Inhibition of neointimal hyperplasia by a specific thrombin inhibitor

Objective—Restenosis secondary to neointimal hyperplasia remains the major limiting factor after vascular interventions. Thrombin generated in high concentrations at the site of vascular injury plays a central role in thrombosis and hemostasis. Thrombin has also been implicated as a mitogen for smooth muscle cell proliferation that contributes to restenosis. This study was designed to determine the effects of a specific thrombin inhibitor on neointimal hyperplasia after balloon injury in a rat carotid artery model.

Design—A total of 47 male Sprague–Dawley rats were divided into five groups. All groups underwent balloon injury of the left carotid artery. A specific thrombin inhibitor, inogatran, was given in four different regimens: low and high dose injections, short‐term infusion for 3?h, and long‐term infusion for 1 week. After 2 weeks the animals were killed and the carotid neointima/media area ratio and the luminal narrowing were calculated.

Results—All treatments significantly reduced the neointimal hyperplasia. Inogatran given as a long‐term infusion for 1 week had the lowest neointima/media ratio compared with the other groups. The percentage of lumen narrowing was also significantly lower in all treatment groups compared with the control group.

Conclusion—A specific direct thrombin inhibitor, inogatran, reduces neointimal hyperplasia after arterial injury in rats. A more prolonged administration of the thrombin inhibitor gave a further reduction of the neointimal hyperplasia. It seems that inhibition of thrombin activity is not only important early after injury, but also later. This could have clinical implications in the treatment of restenosis and needs to be further evaluated.     

The influence of direct and antithrombin-dependent thrombin inhibitors on the procoagulant and anticoagulant effects of thrombin

INTRODUCTION: Clinical trials evaluating direct thrombin inhibitors in unstable coronary artery disease (CAD) have been disappointing. The hypothesis tested in the present study was that these agents may inhibit the anticoagulant effect of thrombin to a further extent than the procoagulant effect of thrombin. MATERIALS AND METHODS: We studied both reversible and irreversible thrombin inhibitors and compared the effects of each inhibitor on activated protein C (APC) generation vs. the effect on fibrinopeptide A (FPA) generation. A mixture of protein C, thrombin inhibitor, fibrinogen, fibrin polymerisation blocker and thrombin was incubated with thrombomodulin (TM)-expressing human saphenous vein endothelial cells (HSVECs). The inhibitors investigated were melagatran, inogatran, hirudin, hirugen, D-Phe-D-Pro-D-arginyl chloromethyl ketone (PPACK), and antithrombin (AT) alone or in combination with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). RESULTS: All agents, except hirugen, inhibited APC and FPA generation in a dose-dependent manner. FPA inhibition/APC inhibition ratios, based on IC50 for inogatran, melagatran, hirudin, PPACK, AT, AT-UFH and AT-LMWH were 1.73, 0.85, 0.55, 2.1, 0.5, 0.65 and 3.1 respectively. CONCLUSIONS: All agents, except hirugen, inhibited APC and FPA generation approximately to a similar extent. Thus, it can be inferred that the poor efficacy of thrombin inhibitors in recent clinical trials in patients with unstable CAD is unlikely to be a consequence of their effects on the protein C system.     

Laparoscopic hernia repair in patients with bilateral groin hernias.

OBJECTIVE: To compare outcome of unilateral and bilateral laparoscopic hernia repair. DESIGN: Prospective consecutive trial. SETTING: University hospital, Sweden. SUBJECTS: 380 patients who had unilateral hernias repaired laparoscopically and 64 patients who had bilateral hernias repaired. The median (range) age in the two groups was 56 (21-86) and 61 (30-85) years, respectively and the median (range) follow-up was 42 (24-58) months. MAIN OUTCOME MEASURES: Operating time, hospital stay, complications, and time to recovery. RESULTS: The median (range) operating time was 70 (25-240) minutes in the unilateral and in the bilateral group 113 (55-330) minutes. The complication rate, recurrence rate, and time to full recovery did not differ between the groups. CONCLUSION: The laparoscopic approach seems to be a good option for patients with bilateral inguinal hernias.     

Influence of branched-chain amino acid infusion on arterial concentrations and brain exchange of amino acids in patients with hepatic cirrhosis

Summary.

• 1 The influence of branched-chain amino acid (BCAA) infusion on arterial concentrations and brain exchange of amino acids was studied in seven patients with hepatic cirrhosis and in six healthy control subjects. Arterial levels and arterial-jugular venous (A-JV) concentration differences for amino acids, glucose, ketone bodies and lactate were measured in the basal state and during a constant rate, 150 min intravenous infusion of a BCAA solution (250 fmiol/min, 70% L-leucine, 20% L-valine and 10% L-isoleucine).
• 2 In the basal state the arterial whole blood concentrations of tyrosine, phenylalanine and methionine were 40–130 % higher in the cirrhotic patients compared to the controls, while the levels of the BCAA were 20–35 % lower. The patients' concentration of aspartic acid was 70% below the corresponding control value.
• 3 During BCAA infusion the arterial leucine concentration rose 4–5 fold while valine increased 60–95% and isoleucine rose 45–50%. The arterial levels of several amino acids decreased progressively in a similar manner in patients and controls. At the end of the 150 min infusion period methionine had decreased 35% (P<001), tyrosine 25% (P<0–001) and phenylalanine 35% (P<0–001) in the patient group.
• 4 Positive A-JV differences in amino acid concentration–indicating net brain uptake–were seen for leucine, isoleucine, valine, serine, tyrosine and lysine in both groups in the basal state. The patients had a greater A-JV difference than the controls for tyrosine (P<0–05) while the uptake of the other amino acids, including the BCAA, was similar in the two groups. The fractional uptake of leucine and valine was significantly increased in the patients.
• 5 During BCAA infusion the A-JV difference for leucine increased 2–3 fold in both patients and controls and the net uptake to the brain of tyrosine and phenylalanine was abolished in the patient group.
• 6 It is concluded that (a) patients with hepatic cirrhosis show a decreased whole blood concentration of aspartate indicating a reduced intracellular concentration of this amino acid, (b) brain uptake of tyrosine and fractional uptake of leucine and valine is augmented in patients with hepatic cirrhosis, demonstrating abnormal brain amino acid uptake in this disorder, and (c) BCAA infusion effectively lowers the arterial concentrations for tyrosine, phenylalanine and methionine in cirrhotic patients as well as in healthy controls and blocks the abnormal brain uptake of tyrosine. These findings provide a biochemical background to the suggested beneficial effect of BCAA infusion in patients with hepatic cirrhosis and portal systemic encephalopathy.

     

Exploring within- and between-gender differences in burnout: 8 different occupational groups

Objectives  

The aim of this study was to examine gender differences in burnout within and between occupations using latent mean analysis.