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The leukocyte integrin alpha(M)beta(2)/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-alpha(M)beta(2) interaction in vivo, gene-targeted mice were generated in which the alpha(M)beta(2)-binding motif within the fibrinogen gamma chain (N(390)RLSIGE(396)) was converted to a series of alanine residues. Mice carrying the Fibgamma(390-396A) allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support alpha(M)beta(2)-mediated adhesion of primary neutrophils, macrophages, and alpha(M)beta(2)-expressing cell lines. The elimination of the alpha(M)beta(2)-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for alpha(M)beta(2), integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function.

Whether clinically stable small abdominal aortic aneurysms should be surgically repaired or monitored with periodic noninvasive imaging is controversial. This study compared the two approaches in patients with aneurysms 4.0 to 5.4 cm in diameter. After a mean follow-up of nearly five years, there was no survival advantage associated with immediate surgical repair. This study compared the two approaches in patients with aneurysms of 4.0 to 5.4 cm. There was no survival advantage with immediate surgical repair. Each year in the United States, 9000 deaths result from rupture of abdominal aortic aneurysms. 1 Another 33,000 patients undergo elective repair of asymptomatic abdominal aortic aneurysms to prevent rupture, which results in 1400 to 2800 operative deaths. 2 , 3 Because most abdominal aortic aneurysms never rupture, 4 elective repair is undertaken only when the risk of rupture is considered high. The strongest known predictor of rupture is the maximal diameter of the aneurysm. 5 , 6 Elective repair has been recommended for patients with aneurysms of 4.0 cm or more in diameter who do not have medical contraindications, 7 although others have advocated the use . . .

In the quest to use carotid duplex to assess carotid occlusive disease, it has been reported that the current velocity criteria to calculate stenosis tends to overestimate the severity when there is a contralateral highly stenotic or occluded carotid artery. Patient records were reviewed for 592 consecutive carotid endarterectomies performed from 1987 to 1994. Preoperative and postoperative duplex scan results were compared in a subset of patients in whom duplex overestimated the degree of stenosis, as compared to preoperative angiography. A total of 146 patients were identified in whom duplex overestimated the degree of stenosis contralateral to a high grade stenosis or an occlusion. Of 76 arteries, 18 (23.7%) contralateral to an occluded artery were overestimated by duplex, and 128 (27.0%) of 474 arteries contralateral to a high grade stenosis were overestimated. Following endarterectomy 44 (51.8%) of 128 nonoperated contralateral stenoses decreased by at least one duplex category. The average peak systolic frequency (PSF) decreased by 1175 Hz ( P=0.0018), and the average end diastolic frequency (EDF) decreased by 475 Hz ( P=0.011). Patients with high grade stenosis have a significant decrease in PSF and EDF in the unoperated carotid after endarterectomy, supporting a compensatory flow phenomenon. This often results in a decrease in the postoperative duplex defined stenosis by at least one category. The clinical significance of these findings is of increasing importance as carotid surgery is being performed more frequently without angiography.

The leukocyte integrin αMβ2/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-αMβ2 interaction in vivo, gene-targeted mice were generated in which the αMβ2-binding motif within the fibrinogen γ chain (N390RLSIGE396) was converted to a series of alanine residues. Mice carrying the Fibγ390–396A allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support αMβ2-mediated adhesion of primary neutrophils, macrophages, and αMβ2-expressing cell lines. The elimination of the αMβ2-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for αMβ2, integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function.

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%). Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing in the United States. Whether surgery is associated with improved survival at the population level is relatively unknown. To address this question, we used a population-based cancer registry to compare survival outcomes between patients receiving and not receiving surgery with similar tumor sizes and health status. By using the Surveillance, Epidemiology, and End Results database, we identified HCC patients who had surgically resectable disease as defined by published expert guidelines. After excluding patients with contraindications to surgery, we performed both survival analysis and Cox regression to identify predictors of improved survival. Of the 4008 patients diagnosed with HCC between 1988 and 1998, 417 were candidates for surgical resection. The mean age was 63.6 years; mean tumor size was 3.3 cm. The 5-year overall survival with surgery was 33% with a mean of 47.1 months; without surgery, the 5-year overall survival was 7% with a mean of 17.9 months (P <.001). In the multivariate Cox regression, surgery was significantly associated with improved survival (P <.001). Specifically, patients who received surgery had a 55% decreased rate of death compared with patients who did not have surgery, even after controlling for tumor size, age, sex, and race. This study shows that surgical therapy is associated with improved survival in patients with unifocal, nonmetastatic HCC tumors <5 cm. If this is confirmed in future studies, efforts should be made to ensure that appropriate patients with resectable HCC receive high-quality care, as well as the opportunity for potentially curative surgery.

In this study of 263 heart, kidney, liver, and pancreas transplant patients, BK virus (BKV) and JC virus (JCV) DNAemia were observed most commonly in kidney and/or pancreas transplant patients (26%), although they were also observed, to a lesser extent, in heart (7%) and liver (4%) transplant patients. The majority of episodes of polyomavirus DNAemia were subclinical, although, in some cases, BKV DNAemia was associated with kidney rejection, and JCV DNAemia was accompanied by nonspecific symptoms. Hence, BKV and JCV DNAemia are not uncommon during the first year after kidney, heart, liver, and pancreas transplantation, and they could be associated with certain clinical syndromes in transplant patients

Hepatic artery thrombosis (HAT) after liver transplantation for biliary atresia (BA) is a serious complication that most often leads to retransplantation (re-OLT). The purpose of the present study was: (1) to identify risk factors associated with HAT and (2) to analyze the impact of recently introduced microsurgical hepatic arterial reconstruction (MHR) on the incidence of HAT, subsequent need for re-OLT, and patient survival. A retrospective review of 194 patients transplanted for BA was performed. One hundred and sixty-six patients (group 1) underwent conventional arterial reconstruction and 28 (group 2) had MHR. Actuarial survival for patients with HAT was significantly worse than for patients without HAT at 1, 2, and 5 years (71%, 61%, and 57% versus 85%, 85%, and 85%, P = 0.0007). Stepwise logistic regression analysis revealed that the risk of HAT correlated best with the type of arterial reconstruction ( P = 0.007) followed by pretransplant bilirubin concentration ( P = 0.04) and the number of acute rejection episodes ( P = 0.03). In group 1, 32 patients developed HAT (19%), and of these, 18 underwent re-OLT for HAT. No patient in group 2 developed HAT ( P = 0.006 versus group 1). One-year actuarial patient survival was 81% in group 1 and 100% in group 2 ( P = 0.02). In OLT for BA, (1) the predominant risk factor for HAT is the technique of arterial reconstruction, and (2) MHR markedly reduces the incidence of HAT and the need for re-OLT while improving patient survival.

A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kgrd]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.