IGF-2 INDUCED HYPOGLYCEMIA ASSOCIATED WITH LUNG SARCOMA.

Hypoglycemia from a non-insulin-secreting extrapancreatic tumor is a paraneoplastic syndrome characterized by the tumor production of a substance with an insulin-like effect (insulin-like growth factor 1 or 2 - IGF 1 or 2). Diagnosis is confirmed by the determination of IGF-1 and IGF-2 and finding an elevated IGF - 2/IGF-1 ratio. The availability of these tests is limited in many laboratories, so prompt recognition and therapies are late. We present the case of a 70-year-old patient diagnosed with right lower lobe bronchopulmonary neoplasm who presented to the emergency department with an altered general condition and hypoglycemic coma. The evaluation revealed low levels of insulin and C-peptide along with an elevated IGF-2/IGF-1 ratio of more than 10, suggesting a diagnosis of lung sarcoma with production of IGF-2. Because the tumor could not be resected in this case, chemotherapy and radiotherapy were performed, along with glucocorticoid therapy to prevent recurrent hypoglycemia. In the case of a patient with lung sarcoma and recurrent hypoglycemia (especially severe hypoglycemia or coma), extrapancreatic non-hyperinsulinemic hypoglycemia should be determinate tumor IGF-2 secretion.

Association Between Opioid Use and Patient-Reported Outcomes in a Randomized Trial Evaluating Basivertebral Nerve Ablation for the Relief of Chronic Low Back Pain.

BACKGROUND: Chronic low back pain (CLBP) is a primary indication for opioid therapy. OBJECTIVE: To evaluate the hypothesis that CLBP patients reporting reduced opioid use have superior functional outcomes following basivertebral nerve (BVN) radiofrequency ablation. METHODS: This post hoc analysis from a sham-controlled trial examined short-acting opioid use from baseline through 1 yr. Opioid use was stratified into 3 groups by two blinded external reviewers. Two-sample t-tests were used to compare Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) measurements between those patients who increased or decreased their opioid usage compared to baseline. RESULTS: Actively treated patients with decreased opioid use at 12 mo had a mean ODI improvement of 24.9 ± 16.0 (n = 27) compared to 7.3 ± 9.8 (n = 18) for patients reporting increased opioid use (P < .001). In the sham arm, the improvements in ODI were 17.4 ± 16.1 (n = 19) and 1.2 ± 14.3 (n = 5; P = .053) for the patients reporting decreased vs increased opioid usage, respectively. Actively treated patients reporting decreased opioid use had a mean improvement in VAS of 3.3 ± 2.5 (n = 27) compared to 0.6 ± 1.8 (n = 18) for patients reporting increased opioid use (P < .001). In the sham arm, the improvements in VAS were 2.5 ± 2.6 (n = 19) and 1.4 ± 1.9 (n = 5; P = .374) for patients reporting decreased vs increased opioid use, respectively. CONCLUSION: Subjects undergoing BVN ablation who decreased opioid use had greater improvement in ODI and VAS scores compared with those reporting increased opioid usage. There is an association between functional benefit from BVN ablation and reduced opioid use.

Baseline and postfusion opioid burden for patients with low back pain.

OBJECTIVES: To evaluate opioid usage patterns for patients with low back pain (LBP) with and without spinal fusion surgery (fusion patients and nonfusion patients, respectively), including long-term prescriptions post fusion. STUDY DESIGN: Claims data of outpatient pharmaceutical prescriptions from privately insured patients. METHODS: The 3-year utilization, cost, and morphine milligram equivalents (MME) of opioid prescriptions were evaluated for patients with LBP with and without lumbar fusion. For fusion patients, opioid prescriptions before and after fusion, as well as prescription use 3, 6, and 12 months following fusion surgery, were analyzed. RESULTS: Thirty-one percent of patients with LBP had opioid prescriptions within the first 6 months of initial diagnosis, which increased to 42.1% within 3 years. More than twice as many fusion patients as nonfusion patients filled opioid prescriptions (87.2% vs 41.5%; P <.001). Fusion patients had 62% and 48% more days with opioid dosages of at least 50 and at least 90 MME/day, respectively, than nonfusion patients (≥50 MME/day, 84 days vs 52 days; ≥90 MME/day, 50 days vs 34 days; both P <.001). Opioid burden was greater for fusion patients following surgery. Fusion patients continued to have 2 months' supply with at least 50 MME/day and 1 month's supply with at least 90 MME/day at least 12 months following surgery. CONCLUSIONS: The opioid burden in the LBP population is high and is further elevated in those who subsequently undergo fusion surgery. Long-term opioid prescriptions persisted in 27% of fusion patients 12 months post surgery. Efforts to identify efficacious alternative therapies to treat LBP may reduce the societal burden of chronic opioid use.

Anisotropic phantom to calibrate high-q diffusion MRI methods.

A silicon oil-filled glass capillary array is proposed as an anisotropic diffusion MRI phantom. Together with a computational/theoretical pipeline these provide a gold standard for calibrating and validating high-q diffusion MRI experiments. The phantom was used to test high angular resolution diffusion imaging (HARDI) and double pulsed-field gradient (d-PFG) MRI acquisition schemes. MRI-based predictions of microcapillary diameter using both acquisition schemes were compared with results from optical microscopy. This phantom design can be used for quality control and quality assurance purposes and for testing and validating proposed microstructure imaging experiments and the processing pipelines used to analyze them.

Chemical looping of metal nitride catalysts: low-pressure ammonia synthesis for energy storage.

The activity of many heterogeneous catalysts is limited by strong correlations between activation energies and adsorption energies of reaction intermediates. Although the reaction is thermodynamically favourable at ambient temperature and pressure, the catalytic synthesis of ammonia (NH3), a fertilizer and chemical fuel, from N2 and H2 requires some of the most extreme conditions of the chemical industry. We demonstrate how ammonia can be produced at ambient pressure from air, water, and concentrated sunlight as renewable source of process heat via nitrogen reduction with a looped metal nitride, followed by separate hydrogenation of the lattice nitrogen into ammonia. Separating ammonia synthesis into two reaction steps introduces an additional degree of freedom when designing catalysts with desirable activation and adsorption energies. We discuss the hydrogenation of alkali and alkaline earth metal nitrides and the reduction of transition metal nitrides to outline a promoting role of lattice hydrogen in ammonia evolution. This is rationalized via electronic structure calculations with the activity of nitrogen vacancies controlling the redox-intercalation of hydrogen and the formation and hydrogenation of adsorbed nitrogen species. The predicted trends are confirmed experimentally with evolution of 56.3, 80.7, and 128 µmol NH3 per mol metal per min at 1 bar and above 550 °C via reduction of Mn6N2.58 to Mn4N and hydrogenation of Ca3N2 and Sr2N to Ca2NH and SrH2, respectively.

Localised amyloidosis of the glans penis presenting as a painless lump with progression after 10 years.

Primary amyloidosis of the genitourinary tract is uncommon, and isolated invasion of the glans penis is exceptionally rare Degos et al. (Bull Soc Fr Dermatol Syphiligr 68:159, 1961). We report a case of localised amyloidosis of the glans penis in a 40-year-old presenting as an asymptomatic penile mass which changed after 10 years prompting treatment. We believe this to be the longest interval recorded between clinical occurrence and histological diagnosis of primary penile amyloidosis.

Cost-effectiveness analysis of treatments for vertebral compression fractures.

BACKGROUND: Vertebral compression fractures (VCFs) can be treated by nonsurgical management or by minimally invasive surgical treatment including vertebroplasty and balloon kyphoplasty. OBJECTIVE: The purpose of the present study was to characterize the cost to Medicare for treating VCF-diagnosed patients by nonsurgical management, vertebroplasty, or kyphoplasty. We hypothesized that surgical treatments for VCFs using vertebroplasty or kyphoplasty would be a cost-effective alternative to nonsurgical management for the Medicare patient population. METHODS: Cost per life-year gained for VCF patients in the US Medicare population was compared between operated (kyphoplasty and vertebroplasty) and non-operated patients and between kyphoplasty and vertebroplasty patients, all as a function of patient age and gender. Life expectancy was estimated using a parametric Weibull survival model (adjusted for comorbidities) for 858 978 VCF patients in the 100% Medicare dataset (2005-2008). Median payer costs were identified for each treatment group for up to 3 years following VCF diagnosis, based on 67 018 VCF patients in the 5% Medicare dataset (2005-2008). A discount rate of 3% was used for the base case in the cost-effectiveness analysis, with 0% and 5% discount rates used in sensitivity analyses. RESULTS: After accounting for the differences in median costs and using a discount rate of 3%, the cost per life-year gained for kyphoplasty and vertebroplasty patients ranged from $US1863 to $US6687 and from $US2452 to $US13 543, respectively, compared with non-operated patients. The cost per life-year gained for kyphoplasty compared with vertebroplasty ranged from -$US4878 (cost saving) to $US2763. CONCLUSIONS: Among patients for whom surgical treatment was indicated, kyphoplasty was found to be cost effective, and perhaps even cost saving, compared with vertebroplasty. Even for the oldest patients (85 years of age and older), both interventions would be considered cost effective in terms of cost per life-year gained.

Hybrid SPECT-CT and PET-CT imaging of differentiated thyroid carcinoma.

Hybrid imaging modalities such as radioiodine single photon emission CT with integrated CT ((131)I SPECT-CT) and 2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography with integrated CT (FDG PET-CT) allow the rapid and efficient fusion of functional and anatomic images, and provide diagnostic information that may influence management decisions in patients with differentiated thyroid carcinoma (DTC). Diagnostic localisation and therapy of these tumours are dependent upon their capacity to concentrate radioiodine ((131)I) via uptake through the sodium-iodide symporter and retention within the tumour. The prognosis for most patients with DTC is favourable, although controversy exists regarding the role of post-operative (131)I therapy in patients at low-risk for disease. Accurate identification of functional thyroid tissue (benign or malignant) using diagnostic (131)I planar scintigraphy complemented by SPECT-CT imaging enables the completion of post-operative staging and patient risk stratification prior to (131)I therapy administration. In patients with non-iodine-avid tumours (negative (131)I scan but elevated thyroglobulin indicative of persistent or recurrent disease), FDG PET-CT is used to identify tumours with enhanced glucose metabolism and to localise the source of thyroglobulin production. The CT component of this hybrid technology provides anatomic localisation of activity and allows CT-based attenuation correction of PET images. Images from 15 patients illustrate the applications of (131)I SPECT-CT and FDG PET-CT.

Posttraumatic neuroma of the radial nerve treated with an autogenous epineural conduit technique. A case report.

We present the outcome of the first clinical application of a new technique using an epineural flap to bridge a short nerve defect. A 28-year-old male had suffered a radial nerve laceration at the lower third of the arm, proximal to the brachioradialis branch, 3 weeks before surgery. During surgery, a neuroma-in-continuity was excised preserving the epineural sleeve. Two longitudinal epineural flaps were created, one from the proximal and one from the distal nerve stump and used to bridge a 1-cm-long nerve defect. Each epineurium flap was sutured to the intact epineurium of the other side and additionally to each other. An electromagnetic nerve stimulator was used to enhance the nerve regeneration process. Nerve regeneration was followed up for 17 months with excellent functional results.

The place of local/regional perforator flaps in complex traumas of the forearm.

BACKGROUND: Our aim was to conduct a retrospective study regarding the advantages of doing the all-in-one reconstruction in the same step with the debridement, and the possibility of using the local/regional perforator flaps to cover the tissue defects. METHODS: We reviewed a series of 137 cases from 1999 until now, for acute traumas with tissue defects of the forearm. We performed a regional perforator flap in 16 cases, and a local perforator flap in 121 cases. These flaps were used for both simple and complex defects coverage, including 26 cases with fractures and devascularization. RESULTS: The follow-up was between 2 months and 2 years. In all the cases the extremity was salvaged and an useful functional recovery was obtained. A very good evolution, with complete survival of the flap was recorded in 133 cases. We completely lost only one flap, and registered minor complications in three cases. CONCLUSION: The local perforator flaps represent a good and safe indication for small and medium defects in the forearm.

PET in the diagnostic evaluation of adrenal tumors.

Early experience with positron emission tomography (PET) has provided exciting results in the evaluation of a broad spectrum of neoplasms, to include primary adrenal tumors, their metastases and metastatic disease to the adrenal glands. By virtue of the well-recognized propensity of malignancies to preferentially use glycolysis as an important energy source and the stimulation of mechanisms designed to absorb substrate glucose, the glucose analog, [18F]fluorodeoxyglucose, has become a successful radiopharmaceutical in the scintigraphic evaluation of adrenal tumors. Building upon prior experience gained with imaging the adrenal gland, other positron-labeled radiopharmaceuticals are finding their way into clinical use. The 11b-hydroxylase inhibitor, metomidate labeled with 11C has been used to scintigraphically identify tissues of adrenocortical origin, to accurately identify recurrent and metastatic adrenocortical carcinoma and may be useful in assessing the malignant potential of these tumors and predicting survival in afflicted patients. Adrenomedulla imaging with 11C- and 18F-labeled catecholamines and catecholamine analogs draws heavily from the experience gained from predecessor compounds, labeled with single photon emitting isotopes and, in some instances, single photon emission tomography, and has been shown to depict with high efficacy pheochromocytomas, neuroblastomas and other neoplasms of neural crest origin. Additional structural and functional information provided by computed tomography (CT), performed as part of hybrid PET/CT imaging directly complements PET and adds measurable diagnostic value in the evaluation of adrenal tumors.

Mechanics of bone/PMMA composite structures: an in vitro study of human vertebrae.

The goal of this study was to provide material property data for the cement/bone composite resulting from the introduction of PMMA bone cement into human vertebral bodies. A series of quasistatic tensile and compressive mechanical tests were conducted using cement/bone composite structures machined from cement-infiltrated vertebral bodies. Experiments were performed both at room temperature and at body temperature. We found that the modulus of the composite structures was lower than bulk cement (p<0.0001). For compression at 37( composite function)C: composite =2.3+/-0.5GPa, cement =3.1+/-0.2GPa; at 23( composite function)C: composite =3.0+/-0.3GPa, cement =3.4+/-0.2GPa. Specimens tested at room temperature were stiffer than those tested at body temperature (p=0.0004). Yield and ultimate strength factors for the composite were all diminished (55-87%) when compared to cement properties. In general, computational models have assumed that cement/bone composite had the same modulus as cement. The results of this study suggest that computational models of cement infiltrated vertebrae and cemented arthroplasties could be improved by specifying different material properties for cement and cement/bone composite.

2006 Otto Aufranc Award Paper: significance of in vivo degradation for polyethylene in total hip arthroplasty.

Our research group developed an implant retrieval program to study in vivo degradation of polyethylene. We now have evidence to support our hypothesis that degradation of radiation-sterilized polyethylene occurs in the body for not only historical gamma air sterilized liners, but also for conventional gamma inert sterilized (ArCom) and annealed highly crosslinked polyethylene (Crossfire) liners as well. Our research has also led to the discovery that the most severe manifestations of in vivo oxidation typically occur in regions of the liner experiencing minimal wear, such as the rim of the component, where the body fluids (containing oxidizing species) have access to the polyethylene. Our data from historical, ArCom, and Crossfire retrievals all point to a similar scenario in which the femoral head limits the in vivo oxidation of polyethylene at the bearing surface. Consequently, provided rim impingement does not occur, and the polyethylene locking mechanisms remain relatively isolated from oxidizing fluid, in vivo oxidation does not seem to be clinically important in the first 10 years of implantation for conventional gamma sterilized polyethylene. We conclude that in vivo degradation should be included among the list of potential long-term failure modes for modular polyethylene components for total hip arthroplasty.

In vivo degradation of polyethylene liners after gamma sterilization in air.

BACKGROUND: Ultra-high molecular weight polyethylene degrades during storage in air following gamma sterilization, but the extent of in vivo degradation remains unclear. The purpose of this study was to quantify the extent to which the mechanical properties and oxidation of conventional polyethylene acetabular liners treated with gamma sterilization in air change in vivo. METHODS: Fourteen modular cementless acetabular liners were revised at an average of 10.3 years (range, 5.9 to 13.5 years) after implantation. All liners, which had been machined from GUR 415 resin, had been gamma-sterilized in air; the average shelf life was 0.3 year (range, 0.0 to 0.8 year). After removal, the components were expeditiously frozen to minimize ex vivo changes to the polyethylene prior to characterization. The average duration between freezing and testing was 0.6 year. Mechanical properties and oxidation were measured with use of the small-punch test and Fourier transform infrared spectroscopy, respectively, in the loaded and unloaded regions of the liners. RESULTS: There was substantial regional variation in the mechanical properties and oxidation of the retrieved liners. The ultimate load was observed to vary by >90% near the surface. On the average, the rim and the unloaded bearing showed evidence of severe oxidation near the surface after long-term in vivo aging, but these trends were not typically observed on the loaded bearing surface or near the backside of the liners. CONCLUSIONS: The mechanical properties of polyethylene that has been gamma-sterilized in air may decrease substantially in vivo, depending on the location in the liner. The most severe oxidation was observed at the rim, suggesting that the femoral head inhibits access of oxygen-containing body fluids to the bearing surface. This is perhaps why in vivo oxidation has not been associated with clinical performance to date.

The biomechanical effects of kyphoplasty on treated and adjacent nontreated vertebral bodies.

It remains unclear whether adjacent vertebral body fractures are related to the natural progression of osteoporosis or if adjacent fractures are a consequence of augmentation with bone cement. Experimental or computational studies have not completely addressed the biomechanical effects of kyphoplasty on adjacent levels immediately following augmentation. This study presents a validated two-functional spinal unit (FSU) T12-L2 finite element model with a simulated kyphoplasty augmentation in L1 to predict stresses and strains within the bone cement and bone of the treated and adjacent nontreated vertebral bodies. The findings from this multiple-FSU study and a recent retrospective clinical study suggest that changes in stresses and strains in levels adjacent to a kyphoplasty-treated level are minimal. Furthermore, the stress and strain levels found in the treated levels are less than injury tolerance limits of cancellous and cortical bone. Therefore, subsequent adjacent level fractures may be related to the underlying etiology (weakening of the bone) rather than the surgical intervention.

A 10-year minimum follow-up of hydroxyapatite-coated threaded cups: clinical, radiographic and survivorship analyses with comparison to the literature.

We evaluated the clinical, radiographic, and survivorship outcomes in a series of 418 threaded hydroxyapatite-coated acetabular cups (Arc2f; Osteonics, Allendale, NJ) implanted in a consecutive series of 384 patients undergoing primary total hip arthroplasty. In all cases, the cup was screwed into the prepared acetabulum. Bone screws were used to provide secondary fixation. At a minimum 10-year follow-up, 304 cups were available for analysis. The cumulative survivorship (mechanical failure as endpoint) at that time was 99.43% +/- 0.0104. Two hundred seventy-six hips were available for full clinical and radiographic review at or after the tenth anniversary. No unstable implants were noted; all implant fixation interfaces were classified as "stable bone ingrown," and the cup migration rate was zero. Based on the survivorship achieved with this implant, our results compare favorably with survivorship reported for the best cemented and cementless acetabular implant designs.

Osteolysis: a disease of access to fixation interfaces.

Long-term clinical studies of total hip replacement suggest a direct relationship between bearing wear and periprosthetic osteolysis, particularly if polyethylene wear is greater than a threshold value of 0.1 mm per year. The current clinical trend to cross-linked polyethylene and hard-to-hard bearings attempts to ensure that bearing wear remains below this threshold. Fluid pressure generated in the hip during patient activity also has been implicated in the formation of periprosthetic lesions. Pressure fluctuation measured during manipulation of the hip at revision, or the identification of modular components that pump fluid during loading, suggest cyclic pressure may be a causative factor in bone resorption. Animal studies show the adverse effect of direct pressure on osteocytes. At more than 10 years followup, the low incidence of osteolytic lesions in retrospective reviews of successful cemented and cementless implant designs suggest that osteolysis is not an inevitable consequence of particle or pressure generation in the hip. If the quality of implant fixation prohibits fluid access to the surrounding bone, the rate of osteolysis is minimal. It is evident that whether the active factor in osteolysis is pressure, wear particles, or both, adverse periprosthetic effects can be minimized if access to the fixation interfaces in the hip is denied.

A literature review of the association between wear rate and osteolysis in total hip arthroplasty.

The establishment of a polyethylene wear rate threshold for the development of osteolysis at the hip would allow surgeons to identify patients at risk for osteolysis and to implement selective, more frequent follow-up. We reviewed publications that met certain criteria for wear and osteolysis measurement. Based on this review, the incidence of osteolysis increases as the rate of wear increases. The literature indicates that osteolysis rarely is observed at a wear rate of <0.1 mm/y. We suggest that a practical wear rate threshold of 0.05 mm/y would eliminate osteolysis. This wear threshold suggests that the new cross-linked polyethylenes would reduce osteolysis, provided that in vivo wear rates mirror those observed in vitro. To facilitate future comparison of published data, we suggest that longitudinal wear studies adopt consistent edge detection-based wear measurement techniques and uniform osteolytic lesion classification and measurement schema.

Euglycemic clamp study in clozapine-induced diabetic ketoacidosis.

OBJECTIVE: To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. CASE SUMMARY: A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. DISCUSSION: Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale. CONCLUSIONS: The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.