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Biomedical subjects

Larry W Kraiss

Publications and source records attributed to Larry W Kraiss.

16 recordsLinked to original sources
PubMed2006

mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets.

New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34+ stem cell-derived megakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin. In contrast, overexpression of Bcl-3 in a surrogate cell line enhanced clot retraction. These studies identify new features of post-transcriptional gene regulation and signal-dependant protein synthesis in activated platelets that may contribute to thrombus and wound remodeling and suggest that posttranscriptional pathways are targets for molecular intervention in thrombotic disorders.

Animals↗
PubMed2006

Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.

Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets-the key cellular effector of thrombosis-express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.

Blood Coagulation↗
PubMed2006

A ruptured pancreaticoduodenal artery aneurysm repaired by combined endovascular and open techniques.

Aneurysms of the pancreaticoduodenal arteries (PDA) are rare, accounting for <2% of all visceral aneurysms. An association with celiac artery stenosis has been reported. Many present with rupture, and a high mortality can be expected. Treatment is therefore challenging. Arterial ligation, anuerysmectomy, or bypass has been the mainstay of treatment. We recently treated a patient (who had no celiac axis) with a ruptured PDA aneurysm with combined open and endovascular techniques. A 46-year-old man was transferred to our hospital with a 1-day history of abdominal pain and syncope. On admission, an abdominal and pelvis computerized tomographic (CT) scan identified a large mesenteric hematoma, a 1.9 cm PDA aneurysm, and an occluded celiac axis. Mesenteric angiography revealed no active aneurysm leak and a stenotic superior mesenteric artery (SMA) origin. All hepatic blood flow originated from the stenotic SMA via markedly enlarged PDA collaterals. The patient was brought to the operating room, where absence of the celiac axis was confirmed. An aorto-to-proper hepatic and SMA bypass was performed using a bifurcated polyester graft. The next day, the patient was brought to the angiography suite, where the PDA aneurysm was coiled. Postprocedure CT scans confirmed thrombosis of the aneurysm. Ruptured mesenteric artery aneurysms are a challenging problem for the vascular surgeon. PDA aneurysms are rare and often occur in an unfavorable location. There appears to be an association with anatomic anomalies of the mesenteric circulation. Prompt invasive and noninvasive diagnostic studies aid in the definitive management of this often fatal problem. Combined endovascular and open techniques can be used for successful treatment.

Aneurysm, Ruptured↗
PubMed2006

Aortoiliac reconstruction in infants and toddlers: replacement with decellularized branched pulmonary artery allograft.

BACKGROUND: Aortic reconstruction in infants and small children has been reported with Dacron or polytef prosthetic material, hypogastric artery autograft, and saphenous vein autograft. In children, synthetic grafts are limited by a concern for late infection and a lack of potential growth. Available autogenous vessels have a limited length and diameter. Conventional allografts have not been durable. When the entire infrarenal aorta and aortoiliac bifurcation must be replaced, none of the historic options are optimal. METHODS: We report 2 cases of infrarenal aorta and aortoiliac bifurcation reconstruction using a new generation of cryopreserved allograft now decellularized for decreased immunogenicity. The branched pulmonary artery allograft is particularly attractive for reconstruction of the aortic bifurcation. RESULTS: The postoperative course in both cases was uncomplicated. Follow-up with serial abdominal duplex ultrasound has shown no evidence of graft stenosis or calcification at 29 and 32 months, respectively. CONCLUSIONS: The use of commercially available, decellularized, and antigen-reduced allograft offers a nonsynthetic option for replacement of the pediatric abdominal aorta. We chose this novel approach in hopes of reducing the lifetime risk for graft infection and maintaining the potential for graft ingrowth by the child.

Aorta↗
PubMed2006

Pneumococcal aortitis: a difficult preoperative diagnosis.

Primary infections of the aorta are rare. We recently treated a patient who was given a diagnosis of noninfectious aortitis after an extensive work-up, but after clinical deterioration, was found to have a pneumococcal mycotic aneurysm at the time of surgery. The difficulty in distinguishing microbial aortitis from noninfectious chronic periaortitis is discussed as well as the need for frequent surveillance imaging of the aorta if immunosuppression is used to treat the latter entity. The infected aortoiliac segment was ultimately repaired with autologous femoral veins.

Aged↗
PubMed2006

Meeting AHA/ACC secondary prevention goals in a vascular surgery practice: an opportunity we cannot afford to miss.

OBJECTIVE: In an effort to reduce cardiovascular mortality, patients with atherosclerotic arterial disease should undergo risk factor modification according to the American Heart Association/American College of Cardiology (AHA/ACC) Secondary Prevention Guidelines (hereafter, Guideline). We assessed compliance with the Guideline in a group of patients seen in a vascular surgery practice. METHODS: We evaluated 200 consecutive patients with lower-extremity occlusive disease, cerebrovascular disease, or abdominal aortic aneurysm seen by a university-based vascular surgery practice. The subjects were patients who had been seen previously in our clinic (ESTABLISHED) and new referrals (NEW). Data pertinent to each of the nine AHA/ACC Guideline goals were collected from patient interviews, medication histories, and laboratory records. Compliance with each of the Guideline goals was evaluated. Differences in compliance between ESTABLISHED and NEW patient groups were also compared. We also recorded whether a patient had a previous endovascular or open surgical vascular intervention (EVENT or NO EVENT). Differences in compliance between the EVENT and NO EVENT groups were compared. RESULTS: Most patients did not achieve the secondary prevention goals recommended in the Guideline. Patients who had a prior vascular intervention (EVENT) were significantly more likely to achieve goals for low-density lipoprotein level (43% vs 23%), and for statin (71% vs 39%), beta-blocker (46% vs 27%), angiotensin-converting enzyme inhibitor (53% vs. 35%), and antiplatelet agent (85% vs. 68%) use (P < .05). ESTABLISHED patients were significantly more likely than NEW patients to have a prior EVENT (87% vs 47%, P < .0005). ESTABLISHED patients were significantly more likely than NEW patients to achieve goals for low-density lipoprotein level, beta-blocker, and statin use; however, these differences were likely due to the higher proportion of EVENT patients in the ESTABLISHED group. CONCLUSION: Compliance with the Guideline is suboptimal in patients with atherosclerotic arterial disease. Secondary prevention goals were more often achieved in the EVENT patient group, suggesting that a vascular intervention may lead to increased patient and physician awareness and compliance with the Guideline. A targeted effort towards risk factor modification in patients with atherosclerotic arterial disease could improve compliance with the Guideline and reduce cardiovascular mortality.

Aged↗
PubMed2006

New roles for an old drug: inhibition of gene expression by dipyridamole in platelet-leukocyte aggregates.

Interactions between platelets and leukocytes link critical thrombotic and inflammatory events that control an array of cardiovascular syndromes. In atherosclerosis alone, inducible gene expression in platelets and leukocytes modulates the initiation and development of vulnerable plaques that increase a patient's risk for acute coronary events. Interruption of gene expression pathways that are triggered when platelets adhere to leukocytes may be a new target for therapeutic intervention. Recent evidence indicates that dipyridamole, an old drug with a diverse history, differentially inhibits gene expression in platelet-leukocyte aggregates by exerting its effect at distinct molecular checkpoints.

Coronary Disease↗
PubMed2005

Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets.

Platelets are specialized hemostatic cells that circulate in the blood as anucleate cytoplasts. We report that platelets unexpectedly possess a functional spliceosome, a complex that processes pre-mRNAs in the nuclei of other cell types. Spliceosome components are present in the cytoplasm of human megakaryocytes and in proplatelets that extend from megakaryocytes. Primary human platelets also contain essential spliceosome factors including small nuclear RNAs, splicing proteins, and endogenous pre-mRNAs. In response to integrin engagement and surface receptor activation, platelets precisely excise introns from interleukin-1beta pre-mRNA, yielding a mature message that is translated into protein. Signal-dependent splicing is a novel function of platelets that demonstrates remarkable specialization in the regulatory repertoire of this anucleate cell. While this mechanism may be unique to platelets, it also suggests previously unrecognized diversity regarding the functional roles of the spliceosome in eukaryotic cells.

Alternative Splicing↗
PubMed2004

Severe coagulopathy following intraoperative use of topical thrombin.

This report describes a case of severe coagulopathy and bleeding related to the intraoperative use of topically applied thrombin. Commercial thrombin preparations contaminated with bovine factor V have been shown to stimulate the production of antibodies directed against factor V. These antibodies can cause coagulopathy. Our patient developed antibodies against factor V after intraoperative exposure to topical thrombin. The resulting antibody-mediated depletion of factor V caused a severe and refractory coagulopathy. Vascular surgeons should be aware that the use of topical bovine thrombin can cause severe coagulopathy.

Administration, Topical↗
PubMed2004

Change in protein phenotype without a nucleus: translational control in platelets.

For most cells the nucleus takes center stage. Not only is it the largest organelle in eukaryotic cells, it carries most of the genome and transcription of DNA to RNA largely takes place in the nucleus. Because transcription is a major step in gene regulation, the absence of a nucleus is limiting from a biosynthetic standpoint. Consequently, the anucleate status of platelets has stereotyped it as a cell without synthetic potential. It is now clear, however, that this viewpoint is far too simplistic. In response to physiologic stimuli, platelets synthesize biologically relevant proteins that are regulated via gene expression programs at the translational level. This process does not require a nucleus; instead, it uses mRNAs and other translational factors that appear to be retained in specialized fashion as megakaryocytes generate platelets during thrombopoiesis. We highlight the molecular machinery and pathways used by platelets to translate mRNA into protein and offer insight into how these synthesized products may regulate thrombotic and inflammatory events.

Animals↗
PubMed2003

Has the changing nature of vascular surgery adversely affected scholarly activity.

OBJECTIVE: Because of reduced reimbursement and introduction of endovascular techniques into practice, vascular surgeons have increased clinical commitments. Therefore we hypothesized that the scholarly productivity of vascular surgeons has decreased. Study design An author-based Medline search was carried out for members of the Society for Vascular Surgery (SVS). The search included the period from 1985 to 1989 (era 1) for members in 1990, and from 1995 to 1999 (era 2) for members in 2000. Citations were assigned a type: basic science, clinical, case report, letter, or other; and a topic: cardiac, vascular, endovascular, transplantation, or miscellaneous. The main outcome measures were the proportion of members who published in each era and the rates of publication among authors. RESULTS: For era 1, 7069 citations were identified for 529 members, and for era 2, 6823 citations were identified for 615 members. Four hundred forty-two members were cited in era 1 (84%), compared with 443 (72%) in era 2 (P =.01). A significantly smaller proportion of members published clinical research, case reports, and other publications, but not basic science or letters. Excluding unpublished members, there was a median of 11 total publications per author in each era. There were significant reductions in the proportion of members publishing papers related to cardiac (from 36% to 21%), transplantation (8% to 4%), and miscellaneous (43% to 31%) topics, and a significant increase in papers related to endovascular topics (from 19% to 28%) from era 1 to era 2. Moreover, there was a significant increase in median number of vascular (from 5 to 8) and endovascular (1 to 2) papers per published member. Further, the proportion of vascular and endovascular citations compared with total citations increased from 44% to 56% in era 1 and from 3% to 10% in era 2. On a yearly basis, there was a steady decrease in the number of citations throughout era 2, whereas the number of citations in era 1 was relatively constant. CONCLUSIONS: Academic productivity was maintained for individual members who published across both eras, but a smaller proportion of the SVS membership published in era 2. There was also a progressive reduction in the number of publications during the 1990s.

General Surgery↗
PubMed2003

Fluid flow regulates E-selectin protein levels in human endothelial cells by inhibiting translation.

OBJECTIVE: The purpose of this study was to determine the mechanism with which fluid flow inhibits endothelial E-selectin expression. METHODS: Cultured human umbilical vein endothelial cells were stimulated with inflammatory agonists (tumor necrosis factor-alpha [TNF-alpha], interleukin-1beta, oncostatin M, or phorbol ester) in the presence or absence of fluid flow (peak shear stress, approximately 12 dynes/cm(2)) imposed with an orbital shaker. E-selectin expression was assessed with ribonuclease protection assay, immunoblotting, enzyme-linked immunosorbent assay, or metabolic labeling as appropriate. RESULTS: All agonists caused human umbilical vein endothelial cells to express E-selectin protein. Fluid flow inhibited E-selectin protein levels by about 50% in response to TNF-alpha but had no effect on total E-selectin messenger RNA (mRNA) expression. Flow inhibited E-selectin protein production even after initiation of E-selectin transcription. Flow did not cause E-selectin to be shed from the cell surface nor was E-selectin degradation accelerated. Although fluid flow did not reduce total cellular E-selectin mRNA levels in response to TNF-alpha, the amount of E-selectin mRNA present in the actively translated polysome fraction was markedly attenuated. CONCLUSION: These findings indicate that E-selectin expression is subject to translational and transcriptional control. Fluid mechanical forces can regulate endothelial phenotype by targeting translational control points.

Blood Flow Velocity↗
PubMed2002

Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix proteins. These enzymes are implicated in a variety of physiological and pathological events characterized by extracellular matrix remodeling. Recent studies suggest that MMPs may have a signaling capacity, but direct evidence supporting this concept is lacking. In the present study, we demonstrate that outside-in signals delivered by exogenous MMP-1 (interstitial collagenase) markedly increase the number of tyrosine-phosphorylated proteins in platelets. Active MMP-1 also targets beta(3) integrins to areas of cell contact and primes platelets for aggregation. Examination of the endogenous enzyme demonstrated that activated platelets process latent MMP-1 into its active form. Neutralization of MMP-1 activity with MMP inhibitors or specific blocking antibodies markedly attenuates agonist-induced phosphorylation of intracellular proteins, movement of beta(3) integrins to cell contact points, and intercellular aggregation. The finding that MMP-1 is rapidly activated in platelets and controls functional responses identifies a new role for this metalloproteinase as a signaling molecule that regulates thrombotic events.

Antigens, CD↗
PubMed2002

Common femoral artery injury secondary to bicycle handlebar trauma.

Blunt trauma from bicycle handlebars is associated with well-described injuries of the abdominal viscera. These injuries result from the forceful compression of the relatively immobile abdominal organs between the handlebar end and the vertebral bodies. The common femoral artery is also immobile as it passes anterior to the superior pubic ramus, rendering this vessel susceptible to a similar mechanism of injury. We have treated two children who sustained thrombosis of the common femoral artery caused by bicycle handlebar trauma. The lack of familiarity with this uncommon mode of injury may contribute to delayed diagnosis and increased morbidity. We therefore wish to draw attention to this mechanism of injury.

Adolescent↗