Outcome of kinematic alignment using patient-specific instrumentation versus mechanical alignment in TKA: a meta-analysis and subgroup analysis of randomised trials.

INTRODUCTION: Kinematic alignment (KA) in total knee arthroplasty (TKA) matches component position to the pre-arthritic anatomy of an individual patient, with the aim of improving functional outcomes. Recent randomised controlled trials (RCTs) comparing KA to traditional neutral mechanical alignment (MA) have been mixed. This collaborative study combined raw data from RCTs, aiming to compare functional outcomes between KA using patient-specific instrumentation (PSI) and MA, and whether any patient subgroups may benefit more from KA technique. MATERIALS AND METHODS: A literature search in PubMed, EMBASE and Cochrane databases identified four randomised controlled trials comparing patients undergoing TKA using PSI-KA and MA. Unpublished data including Western Ontario McMaster Universities Arthritis Index (WOMAC) and Knee Society Score (KSS) were obtained from study authors. Meta-analysis compared MA to KA change (post-op minus pre-op) scores. Subgroup-analysis on KA patients looked for subgroups more likely to benefit from KA and the impact of PSI accuracy. RESULTS: Meta-analyses of change scores in 229 KA patients versus 229 MA patients were no different from WOMAC (mean difference 3.4; 95% confidence interval - 0.5 to 7.3), KSS function (1.3, - 3.9 to 6.4) or KSS combined (7.2, - 0.8 to 15.2). A small advantage was seen for KSS pain in the KA group (3.6, 95% CI 0.2-7.1). Subgroup-analysis showed no difference between varus, valgus and neutral pre-operative alignment groups, and those who did and did not achieve KA plans. Pain-free patients at 1-year were more likely to achieve KA plans. CONCLUSION: Patient-reported outcome scores following TKA using PSI-KA are similar to MA. No identifiable subgroups benefited more from KA, and long-term results remain unknown. Inaccuracy of the PSI system used in KA patients could potentially affect outcome.

Resting host and tumor perfusion as determinants of tumor vascular responses to norepinephrine.

Blood flow determinations and arteriograms were obtained in rat (Walker carcinoma) and rabbit (V2 carcinoma) liver tumors at rest and after norepinephrine administration. Resting tumor blood flow exceeded resting hepatic flow in both models, and both tumors responded with vasoconstriction and reduced blood flow. In tumors and the surrounding normal host tissue, the greater the perfusion prior to drug administration, the greater is the response (decrease in perfusion) to the vasoconstrictor. Although tumor perfusion decreased after vasoconstrictor, post-norepinephrine angiograms revealed an improved diagnostic image because of the enlarged but unresponsive tumor feeder vessels, persistent tumor blush, and simultaneous vasoconstriction in the normal liver. In these models, improved tumor visualization resulted even though a decrease in tumor blood flow had occurred. The angiographic image is related therefore to the lack of vasoconstriction in the tumor feeder vessel, which has, however, a decreased blood flow and the correspondingly greater volume of normally constricting hepatic arteries which results in a marked decrease in the background of vessels upon which the tumor image is superimposed.

The impact of patient and surgical factors on the rate of infection after primary total knee arthroplasty: an analysis of 64,566 joints from the New Zealand Joint Registry.

AIMS: The aim of this study was to identify risk factors for prosthetic joint infection (PJI) following total knee arthroplasty (TKA). PATIENTS AND METHODS: The New Zealand Joint Registry database was analysed, using revision surgery for PJI at six and 12 months after surgery as primary outcome measures. Statistical associations between revision for infection, with common and definable surgical and patient factors were tested. RESULTS: A total of 64 566 primary TKAs have been recorded on the registry between 1999 and 2012 with minimum follow-up of 12 months. Multivariate analysis showed statistically significant associations with revision for PJI between male gender (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.24 to 2.74), previous surgery (osteotomy (OR 2.45 95% CI 1.2 to 5.03), ligament reconstruction (OR 1.85, 95% CI 0.68 to 5.00)), the use of laminar flow (OR 1.6, 95% CI 1.04 to 2.47) and the use of antibiotic-laden cement (OR 1.93, 95% CI 1.19 to 3.13). There was a trend towards significance (p = 0.052) with the use of surgical helmet systems at six months (OR 1.53, 95% CI 1.00 to 2.34). CONCLUSION: These findings show that patient factors remain the most important in terms of predicting early PJI following TKA. Furthermore, we found no evidence that modern surgical helmet systems reduce the risk of PJI and laminar flow systems may actually increase risk in TKA. The use of this registry data assists the estimation of the risk of PJI for individual patients, which is important for both informed consent and the interpretation of infection rates at different institutions. TAKE HOME MESSAGE: Infection rates in TKA are related to both individual patient and surgical factors, and some modern methods of reducing infection may actually increase infection risk.

Photodynamic therapy of B16F10 murine melanoma with lutetium texaphyrin.

Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.

Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen-activated protein kinase. Comparison with the effects of insulin, growth factors and phorbol esters.

It has been proposed previously that the sustained activation of mitogen-activated protein kinase may be necessary for the differentiation of PC12 cells. Differentiation of PC12 cells is induced by many extracellular agonists including nerve growth factor (NGF) and cyclicAMP analogues, but not epidermal growth factor (EGF), insulin or phorbol esters. Our results demonstrate that: (i) 8-(4-chlorophenylthio)-cyclicAMP (CPT-cAMP) activates MAP kinase; this raises the possibility that the MAP kinase pathway may be activated by agents that act through adenylate cyclase; (ii) NGF and CPT-cAMP as well as phorbol esters promote sustained activation of MAP kinase. This suggests that while sustained MAP kinase activation may be associated with differentiation it may not be sufficient, and that other as yet unidentified parallel pathways may be involved.

Activation of mitogen-activated protein kinase by protein kinase C isotypes alpha, beta I and gamma, but not epsilon.

Treatment of CHO.T cells with either PMA or insulin led to the activation of MAP kinase by approximately 3-fold, and p90rsk by approximately 4-fold. Over-expression of the alpha, beta I or gamma isoforms of protein kinase C caused a substantial enhancement of the effect of PMA on the activation of MAP kinase and p90rsk, however, the effect of insulin was unchanged. Over-expression of the epsilon isoform of protein kinase C did not alter the effect of either PMA or insulin on the activation of MAP kinase and p90rsk. The results suggest that protein kinase C isotypes, alpha, beta I and gamma, but not epsilon, can mediate MAP kinase activation by PMA, and strongly support the hypothesis that protein kinase C isoforms can initiate distinct signalling pathways.

Effect of glucagon on insulin receptor phosphorylation in intact liver cells.

Evidence is presented that incubation of rat liver cells with glucagon leads to an increase in the phosphorylation of specific serine residues within insulin receptors, particularly in the presence of insulin. However, no changes in either the tyrosine phosphorylation of the receptors or the tyrosine kinase activity towards a synthetic peptide substrate was detected.

Effects of tyrosine kinase inhibitors on protein kinase-independent systems.

Tyrosine kinase inhibitors have been widely used to probe the role of tyrosine phosphorylation in cellular signalling. These inhibitors exhibit an apparent specificity for tyrosine kinases over the serine/threonine kinases but little is known about their effects on other enzymes or biological systems. We demonstrate that genistein, erbstatin and alpha-cyanocinnamamides (tyrphostins) have inhibitory effects on fatty acid synthesis, lactate transport, mitochondrial oxidative phosphorylation and aldehyde dehydrogenase. We propose, therefore, that results obtained using tyrosine kinase inhibitors should be interpreted with caution, particularly if used at concentrations sufficient to inhibit these non-protein kinase-dependent events.

Imaging of human colon cancer xenograft with gadolinium-texaphyrin.

RATIONALE AND OBJECTIVES: The authors explore the efficacy of gadolinium (Gd)-texaphyrin (PCI-0101), an expanded porphyrin, as a contrast medium for magnetic resonance imaging of nude mice implanted with the human colon cancer xenograft LS174T. METHODS: Magnetic resonance images were obtained in six nude mice 7 to 8 days after implantation of LS174T cells in dorsal subcutaneous tissues. Spin-echo T1-weighted images were obtained at baseline and at 5, 15, and 60 minutes after injection of 10 or 20 mumols/kg of Gd-texaphyrin. Delayed images were obtained at 24 and 48 hours after injection. Region-of-interest measurements were taken of the tumors and of enhancing tumor rims at all time points. Percent enhancement was calculated and compared among the various time points. RESULTS: All tumors were enhanced after injection of Gd-texaphyrin. Heterogeneous patterns of enhancement were seen, with peak enhancement seen at the 15-minute time point; however, greater enhancement was seen at 48 hours than at 24 hours after Gd-texaphyrin intravenous injection. CONCLUSIONS: Gadolinium-texaphyrin may prove to be a useful contrast medium for magnetic resonance imaging of tumors.

Time-related contrast enhancement of blood, normal muscle, and V2 carcinoma in the rabbit as determined by CT scanning.

After a bolus of intravenous Renografin, the delivery and washout of contrast in malignant V2 carcinoma, normal muscle, and blood using CT scanning was evaluated over a two-hour period. Diagnostically useful differences in enhancement between V2 carcinoma and muscle predictably lasted one hour, but in selected rabbits lasted longer. Delivery and washout was greater in tumor than in normal muscle, and it was these differences which accounted for the diagnostically useful differences in enhancement. After two hours, attenuation in V2 and normal muscle remained elevated, while blood returned to nearly control levels, suggesting a large amount of contrast distributed throughout the extravascular space and probably in equilibrium with excretion.

Dynamic computed tomography time--density study of normal human tissue after intravenous contrast administration.

Dynamic sequential 3-second CT scans of human abdominal organs were obtained after an intravenous bolus injection of diatrizoate. Time--density curves obtained from the renal cortex and medulla were compared with similar curves obtained from the aorta, inferior vena cava, muscle, and normal liver. CT scans revealed the changes in density produced by the contrast agent reflecting the differential phases of blood flow in the aorta and inferior vena cava. Changes in density in the liver, muscle, and the cortex and medulla of the kidney undoubtedly were related to vascular and extravascular contrast agent. Renal cortical density increased rapidly after bolus administration and peaked approximately 6 seconds after the peak in aortic contrast and slowly declined over the observation period. Renal medullary density increased slowly and at first remained significantly below the cortex but was slightly above cortical values after 30 seconds. These studies indicate that dynamic CT scanning is an effective way of monitoring the contrast media pharmacokinetics within tissue and that human renal function can be monitored and evaluated by using this technique.

CT contrast enhancement of kidney V2 carcinoma after norepinephrine and acetylcholine injection.

CT attenuation values of kidney V2 carcinomas and normal kidneys in 15 rabbits were obtained before and after the simultaneous administration of an intravenous bolus infection of diatrizoate and an intraarterial bolus injection of norepinephrine or acetylcholine. After 6 micrograms norepinephrine, peak V2 density was 15 Hounsfield units (HU) less and renal cortex peak density 41 HU less than baseline, which resulted in a decrease in V2 contrast enhancement. After 20 micrograms acetylcholine, peak V2 density was 10 HU less and renal cortex peak density 13 HU less than baseline; the magnitude of contrast enhancement remained essentially unchanged.

Time-density evaluation of the liver after iosulamide meglumine: a tissue-specific CT contrast agent.

Iosulamide meglumine, a new intravenous biliary contrast agent, was evaluated as a potential hepatic contrast agent utilizing computed tomographic scanning. Time-density data in dogs were generated following 56.7 and 75.6 mg iodine/kg body weight. The iodine was administered both as an iosulamide meglumine bolus injection and a 0.77 ml/min infusion. The greatest increase in x-ray attenuation (24 HU) was observed within 45 minutes after the 75.6 mg iodine/kg body weight infusion technique, which resulted in excellent hepatic opacification. The long duration of increased x-ray attenuation of hepatocytes produced by iosulamide meglumine would be useful in the CT detection of hepatic mass lesions which do not contain normally functioning hepatic cells.

Experimental acute cerebral ischemia with reperfusion. Evaluation with gadolinium-texaphyrin.

RATIONALE AND OBJECTIVES: The authors explore the potential usefulness of the new contrast medium gadolinium (Gd)-texaphyrin (PCI-0101) in magnetic resonance imaging of experimental acute cerebral ischemia with reperfusion. METHODS: Four New Zealand white rabbits underwent 2 hours of transorbital occlusion of the left internal carotid, anterior, and middle cerebral arteries, followed by 2 hours of reperfusion with normal saline. Immediately thereafter, the rabbits were injected with 25 mumol/kg of 2 mmol/L Gd-texaphyrin and killed by barbiturate overdose. Postmortem T1- and T2-weighted coronal scans were performed at 1.5 Tesla and correlated with histopathologic findings. RESULTS: Postcontrast T1-weighted images showed high signal within extensive cortical and basal ganglia infarcts. Areas of high signal on T1-weighted images were less extensive than on T2-weighted images, and corresponded to only a portion of the region of neuronal damage seen histologically. Signal intensity of infarcted brain on postcontrast T1-weighted images was significantly greater than normal brain in the contralateral hemisphere (P < 0.0014). CONCLUSIONS: Experimental reperfused infarcts only 2 hours old demonstrate contrast enhancement with Gd-texaphyrin.

Magnetic susceptibility effects and their application in the development of new ferromagnetic catheters for magnetic resonance imaging.

Newly developed ferromagnetic catheters (Fe-Caths) are more conspicuous than conventional radiographic catheters (Rad-Caths) on magnetic resonance (MR) images because they produce recognizable ferromagnetic signal patterns (FSPs). To determine how MRI parameters influence these patterns, the imaging characteristics of nine Fe-Caths (ferromagnetic concentration 0.01 to 1.0 weight/weight %) were studied systematically and compared with three Rad-Caths. All catheters were studied in stationary and moving phantoms at mid-field (0.38 T) and high-field (1.5 T) strength using spin-echo and gradient-echo pulse sequences. Rad-Caths always produced a signal void. Fe-Caths produced FSPs, the size of which depended on the orientation of the catheter with respect to the main magnetic field, the concentration of ferromagnetic agent in the catheter, and the direction and strength of the frequency encoding gradient. When Fe-Caths were positioned perpendicular to the main magnetic field, they produced FSPs; however, when they were parallel to the main magnetic field, Fe-Caths produced no FSP, thus having a similar appearance to the Rad-Caths. Ferromagnetic catheters produce conspicuous patterns on MR images that depend on catheter orientation in the main magnetic field and vary predictably with the MRI parameters.

Microsphere distribution in normal and tumor-bearing (DMBA-induced carcinogenesis) hamster cheek pouch.

This study evaluates, for the first time by direct visualization, the microvascular distribution of microspheres in normal hamster cheek pouch and in hamster cheek pouch bearing tumor induced by 7, 12 Dimethylbenz (A) Anthracene solution (DMBA). In contrast to the results of the previously used open-chest technique, this carotid injection technique does not lead to irregular distribution of 15-mu carbonized microspheres, chain, or impaction phenomena. It is concluded that methodology differences may account for different results.

Induction of fracture healing using fibrous calcium phosphate composite spherulites.

The healing of large fractural defects is a difficult clinical problem, especially if it occurs in elderly or otherwise debilitated patients. The objective of this study is to determine if a new formulation of fibrous calcium phosphate crystals would induce fracture healing in vivo. Fibrous calcium phosphate (FCP) can be grown with unique size, shape, and surface area characteristics as a resorbable or nonresorbable, osteoconductive or osteoinductive material. In comparison with other conventional calcium phosphate particulates, FCP particles possess approximately x 100 to x 1000 more surface area. One-and-one-half centimeter sections were removed from the ulnas of 12 rabbits. Three groups had fibrous calcium phosphate spherulites (4-8 microns, 150-300 microns, 400-600 microns) mixed with collagen and a growth factor-bonding agent injected into the ulnar defect. One site per group was not treated. X-rays were obtained during the study and the percentage of the ulna defect filled in by callous was measured. The percentage was recorded as the amount of fracture healing for each site. Histologic examination of the ulnas was performed following sacrifice at 12 weeks. Fracture sites treated with fibrous calcium phosphate showed significantly greater healing (0.79 +/- 0.3) than control animals (0.36 +/- 0.1) (P less than .05, unpaired t-test) radiographically. Histologic examination showed that the spherulites remain in situ and become embedded within the new growth of fibrous tissue, collagen and new bone. Radiographically and histologically, FCP preparations appear to accelerate fracture healing by inducing new bone formation, into which they often become embedded.

Gelatin encapsulated nitrogen microbubbles as ultrasonic contrast agents.

Gelatin encapsulated nitrogen microbubbles were effective ultrasonic contrast agents in in vitro phantom and in vivo rabbit V2 carcinoma studies. Intra-arterial injection of 80-micrometer gelatin encapsulated nitrogen microbubbles appeared to improve tumor visualization by rim enhancement, which persisted for several minutes.

Manganese dipyridoxal diphosphate-enhanced magnetic resonance imaging in the evaluation of hepatocyte function.

RATIONALE AND OBJECTIVES: To determine whether contrast-enhanced magnetic resonance imaging can detect ethanol hepatotoxicity in rats. METHODS: Rats were treated with a single high dose of ethanol (acute) intraperitoneally or with a 36% ethanol diet (chronic) for up to 5.5 months. Magnetic resonance imaging was performed before and after intravenous administration of manganese dipyridoxal diphosphate (Mn-DPDP). RESULTS: Enhancement (acute group) was significantly lower in ethanol treated animals on T1-weighted scans (P < .02). Precontrast, a significant difference in intensity was seen on T2-weighted scans (P < .01). Electron microscopy revealed severe hepatocyte damage. In the chronic groups, there was no significant difference in intensity precontrast. Postcontrast, enhancement (ethanol group) was significantly lower on T1-weighted scans only at 2 weeks (P < .05). Electron microscopy demonstrated progressive ethanol hepatotoxicity. CONCLUSIONS: Magnetic resonance imaging can distinguish between normal and certain types of ethanol damaged livers on T1-weighted scans. Enhancement, however, does not correlate with progressive microscopic liver damage.

Solid-state phosphorus-31 nuclear magnetic resonance differentiation of bone mineral and synthetic apatite used to fill bone defects.

Bioabsorption of synthetic apatite compounds used to promote bone healing and remodeling has been difficult to evaluate. In this study, solid-state phosphorus-31 nuclear magnetic resonance (NMR) has been used to characterize and quantitate bone mineral and a synthetic apatite in order to establish a model for bioabsorption studies. Pulverized solid samples of cortical rabbit bone and a synthetic fluoridated apatite were examined in vitro at variable degrees of hydration. A 9.4 T superconducting spectrometer was used to obtain 31P magic angle spinning NMR spectra and T1 relaxation times. Quantitation was attempted in mixed samples using T1 recovery data. Bone mineral and synthetic apatite could be distinguished by chemical shift and T1 relaxation time in variable hydration states, and were readily differentiated in mixtures by their T1 relaxation time. NMR estimates of relative proportions of components in mixed samples were accurate within 2% of evaluations based on weight. Solid-state 31P NMR therefore provides a suitable method for monitoring the bioabsorption of synthetic apatites.