Radiation recall dermatitis: A review of the literature.

PURPOSE/OBJECTIVES: Radiation recall dermatitis (RRD) is a skin reaction limited to an area of prior radiation triggered by the subsequent introduction of systemic therapy. To characterize RRD, we conducted a literature search, summarized RRD features, and compared the most common drug classes implicated in this phenomenon. MATERIALS/METHODS: PubMed, Embase, Scopus, Web of Science, and Cochrane DBSR databases were queried through July 1, 2019 using key words: radiation recall, RRD, and radiodermatitis (limited to humans and English language). Studies included case reports in which patients treated with radiotherapy were initiated on a new line of systemic therapy and subsequently developed a skin reaction in the irradiated area. RRD cases were organized by whether RRD occurred after a single drug or multiple drug administration. RESULTS: One-hundred fifteen studies representing 129 RRD cases (96 single-drug RRD, 33 multi-drug) were included. Sixty-three drugs were associated with RRD. Docetaxel (22) and gemcitabine (18) were the two drugs most commonly associated with RRD. Breast cancer (69 cases) was the most commonly associated tumor type. For single-drug RRD, the median radiotherapy dose was 45.0 Gy (range, 30.0-63.2 Gy). The median time from radiotherapy to drug exposure, time from drug exposure to RRD and time to significant improvement was 8 weeks (range, 2-132 weeks), 5 days (range, 2-56 days), and 14 days (range, 7-49 days), respectively. Variables significantly associated with grade ≥2 toxicity were docetaxel (P = 0.04) and non-antifolate antimetabolite (P = 0.05). The only variable significantly associated with grade ≥3 toxicity was capecitabine (P = 0.04). CONCLUSIONS: RRD is a complex toxicity that can occur after a wide range of radiotherapy doses and many different systemic agents. Most commonly, it presents in patients diagnosed with breast cancer and after administration of a taxane or antimetabolite medication. RRD treatment generally consists of corticosteroids with consideration of antibiotics if superinfection is suspected. Drug re-challenge may be considered after RRD if the initial reaction was of mild intensity.

Muscle as an osteoinductive niche for local bone formation with the use of a biphasic calcium sulphate/hydroxyapatite biomaterial.

OBJECTIVES: We have observed clinical cases where bone is formed in the overlaying muscle covering surgically created bone defects treated with a hydroxyapatite/calcium sulphate biomaterial. Our objective was to investigate the osteoinductive potential of the biomaterial and to determine if growth factors secreted from local bone cells induce osteoblastic differentiation of muscle cells. MATERIALS AND METHODS: We seeded mouse skeletal muscle cells C2C12 on the hydroxyapatite/calcium sulphate biomaterial and the phenotype of the cells was analysed. To mimic surgical conditions with leakage of extra cellular matrix (ECM) proteins and growth factors, we cultured rat bone cells ROS 17/2.8 in a bioreactor and harvested the secreted proteins. The secretome was added to rat muscle cells L6. The phenotype of the muscle cells after treatment with the media was assessed using immunostaining and light microscopy. RESULTS: C2C12 cells differentiated into osteoblast-like cells expressing prominent bone markers after seeding on the biomaterial. The conditioned media of the ROS 17/2.8 contained bone morphogenetic protein-2 (BMP-2 8.4 ng/mg, standard deviation (sd) 0.8) and BMP-7 (50.6 ng/mg, sd 2.2). In vitro, this secretome induced differentiation of skeletal muscle cells L6 towards an osteogenic lineage. CONCLUSION: Extra cellular matrix proteins and growth factors leaking from a bone cavity, along with a ceramic biomaterial, can synergistically enhance the process of ectopic ossification. The overlaying muscle acts as an osteoinductive niche, and provides the required cells for bone formation.Cite this article: D. B. Raina, A. Gupta, M. M. Petersen, W. Hettwer, M. McNally, M. Tägil, M-H. Zheng, A. Kumar, L. Lidgren. Muscle as an osteoinductive niche for local bone formation with the use of a biphasic calcium sulphate/hydroxyapatite biomaterial. Bone Joint Res 2016;5:500-511. DOI: 10.1302/2046-3758.510.BJR-2016-0133.R1.

Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute: In vitro and clinical release studies.

OBJECTIVES: Deep bone and joint infections (DBJI) are directly intertwined with health, demographic change towards an elderly population, and wellbeing.The elderly human population is more prone to acquire infections, and the consequences such as pain, reduced quality of life, morbidity, absence from work and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets.DBJIs are less responsive to systemic antibiotics because of poor vascular perfusion in necrotic bone, large bone defects and persistent biofilm-based infection. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently needed to curb its current trajectory. MATERIALS AND METHODS: We present a new biphasic ceramic bone substitute consisting of hydroxyapatite and calcium sulphate for local antibiotic delivery in combination with bone regeneration. Gentamicin release was measured in four setups: 1) in vitro elution in Ringer's solution; 2) local elution in patients treated for trochanteric hip fractures or uncemented hip revisions; 3) local elution in patients treated with a bone tumour resection; and 4) local elution in patients treated surgically for chronic corticomedullary osteomyelitis. RESULTS: The release pattern in vitro was comparable with the obtained release in the patient studies. No recurrence was detected in the osteomyelitis group at latest follow-up (minimum 1.5 years). CONCLUSIONS: This new biphasic bone substitute containing antibiotics provides safe prevention of bone infections in a range of clinical situations. The in vitro test method predicts the in vivo performance and makes it a reliable tool in the development of future antibiotic-eluting bone-regenerating materials.Cite this article: M. Stravinskas, P. Horstmann, J. Ferguson, W. Hettwer, M. Nilsson, S. Tarasevicius, M. M. Petersen, M. A. McNally, L. Lidgren. Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute: In vitro and clinical release studies. Bone Joint Res 2016;5:427-435. DOI: 10.1302/2046-3758.59.BJR-2016-0108.R1.

Prediction of survival after surgery due to skeletal metastases in the extremities.

AIMS: The purpose of this study was to develop a prognostic model for predicting survival of patients undergoing surgery owing to metastatic bone disease (MBD) in the appendicular skeleton. METHODS: We included a historical cohort of 130 consecutive patients (mean age 64 years, 30 to 85; 76 females/54 males) who underwent joint arthroplasty surgery (140 procedures) owing to MBD in the appendicular skeleton during the period between January 2003 and December 2008. Primary cancer, pre-operative haemoglobin, fracture versus impending fracture, Karnofsky score, visceral metastases, multiple bony metastases and American Society of Anaesthesiologist's score were included into a series of logistic regression models. The outcome was the survival status at three, six and 12 months respectively. Results were internally validated based on 1000 cross-validations and reported as time-dependent area under the receiver-operating characteristic curves (AUC) for predictions of outcome. RESULTS: The predictive scores obtained showed AUC values of 79.1% (95% confidence intervals (CI) 65.6 to 89.6), 80.9% (95% CI 70.3 to 90.84) and 85.1% (95% CI 73.5 to 93.9) at three, six and 12 months. DISCUSSION: In conclusion, we have presented and internally validated a model for predicting survival after surgery owing to MBD in the appendicular skeleton. The model is the first, to our knowledge, built solely on material from patients who only had surgery in the appendicular skeleton. TAKE HOME MESSAGE: Applying this prognostic model will help determine whether the patients' anticipated survival makes it reasonable to subject them to extensive reconstructive surgery for which there may be an extended period of rehabilitation. Cite this article: Bone Joint J 2016;98-B:271-7.

Strain Elastography for Prediction of Malignancy in Soft Tissue Tumours--Preliminary Results.

PURPOSE: To evaluate the ability of strain elastography to predict malignancy in patients with soft tissue tumors, and to compare three evaluation methods of strain elastography: strain ratios, strain histograms and visual scoring. MATERIALS AND METHODS: 60 patients with 61 tumors were analyzed in the study. All patients were referred due to suspicion of malignant soft tissue tumors after diagnostic imaging (contrast-enhanced MRI, CT or PET-CT). Ultrasound-guided biopsy was preceded by the recording of strain elastography video clips, which were evaluated in consensus between three investigators. Strain ratio, strain histogram analysis and visual scoring using a five-point visual scale were compared with the final pathology from either biopsy or resection of the tumors. RESULTS: The difference between the mean strain ratio for malignant and benign tumors was significant (p = 0.043). The mean strain ratios for malignant and benign tumors were 1.94 (95% CI [0.37; 10.21]) and 1.35 (95% CI [0.32; 5.63]), respectively. There were no significant differences for strain histograms or visual scoring. Liposarcomas had lower mean strain ratio, strain histogram values, and visual scoring than other malignant tumors. When analyzing a subgroup of patients without fat-containing tumors (n = 46), based on appearance on MRI or CT, the difference between the mean strain ratios for malignant and benign tumors increased (p = 0.014). CONCLUSION: The mean strain ratios of malignant tumors were significantly higher than the mean strain ratios of benign tumors. There was no significant difference for strain histograms and visual scoring. Strain ratios may be used as an adjunct in soft tissue tumor diagnosis, possibly minimizing the number of biopsies.

Flow-mediated vasodilation and dietary intake of n-3 polyunsaturated acids in healthy subjects.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major marine n-3 polyunsaturated fatty acids (PUFA), have been proposed to decrease the risk of atherosclerosis and coronary heart disease. An early event during atherogenesis is endothelial dysfunction. We studied the correlation between fish consumption, serum phospholipid (sPL) levels of DHA and EPA and flow-mediated vasodilation (FMD), a measure of endothelial function. Furthermore, subjects were classified according to whether they did (Fish+, n = 19) or did not (Fish-, n = 21) follow the Danish recommendations, consuming at least 300 g fish/week. Neither the fish intake, sPL EPA nor sPL DHA significantly correlated with FMD, -0.20 (p = 0.23), -0.23 (p = 0.15) and -0.06 (p = 0.72), respectively. Also, when comparing the Fish+ and the Fish- group we did not find any significant differences in FMD (p = 0.33). In conclusion, our results did not show any correlation between intake and sPL levels of marine n-3 PUFA and FMD in healthy subjects.

Influence of pre-operative bone mineral content of the proximal tibia on revision rate after uncemented knee arthroplasty.

Between 1986 and 1991, 106 patients (127 knees) underwent uncemented knee arthroplasty for osteoarthritis. There were 106 total knee arthroplasties and 21 medial unicompartmental knee arthroplasties. The arthroplasties were evaluated for aseptic loosening during the year 2000. For total arthroplasty we used 77 porous-coated anatomic prostheses and 29 press-fit condylar prostheses. The mean bone mineral content of the proximal tibia, measured the day before surgery using dual-photon absorptiometry was 5.48 g/cm for the porous-coated anatomic prostheses which were revised for aseptic loosening (n = 9). This was significantly higher (p = 0.02) than the mean of 4.33 g/cm for those which were not revised. Values for the two revised press-fit condylar knees (4.78 and 4.93 g/cm) were above the mean value (4.23 g/cm) for those which were not revised. We found no statistically significant (p = 0.38) difference between the bone mineral content of the 12 revised and nine unrevised unicompartmental arthroplasties. Low trabecular bone quality, measured as the pre-operative bone mineral content of the proximal tibia, was not a predictor for later revision surgery following uncemented total knee or unicompartmental knee arthroplasty.

Loss of bone mineral of the hip and proximal tibia following rupture of the Achilles tendon.

In a prospective uncontrolled study 12 patients suffering from a rupture of the Achilles tendon treated operatively with surgical repair and post-operative immobilization in a short plaster cast for 6 weeks had bilateral measurements of bone mineral content (BMC) of the proximal tibia and bone mineral density (BMD) of the femoral neck and greater trochanter. The measurements were performed by dual energy X-ray absorptiometry (DEXA) and scans were performed post-operatively within 7 days after the operation and with follow up after 6 weeks, 3, 6, and 12 months. In the operated legs, BMC of the proximal tibia showed a progressive decrease reaching a total bone loss of 6.4% (95%-CL: -10.6%; -2.3%) 1 year after the injury. Bone mineral density at the hip of the operated legs also decreased significantly and 1 year after the injury BMD was 2.5% (95%-CL: -5.5%; 0.5%) and 6.8% (95%-CL: -9.8%; -3.7%) below the initial value in, respectively, the femoral neck and greater trochanter. Patients with a previous Achilles tendon rupture must be considered to be some years ahead in their natural osteoporotic process of the bones of the affected legs, and an increased risk of osteoporotic fractures must be considered not to be only theoretical.

Dual energy X-ray absorptiometry in small rats with low bone mineral density.

The feasibility of dual energy X-ray absorptiometry (DXA) using the Norland XR-26 Mark II bone densitometer for measurements of bone mineral content (BMC) and bone mineral density (BMD) in small rats was evaluated. Thirty-two young, isogenic, Lewis rats (weights from 119 g to 227 g) were used; normal rats (n = 7) and rats with low BMD obtained from three different vitamin D-depleted models (n = 25). DXA measurements were performed using the special software for small animals. Duplicate scans of excised femurs performed at 2 mm/second (pixel size of 0.5 mm x 0.5 mm) were very precise measurements with a coefficient of variation (CV) below 1.6% in animals with normal BMD; in rats with low BMD, the CV was significantly higher (P = 0.02-0.04), 7.8% and 4.4% for BMC and BMD, respectively. Regression analysis demonstrated that these measurements were related to the ash weight (R2 > 98.6%). The CV for measurements of the lumbar spine at 10 mm/second (pixel size 0.5 mm x 0.5 mm) was 2.6% and 2.2% for BMC and BMD, respectively in rats with normal BMD, and again higher (P = 0.03-0.14) in rats with low BMD, 7.3% and 4.7%, respectively, for BMC and BMD. Even though low CVs were obtained for total body duplicate scans (scan speed of 20 mm/second and a pixel size of 1.5 mm x 1.5 mm), the measurements were problematic for accuracy because of an overestimation of both BMC and the area of bone. Using these scan parameters the measurements of total body bone mineral could not be recommended in small rats with low BMD.

Early changes in muscle strength after total knee arthroplasty. A 6-month follow-up of 30 knees.

We studied 30 patients with arthrosis in one knee operated on with a cemented (n 26) or an uncemented total knee arthroplasty (TKA) (n 4). Full weight-bearing from the first postoperative day was allowed in all patients, and they received standard postoperative physiotherapy. 1 week prior to surgery, and after 3 and 6 months, isokinetic and isometric muscle strength in both legs were measured, using a Cybex 6000 dynamometer. Isokinetic tests showed a bilateral, significant, and progressive increase (30-53%) in flexor muscle strength most pronounced in the operated legs. Isokinetic extensor strength increased significantly (14-18%) in the operated legs, while in the contralateral legs, a limited increase was found. Isometric flexion strength significantly decreased in the operated knees (17%). Isometric extension strength showed a temporary decrease at 3 months, which returned to the preoperative level. No significant change in isometric strength was observed in the contralateral legs. The knee pain during the muscle strength measurements decreased significantly from the preoperative level, which may indicate that the substantial pain relief within 3 months after a TKA is an important factor for evaluation of muscle strength.

Preoperative bone mineral density of the proximal tibia and migration of the tibial component after uncemented total knee arthroplasty.

Twenty-two patients with primary osteoarthrosis of the knee all operated on with insertion of an uncemented total knee arthroplasty had a preoperative measurement of bone mineral density (BMD) in the coronal plane of the proximal tibia performed by dual-photon absorptiometry. Postoperatively and with follow-up after 6 weeks (n = 21), 1 year (n = 22), and 3 years (n = 19), radiographs suitable for radiostereometric analysis of the tibial component migration were obtained. One year postoperatively, stress examinations were performed with the aim of measuring inducible displacement of the tibial component. Most of the migration, expressed as maximal total point motion (MTPM), occurred during the first year with an average migration of approximately 1 mm. Regression analysis showed a positive relation between BMD and MTPM after 6 weeks (P = .03, r = .47), 1 year (P = .0005, r = .68), and 3 years (P = .02, r = .54). Inducible displacement did not reveal any significant relation to BMD. MTPM between 1 and 3 years, which is the clinically most important parameter with respect to later loosening of the tibial component, showed a negative relation to BMD (P = .04, r = -.47). Thus, tibial components of knees with preoperative high tibial BMD showed less continuous migration.

Changing tradition -- a Danish approach to female genital mutilation.

PIP: This article reviews the video film "Let us talk" and the book "Preventing FGM", the Danish response to the challenge of FGM (female genital mutilation). The video film, produced in Somali in 1998, presents different Somali views on the harmfulness of FGM. Also included are the opinions of Somali men, a religious leader and professionals in the fields of psychology and medicine. The main points against FGM cited in the video include the physical and mental impact of FGM, religious aspects of FGM, and violation of human rights. This is meant to raise consciousness, induce discussions and sway common opinion on the subject. Meanwhile, the book published by the Danish National Board of Health in 1999 aims at the professionals working in the public sector. It deals with the prevention of FGM and supplies the reader with important background information, statistics and diagrams. Guidelines on how to address specific situations involving FGM are offered.^ieng

Effect of nasal salmon calcitonin on post-traumatic osteopenia following ankle fracture. A randomized double-blind placebo-controlled study in 24 patients.

With the aim of preventing postfracture osteopenia, we randomized 24 patients with internally fixed ankle fractures to 3 months of treatment with placebo or 200 IU nasal salmon calcitonin (sCT) in a prospective, double-blind design. 3 patients were excluded, leaving 11 patients in the placebo group and 10 in the sCT group for study. Bilateral measurements of bone mineral content (BMC) in the coronal plane of the proximal tibia were performed by dual photon absorptiometry (DPA) postoperatively within 7 days of the fracture and after 1.5, 3 and 6 months. 3 months after the fracture, BMC in the injured legs had decreased by 14% in the placebo group and 2.1% in the sCT group. This difference was not statistically significant. In the healthy legs, a statistically significant intergroup difference was seen 6 weeks after the fracture, caused by a tendency towards a decrease in BMC of 4.6% in the placebo group, while BMC in the sCT group had increased by 7.4%. Nasal sCT may to some extent, but in this study not significantly, reduce postfracture osteopenia, and cause a significant effect on BMC in the healthy leg.

Loss of bone mineral of the hip assessed by DEXA following tibial shaft fractures.

We measured prospectively early changes (0-6 months) in bone mineral of the hip, the lumbar spine, and the tibia following tibial shaft fractures (n = 12), and in a cross-sectional study we evaluated the maximal amount of bone loss possible at the hip and tibia following long-term (average 3 years) impaired limb function as a consequence of complicated tibial shaft fractures [delayed union or nonunion (n = 7), chronic osteomyelitis (n = 5), decreased limb length (n = 1), or bone defect (n = 1)]. Bone mineral measurements were performed by dual energy X-ray absorptiometry. Following tibial shaft fractures, a significant decrease in bone mineral density (BMD) was seen at the hip reaching 7% [confidence limits (CL): -10.2%; -3.5%] and 14% (CL: -19.6; -7.8%) after 6 months for the femoral neck and greater trochanter, respectively. In the proximal tibia, bone mineral content (BMC) decreased and was 19% (CL: -27.4%; -9.9%) below the initial value after 6 months. BMD of the lumbar spine remained unchanged. In the cross-sectional study, BMC in the tibia of the injured legs was 43% (CL: -53.2%; -31.9%) below the value in the healthy contralateral legs, and BMD in the femoral neck and greater trochanter, respectively, was 22% (CL: -27.4%; -17.6%) and 24% (CL: -36.3%; -12.1%) below the values in the healthy contralateral legs. With respect to the expected age-related decay of bone mineral after peak bone mass, the loss of bone mineral of the hip and tibia associated with tibial shaft fractures may be considered of clinical importance with increased risk of sustaining a fragility fracture of the lower extremity later in life; and the complicated fractures may even represent a present risk of fracture.

Body composition and muscle strength in women scheduled for a knee or hip replacement. A comparative study of two groups of osteoarthritic women.

It is unclear whether patients with knee osteoarthritis (OA) and hip OA differ regarding soft tissue composition and bone mineral density (BMD). A total of 42 women waiting for a replacement of the hip (n = 20) or the knee (n = 22) due to OA were examined. Fat mass (FM), percent body fat (%fat), lean mass (LM) and BMD were measured by dual energy X-ray absorptiometry (DEXA). Knee extensor and flexor strength was measured by an isokinetic dynamometer. No significant differences in age, height, disease duration, Lequesne score or pain scores were found between the groups. Comparing the radiographic changes of the knees with those of the hips, changes were most severe in the joints which were to be replaced. Body weight, body mass index, total and regional FM, and %fat were more than 15% higher in patients waiting for a knee replacement (p < 0.001). Also lean mass tended to be higher in the knee patients. Differences in BMD did not remain statistically significant after correction for body weight. Muscle strength was similar in the two groups but was reduced by 20% in the legs in which the joint was to be replaced compared to the contralateral legs. However, the mean difference in lean mass between the two legs was only 3% (p < 0.05). The scores for pain felt during strength testing were significantly higher for the involved legs than for the contralateral legs. In conclusion, fat mass values were considerably higher in patients scheduled for a knee replacement. Impaired strength performance in OA may be more strongly associated with pain than with reduced muscle mass.

The relation between trabecular bone strength and bone mineral density assessed by dual photon and dual energy X-ray absorptiometry in the proximal tibia.

The feasibility of two noninvasive methods [dual photon absorptiometry (DPA) and dual energy X-ray absorptiometry (DXA)] for prediction in vivo of local variations of trabecular bone strength within the proximal tibia was evaluated in 14 cadaveric knees. Trabecular bone strength was measured using an osteopenetrometer and from destructive compression tests performed on bone cylinders, thus measuring the penetration strength and ultimate strength in the medial, lateral, and central part of the tibial bone specimens. Linear regression analysis showed significant relations between BMD measured by DPA (r2 = 72%) or DXA (r2 = 73%) and ultimate strength. Even closer relations between BMD (DPA: r2 = 80%, DXA r2 = 81%) and penetration strength of trabecular bone were found. We conclude that DPA and DXA are suitable methods for evaluation in vivo of local variations in trabecular bone strength within the proximal tibia, and could easily be performed preoperatively before insertion of total knee arthroplasty.

Decreased bone density of the distal femur after uncemented knee arthroplasty. A 1-year follow-up of 29 knees.

We measured the early adaptive bone remodeling of the distal femur prospectively for 1 year after uncemented total knee arthroplasty (TKA) in 29 knees with primary arthrosis. 18 patients were randomized to receive a PCA Modular femoral component (n 9) or a modified version of the same prosthesis (n 9) with an altered location of the porous coating. The other 11 patients (n 11) formed a consecutive series with the Duracon femoral component. In the trabecular bone above the femoral component, bone mineral density (BMD) was measured in 2 regions of interest (ROI) anteriorly to the fixation pegs (ROI 1) and above the pegs (ROI 2), using dual photon absorptiometry (DPA). There were no differences between the Modular component and the modified version regarding the postoperative decrease in BMD. There was a decrease in BMD in both ROI 1 and ROI 2 with all 3 different femoral components, and in both ROIs the highest bone loss rate was observed during the first 3 months after surgery. On average (n 29), a significant bone loss of 44% and 19% in ROI 1 and ROI 2, respectively, was reached at the 1-year follow-up, compared to the initial values. A decrease of this magnitude in BMD in the anterior distal femur 1 year after TKA may be an important determinant of periprosthetic fracture and later failure of the femoral component. In this experimental set-up, a modified femoral component with an altered location of the porous coating did not influence the development of bone loss.

CD11b/CD18-dependent stimulation of leukotriene B4 synthesis by human neutrophils (PMN) is synergistically enhanced by tumour necrosis factor alpha and low dose diacylglycerol.

Unopsonised zymosan particles bind to the CD11b/CD18 integrin on human neutrophils (PMN) and are phagocytosed. Binding stimulates the release of leukotriene (LT) B4. The present study examined the effect on this interaction of two agents that 'prime' PMN for augmented responses to a variety of agonists. The cell permeable diacyl glycerol, 1,2-dioctanoyl-glycerol (DiC8) and TNF alpha each increased CD11b/CD18 expression on PMN [maximal at 10-9 M TNF alpha or 10-8 M DiC8]. There was a decrease, however, in CD11b/CD18 expression above 10-8 M DiC8, which was not observed at high concentrations of TNF alpha. Pre-treatment with either DiC8 or TNF alpha dose-dependently augmented the zymosan-stimulated release of LTB4 from PMN. DiC8 and TNF alpha in combination, however, synergistically increased LTB4 release. In contrast, at concentrations above 10-8 M DiC8, whether in the presence or absence of TNF alpha, LTB4 release was inhibited and this was ameliorated by protein kinase C inhibitors. The response to neither TNF alpha nor DiC8 (below 10-8 M) was kinase inhibitor sensitive. Doses of DAG, which activate protein kinase C, inhibit CD11b/CD18-dependent responses by down-regulating receptor expression. In contrast, the mechanisms of TNF alpha and low dose DAG 'priming' are not clear but are independent of PKC activation. The synergy between these two priming agents, however, suggests independent, complementary signalling pathways that provide a novel, potentially important mechanism for the control of PMN CD11b/CD18 integrin-dependent activation.