Inhibition of c-Jun N-terminal kinase pathway attenuates cerebral vasospasm after experimental subarachnoid hemorrhage through the suppression of apoptosis.

BACKGROUND: Recent studies have demonstrated that apoptosis in cerebral arteries could play an essential role in cerebral vasospasm after subarachnoid hemorrhage (SAH) and that SP600125, an inhibitor of c-Jun N-terminal kinase (JNK) could suppress apoptosis. The present study examined whether SP600125 could reduce cerebral vasospasm through the suppression of apoptosis. METHOD: Fifteen dogs were assigned to 3 groups: control, SAH, and SAH + SP600125 (30 micromol/l). SAH was induced by the injection of autologous blood into the cisterna magna on day 0 and day 2. Angiograms were evaluated on day 0 and day 7. The activation of the JNK pathway and caspase-3 were also evaluated using Western blot. To determine the distribution, TUNEL staining and immunohistochemistry for phosphorylated c-jun and cleaved caspase-3 were performed. FINDINGS: Severe vasospasm was observed in the basilar artery of the SAH dogs. SP600125 reduced angiographic and morphological vasospasm and reduced the expression of cleaved caspase-3, thereby suppressing apoptosis. CONCLUSIONS: These results demonstrate that SP600125 attenuates cerebral vasospasm through the suppression of apoptosis, which may provide a novel therapeutic target for cerebral vasospasm.

Statin therapy and myocardial no-reflow.

HMG-CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial 'no-reflow' after ischemia and reperfusion by activating the mitochondrial K(ATP) channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.

Oromandibular reconstruction with vascularized free flaps: a review of 50 cases.

Fifty cases of oromandibular reconstruction using vascularized free flaps to evaluate functional parameters of results were evaluated. There were 23 iliac crest flaps, 17 fibula flaps, 30 ulnar forearm flaps, and 3 radial forearm flaps with bone. Thirteen female and 37 male patients comprised the study, with a mean age of 57.66 years. Squamous-cell carcinoma (SCC) constituted 86% of cases, of which 60% were T4 lesions and 13.9% were recurrent. Anterolateral mandibular defects constituted 48.7%, and the mean bone gap was 8.13 cm. Functional evaluation was based on the University of Washington Questionnaire (UWQ) through phone calls and personal communication. The mean hospital stay was 12.42 days. The external carotid (75%) and facial (18.3%) were the main recipient arteries. The internal jugular (47.05%) was the main recipient vein. Overall flap survival was 95.9%. Three flaps were lost due to unsalvageable venous thrombosis. Major local complications such as partial flap loss, hematoma, and orocervical fistula constituted 10% of cases. Speech was classified as "excellent" and "good" in 43.3% of cases. Swallowing was identified as "excellent" and "good" in 53.3% of cases. Cosmetic acceptance was rated "good" in 63.3% of cases. Vascularized free flap reconstruction of oromandibular defects provides excellent functional and aesthetic results. The majority of patients are able to tolerate a regular diet. Intelligible speech and acceptable appearance are restored, providing patient satisfaction.

Neurovascular protection reduces early brain injury after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cell death, especially apoptosis, occurred in brain tissues after subarachnoid hemorrhage (SAH). We examined the relationships between apoptosis and the disruption of blood-brain barrier (BBB), brain edema, and mortality in an established endovascular perforation model in male Sprague-Dawley rats. METHODS: A pan-caspase inhibitor (z-VAD-FMK) was administered intraperitoneally at 1 hour before and 6 hours after SAH. Expression of caspase-3 and positive TUNEL was examined as markers for apoptosis. RESULTS: Apoptosis occurred mostly in cerebral endothelial cells, partially in neurons in the hippocampus, and to a lesser degree in the cerebral cortex. Accordingly, increased BBB permeability and brain water content were observed, accompanied by neurological deficit and a high mortality at 24 hours after SAH. z-VAD-FMK suppressed TUNEL and caspase-3 staining in endothelial cells, decreased caspase-3 activation, reduced BBB permeability, relieved vasospasm, abolished brain edema, and improved neurological outcome. CONCLUSIONS: The major effect of z-VAD-FMK on early brain injury after SAH was probably neurovascular protection of cerebral endothelial cells, which results in less damage on BBB.

Role of ulnar forearm free flap in oromandibular reconstruction.

The ulnar forearm flap is not frequently utilized for oromandibular reconstruction. This study evaluated the usefulness of the ulnar free flap for reconstruction. A retrospective study of 32 patients was conducted. The ulnar forearm flap was combined with an osseous flap in 24 patients. Nine females and 23 males with a mean age of 58.15 years comprised our study population. Squamous-cell carcinoma was the diagnosis in 93.75% of cases (56.25% T4), of which 20% were recurrent. Functional evaluation of swallowing was based on the University of Washington Questionnaire (UWQ). The mean hospital stay was 9.8 days. The external carotid (100%) was the recipient artery, and the internal jugular (74.07%) was the main recipient vein. Overall flap survival was 96.8%. One flap was lost due to unsalvageable venous thrombosis. Major local complications were seen in 9.4% of cases and included partial flap loss, hematoma, and an orocutaneous fistula. At the time of this study, 21 patients were available for functional evaluation. Speech was rated excellent and good in 33.3% of patients. Swallowing was found good in 28.6% of patients. Chewing was rated excellent and good in 47.6% of patients. Cosmetic acceptance was rated good in 71.4% of cases. The ulnar forearm is a useful free flap in oromandibular reconstruction. It is available when the radial artery is the dominant artery of the hand. Being more hidden, it may be more cosmetically accepted. It affords pliable soft tissue for lining and/or covering of oromandibular defects, and can be used as a second choice after other free-flap failures.

Rabbit calvarial wound healing by means of seeded Caprotite scaffolds.

Autologous bone is the most successful bone-grafting material; however, limited supply and donor site morbidity are problematic. Synthetic bone substitutes are effective, but healing is slow and unpredictable. Osseous wound healing may be enhanced if bone substitutes are combined with autologous bone marrow cells. To test this hypothesis, we created 40 calvarial defects in 20 12-week-old New Zealand White rabbits, divided into four groups: (1) unrepaired controls, (2) autologous bone grafts, (3) unseeded Caprotite (a polymer-ceramic composite) grafts, and (4) Caprotite grafts seeded with autologous bone marrow stromal cells. CT scans were obtained at 0, 6, and 12 weeks post-operatively, and defects were harvested for histology. Defects repaired with autologous bone had significantly (p < 0.05) more bone than the other three groups, although seeded Caprotite defects showed different wound-healing sequelae. Results suggest that seeded Caprotite scaffolds did not significantly enhance osseous defect healing compared with controls.

Upregulation of small GTPase RhoA in the basilar artery from diabetic (mellitus) rats.

The goal of this study was to determine whether RhoA, a small GTPase, might be involved in the development of cerebral pathogenesis in diabetes. Male SD rats (n = 120) were divided into six groups: diabetic for 2, 4, 8 weeks, and an age-matched control group. Diabetes was induced by intravenous injection of streptozotocin (50 mg/kg). RhoA mRNA expression in basilar artery was measured by competitive RT-PCR. RhoA mRNA level was significantly increased in 4 weeks (184.1 +/- 28.5%, n = 7) and 8 weeks (218.7 +/- 24.5%, n = 7) after STZ injection compared to the age matched control basilar arteries (P < 0.05). Western blot was used to measure the membrane binding RhoA level to represent the activity of RhoA. We found that RhoA activity was strikingly increased in the diabetic basilar artery (n = 10 in each groups) compared to control basilar artery after STZ injection. Our data demonstrated that there was an upregulation of RhoA in the basilar artery of STZ induced diabetic rats, suggesting that RhoA might be involved in the cerebral vascular pathogenesis during diabetes mellitus.

Age-related RhoA expression in blood vessels of rats.

Aging is a major risk factor for the development of vascular diseases that lead to stroke and heart failure. Several cellular factors such as cell adhesion, motility, contractile response, and cytokinesis are involved in the aging process. RhoA, a member of the Rho family, plays a primary role in the regulation of these cellular factors. This study aims to investigate whether RhoA is involved in these age-related responses to vascular change. We found that in older rats (19 months ole), RhoA mRNA increased 1.9-fold in the aortic arteries and 2.4-fold in the basilar arteries compared to the younger rats (2 months old). Membrane binding, but not cytosol RhoA, levels were found to significantly increase in the aortic and basilar arteries with age, which suggests that RhoA activity increases in older rats. Staining of RhoA increased markedly with age in both the medial and endothelial layers of the collected aortic and basilar arteries. These results show that RhoA expression and activity in the aortic and basilar arteries increased as a function of age, thereby suggesting that RhoA might be altered in the vascular response change of aged rats.

Characterization of osteoblast-like behavior of cultured bone marrow stromal cells on various polymer surfaces.

The creation of novel bone substitutes requires a detailed understanding of the interaction between cells and materials. This study was designed to test certain polymers, specifically poly(caprolactone) (PCL), poly(D,L-lactic-CO-glycolic acid) (PLGA), and combinations of these polymers for their ability to support bone marrow stromal cell proliferation and differentiation. Bone marrow stromal cells were cultured from New Zealand White rabbits and were seeded onto glass slides coated with a thin layer of PCL, PLGA, and combinations of these two polymers in both a 40:60 and a 10:90 ratio. Growth curves were compared. At the end of 2 weeks, the cells were stained for both matrix mineralization and alkaline phosphatase activity. There was no statistically significant difference in growth rate of the cells on any polymer or polymer combination. However, there was a striking difference in Von Kossa staining and alkaline phosphatase staining. Cells on PCL did not show Von Kossa staining or alkaline phosphatase staining. However, in the 40:60 and 10:90 blends, there was both positive Von Kossa and alkaline phosphatase staining. These data indicate that PCL alone may not be a satisfactory material for the creation of a bone substitute. However, it may be used in combination with PLGA for the creation of a bone substitute material.