Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells.

The HOX genes encode a family of transcription factors that are dysregulated in several malignancies and have been implicated in oncogenesis and cancer cell survival. Disruption of HOX protein function using the peptide HXR9 has shown anti-tumor effects against melanoma, lung cancer and renal cancer. In this report, we evaluated the expression of all 39 HOX genes in a panel of six malignant B-cell lines, including multiple myeloma cells and found different levels of expression of HOX family members suggesting that they also have a role in malignant B-cell survival. We show that disrupting HOX function using the peptide HXR9 induces significant cytotoxicity in the entire panel of cell lines. Importantly, we found that the cytotoxic effects of HXR9 can be enhanced by combining it with ch128.1Av, an antibody-avidin fusion protein specific for the human transferrin receptor 1 (CD71). Iron starvation induced by the fusion protein contributes to the enhanced effect and involves, at least in part, the induction of a caspase-independent pathway. These results show the relevance of HOX proteins in malignant B-cell survival and suggest that our therapeutic strategy may be effective in the treatment of incurable B-cell malignancies such as multiple myeloma.

Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species.

The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.

Anterolateral ankle impingement: mr arthrographic assessment of the anterolateral recess.

PURPOSE: To determine the accuracy of magnetic resonance (MR) arthrography in assessing the anterolateral recess of the ankle. MATERIALS AND METHODS: Thirty-two patients with chronic ankle pain prospectively underwent gadolinium-enhanced MR arthrography of the tibiotalar joint. All underwent clinical examination and were included if anterolateral impingement (n = 13) or a control condition (n = 19; suspected osteochondral defect, intraarticular bodies, instability, osteoarthritis) was diagnosed. MR imaging included transverse and coronal T1-weighted and sagittal T2-weighted imaging sequences. Images were prospectively analyzed by two readers blinded to the clinical diagnosis. The anterolateral gutter contour was assessed. MR arthrographic findings were correlated with subsequent arthroscopic appearances. RESULTS: MR arthrographic assessment of the anterolateral soft tissues had an accuracy of 97%, sensitivity of 96%, specificity of 100%, negative predictive value of 89%, and positive predictive value of 100%. Accuracy was 100% with clinical anterolateral impingement, with an arthroscopically confirmed abnormality in 12 cases and a normal appearance in one. Anterolateral soft-tissue thickening was identified at MR arthrography in 11 control cases, with arthroscopic confirmation in all. The remaining cases had normal appearances, with an arthroscopic soft-tissue abnormality in one case and a normal appearance in seven. CONCLUSION: MR arthrography of the tibiotalar joint is accurate in assessing the anterolateral recess of the ankle.

Outcomes following cheilectomy and interpositional arthroplasty in hallux rigidus.

Surgical management of hallux rigidus remains controversial. Arthrodesis is considered the gold standard. However, many patients are reluctant to undergo fusion. This paper reviews two commonly used procedures that are reasonable alternatives. A retrospective review of 19 patients (24 feet) with grade 2 osteoarthritis and 11 patients (11 feet) with grade 3 osteoarthritis was performed. The patients with grade 2 osteoarthritis were managed with a cheilectomy and the patients with grade 3 osteoarthritis with an interpositional arthroplasty. All patients were individually assessed with a subjective questionnaire, physical exam, AOFAS hallux scale, SF-36 and pedobarographic analysis. Cheilectomy patients (51.9 years) were younger than interpositional arthroplasty (59 years). Follow up between the interpositional arthroplasties (2.0 years) and cheilectomies (2.1 years) were comparable. Postoperative motion, visual analogue pain scale and SF-36 scores were comparable between groups. Cheilectomies had a higher mean AOFAS score (77.3) than interpositional arthroplasties (71.6). Weakness of the great toe was reported in 72.7% of interpositional arthroplasty patients compared to only 16.7% of patients with a cheilectomy. Patient satisfaction was 87.5% in cheilectomies and 72.7% in interpositional arthroplasties. Pedobarographic analysis demonstrated a decreased load under the great toe with increased weight transfer to the lesser metatarsal heads in all patients. The weight transfer to the lesser metatarsal heads was greatest in patients with interpositional arthroplasty. Management of moderate hallux rigidus with a cheilectomy and phalangeal osteotomy is a reliable method of relieving pain and improving function. Management of severe osteoarthritis of the joint with an interpositional arthroplasty should be considered a salvage procedure with less reliable results.

Midfoot and hindfoot arthrodeses in diabetic Charcot arthropathy.

OBJECTIVES: To review the clinical outcome of arthrodesis of the foot in patients with diabetic Charcot arthropathy and to review the pathophysiology, clinical and radiographic features of Charcot arthropathy. DESIGN: A retrospective review and clinical follow-up of a series of patients. SETTING: St. Michael's Hospital, Toronto, a tertiary care teaching hospital. PATIENTS: Ten diabetic patients treated between 1996 and 1998 who required an arthrodesis of the midfoot or hindfoot secondary to deformity of diabetic neuropathic joints. INTERVENTIONS: Three midfoot (Lisfranc) and 7 hindfoot arthrodeses with autogenous iliac-crest bone grafting and internal fixation. OUTCOME MEASURES: Patient satisfaction, maintenance of the correction of the deformity and avoidance of amputation. Western Ontario/McMaster University score and midfoot/hindfoot American Orthopaedic Foot and Ankle Society foot ratios. Clinical examination including E-MED pedographic examination. Correction and evidence of bony or fibrous union assessed radiologically. RESULTS: The postoperative correction was maintained, no further skin ulceration occurred and amputation was avoided in 9 of 10 patients. Because this is a salvage procedure and there was often significant concomitant illness, the results of clinical rating systems were poor. Five of 9 patients had clinical and radiographic evidence of a solid bony arthrodesis; 4 had a stable fibrous union. CONCLUSIONS: With careful surgical technique, a reasonable number of feet can be salvaged by an arthrodesis of a diabetic neuropathic joint when nonoperative measures fail. Patient selection is important because there is a significant complication rate.

Effect of increasing distal medial closing wedge metatarsal osteotomies on the distal metatarsal articular angle.

The recognition, definition, and management of the congruent hallux valgus deformity continue to evolve. To correct the skeletal deformity and maintain joint congruity, many authors have emphasized the importance of extra-articular procedures. One such procedure is a distal medial closing wedge osteotomy of the first metatarsal. Unfortunately, there are few guidelines to help determine the pre- and intraoperative size of the medial wedge to obtain the desired correction of the distal metatarsal articular angle (DMAA). The purpose of this study was to quantify the effects of increasing distal medial closing wedge osteotomies on the DMAA in an in vitro cadaver model. In this study, a closing wedge osteotomy was performed 2 cm proximal to the articular surface, removing wedges measuring 2 mm, 4 mm, and 6 mm in width. The mean preoperative DMAA was 8.5 degrees, and the mean postoperative DMAAs after 2-mm, 4-mm, and 6-mm closing wedge osteotomies were -2.6 degrees, -10.2 degrees, and -20.2 degrees, respectively. The data showed that for every 1 mm of closing wedge osteotomy, the DMAA decreased by 4.7 degrees +/- 0.6 degrees. These results can be used for pre- and intraoperative planning when surgically correcting a congruent hallux valgus deformity with a distal medial closing wedge osteotomy of the first metatarsal. Additional information obtained from this cadaver study includes (1) increased shortening of the first metatarsal and (2) incongruity produced at the joint after the medial-based osteotomy. The amount of shortening of the first metatarsal correlated directly with the size of the medial-based wedge. The second point indicates that a lateral soft-tissue release may still be required when using this method of reorienting the DMAA.

Tarsal tunnel syndrome: a review of the literature.

Tarsal tunnel syndrome is an uncommon clinical entity. This article will review the published reports on tarsal tunnel syndrome with respect to its anatomy, cause, pathophysiology, clinical presentation, diagnosis, treatment, and results of treatment in an attempt to improve understanding of this problem.

Effects of tarsal tunnel release and stabilization procedures on tibial nerve tension in a surgically created pes planus foot.

An in vitro study was performed on 11 cadaver legs to study the effects of tarsal tunnel release, distraction calcaneocuboid arthrodesis, and triple arthrodesis on tibial nerve tension in surgically created pes planus feet. Baseline tibial nerve tension was measured during maximal dorsiflexion, eversion, combined dorsiflexion-eversion, and cyclical load with varying degrees of internal rotation. These measurements were repeated on the same leg after each surgical procedure. This study demonstrated that a tarsal tunnel release significantly increased nerve tension during eversion, dorsiflexion-eversion, and cyclical load compared with the pes planus foot. Both triple arthrodesis and distraction calcaneocuboid arthrodesis were effective at decreasing tibial nerve tension; the former was more effective than the latter. Procedures producing skeletal instability, such as ligament release producing a pes planus deformity and a tarsal tunnel release, increased tibial nerve tension. Procedures that corrected deformity and increased stability decreased tibial nerve tension. If increased tibial nerve tension plays a role in the pathophysiology of tarsal tunnel syndrome, then this needs to be considered for treatment of patients with this syndrome.

Diabetic foot ulcerations: an overview.

The development of a diabetic neuropathic ulcer is a multifactorial process with an emphasis on mechanical abnormalities. In the absence of vascular compromise, up to 90 percent of neuropathic ulcers will heal with proper ulcer debridement, treatment of infection and relief of weight from the ulcerated area. A thorough understanding of the etiology of a neuropathic ulcer is an essential component in the appropriate management of these patients. Treatment of the diabetic neuropathic ulcer is a multidisciplinary clinical problem and each member of the team has a unique role to play.

The effects of foot position and load on tibial nerve tension.

Patients with tarsal tunnel syndrome of unknown etiology do poorly after surgical decompression. Although surgical decompression addresses the soft tissue constraints, it ignores the role of osseous support. Some authors have suggested that a pes planus deformity (i.e., valgus hindfoot and abducted forefoot) is an unrecognized cause of tarsal tunnel syndrome due to increased tibial nerve tension. An in vitro study was performed on nine cadaveric feet to determine the effects of foot position and load on tibial nerve tension. Tensile forces placed through the tibial nerve were measured when the foot was placed in dorsiflexion, eversion, combined dorsiflexion-eversion, and then under cyclical load and increasing internal rotation at 5 degrees increments from 0 degrees to 20 degrees. The nerve tension was reassessed after the creation of a pes planus deformity under the previous conditions. Tibial nerve tension in the stable and unstable foot was significantly increased by eversion, dorsiflexion, and combined dorsiflexion-eversion. Tibial nerve tension was significantly greater in an unstable foot when compared with a stable foot during eversion, dorsiflexion, and combined dorsiflexion-eversion. In the stable foot, tibial nerve tension was significantly increased during axial loading with increasing internal rotation when compared with 0 degrees rotation. The increased tibial nerve tension in the stable foot was significant with increasing internal rotation when 0 degrees was compared with 10 degrees, 15 degrees, and 20 degrees. In the unstable foot, the tibial nerve tension was significantly increased with increasing internal rotation compared with the nerve tension at 0 degrees of rotation. The increased tibial nerve tension in the unstable foot was significant with increasing internal rotation when 0 degrees was compared with 5 degrees, 10 degrees, 15 degrees, and 20 degrees. When stability of the foot and internal rotation were compared independently, each factor increased tibial nerve tension. However, these factors acting together did not significantly compound the increase in nerve tension. This study demonstrates that tibial nerve tension is increased in an unstable foot compared with a stable foot during eversion, dorsiflexion, combined dorsiflexion-eversion, and cyclical load with increasing internal rotation.

Varus malalignment of the talar neck. Its effect on the position of the foot and on subtalar motion.

We performed an in vitro study on twelve specimens of the foot and ankle from cadavera to determine whether varus malalignment of the talar neck alters the position of the foot and subtalar motion. An osteotomy of the talar neck was performed, and the specimens were studied with and without removal of a medially based wedge of bone. Removal of the wedge produced an average varus malalignment of the talar neck of 17.1 +/- 2.4 degrees (range, 12.5 to 21.0 degrees). In the coronal plane, the average arc of motion of the subtalar joint decreased from 17.2 +/- 3.3 degrees before the osteotomy to 11.7 +/- 2.9 degrees after the osteotomy and removal of the wedge. In the transverse plane, it decreased from 17.5 +/- 2.9 degrees to 11.9 +/- 2.4 degrees. In the sagittal plane, it decreased from 8.9 +/- 2.4 degrees to 6.8 +/- 2.3 degrees. The decrease in subtalar motion was characterized by an inability to evert the foot; inversion was not limited, however. The malalignment produced an average of 4.8 +/- 1.2 degrees of varus deformity and 8.7 +/- 2.3 degrees of internal rotation of the hindfoot and an average of 5.5 +/- 2.0 degrees of varus deformity and 11.5 +/- 2.4 degrees of adduction of the forefoot. A linear correlation analysis was used to compare the change in subtalar motion and the position of the foot with the degree of varus malalignment at the talar neck. The correlation coefficient was 0.90 (p < 0.01) for subtalar motion, 0.76 (p < 0.01) for internal rotation of the calcaneus, and 0.81 (p < 0.01) for adduction of the forefoot. This indicated a direct correlation between the degree of varus malalignment at the talar neck and the change in the position of the foot and in subtalar motion.

Talar neck fractures.

Talar neck fractures represent a serious injury, and a review of the literature reveals the controversies surrounding the treatment options. In spite of the differences, there are many aspects of management where little disagreement exists. Anatomic reduction is the goal in situations where a primary salvage procedure is not performed. If closed treatment is chosen, careful follow-up is necessary to prevent unrecognized displacement as swelling subsides in the cast. Weight-bearing should be delayed until radiographic signs of fracture healing are obvious. There is a growing tendency toward open reduction and internal stabilization of talar neck fractures. Results suggest improved maintenance of reduction, decreased time to union, and a better end result. Prior to attempting any type of salvage procedure, careful assessment of both the tibiotalar and subtalar complex is necessary. The incidence of poor results following a talar neck fracture is disappointingly high. Additional studies of the pathoanatomy and biomechanics may improve our understanding. Controlled prospective clinical series will help clarify the advantages of specific treatment approaches and lead to better clinical results.

The comparative effect of administration of substances via the hepatic artery or portal vein on hepatic arterial resistance, liver blood volume and hepatic extraction in cats.

Compounds reaching the liver do so via either the hepatic artery or the portal vein. This paper reports on the effectiveness of administration of compounds into these alternate routes for their effects on the hepatic parenchymal cells, the hepatic arterial resistance vessels (blood flow) and hepatic capacitance (blood volume responses). All tests were done on cats under pentobarbital anesthesia. Perfusion of the parenchymal cell mass was assessed by comparing the hepatic elimination of indocyanine green (ICG) administered via the two vascular routes. The ICG uptake was assessed by measuring relative areas under the hepatic venous outflow curve obtained following bolus injections of ICG into the artery and portal vein. In a separate series, using different methods, the hepatic venous levels reached early (2 min) and later (5 min) during a constant infusion were compared during administration via the two routes and found to be equal. Parenchymal cell functions (ICG extraction, bile salt stimulation of bile flow) indicate that blood from the artery and portal vein supplies the hepatic parenchymal cells equally well. This suggests a well-mixed blood supply prior to exposure of either blood stream to parenchymal cells. Substances being processed by the liver are thus equally well handled if reaching the liver via either the arterial or portal blood stream. This has significance in validating the use of some isolated liver perfusion methods that perfuse only via the portal vein. Access of vasoactive compounds in the two blood streams to hepatic arterial resistance vessels was assessed using electromagnetic flow probes.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effect of taurocholic acid on hepatic arterial resistance vessels and bile flow.

The "hepatic arterial buffer response" hypothesis states that the hepatic artery is not controlled by liver parenchymal cell metabolic activity. Bile salts stimulate liver metabolism (elevate bile formation) and dilate the hepatic artery. The present data show that the vascular and metabolic effects in cats anesthetized with pentobarbital sodium are independent. Low doses of taurocholate (1 microM . min-1 . kg-1) produce metabolic but not vascular responses. At higher doses both the hepatic artery and superior mesenteric artery dilate with equal sensitivity. Taurocholate into the portal vein produced elevated bile flow and hepatic arterial dilation; infusion via the hepatic artery resulted in equal metabolic responses but much greater vascular effects. In addition, the time course of onset and termination of the metabolic and vascular responses supports the conclusion that the effects of taurocholic acid on hepatic bile flow and hepatic arterial flow are independent actions. This adds further support for the hepatic arterial buffer response being controlled by factors other than local hepatic metabolic demands.