Relationship of plasma and synovial fluid vascular endothelial growth factor with radiographic severity in primary knee osteoarthritis

Purpose

Recent evidence suggests that angiogenesis and inflammation contribute to the development and progression of osteoarthritis (OA). The purpose of this study was to investigate vascular endothelial growth factor (VEGF) levels in plasma and synovial fluid of patients with knee OA and to determine the relationship of VEGF levels with disease severity in knee OA.

Methods

A total of 100 subjects were enrolled in this study (80 knee OA patients and 20 healthy controls). Plasma and synovial fluid VEGF levels were analysed using enzyme-linked immunosorbent assay. VEGF expressions in synovial membrane and articular cartilage samples were assessed using immunohistochemistry.

Results

VEGF level in synovial fluid of knee OA patients was tenfold higher than that in paired plasma (P < 0.001). Both plasma and synovial fluid VEGF exhibited a positive correlation with radiographic severity (r = 0.454 and r = 0.727, P < 0.001, respectively). VEGF expression was highly detectable in synovial lining cells and articular chondrocytes of knee OA patients.

Conclusions

VEGF levels in both plasma and synovial fluid were positively correlated with the severity of knee OA. Therefore, VEGF may be useful for monitoring OA severity and could play a substantial role in the development and progression of knee OA.     

Indolinone tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells

Six indolinone tyrosine kinase inhibitors were characterized for their ability to inhibit Kit kinase and for their effects on the growth of small cell lung cancer (SCLC) cell lines. All of the six compounds were potent inhibitors of Kit kinase in a biochemical assay. A homology model of compound binding to the ATP binding site could account for the increased potency observed with the addition of a propionate moiety to the indolinone core but not the increase observed with addition of a chloride moiety. Although all of the compounds tested were potent in the biochemical assay, several exhibited significantly less potency in cellular kinase assays. Their effects on stem cell factor (SCF)-dependent Kit autophosphorylation and SCLC cell growth were also examined. Inhibition of SCF-stimulated Kit activation and cell growth in the H526 cell line was dose-dependent. At concentrations that inhibited SCF-stimulated H526 cell growth, there was little effect on insulin-like growth factor-1-stimulated growth, suggesting that these compounds exhibit reasonable selectivity for inhibition of Kit-mediated proliferation. Higher doses of the compounds were needed to inhibit serum-stimulated growth. Of the six compounds examined, SU5416 and SU6597 demonstrated the best cellular potency and, therefore, their effect on the growth of multiple SCLC cell lines in serum-containing media was examined. In addition to inhibiting proliferation, these compounds also induced significant cell death of several SCLC cell lines, but not of normal human diploid fibroblasts, in complete media. These observations suggest that Kit kinase inhibitors such as these may offer a new approach for inhibiting Kit-mediated proliferation of tumors such as SCLC, gastrointestinal stromal tumors, seminomas, and leukemias.     

No Difference in Pain After Spine Surgery with Local Wound Filtration of Morphine and Ketorolac: A Randomized Controlled Trial

BackgroundControlling postoperative pain after spinal surgery is important for rehabilitation and patient satisfaction. Wound infiltration with local anesthetics may improve postoperative pain, but true multimodal approaches for achieving analgesia after spinal surgery remain unknown.Questions/purposesIn this randomized, controlled, double-blind trial after lumbar interbody fusion, we asked: (1) Does multimodal analgesia reduce VAS pain scores by a clinically important amount? (2) Does this analgesic approach reduce the amount of morphine patients consume after surgery? (3) Is this approach associated with fewer opioid-related side effects after surgery?MethodsThis study included 80 adult patients undergoing lumbar interbody fusion who were randomized into two groups: A control group (n = 40) who received infiltration of the surgical incision at the end of the procedure with an injection of 0.5% bupivacaine 100 mg (20 mL) and epinephrine 0.5 mg (0.5 mL), and the multimodal group (n = 40), who received wound infiltration with the same approach but with different medications: 0.5% bupivacaine 92.5 mg (18.5 mL), ketorolac 30 mg (1 mL), morphine 5 mg (0.5 mL), and epinephrine 0.5 mg (0.5 mL). There were no between-group differences in the proportion of patients who were male, nor in the mean age, height, weight, preoperative pain score, or surgical time. All treatments were administered by one surgeon. All patients, the surgeon, and the researchers were blinded to the allocation of patients to each group. Pain at rest was recorded using the VAS. Postoperative morphine consumption (administered using a patient-controlled analgesia pump) and opiod-associated side effects including nausea/vomiting, pruritus, urinary retention, and respiratory depression were assessed; this study was analyzed according to intention-to-treat principles. No loss to follow-up or protocol deviations were noted. We considered a 2-cm change on a 10-cm scale on the VAS as the minimum clinically important difference (MCID). Differences smaller than this were considered unlikely to be important.ResultsAt no point were there between-group differences in the VAS scores that exceeded the MCID, indicating no clinically important reductions in pain associated with administering multimodal injections. The highest treatment effect was observed at 3 hours that showed only a -1.3 cm mean difference between the multimodal and the control groups (3.2 ± 1.8 versus 4.5 ± 1.9 [95% CI -1.3 to -0.3]; p < 0.001), which was below the MCID. Morphine consumption was very slightly higher in the control group than in the multimodal group (2.8 ± 2.8 versus 0.3 ± 1.0, mean difference 2.47; p < 0.001). The percentage of patients reporting opioid-related side effects was lower in the multimodal group than in the control group. The proportions of nausea and vomiting were higher in the control group (30% [12 of 40] than in the multimodal group (3% [1 of 40]; p = 0.001). All of these side effects were transient and none was severe.ConclusionsMultimodal wound infiltration with an NSAID and morphine did not yield any clinically important reduction in pain or opioid consumption. Since no substantial benefit of adding these drugs to a patient’s aftercare regimen was achieved, and considering the potential risks of administering opioids and NSAIDs (such as, polypharmacy in older patients, serious adverse effects of NSAIDs), we recommend against routine use of this approach in clinical practice.Level of EvidenceLevel I, therapeutic study.     

The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth.

At least 70% of small cell lung cancers express the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Numerous lines of evidence have demonstrated that this coexpression constitutes a functional autocrine loop, suggesting that inhibitors of Kit tyrosine kinase activity could have therapeutic efficacy in this disease. STI571, formerly known as CGP 57148B, is a p.o. bioavailable 2-phenylaminopyrimide derivative that was designed as an Abl tyrosine kinase inhibitor, but also has efficacy against the platelet-derived growth factor receptor and Kit in vitro. Pretreatment of the H526 small cell lung cancer (SCLC) cell line with STI571 inhibited SCF-mediated Kit activation with an IC50 of 0.1 microM as measured by inhibition of receptor tyrosine phosphorylation and 0.2 microM as measured by immune complex kinase assay. This paralleled the inhibition of SCF-mediated growth by STI571, which had an IC50 of approximately 0.3 microM. Growth inhibition in SCF-containing medium was accompanied by induction of apoptosis. STI571 efficiently blocked SCF-mediated activation of mitogen-activated protein kinase and Akt, but did not affect insulin-like growth factor-1 or serum-mediated mitogen-activated protein kinase or Akt activation. Growth of five of six SCLC cell lines in medium containing 10% FCS was inhibited by STI571 with an IC50 of approximately 5 microM. Growth inhibition in serum-containing medium appeared to be cytostatic in nature because no increase in apoptosis was observed. Despite this growth inhibition, STI571 failed to enhance the cytotoxicity of either carboplatinum or etoposide when coadministered. However, taken together with the minimal toxicity that this compound has shown in preclinical studies, these data suggest that STI571 could have a role in the treatment of SCLC, possibly to block or slow recurrence after chemotherapy-induced remissions.     

Cytokines as biochemical markers for knee osteoarthritis

Osteoarthritis (OA) is a debilitating degenerative joint disease particularly affecting weightbearing joints within the body, principally the hips and knees. Current radiographic techniques are insufficient to show biochemical changes within joint tissue which can occur many years before symptoms become apparent. The need for better diagnostic and prognostic tools is heightened with the prevalence of OA set to increase in aging and obese populations. As inflammation is increasingly being considered an important part of OAs pathophysiology, cytokines are being assessed as possible candidates for biochemical markers. Cytokines, both pro- and anti-inflammatory, as well as angiogenic and chemotactic, have in recent years been studied for relevant characteristics. Biochemical markers show promise in determination of the severity of disease in addition to monitoring of the efficacy and safety of disease-modifying OA drugs, with the potential to act as diagnostic and prognostic tools. Currently, the diagnostic power of interleukin (IL)-6 and the relationship to disease burden of IL-1β, IL-15, tumor necrosis factor-α, and vascular endothelial growth factor make these the best candidates for assessment. Grouping appropriate cytokine markers together and assessing them collectively alongside other bone and cartilage degradation products will yield a more statistically powerful tool in research and clinical applications, and additionally aid in distinguishing between OA and a number of other diseases in which cytokines are known to have an involvement. Further large scale studies are needed to assess the validity and efficacy of current biomarkers, and to discover other potential biomarker candidates.     

Circulating leptin levels and bone mineral density in children with biliary atresia

AIM: To investigate circulating leptin levels in biliary atresia (BA) patients and the association of leptin with bone mineral density (BMD) and the severity of BA. METHODS: We have examined 50 patients with BA and 15 matched healthy controls. Serum leptin, osteocalcin and C-terminal telopeptide of type I collagen (CTX) levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). BMD of the lumbar spine was measured by dual energy X-ray absorptiometry. RESULTS: Serum leptin levels of BA patients were lower than those of healthy controls (2.7 +/- 0.3 vs. 7.1 +/- 1.7 ng/mL, p = 0.0001). Among the BA patients, serum leptin levels were significantly lower in patients with jaundice than patients without jaundice (1.7 +/- 0.2 vs. 3.4 +/- 0.4 ng/mL, p = 0.001). BMD of BA patients was correlated (p < 0.001) with leptin levels, age and BMI (r = 0.55, r = 0.75 and r = 0.58, respectively). The serum CTX levels were significantly higher in jaundice patients compared with jaundice-free patients and the healthy controls (0.6 +/- 0.2 vs. 0.2 +/- 0.1 ng/mL, p = 0.01), whereas the serum osteocalcin levels in BA patients were not different from those in the controls. CONCLUSION: Circulating leptin levels are correlated with BMD and the presence of jaundice in BA, suggesting that the leptin may play a physiological role in maintaining bone mass of BA patients with jaundice.     

First trimester serum inhibin A in normal pregnant women

Objectives To establish reference ranges for maternal serum inhibin A in normal first trimester pregnant women. Materials and methods This was a cross-sectional study. We measured maternal serum inhibin A in normal pregnant women gestation age between 6⁺⁰ and 14⁺⁶ weeks using the enzyme-linked immunosorbent assay (ELISA) method. Maternal serum inhibin A was analyzed according to gestational ages (GA). Results Serum of 300 pregnancies was analyzed and the outcome demonstrated the median of maternal serum inhibin A according to gestational age. The levels of maternal serum inhibin A during the 6⁰–6⁺⁶ week of gestations are lowest when compared with other gestational age. The levels of maternal serum inhibin A during 9⁰–9⁺⁶ week of gestations are maximal. Maternal serum inhibin A then declined until 14 weeks of gestation. Conclusion Serum inhibin A can be measured during the first trimester of pregnancy by using the recent ELISA technique. Our reference ranges might be useful for further studies, such as prediction of adverse pregnancy outcome in threatened abortion.