-induced deficits in balance and gait. Quantification of Ia axon innervation of spindles was carried out using immunohistochemistry and confocal microscopy on STZ-injected C57BL/6 and db/db mice.
STZ-injected C57BL/6 mice displayed significant and progressive sensorimotor dysfunction. Analysis of Ia innervation patterns of diabetic C57BL/6 spindles revealed a range of abnormalities suggestive of Ia axon degeneration and/or regeneration. The multiple abnormal Ia fiber morphologies resulted in substantial variability in axonal width and inter-rotational distance (IRD). Likewise, db/db mice displayed significant variability in their IRDs compared with db(+) mice, suggesting that damage to Ia axons occurs in both type 1 and type 2 diabetes models. Insulin treatment improved behavioral deficits and restored Ia fiber innervation in comparison with nondiabetic mice.
Similar to small fibers, Ia axons are vulnerable to diabetes, and their damage may contribute to balance and gait deficits. In addition, these studies provide a novel method to assay therapeutic interventions designed for diabetes-induced large-fiber dysfunction.
•Consumption of a ketogenic diet prevents pain-like responses to various stimuli.•Ketolysis and KATP channels are required for antinociception by a ketogenic diet.•Opening KATP channels provides ...antinociception in the absence of a ketogenic diet.•Effect of peripheral KATP channels on antinociception may be subunit specific.
Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
Zirconia-toughened alumina ceramic was introduced as a femoral head material for total hip arthroplasty. The material combines the stability of alumina with the toughness of zirconia. Despite ...inherent benefits for bearing surfaces, concern exists in the medical field that phase transformation of the zirconia grains could worsen wear resistance and lower the strength of the head. We examined these concerns in retrieved and artificially aged ceramic heads.
Twenty-eight ceramic composite heads retrieved at revision surgery were combined with 5 pristine heads (as negative controls for phase transformation) and 5 artificially aged pristine heads (as positive controls). The extent of zirconia phase transformation at the bearing surfaces was examined through confocal Raman spectroscopy and X-ray diffraction. Burst testing was conducted on all pristine and aged heads and the 4 retrieved implants with the longest lengths of implantation.
Retrieved heads had higher maximum average volume fractions of the monoclinic phase compared to pristine or aged heads. Length of implantation was not correlated to the volume fraction of the monoclinic phase. All the heads achieved a burst load far above the 46 kN Food and Drug Administration acceptance criterion; 3 of the 4 retrieved heads had burst strengths exceeding 100kN.
Our results showed that phase transformation occurs in vivo in ceramic composite femoral heads, but the amount transformed did not increase with the length of time the head had been implanted. The negligible effect upon burst strength of the retrieved and artificially aged heads is reassuring. These results support continued clinical use of this alumina-zirconia composite material as a head material.
Peptidergic and nonpeptidergic nociceptive neurons represent parallel yet distinct pathways of pain transmission, but the functional consequences of such specificity are not fully understood. Here, ...we quantified the progression of peptidergic and nonpeptidergic axon loss within the epidermis in the setting of a dying-back neuropathy induced by diabetes. STZ-induced diabetic MrgD mice heterozygous for green fluorescent protein (GFP) in nonpeptidergic DRG neurons were evaluated for sensitivity to mechanical and noxious thermal and chemogenic stimuli 4 or 8 weeks post-STZ. Using GFP expression in conjunction with PGP9.5 staining, nonpeptidergic (PGP+/GFP+) and peptidergic (PGP+/GFP-) intraepidermal nerve fibers (IENFs) were quantified at each time point. At 4 weeks post-STZ, nonpeptidergic epidermal innervation remained unchanged while peptidergic innervation was reduced by 40.6% in diabetic mice. By 8 weeks post-STZ, both nonpeptidergic innervation and peptidergic innervation were reduced in diabetic mice by 34.1% and 43.8%, respectively, resulting in a 36.5% reduction in total epidermal IENFs. Behavioral deficits in mechanical, thermal, and chemogenic sensitivity were present 4 weeks post-STZ, concomitant with the reduction in peptidergic IENFs, but did not worsen over the next 4 weeks as nonpeptidergic fibers were lost, suggesting that the early reduction in peptidergic fibers may be an important driving force in the loss of cutaneous sensitivity. Furthermore, behavioral responses were correlated at the 4 week time point with peptidergic, but not nonpeptidergic, innervation. These results reveal that peptidergic and nonpeptidergic nociceptive neurons are differentially damaged by diabetes, and behavioral symptoms are more closely related to the losses in peptidergic epidermal fibers.
Exercise is recommended for people with diabetes, but little is known about exercise in people with diabetic peripheral neuropathy (DPN).
The primary purpose of this preliminary study was to examine ...adverse events (AEs) during moderate-intensity, supervised aerobic exercise in people with DPN. The secondary purpose was to examine changes in fatigue, aerobic fitness, and other outcomes after intervention.
This was a single-group preliminary study.
The setting was an academic medical center.
Participants were 18 people who were sedentary and had type 2 diabetes and peripheral neuropathy (mean age=58.1 years, SD=5).
The intervention was a supervised 16-week aerobic exercise program (3 times per week at 50% to >70% oxygen uptake reserve).
Adverse events were categorized as related or unrelated to the study, anticipated or unanticipated, and serious or not serious. Outcomes included fatigue (Multidimensional Fatigue Inventory), cardiovascular fitness (peak oxygen uptake), body composition (dual-energy x-ray absorptiometry), sleep quality, plasma metabolic markers, and peripheral vascular function.
During the study, 57 nonserious AEs occurred. Improvements were found in general fatigue (mean change=-3.5; 95% confidence interval 95% CI=-1.3, -5.3), physical fatigue (mean change=-3.1; 95% CI=-1.2, -5.0), peak oxygen uptake (mean change=1.1 mL·kg(-1)·min(-1); 95% CI=0.2, 1.9), total body fat (mean change=-1%; 95% CI=-0.3, -1.7), fat mass (mean change=-1,780 g; 95% CI=-616.2, -2,938.7), and peripheral blood flow (mean change=2.27%; 95% CI=0.6, 4.0).
This was a small-scale, uncontrolled study. A future randomized controlled trial is needed to fully assess the effects of exercise on the outcomes.
This study provides new support for supervised aerobic exercise in people with DPN. However, it is important for physical therapists to carefully prescribe initial exercise intensity and provide close monitoring and education to address the anticipated AEs as people who are sedentary and have DPN begin an exercise program.
Present literature and clinical practice provide strong support for the use of aerobic exercise in reducing pain and improving function for individuals with chronic musculoskeletal pain syndromes. ...However, the molecular basis for the positive actions of exercise remains poorly understood. Recent studies suggest that neurotrophin-3 (NT-3) may act in an analgesic fashion in various pain states.
The purpose of the present study was to examine the effects of moderate-intensity aerobic exercise on pain-like behavior and NT-3 in an animal model of widespread pain.
This was a repeated-measures, observational cross-sectional study.
Forty female mice were injected with either normal (pH 7.2; n=20) or acidic (pH 4.0; n=20) saline in the gastrocnemius muscle to induce widespread hyperalgesia and exercised for 3 weeks. Cutaneous (von Frey monofilament) and muscular (forceps compression) mechanical sensitivity were assessed. Neurotrophin-3 was quantified in 2 hind-limb skeletal muscles for both messenger RNA (mRNA) and protein levels after exercise training. Data were analyzed with 2-factor analysis of variance for repeated measures (group x time).
Moderate-intensity aerobic exercise reduced cutaneous and deep tissue hyperalgesia induced by acidic saline and stimulated NT-3 synthesis in skeletal muscle. The increase in NT-3 was more pronounced at the protein level compared with mRNA expression. In addition, the increase in NT-3 protein was significant in the gastrocnemius muscle but not in the soleus muscle, suggesting that exercise can preferentially target NT-3 synthesis in specific muscle types.
Results are limited to animal models and cannot be generalized to chronic pain syndromes in humans.
This is the first study demonstrating the effect of exercise on deep tissue mechanical hyperalgesia in a rodent model of pain and providing a possible molecular basis for exercise training in reducing muscular pain.
Mobile bearing designs are intended to reduce wear, but mixed results were reported from retrieval analyses. Postmortem evaluation (PM) provides the opportunity to assess polyethylene damage in ...successful implants. We compared damage patterns, MRI presentation, and histology between mobile-bearing and fixed tibial inserts retrieved postmortem and compared these results to our prior findings from implants retrieved at revision.
Eleven postmortem knees with rotating platform (RP) implants and 13 with fixed bearing (FB) implants were examined. All were MRI scanned, and tissue samples were collected from standardized regions for histology. Polyethylene inserts were subjectively scored to assess articular, backside, and PS post surfaces for damage modes and severity.
Average duration of implantation was 9.3 years (1.7-19.6 years). Surface burnishing was the most common polyethylene damage mode. Average damage scores were higher for RP (53.4) compared to FB inserts (34.4) due to greater backside damage (13.4 for RP vs 1.4 for FB). A minimal difference in damage was observed on the articular surfaces (37.4 RP vs 30.0 FB). Mild innate macrophage reactions were seen in 8 (72.7%) RP and 5 (45.5%) FB specimens. Polyethylene particles were identified in 7 (63.6%) RP and 3 (27.7%) FB specimens.
Postmortem inserts showed low damage levels and mild tissue reactions compared to those reported for implants removed at revision arthroplasty. Nonetheless, trends in comparing RP and FB inserts were consistent with those seen in retrieval analyses, demonstrating the usefulness of retrieval studies in capturing performance differences among TKA designs.
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