Low-dose retinoic acid enhances in vitro invasiveness of human oral squamous-cell-carcinoma cell lines.

Retinoids inhibit the proliferation of several types of tumour cells, and are used for patients with several malignant tumours. In this study, we examined the effect of retinoic acids (RAs) on the invasive potentials of the oral squamous cell carcinoma (SCC) cells, BHY and HNt. BHY cells expressed all of retinoid nuclear receptors (RARalpha, beta, gamma, and RXRalpha) and cytoplasmic retinoic acid binding proteins (CRABP1 and CRABP2). HNt cells lacked the expression of RARbeta, but expressed other nuclear receptors and CRABPs. All-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-cisRA) (10(-6)and 10(-7)M) inhibited the growth of the cells, but low-dose ATRA and 13-cisRA (10(-8)M) marginally affected the growth of the cells. Surprisingly, low-dose RAs enhanced the activity of tissue-type plasminogen activator (tPA), and activated pro-matrix metalloproteinases (proMMP2 and proMMP9). Activation of proMMP2 and proMMP9 was inhibited by aprotinin, a serine-proteinase, tPA inhibitor. Furthermore, low-dose RAs enhanced the in vitro invasiveness of BHY cells. These results indicate that low-dose RAs enhances the in vitro invasiveness of oral SCC cells via an activation of proMMP2 and proMMP9 probably mediated by the induction of tPA.     

Thrombolysis for Frostbite: A Case Study and Clinical Considerations

Frostbite injuries are becoming more common in the civilian population and are frequently associated with homelessness, mental illness, and alcohol and drug use and abuse. Taking care of these patients requires a multidisciplinary approach, initially by emergency medicine, the burn service, and interventional radiology, and eventually involving case management, social services, and occupational and physical therapy. Timely and rapid rewarming in conjunction with catheter-directed intravascular thrombolysis interventions can restore adequate perfusion to the patient's compromised digits. To improve patient outcomes, it is essential to obtain proper imaging and, if appropriate, immediately initiate an interventional radiology consultation for urgent thrombolysis treatment. This article presents a clinical case study of a patient who suffered frostbite injuries and underwent intravascular thrombolysis interventions that spanned a 24-hour period and required two interventional radiology procedures. Nursing care considerations and thrombolysis management in the emergency department, radiology department, and intensive care unit are reviewed.     

Idiopathic osteonecrosis,hypofibrinolysis, high plasminogen activator inhibitor,high lipoprotein(a), and therapy with stanozolol

In five patients with idiopathic osteonecrosis (ON) of the hip, four having hypofibrinolysis mediated by high plasminogen activator inhibitor (PAI-Fx), and one with high Lp(a), our specific aim was to determine whether therapy (Rx) with the anabolic-androgenic steroid, Stanozolol(6 mg/day), would normalize PAI-Fx and Lp(a) and thus potentially ameliorate ON. Prior to Rx, none of the four patients with high PAI-Fx could normally elevate tissue plasminogen activator (tPA-Fx) after 10 min venous occlusion at 100 mm Hg. After 12-18 weeks on Rx, PAI-Fx and stimulated tPA-Fx normalized in all four patients. Prior to Rx, mean (SD) stimulated tPA-Fx was low, 0.4 ± 0.3 IU/ml (lower limit of normal 2.28 IU/ml). On Rx, stimulated tPA-Fx normalized, rising to 2.83 ± 1.9 IU/ml, P = 0.004. Prior to Rx, mean (SD) basal PAI-Fx was high, 99 ± 68 (upper limit of normal 26.9 U/ml), and fell on Rx to 22.5 ± 22, P = 0.004. In two of the five patients normalization of hypofibrinolysis or high Lp(a) was accompanied by major symptomatic improvement. Prior to Rx, and 2 years after onset of unilateral hip pain, one of the four patients with high PAI-Fx and low stimulated tPA-Fx could walk only one block painfully. After 8 weeks on Stanozolol Rx, and continuing through 54 weeks on Rx, he walked 2 miles per day without pain, despite radiographic progression of ON. In three of the four patients with high PAI and with osteonecrosis present 0.3, 2, and 6 years prior to Stanozolol Rx, there was no clinical improvement after 14-156 weeks of Rx despite normalization of stimulated tPA-Fx and PAI-Fx. The fifth patient, 1 month after onset of disabling hip pain, had normal PAI-Fx but high Lp(a) (27 mg/dl), and MRI evidence of bone marrow edema (“transient osteoporosis”). After 3 weeks on Rx, Lp(a) normalized (14 mg/dl) and there was marked amelioration of symptoms. For the subsequent 11 weeks on Rx, this patient's Lp(a) was 5 mg/dl, and he became totally asymptomatic and remains asymptomatic 14 months later. We speculate that when ON is diagnosed prior to segmental collapse of the femoral head, it may be possible to reverse hypofibrinolysis, and/or to arrest the progression of ON. We postulate that high PAI or high Lp(a) lead to inadequate lysis of venous thrombi in bone, impaired bone venous circulation, venous hypertension of bone, and subsequent, potentially reversible development of ON. © 1995 Wiley-Liss, Inc.     

New in vivo model to assess venous endothelial cell functions. Effect of defibrotide

In the past few years there has been increasing interest in the role of the vascular endothelium as an active modulator of biological responses. Endothelial cells exert antithrombotic activity by the release of prostacyclin [23] and adenine nucleotides [16], the availability on the cell surface of heparin-like substances [3], and thrombomodulin-mediated activation of protein C [8]. In addition, endothelium is involved in the regulation of fibrinolysis by releasing soluble factors, such as tissue plasminogen activator (tPA; [10]) and plasminogen activator inhibitor (PAI; [22, 11]), as well as in the control of vascular responsiveness by the production of smooth muscle relaxing and contracting factors. Endothelial cells have also been shown to synthesize and to express procoagulant activities [18].Many data on endothelial cell functions has been obtained from two experimental models, namely endothelial cell cultures and perfused segments of animal and human vessels. Both are subject to methodological criticism since they only represent in part in vivo conditions, and the necessary experimental manipulations and laboratory procedures greatly modify the naturally occurring cellular functions.In order to overcome such difficulties as far as possible, a new in vivo model has been employed to provide easily assessable and reliable data on the properties of endothelial cells in man. A venous segment was isolated functionally by cannulating a dorsal vein in the hand and a cubital vein in the same arm. Changes observed ex vivo in blood from the cubital vein following infusion into the hand vein of an active drug, can mainly be attributed to its local effect on the venous wall. At the same time, a cubital vein in the other arm was cannulated in order to provide information to distinguish systemic from regional effects.     

Hemorrhagic transformation after fibrinolytic therapy with tissue plasminogen activator in a rat thromboembolic model of stroke

In this study, the effects of early vs. delayed tPA treatment on the development of hemorrhagic transformation was compared in a rat thromboembolic model of stroke. Fibrinolysis was performed by administering tPA intravenously at 2 or 6 h after ischemic onset. Twenty-four hours later, confluent hemorrhagic infarction was observed only in rats treated with tPA at 6 h at the rate of 50%. In this delayed treatment group, significantly increased numbers of polymorphonuclear leukocytes (PMNL) were observed to accumulate inside microvessels within the ischemic core. PMNL accumulation may be related to the induction of hemorrhagic infarction after delayed tPA treatment.     

Intracochlear tPA infusion may reduce fibrosis caused by cochlear implantation surgery

Background: Experiments show that the extent of ongoing fibrotic change within the cochlea can be determined by the volume and pattern of bleeding within the first 24?h following cochlear implantation. Tissue-type plasminogen activator (tPA) is effective at reducing thrombus volume when administered both within and external to the systemic circulation.

Aims/Objectives: To determine if tPA delivered into the scala tympani immediately following implantation will reduce thrombus volume within the lower basal turn of the cochlea.

Materials and Methods: Guinea pigs were implanted with either ‘soft’ or ‘hard’ arrays and administered tPA or saline via an intra-cochlear infusion immediately after implantation. Hearing was checked prior to, and 2 weeks after implantation. Cochleae were then harvested and imaged.

Results: Animals implanted with ‘soft’ arrays had 4.2% less tissue response compared with animals implanted with ‘hard’ arrays. In animals receiving ‘soft’ arrays, tPA reduced the volume of tissue response (measured by the percentage of the lower basal turn of the scala tympani occupied by tissue response) compared with saline.

Conclusions and Significance: tPA may be effective in reducing the overall volume of tissue response in routine ‘soft’ cochlear implantation and may have a greater effect in the event of significant surgical trauma.     

Financial relationships with industry among guideline authors for the management of acute ischemic stroke

Objective

To characterize the prevalence of industry relationships among authors of acute ischemic stroke (AIS) guidelines and its association with graded evidence.