DVT and Pulmonary Embolism Following Knee Arthroscopy: The Role of Genetic Predisposition and Autoimmune Antibodies: A Report of 3 Cases.

Deep vein thrombosis (DVT) after arthroscopy has been considered a rare event; however, recent studies using ultrasound and venography have shown that the incidence of DVTs is underestimated. CASES:: This report describes 3 patients with DVT and/or PE after knee arthroscopy who were attributed to a genetic predisposition of hypercoagulability unknown to the patient and surgeon. CONCLUSIONS:: Genetic predisposition and autoimmune antibodies may play a role in the development of DVT after knee arthroscopy. We recommend focused questions regarding family history be added to the standard DVT/PE preoperative questionnaire.

TNF-alpha-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture.

Intracranial aneurysm (IA) rupture is one of the leading causes of stroke in the United States and remains a major health concern today. Most aneurysms are asymptomatic with a minor percentage of rupture annually. Regardless, IA rupture has a devastatingly high mortality rate and does not have specific drugs that stabilize or prevent aneurysm rupture, though other preventive therapeutic options such as clipping and coiling of incidental aneurysms are available to clinicians. The lack of specific drugs to limit aneurysm growth and rupture is, in part, attributed to the limited knowledge on the biology of IA growth and rupture. Though inflammatory macrophages and lymphocytes infiltrate the aneurysm wall, a link between their presence and aneurysm growth with subsequent rupture is not completely understood. Given our published results that demonstrate that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), is highly expressed in human ruptured aneurysms, we hypothesize that pro-inflammatory cell types are the prime source of TNF-alpha that initiate damage to endothelium, smooth muscle cells (SMC) and internal elastic lamina (IEL). To gain insights into TNF-alpha expression in the aneurysm wall, we have examined the potential regulators of TNF-alpha and report that higher TNF-alpha expression correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium (Ca2+), and Toll like receptors (TLR) that mediate innate immunity. Moreover, the reduction of tissue inhibitor of metalloproteinase-1 (TIMP-1) expression provides insights on why higher matrix metalloproteinase (MMP) activity is noted in ruptured IA. Because TNF-alpha is known to amplify several signaling pathways leading to inflammation, apoptosis and tissue degradation, we will review the potential role of TNF-alpha in IA formation, growth and rupture. Neutralizing TNF-alpha action in the aneurysm wall may have a beneficial effect in preventing aneurysm growth by reducing inflammation and arterial remodeling.

Decreased neurotrophin TrkB receptor expression reduces lesion size in the apolipoprotein E-null mutant mouse.

BACKGROUND: Accumulation of macrophages and smooth muscle cells in the vascular wall is critical for the development of atherosclerotic lesions. Although much is known about the factors that regulate macrophage recruitment to the vascular wall, the ability of growth factors to regulate smooth muscle cell recruitment in lesion development in vivo is unclear. Our previous studies demonstrated that neurotrophins and their receptors, the Trk receptor tyrosine kinases, are potent chemotactic factors for smooth muscle cells, and the expression of brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, is upregulated in human atherosclerotic lesions. METHODS AND RESULTS: TrkB(+/-) mice on a 129/B6 background were backcrossed to apolipoprotein E (ApoE)-null (ApoE(-/-)) mice on the C57Bl/6 background for 6 to 8 generations. Immunohistochemical analysis demonstrated BDNF immunoreactivity in areas of macrophage and smooth muscle cell infiltration, whereas TrkB immunoreactivity was predominant in areas of neointimal smooth muscle cells. Moreover, haplodeficient expression of TrkB in ApoE(-/-) mice was associated with a 30% to 40% reduction in lesion size compared with ApoE(-/-) mice with normal expression of TrkB and a 45% decrease in smooth muscle cell accumulation in the lesions. Finally, reconstitution with bone marrow from ApoE(-/-) mice with normal TrkB expression did not restore lesion development in TrKB(+/-)/ApoE(-/-) mice. CONCLUSIONS: These results suggest that TrkB expression on smooth muscle cells contributes to lesion development in the cholesterol-fed ApoE-null mutant mouse. These data demonstrate, for the first time, a role for the neurotrophin TrkB receptor in atherosclerotic lesion development.

Tumor necrosis factor alpha is a key modulator of inflammation in cerebral aneurysms.

OBJECTIVE: Although intracranial aneurysms (IAs) are a major public health problem in the United States, few etiological factors are known. Most aneurysms remain asymptomatic until they rupture, producing subarachnoid hemorrhage, one of the most severe forms of stroke. Despite the technical advances in endovascular and microsurgical treatment, these patients still have high mortality and morbidity rates. Hence, the biology of aneurysm formation and growth is of intense interest. The presence of T and B lymphocytes, as well as macrophages, in human IA tissues suggests a role for inflammation in IA pathogenesis. However, the types of cytokines that are involved and regulated during cerebral aneurysm formation and growth are not known. To study the underlying pathogenesis of IA, we analyzed the expression of cytokines that participate in proinflammatory and anti-inflammatory responses. METHODS: Polymerase chain reaction was used to assess relative messenger ribonucleic acid expression levels of cytokines and an apoptotic modulator, Fas-associated death domain protein. Western blot analysis was used to determine protein expression from these genes. RESULTS: We show that the proinflammatory cytokine, tumor necrosis factor alpha and its proapoptotic downstream target, Fas-associated death domain protein, are increased in human aneurysms. In contrast, interleukin 10, which is secreted predominantly by T helper 2 cells, was absent in aneurysms. Polymerase chain reaction-derived gene expression data were confirmed by Western blotting using specific antibodies. CONCLUSION: Increased tumor necrosis factor alpha and Fas-associated death domain protein may have deleterious primary and secondary effects on cerebral arteries by promoting inflammation and subsequent apoptosis in vascular and immune cells, thereby weakening vessel walls.

Creation of four experimental aneurysms with different hemodynamics in one dog.

We developed an experimental canine model in which four types of aneurysm--bifurcation, side-wall, small branch-artery, and arterial-stump--were surgically created in the same animal. These experimental aneurysms are exposed to simultaneous but different hemodynamic stresses correlating to human intracranial aneurysms in different locations. Because this model allowed for the creation of four aneurysms, each with different hemodynamic features, it seems to offer advantages from ones previously described. This model may foster investigation of new and current endovascular devices.

Inositol 1,4,5-trisphosphate receptor phosphorylation in breast cancer.

The aim of this study was to establish the type(s) of inositol 1,4,5-trisphosphate receptors (IP3Rs) in T47D breast cancer cells that regulate intracellular calcium (Ca2+) and whether they interact with cyclin (Cy), an important regulator of cyclin-dependent kinases (cdk), during cell cycle progression. Immunoblotting, immunoprecipitation, and pull-down assays were used to identify IP3R expression and interaction with Cy. The relative IP3R3 expression, as compared to IP3R1, was higher in these cells. Pull-down analysis showed that IP3R3 interacted with both CyA and CyB. The interaction with Cys and the phosphorylation of IP3Rs by Cy/cdk complexes provide a novel mechanism of regulating intracellular Ca2+ release and Ca2+-dependent signaling events in breast cancer.

Endovascular treatment of intracranial aneurysms: comparative evaluation in a terminal bifurcation aneurysm model in dogs.

OBJECT: The authors investigated whether HydroCoils decreased coil compaction and aneurysm recanalization in a canine model of a large, wide-necked, high-flow bifurcation aneurysm. METHODS: Eleven experimental aneurysms were created. Two aneurysms were untreated (Group 1); three were treated with standard platinum coils (Guglielmi Detachable Coils; Group 2); and six were treated with platinum framing coils and filling HydroCoils (Group 3). Comparative angiographic and histopathological data were analyzed at 2 weeks and again at 3 months. At 3 months, the Group 1 aneurysms remained patent without spontaneous thrombosis. After coil placement the percentage of aneurysm filling by volume ranged from 59 to 90% (mean 75.4%) for Group 3 (HydroCoil-treated) and 34.3 to 48.9% (mean 39.6%) for Group 2 (GDC-treated) (p < 0.05). At 14 days, two of the three Group 2 aneurysms exhibited coil compaction and aneurysm recanalization at the neck; in both cases the condition worsened at 3 months. At 14 days and 3 months, five of the six Group 3 aneurysms were 100%, and one of six was 90% occluded and remained stable. At 3 months, the neointima of the aneurysm neck was significantly thicker in the Group 3 lesions, which had been treated by HydroCoils (0.329 +/- 0.191 mm), than in Group 2 lesions, which had been treated with GDCs (0.026 +/- 0.018 mm) (p < 0.001). No thrombus formation occurred in Group 2; however, in two of the six aneurysms in Group 3, thrombus formed at the coil-neck interface. CONCLUSIONS: The experimental canine bifurcation aneurysm model overcomes the limitations of side-wall aneurysm models. In this model, HydroCoils resulted in significantly denser coil packing, less follow-up coil compaction, and thicker neointimal tissue at the neck of the lesion. HydroCoils also appeared more thrombogenic at the aneurysm neck-parent artery interface.

Intracellular calcium release is required for caspase-3 and -9 activation.

Increase in intracellular Ca2+ [Ca2+]i regulates many biological functions including apoptosis, but the protein(s) linking [Ca2+]i and apoptosis are not completely understood. We have previously shown that IP3R-deficient cells are resistant to T-cell receptor (TCR)-induced apoptosis due to lack of Ca2+ release from endoplasmic reticulum (ER) and calcineurin activation. Here we show that caspase-9 and -3 are not activated in IP3R-deficient cells after TCR stimulation, consistent with the resistance of these cells to apoptosis. However, we also demonstrate that Bcl-2 expression in IP3R-deficient cells is comparable to control cells. Taken together, these results strongly suggest that IP3R-mediated Ca2+ release plays a critical role in regulating the activity of caspases-3 and -9 independent of Bcl-2.

Inositol 1,4,5-trisphosphate receptor (type 1) phosphorylation and modulation by Cdc2.

Calcium (Ca2+) release from the endoplasmic reticulum (ER) controls numerous cellular functions including proliferation, and is regulated in part by inositol 1,4,5-trisphosphate receptors (IP3Rs). IP3Rs are ubiquitously expressed intracellular Ca2+-release channels found in many cell types. Although IP3R-mediated Ca2+ release has been implicated in cellular proliferation, the biochemical pathways that modulate intracellular Ca2+ release during cell cycle progression are not known. Sequence analysis of IP3R1 reveals the presence of two putative phosphorylation sites for cyclin-dependent kinases (cdks). In the present study, we show that cdc2/CyB, a critical regulator of eukaryotic cell cycle progression, phosphorylates IP3R1 in vitro and in vivo at both Ser(421) and Thr(799) and that this phosphorylation increases IP3 binding. Taken together, these results indicate that IP3R1 may be a specific target for cdc2/CyB during cell cycle progression.