Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is an endogenous glycoprotein with a potential role as a therapeutic for osteosarcoma. Animal studies have demonstrated the biological effects of PEDF on osteosarcoma; however, these results are difficult to extrapolate for human use due to the chosen study design and drug delivery methods. METHODS: In this study we have attempted to replicate the human presentation and treatment of osteosarcoma using a murine orthotopic model of osteosarcoma. The effects of PEDF on osteosarcoma cell lines were evaluated in vitro prior to animal experimentation. Orthotopic tumours were induced by intra-tibial injection of SaOS-2 osteosarcoma cells. Treatment with PEDF was delayed until after the macroscopic appearance of primary tumours. Pigment epithelium-derived factor was administered systemically via an implanted intraperitoneal micro-osmotic pump. RESULTS: In vitro, PEDF inhibited proliferation, induced apoptosis and inhibited cell cycling of osteosarcoma cells. Pigment epithelium-derived factor promoted adhesion to Collagen I and inhibited invasion through Collagen I. In vivo, treatment with PEDF caused a reduction in both primary tumour volume and burden of pulmonary metastases. Systemic administration of PEDF did not cause toxic effects on normal tissues. CONCLUSION: Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma.

Bronchomegaly as a complication of fetal endoscopic tracheal occlusion. A caution and a possible solution.

Fetal medicine is developing rapidly and aims to improve the outcome for fetuses with congenital anomalies. Fetal endoscopic tracheal occlusion (FETO) has been developed for fetuses with congenital diaphragmatic hernia to counterbalance the compression of the lung by the abdominal viscera, preserving the pulmonary maturation. Because the perinatal morbidity and mortality of patients treated with FETO have decreased, new complications are emerging in the older survivors. Tracheomegaly has been reported to be a late complication of FETO, sometimes requiring tracheostomy. We report a case of bronchial dilatation after FETO and suggest an alternative surgical treatment.

The pathophysiological role of PEDF in bone diseases.

First discovered in 1991 as a factor secreted by retinal pigment epithelial cells, the potency of pigment epithelium derived factor (PEDF) as an anti-angiogenic has led to examination of its role in active bone growth, repair and remodelling. In the musculoskeletal system, PEDF expression occurs particularly at sites of active bone formation. Expression has been noted in osteoblasts and to a lesser degree osteoclasts, the major classes of bone cells. In fact, PEDF is capable of inducing differentiation of precursor cells into mature osteoblasts. Expression and localisation are closely linked with that of vascular endothelial growth factor (VEGF). Studies at the epiphyseal plate have revealed that PEDF expression plays a key role in endochondral ossification, and beyond this may account for the epiphyseal plate's innate ability to resist neoplastic cell invasion. Collagen-1, the major protein in bone, is avidly bound by PEDF, implicating an important role played by this protein on PEDF function, possibly through MMP-2 and -9 activity. Surprisingly, the role of PEDF has not been evaluated more widely in bone disorders, so the challenge ahead lies in a more diverse evaluation of PEDF in various osteologic pathologies including osteoarthritis and fracture healing.

KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo.

BACKGROUND: Endothelial dysfunction contributes to ischemia-reperfusion injury (IRI) and is reduced by ischemic preconditioning (IPC). IPC may involve activation of ATP-sensitive potassium channels (K(ATP)). We determined whether modulation of K(ATP) channels occurs in endothelial IPC in humans. METHODS AND RESULTS: IRI of the forearm was induced by inflating a blood pressure cuff to 200 mm Hg for 20 minutes in healthy volunteers. K(ATP) activation was modulated by intra-arterial glibenclamide (blocker) and diazoxide (opener). Endothelial function (response to intra-arterial acetylcholine) was assessed with forearm plethysmography before and after (1) 15-minute reperfusion, (2) IRI preceded by IPC (3 five-minute periods of ischemia), (3) IRI preceded by IPC with glibenclamide, (4) IPC followed by glibenclamide before IRI, (5) IRI preceded by diazoxide, and (6) IRI preceded by coinfusion of glibenclamide with diazoxide. IRI caused endothelial dysfunction (P=0.002), which IPC prevented (P=0.40). Glibenclamide abolished IPC when given contemporaneously with (P=0.003) or during IRI (P=0.0005). Diazoxide prevented endothelial dysfunction after IRI (P=0.68) but not when coinfused with glibenclamide. CONCLUSIONS: Glibenclamide abolishes and diazoxide mimics endothelial IPC in humans. The time course of the effect of glibenclamide suggests involvement of K(ATP) channels as effectors of endothelial IPC in vivo. These data may have implications for understanding the therapeutic role of agents that modulate K(ATP) channel function.

The walk-in anergic patient. How best to assess the risk of sepsis following elective surgery.

This prospective study evaluated host resistance in a surgical population who walked into the hospital for elective surgery. Patients were stratified into Hospital Reactive (HR, n = 19) if they reacted to two or more of five recall skin test antigens and Walk-in Anergic (WA, n = 26) if they did not react to the antigens. The WA patients were slightly older (74.4 +/- 1.8 years, +/- SEM versus 66.7 +/- 2.7 p less than 0.05). Diagnosis in the HR and WA group were: tumors 13/19 versus 21/26, diverticulitis 3/19 versus 0/19, and miscellaneous 3/19 versus 5/26. Twenty-five laboratory normal controls (LN) were also studied. There were no significant differences in the following parameters between the HR and WA groups: stage of disease; hemoglobin; circulating leukocyte count; polymorphonuclear cell counts; total lymphocyte counts (both groups lower than LN, p less than 0.05), monocyte counts (both higher than LN, p less than 0.05); per cent E-rosettes and lymphocyte blastogenesis to mitogens (phytohemagglutinin, concanavalin-A) and antigens (purified protein derivative and tetanus); phagocytosis of preopsonised Staphylococcus aureus 502A, at 5, 10, and 20 minutes; alpha, beta, and gamma globulins; C3, and total hemolytic complement (CH50) levels; C-reactive protein; and ANA and DNA levels. The HR group demonstrated an increase in the rate of killing of Staphylococcus 502A at 10, 20, 40, and 80 minutes compared to the LN group but the WA group did not show this augmentation (p less than 0.001). The serum albumins were: LN = 4.46, HR = 3.98, WA = 3.43 g/dl (p less than 0.05). Degree and duration of surgery was the same in the HR and WA groups. There were no major sepsis episodes (bacteremia or proven intracavitary abscess) in the HR patients versus 25% in the WA patients (p less than 0.05). There was one death (6%, pulmonary embolus) in the HR group and 8 (40%) in the WA group (p less than 0.05). Antibiotic prophylaxis was equal but the WA patients received therapeutic antibiotics more frequently (65% versus 11% p less than 0.05). Of all the host immunocompetence tests measured in this study, the delayed type hypersensitivity skin test response and the serum albumin were variables abnormal between the survivors and those who died.