Biomedical subjects

D H Adams

Publications and source records attributed to D H Adams.

At least 73 records · Page 4Linked to original sources

PubMed1999

Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion.

This study demonstrates a novel role for the Fas pathway in the promotion of local tumor growth by inducing apoptotic cell death in normal hepatocytes at the tumor margin in colorectal hepatic metastases. Our results show that >85% of lymphocytes infiltrating colorectal liver cancer express high levels of Fas-ligand (Fas-L) by flow cytometry. Using immunohistochemistry of tumor tissue we showed strong Fas expression in noninvolved hepatocytes, whereas Fas-L expression was restricted to tumor cells and infiltrating lymphocytes at the tumor margin. Apoptosis was observed in 45 +/- 13% of the Fas(high) hepatocytes at the tumor margin whereas only 7 +/- 3% tumor cells were apoptotic (n = 10). In vitro, primary human hepatocytes expressed Fas receptor and crosslinking with anti-Fas antibody induced apoptosis in 44 +/- 5% of the cells compared with 4. 6 +/- 1.0% in untreated controls (P = 0.004). Both tumor-infiltrating lymphocytes (TIL) and human metastatic colon cancer cells cells are able to induce Fas-mediated apoptosis of primary human hepatocytes in coculture cytotoxic assays. TIL induced apoptosis in 47 +/- 9% hepatocytes compared with control 4.3 +/- 1. 0% (P = 0.009) and this effect was reduced by anti-human Fas-L mAb (18.7 +/- 1.3%, P = 0.009). SW620 cells induced apoptosis in 26 +/- 2% hepatocytes compared with control 5.6 +/- 1.7% (P = 0.004) and this was reduced to 11.2 +/- 1.8% (P = 0.004) in the presence of anti-human Fas-L mAb. These data suggest that the inflammatory response at the margin of colorectal liver metastases induces Fas expression in surrounding hepatocytes, allowing them to be killed by Fas-L-bearing TIL or tumor cells and facilitating the invasion of the tumor into surrounding liver tissue.

Aged↗

PubMed1999

Innominate vein cannulation for venous drainage in minimally invasive aortic valve replacement.

Minimally invasive aortic valve or aortic root replacement may be carried out through a mini-hemisternotomy. Venous cannulation of the right atrium may be difficult, at best, and obstruct the limited operative field. We have carried out cannulation of the innominate vein with 25F or 27F thin-walled femoral venous cannulae in 20 patients. Transesophageal echocardiographic guidance is invaluable in safely passing the guidewire and subsequently the cannula into the right atrium. This approach results in an unobtrusive method of complete intrathoracic cannulation through a mini-hemisternotomy with the risks of femoral cannulation.

Adult↗

PubMed1999

Technique for heterotopic pig heart xenotransplantation in primates.

The primate is a commonly utilized model for the human immune response after heart transplantation. This report describes our experience with heterotopic abdominal transplantation of porcine hearts into primate recipients. Abdominal graft placement was surprisingly well tolerated, and we found this approach to be particularly useful in the setting of significant donor-recipient size mismatch. Continuous monitoring with an implantable monitoring system facilitated assessment of graft viability in awake recipients; progressive graft bradycardia and decreasing QRS amplitude were predictive of ensuing graft failure.

Abdomen↗

PubMed1999

The logistics and cost-effectiveness of circulatory support: advantages of the ABIOMED BVS 5000.

BACKGROUND: In 1994, the ABIOMED BVS 5000 was incorporated into our acute cardiac assist armamentarium. This report is a general overview of our experience. A hypothetical cost analysis focusing on specific devices and device-related personnel contrasted the BVS 5000 with our prior model of centrifugal pump use. METHODS: In 3 years, 22 patients were supported with the BVS 5000, as a biventricular assist device in 40%, right ventricular assist device in 27%, and left ventricular assist device in 32%. Indications were postcardiotomy support in 12, acute myocarditis in 2, bridge to transplant in 4, and failed heart transplant in 4. The cost analysis was performed retrospectively. The actual cost of disposable blood pumps, including replacement pumps, and cannulae constituted the BVS cost. The hypothetical centrifugal costs included the disposables, replacement cones, as well as the labor costs of the continuous perfusionist coverage. RESULTS: Of the 22 patients, 10 (45%) were weaned and 13 (59%) were successfully discharged. Five patients were transplanted while on BVS 5000 support, accounting for a higher rate of discharge. Comparison of "actual" BVS costs with "projected" centrifugal costs revealed differences based upon the intended application of the BVS. In bridge-to-transplant patients with long duration of support, the daily cost of support was dramatically lower with the BVS 5000. For short-term postcardiotomy support, acute myocarditis, or failed transplant, the differences were small. CONCLUSIONS: Because the BVS 5000 was readily managed by the intensive care unit nursing staff, this system displaced centrifugal systems in our program. Outcome measures of weaning and successful discharge were improved relative to our prior experience with centrifugal pumps. Even without taking indirect costs into account, the hypothetical cost analysis supported continued use of the BVS system for acute cardiac assistance.

Adult↗

PubMed1999

Mitral valve surgery after previous CABG with functioning IMA grafts.

BACKGROUND: Mitral valve surgery after previous coronary artery bypass grafting presents a challenging problem for the cardiac surgeon. An injury to patent coronary artery bypass grafts, especially internal mammary artery grafts, during reoperation via a redo sternotomy, may be fatal. Therefore, a reliable alternative to the redo sternotomy is desirable to minimize potential injury to internal mammary artery grafts. METHODS: Between February 1987 and October 1998, we performed 59 consecutive mitral valve operations after previous coronary artery bypass grafting surgery (CABG). A total of 24 patients (41%) had functioning internal mammary artery (IMA) grafts and represent the population for this study. No patients were excluded for any reason. Of the 24 patients, 20 (83%) were men. Mean age was 66+/-13 years (range 41 to 83 years) and the mean duration from CABG was 5.3+/-3.6 years (range 0.1 to 12 years). Four (17%) had functioning bilateral internal mammary artery grafts. All had 3 to 4+ mitral regurgitation (MR) at the time of mitral valve surgery and the mean preoperative ejection fraction (EF) was 40%+/-14% (range 20% to 74 %). RESULTS: Twenty-one (88%) patients underwent mitral valve surgery through an anterolateral right thoracotomy and 3 (12%) through a redo sternotomy. Twenty-two (92%) patients, including the 3 patients in whom a redo sternotomy was used, had cannulation of the femoral artery and vein. Two patients required axillary artery cannulation. All 21 patients in whom the mitral valve was approached through a right thoracotomy underwent deep hypothermia (19.6 degrees+/-2.1 degrees C, range 14 degrees to 25 degrees C) without aortic clamping, with a mean duration of CPB of 138+/-46 minutes (range 65 to 249 minutes). In 18 (75%), the MR was ischemic in origin and in 6 (25%) there was myxomatous degeneration. Nine (34%) required valve replacement and 15 (66%) underwent repair. There were no operative or hospital deaths and all patients were discharged to home or to a rehabilitation facility. There were 4 (17%) major complications. Two patients suffered respiratory failure requiring tracheotomy, 1 patient developed a perioperative MI requiring an intraaortic balloon pump and 1 developed heart block requiring a permanent pacemaker. There were no neurologic, peripheral vascular, bleeding, or wound complications. CONCLUSIONS: Reoperative mitral valve surgery in the setting of functioning IMA grafts, even in the face of depressed LV function, can be done safely and with minimal morbidity.

Adult↗

PubMed1999

Impact of small prosthetic valve size on operative mortality in elderly patients after aortic valve replacement for aortic stenosis: does gender matter?

OBJECTIVE: Ideal management of the elderly patient with a small aortic root remains controversial. This retrospective analysis was performed to determine whether small prosthetic valve size is related to outcome in patients 70 years of age or older undergoing aortic valve replacement for aortic stenosis. METHODS: Between December 1991 and July 1998, 366 patients 70 years of age or older (median age 77 years, range 73-81 years, 49% male) underwent isolated aortic valve replacement or aortic valve replacement with coronary bypass grafting with standard Carpentier-Edwards bovine pericardial valves (Baxter Healthcare Corp, Edwards Division, Santa Ana, Calif) (n = 277; 76%) or St Jude Medical mechanical valves (St Jude Medical, Inc, St Paul, Minn) (n = 89; 24%). Propensity scoring and multivariable regression models were used to evaluate the risks associated with implantation of 19-mm valves. RESULTS: Operative mortality was 16.7% (17/102) in patients who received 19-mm valves and 3% (8/264) among those receiving >/=21-mm valves (P </=.0005). The univariable odds ratio for operative death for 19-mm versus >/=21-mm valves was 6.4 (95% CI 2.7, 15.4; P </=.0005). In the final multivariable model, receipt of a 19-mm valve alone was not a statistically significant predictor of operative death (odds ratio 2. 1; 95% CI 0.7, 6.4; P =.21). However, the combination of male sex and 19-mm valve resulted in a significant risk of operative death (4/9 patients; odds ratio 17.5; 95% CI 2.2, 139; P =.007). Use of a 19-mm valve was not related to late death in either the univariable (hazard ratio 1.0; 95% CI 0.5, 2.0; P =.95) or the multivariable analysis (hazard ratio 0.7; 95% CI 0.3, 1.8; P =.51). CONCLUSIONS: Implantation of a standard 19-mm aortic valve in elderly men with aortic stenosis may be associated with an increased risk of operative mortality. A higher performance valve and/or a root enlargement procedure should be considered in men with a measured 19-mm anulus.

Aged↗

PubMed1999

Impact of body mass index and albumin on morbidity and mortality after cardiac surgery.

OBJECTIVE: Extremely thin and overly obese patients may not tolerate cardiac surgery as well as other patients. A retrospective study was conducted to determine whether the extremes of body mass index (weight/height(2) [kg/m(2)]) and/or cachexia increased the morbidity and mortality associated with cardiac operations. METHODS: Body mass index was used to objectively measure "thinness" (body mass index < 20) and "heaviness" (body mass index > 30); preoperative serum albumin was used to quantify nutritional status and underlying disease. Data were gathered between 1993 and 1997 from 5168 consecutive patients undergoing coronary artery bypass or valve operations, or both. RESULTS: No significant correlations were observed between body mass index and preoperative albumin levels. Low body mass index (<20) and low albumin level (<2.5 g/dL) were each independently associated with increased mortality after cardiopulmonary bypass (P </=.0005). Operative mortality was highest among those with both low body mass index and low albumin level. Multivariable logistic regression, adjusting for potentially confounding variables, demonstrated that an albumin level of less than 2.5 g/dL was independently associated with increased risk of reoperation for bleeding, postoperative renal failure, and prolonged ventilatory support, intensive care unit stay, and total length of stay. A body mass index of more than 30 was associated with increased sternal wound infection and saphenous vein harvest site infection. CONCLUSIONS: Hypoalbuminemia and low body mass index each independently predict increased morbidity and mortality after cardiac operations. Preoperative risk stratification with the use of body mass index and serum albumin may help to identify subgroups of patients at high risk for adverse outcomes after cardiac operations.

Aged↗

PubMed1999

Reoperative aortic valve replacement: partial upper hemisternotomy versus conventional full sternotomy.

OBJECTIVE: We developed techniques for partial upper hemisternotomy for reoperative aortic valve replacement and compared the results with those of reoperative aortic valve replacement by way of conventional full resternotomy. METHODS: We retrospectively analyzed data from 19 patients who underwent conventional full sternotomy and 20 patients who underwent partial hemisternotomy for isolated elective reoperative aortic valve replacements performed between November 1996 and September 1998. Univariable and multivariable analyses were used to document the differences between the groups. RESULTS: The 2 groups were similar with respect to age, sex, New York Heart Association functional class, valve pathologic characteristics, and numbers and types of previous operations. There were neither any operative deaths nor any postoperative valve-related morbidities in either group. There was 1 injury to a cardiac structure, which occurred in the conventional full sternotomy group. Univariable analysis documented that patients in the conventional full sternotomy group were significantly more likely to have at least 1000 mL blood loss during the first 24 hours after the operation (odds ratio 8.1, P =.02), were more likely to require transfusion of more than 5 units of packed red blood cell (odds ratio 3.6, P =.08), and were more likely to have a total operative duration longer than 5 hours (odds ratio 3.6, P =.08). In the multivariable analysis conventional full resternotomy remained a risk factor for greater blood loss (odds ratio 5.7, P =.06), greater transfusion requirement (odds ratio 2.4, P =.25), and longer total operative duration (odds ratio 7.7, P =.03). CONCLUSIONS: Partial upper hemisternotomy for reoperative aortic valve replacement avoids unnecessary lower mediastinal dissection, thereby reducing blood loss, transfusion needs, and total operative duration. These beneficial effects, which are accomplished without compromising the efficacy of the valve operation, make the partial upper hemisternotomy an excellent alternative to conventional full resternotomy for reoperative aortic valve replacement.

Adult↗

PubMed1999

Minimally invasive direct access mitral valve surgery.

We reviewed our experience with minimally invasive direct-access mitral valve surgery in 207 patients through February 1999. Three patients underwent associated procedures, a coronary artery bypass graft (CABG) with right internal mammary artery to right carotid artery (RIMA-RCA), a left ventricular outflow tract (LVOT) debridement for endocarditis, and a primum atrial septal defect (ASD) repair, and were excluded from analysis. Of the 204 remaining patients, 120 (59%) patients were men, aged 58.7 +/- 13.2 years, functional class of 2.3 +/- 0.5. The cause was myxomatous in 162 (79%) patients, rheumatic in 28 (14%) patients, endocarditis in 8 (4%) patients, congenital in 3 (2%) patients, and ischemic in 3 (2%) patients. Mean preoperative EF was 60% +/- 10%, with 184 (90%) patients showing ejection fraction (EF) greater than 50%. The valve was approached through a 5- to 8-cm right parasternal (n = 180, 88%) or right inframammary (n = 24, 12%) incision. One hundred nineteen (58%) patients had open femoral artery-femoral vein cannulation, and 85 (42%) patients had direct cannulation of the aorta and percutaneous cannulation of the femoral vein. One hundred seventy (83%) patients underwent successful valve repair, and 34 (17%) patients required valve replacement. The mean duration of aortic clamping and cardiopulmonary were, respectively, 100 +/- 34 and 146 +/- 44 minutes. There were 2 (1%) surgical deaths. Nonfatal perioperative complications included 3 (1.5%) ascending aortic complications, 3 (1.5%) reoperations for bleeding, 4 (2%) strokes, 2 (1%) transient ischemic attacks (TIAs), 2 (1%) myocardial infarctions, 3 (1.5%) pericardial effusions requiring drainage, 9 (4.5%) vascular complications, and 3 (1.5%) wound complications. Mean length of stay (LOS) was 6.1 +/- 3 days, with 63 (31%) patients being discharged in less than 5 days. One hundred twenty-nine (63%) patients did not require blood transfusions. Follow-up was complete in 165 (81%) patients, with mean follow-up of 13.2 +/- 8 months. Late complications included 1 (0.5%) myocardial infarction, 3 (1.5%) reoperations, all converting repairs to replacements, 3 (1.5%) wound hernias requiring reoperation and repair with mesh, 5 (2.5%) thromboembolic events, and 3 (1.5%) deaths of suicide, pneumonia, and sudden death, respectively. Mean follow-up New York Heart Association (NYHA) functional class was 1.2 +/- 0.5. We conclude that minimally invasive direct-access mitral valve surgery is safe, effective, and applicable for most patients presenting for isolated mitral valve surgery. We now consider it the standard of care for selected patients.

Adult↗

PubMed1999

Hearts from transgenic pigs constructed with CD59/DAF genomic clones demonstrate improved survival in primates.

We have previously created transgenic pigs bearing the human complement regulatory proteins CD59 and decay-accelerating factor (DAF) by either the intercellular transfer or the cDNA transgenic method. To achieve more physiologic protein expression, we constructed a new line of transgenic pigs with CD59 and DAF human genomic clones. We transplanted these CD59/DAF transgenic pig hearts into baboons immunosuppressed with cyclosporine, methylprednisone or leflunomide/mofetil mycophenolate. The four wild-type hearts survived for 20-80 min, whereas the four CD59/DAF hearts functioned for 85-130 h. Immunohistochemical staining showed levels of CD59 and DAF protein expression similar to that in human hearts. Wild-type and transgenic hearts demonstrate a similar level of IgM deposition, although transgenic hearts suffered less hyperacute rejection and thus less membrane attack complex deposition. The histology of the transgenic grafts after explant was consistent with acute vascular rejection, with a high level of IgG deposit compared with wild-type control. We conclude that this new line of CD59/DAF transgenic pigs express high levels of the transgene products, which conferred longer survival because of better protection from hyperacute rejection. Similar to previous transgenic pigs, however, these animals suffered from delayed xenograft rejection.

Animals↗

PubMed1999

Differential galactose alpha(1,3) galactose expression by porcine cardiac vascular endothelium.

Galactose alpha(1,3) galactose (Gal) is the terminal carbohydrate moiety recognized by xenoreactive natural antibodies during hyperacute rejection (HAR). Binding of these antibodies in HAR triggers rapid microvascular thrombosis. We examined the distribution of Gal on the endothelium of porcine hearts before and after heterotopic xenotransplantation into baboons. We found that Gal is strongly expressed on the endothelium of porcine capillaries with less expression on the endothelium of larger vessels. The distribution of Gal staining remains unchanged after xenotransplantation and correlates with the intensity of IgM and membrane attack complex (MAC) deposition. Thus, the Gal epitope is differentially expressed in the pig vasculature, which affects the pattern of xenoreactive antibody and MAC deposition and directs the distribution of vascular thrombosis.

Animals↗

PubMed1999

Serum concentrations and peripheral secretion of the beta chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha in alcoholic liver disease.

BACKGROUND: Alcoholic liver disease is associated with increased hepatic expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1alpha (MIP-1alpha). AIMS: To determine whether concentrations of chemokines in the peripheral circulation reflect disease activity, and whether chemokine secretion is restricted to the liver or is part of a systemic inflammatory response in alcoholic liver disease. PATIENTS: Fifty one patients with alcoholic liver disease and 12 healthy controls. METHODS: Peripheral vein (and hepatic vein in patients undergoing transjugular liver biopsy) chemokine concentrations were measured by ELISA. Chemokine secretion and transcription in isolated peripheral mononuclear cells were assessed using ELISA and in situ hybridisation in patients with severe alcoholic hepatitis. RESULTS: Serum MCP-1 concentrations were higher in alcoholic hepatitis compared with cirrhosis or healthy controls. MIP-1alpha concentrations were below the assay sensitivity in most patients. Serum MCP-1 concentrations correlated significantly with serum aspartate aminotransferase and creatinine. In severe alcoholic hepatitis, MCP-1 concentrations were higher in hepatic compared with peripheral veins; in mild alcoholic hepatitis there was no difference. Mononuclear cell secretion of both MCP-1 and MIP-1alpha was higher in severe alcoholic hepatitis compared with healthy controls, and chemokine mRNA was identified in monocytes. CONCLUSIONS: Serum MCP-1 concentrations are raised in alcoholic liver disease and reflect severity of hepatic inflammation. Monocyte secretion of both MCP-1 and MIP-1alpha is increased in severe alcoholic hepatitis. Both intrahepatic sources and peripheral mononuclear cells contribute to the raised serum MCP-1 concentrations.

Biomarkers↗

PubMed1999

Adhesion of lymphocytes to hepatic endothelium.

Chronic inflammation occurs when factors that regulate the process of leucocyte recruitment are disrupted, and it is dependent on recruitment, activation, and retention of lymphocytes within tissue microenvironments. The molecular mechanisms that mediate lymphocyte adhesion to vascular endothelial cells have been described by several groups, but the signals involved in the recruitment of lymphocytes via the hepatic circulation have yet to be elucidated fully. This article considers the liver as a model of organ specific lymphocyte recruitment. In this context, the roles of leucocyte and endothelial adhesion molecules and chemokines in lymphocyte recruitment are discussed. The article also reviews the mechanisms that regulate lymphocyte recirculation to the liver under both physiological and pathological conditions and draws parallels with other organs such as the gut and skin.

Cell Adhesion↗

PubMed1999

Minimally-invasive aortic root replacement.

PURPOSE: We retrospectively analyzed our early results with minimally invasive aortic root replacement. METHODS: Between August 1996 and April 1999, our center performed 137 aortic root replacements. Thirty-seven (27%) were accomplished through a 5 to 8 cm minimally invasive upper hemi-sternotomy incision. All minimally invasive operations were elective. The mean age for this cohort was 46 +/- 12 yrs. Thirty one (84%) of the patients were male and 3 (8%) were reoperations. The average preoperative NYHA classification was 2.4 +/- 0.6 and ejection fraction (EF) was 58% +/- 12%. Valve pathology was congenitally bicuspid in 19 (51%), endocarditis (SBE ) in 5 (14%), calcific degeneration in 4 (11%), annuloaortic ectasia in 3 (8%), rheumatic in 2 (5%) and other etiologies in 4 (11%). Nine patients (24%) had associated ascending aortic or arch aneurysms. RESULTS: The surgical techniques performed through mini-hemisternotomy consisted of 1) full root replacement in 31 (84%), 2) subcoronary replacement in 4 (11%), and 3) hemiroot in 2 (5%). Valve implants consisted of a homograft in 30 (81%), "Freestyle" bioprosthesis in 4 (11%) and a St Jude valved conduit in 3 (8%). Mean cardiopulmonary bypass duration was 193 +/- 47 min. and aortic cross-clamp duration was 157 +/- 40 min. Myocardial protection included systemic hypothermia in all (24 +/- 4 degrees C), antegrade cardioplegia (CP) in 35 (95%) with supplemental retrograde CP in 23 (62%). Three patients (8%) experienced postoperative low cardiac output syndrome (LCO). There was one operative death (3%). There was one (3%) reoperation for bleeding and 13 patients (35%) required blood transfusions. New onset atrial fibrillation occurred in 7 patients (19%) and there were 3 (8%) minor complications. Hospital length of stay (LOS) was 6.7 +/- 4.3 days and LOS was less than 7 days in 29 patients (78%). CONCLUSIONS: Minimally invasive aortic root replacement is feasible for a broad range of aortic valve pathology, can incorporate full root, hemiroot and subcoronary techniques, can be used for homografts and "Freestyle" valves as well as valved conduits, and can be accomplished with acceptable morbidity and mortality. However, the operation takes longer through the smaller incision and therefore requires more careful attention to myocardial protection.

Adult↗

PubMed1998

Mitral valve repair in cardiomyopathy.

BACKGROUND: Volume overload secondary to mitral regurgitation (MR) in cardiomyopathy is considered critical in the pathogenesis of subsequent ventricular dysfunction. Open mitral valve repair (OMVP) is hypothesized to improve symptomatology and ventricular function by reducing the volume overload of the left ventricle. METHODS AND RESULTS: All patients who underwent OMVP with a left ventricular ejection fraction (EF) of < 0.30 (n = 81) from 1984 through 1997 were reviewed (1 patient was lost to follow-up). Fifteen operations (18.5%) were repeat operations after previous coronary artery bypass graft surgery. Preoperative and postoperative EFs and NYHA class were compared. Survival probabilities were calculated, and multivariate analysis was performed. The average age of all patients was 67.1 years (range, 41 to 83 years). Mean follow-up was 1.7 years (range, 2 months to 8.5 years). The most common mitral repair was ring annuloplasty. Sixty-two patients (77%) had concomitant coronary artery bypass graft surgery. The surgery mortality rate was 11% (9 of 81); 6 of these 9 patients were > 70 years old. The overall Kaplan-Meier survival probability rate at 1, 2, 3, 4, and 5 years was 0.73, 0.68, 0.58, 0.50, and 0.38, respectively. EF improved significantly (0.24 to 0.32; P < 0.0001), as did the NYHA class (3.2 to 1.6; P < 0.0001), at follow-up. There was no difference in late survival between patients with an EF of < 0.20 (21 patients) and those with an EF between 0.20 and 0.30 (P = NS). Risk factors for death included heart failure and old age. CONCLUSIONS: OMVP for MR in the setting of ischemic cardiomyopathy and low EF appear to improve ventricular function, medium-term patient symptomatology, and survival.

Adult↗

PubMed1998

Response of "naive" cutaneous and muscle afferents to potential targets in vitro.

It is now well documented that motoneurons are specified to innervate particular target muscles prior to axon outgrowth. Here we investigate whether sensory neurons are similarly specified to innervate target skin or muscle, taking advantage of the avian trigeminal system where cutaneous and muscle afferents are anatomically separate. Using this system, we have previously shown that by embryonic day 10 (E10) (approximately 4-5 days after target innervation), regenerating cutaneous and muscle afferents differ in their response to various potential targets in vitro, in manners consistent with their normal innervation patterns in vivo. Thus, by E10 these two populations of sensory neurons have distinct identities as skin and muscle afferents. In contrast, we report here that the responses of younger, naive cutaneous and muscle afferents that have not yet, or only recently, innervated peripheral targets are indistinguishable, regardless of the target tissue tested. These findings suggest that at stages when innervation is being established, cutaneous and muscle afferents, unlike motoneurons, may not yet have acquired rigidly specified identities and/or the ability to recognize and respond selectively to their appropriate peripheral targets.

Animals↗

PubMed1998

Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases.

Vascular adhesion protein-1 (VAP-1) is a dimeric 170-kDa endothelial transmembrane molecule that under normal conditions is most strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. It is a glycoprotein that mediates tissue-selective lymphocyte adhesion in a sialic acid-dependent manner. In this study, we report the detection of a soluble form of VAP-1 in circulation. We developed a quantitative sandwich ELISA using novel anti-VAP-1 mAbs and used it to determine the levels of soluble VAP-1 (sVAP-1) in the serum of healthy individuals and in patients with inflammatory diseases. In healthy persons, circulating sVAP-1 concentrations were 49 to 138 ng/ml. Immunoblotting studies revealed that the apparent molecular mass of dimeric sVAP-1 is slightly (approximately 10 kDa) higher than that of transmembrane VAP-1 under nonreducing conditions. In contrast, the electrophoretic mobilities of monomeric sVAP-1 and transmembrane VAP-1 were similar after reduction and boiling. Adhesion assays showed that the circulating sVAP-1 modulates lymphocyte binding to endothelial cells. Inflammation can cause an elevation of serum sVAP-1 levels, because sVAP-1 concentrations in patients with certain liver diseases were two- to fourfold higher than those in normal individuals. In contrast, rheumatoid arthritis and inflammatory bowel diseases were not associated with elevated levels of sVAP-1. These findings indicate that there is a functionally active, soluble form of VAP-1 in circulation and suggest that the serum level of sVAP-1 might be a useful marker of disease activity in inflammatory liver diseases.

Adult↗

PubMed1998

Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma.

T cell-mediated mechanisms are important in the defense against solid organ tumors. Why some tumors are more heavily infiltrated by T cells than others is poorly understood but is likely to depend upon adhesive interactions between circulating lymphocytes and tumor endothelium. In support of this hypothesis, the present study shows that primary human hepatocellular carcinomas (HCC) are more heavily infiltrated with T cells than colorectal hepatic metastases (CHM), and that their tumor vessels express high levels of several adhesion molecules. In HCC, an intense T cell infiltrate is observed within the tumor associated with strong expression of ICAM-1 and vascular adhesion protein-1 (VAP-1) on tumor endothelium. In contrast, fewer T cells infiltrated CHM and these tumors have little ICAM-1 and no detectable VAP-1 or VCAM-1 on tumor endothelium. T cells infiltrating both tumors are LFA-1 and very late Ag (VLA)-4 high. In vitro tissue-binding studies demonstrated that T cells bound readily to tumor endothelium in HCC, and Abs to ICAM-1, VAP-1, and to a lesser extent VCAM-1 could inhibit this binding. VAP-1 supported sialic acid-dependent adhesion under shear stress, suggesting that VAP-1 and ICAM-1 mediate, respectively, tethering and firm adhesion. In contrast, very few T cells bound to tumor vessels in CHM. Thus our data suggest that the VAP-1/VAP-1 receptor and ICAM-1/LFA-1 pathways are important in the recruitment of T cells to HCC. The strong expression of VAP-1 on tumor endothelium distinguishes HCC from CHM and supports our previous hypothesis that VAP-1 is an important hepatic endothelial adhesion molecule.

Adult↗