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Biomedical subjects

D H Adams

Publications and source records attributed to D H Adams.

At least 19 recordsLinked to original sources
PubMed1999

CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.

Antibodies, Monoclonal↗
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↗
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↗
PubMed1998

Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis.

Alcoholic liver disease is associated with three histologically distinct processes: steatosis (parenchymal fat accumulation), alcoholic hepatitis (characterized by parenchymal infiltration by neutrophil polymorphs), and alcoholic cirrhosis (in which chronic inflammation and fibrosis dominate). Chemokines are cytokines that promote subset-specific leukoycte recruitment to tissues and could therefore play a crucial role in determining which leukocyte subsets are recruited to the liver in alcoholic liver disease. This paper reports that chemokine expression is increased in the liver of patients with alcoholic liver disease and, moreover, that distinct patterns of chemokine expression are associated with the different inflammatory responses to alcohol. Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were all detected in the parenchyma at sites of inflammation in alcoholic hepatitis, whereas in alcoholic cirrhosis, chemokines were restricted to inflammatory cells and endothelium in the fibrous septa and portal tracts. In alcoholic hepatitis, chemokine transcription was localized to sinusoidal cells, leukocytes, and fibroblasts in areas of parenchymal inflammation, but hepatocytes, despite staining strongly for chemokine protein, were negative. In alcoholic cirrhosis, chemokine mRNA was detected in portal tract endothelium, leukocytes, and fibroblasts. Thus, alcoholic hepatitis and alcoholic cirrhosis are associated with distinct patterns of chemokine expression that are likely to be important factors in determining whether a patient develops acute parenchymal inflammation and alcoholic hepatitis, or chronic septal inflammation and alcoholic cirrhosis.

Chemokine CCL2↗
PubMed1998

Twenty-year follow-up of the Hancock modified orifice porcine aortic valve.

BACKGROUND: The entire experience with the Hancock modified orifice porcine bioprosthetic aortic valve from 1976 to 1996 at the Brigham and Women's Hospital has been reviewed. Eight hundred forty-three patients received this valve with a total follow-up of 61,114 months, and a mean follow-up of approximately 72.5 months. There were 490 men and 353 women, and the predominate lesion was aortic stenosis (636 of 843); 365 (43%) patients required a concomitant coronary artery bypass graft operation. METHODS: Patients were followed prospectively in the Brigham Cardiac Valve Data Registry, and the data were analyzed by the SAS statistical package, using actuarial survival curves and incidence per patient-year of morbidity and mortality. RESULTS: The overall operative mortality was 45 of 843 (5.3%) with 23 of 478 (4.8%) for isolated aortic valve replacement and 22 of 365 (6.0%) for aortic valve plus coronary artery bypass graft operation. The major morbidity of this valve was structural valve dysfunction, which was significantly related to the age of the patient in whom the valve was placed. Actuarial probability of freedom from structural valve degeneration at 5, 10, and 15 years overall was 99%+/-1%, 79%+/-3% and 57%+/-4%, at 15 years, respectively. In patients younger than 50 years, freedom from structural valve dysfunction was 16%+/-8%, whereas in the age group older than 70 years it was 87%+/-5% (p = 0.0005). Thromboembolism at 10 and 15 years was 81%+/-3% overall, 84%+/-2% in patients in normal sinus rhythm, and 57%+/-13% in patients with chronic atrial fibrillation. CONCLUSIONS: The Hancock modified orifice aortic valve, despite its more complicated fabrication, has been a reliable porcine bioprosthetic valve and can be used reliably in patients older than 70 years because of its low structural valve degeneration rate, and protection from stroke and anticoagulant hemorrhage in those patients in sinus rhythm.

Actuarial Analysis↗
PubMed1998

Techniques and results of direct-access minimally invasive mitral valve surgery: a paradigm for the future.

OBJECTIVES: Our objective was to determine whether direct-access minimally invasive mitral valve surgery can improve recovery and cost while maintaining the efficacy of conventional surgery. METHODS: Minimally invasive mitral valve operations were performed on 106 patients, 58% male, average age 58.1 years, with good ventricular function. Ninety underwent repair of a regurgitant, myxomatous valve, and 16 underwent mitral valvuloplasty for prematurely calcified mitral stenosis. The valve was approached with standard instruments through a 5- to 8-cm right parasternal incision. Eighty-five had open femoral artery-femoral vein cannulation, but this technique has recently been replaced by direct cannulation of the aorta and percutaneous cannulation of the femoral vein for most patients. RESULTS: There were no operative deaths. The mean mitral regurgitation score (0-4) decreased from 3.7 to 0.7 after the operation. Although ischemic and bypass times were increased, postoperative recovery was accelerated. Ventilatory support time, intensive care unit stay, hospital stay, need for rehabilitation, and return to "normal activities" all improved. Hospital charges, pain medications, and blood transfusions were also reduced. New atrial fibrillation contributed significantly to increased length of stay and charges. There were no deep wound infections. Other complications included re-exploration for bleeding (n = 1), transient ischemic attacks (n = 2), stroke (n = 1), femoral artery injury (n = 5), pseudoaneurysm (n = 2), and antegrade dissection of the ascending aorta (n = 1). Two patients died and 1 required reoperation during a mean follow-up of 8.8 months. CONCLUSIONS: Direct-access minimally invasive mitral valve surgery can accelerate recovery, decrease charges, and decrease pain, while maintaining overall surgical efficacy. It has become our standard approach for isolated primary mitral valve operations.

Adult↗
PubMed1998

A dual pathway for the transmission of spongiform encephalopathy disease.

The nature of the infective process in the transmissible spongiform encephalopathy (SE) diseases has been a longstanding problem--in particular, whether the causative agents are (unusual) nucleic-acid-mediated viruses, or replicating non-nucleic acid molecules such as protein. Although there is much (conflicting) evidence supporting both views, it does not seem to have been considered that many of the outstanding problems could be resolved if both mechanisms are operating--either separately or together--i.e. that there is a dual, but interconnected, pathway leading to disease development. It is suggested that this is in fact the case, and the implications are discussed.

Animals↗
PubMed1998

Interleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases.

Metastatic colorectal cancer is usually progressive despite infiltration of the tumours by T lymphocytes, suggesting that these tumour-infiltrating lymphocytes (TILs) are functionally deficient. Recently, TILs from other tumours have been shown to express reduced levels of the T-cell receptor signal-transducing CD3-zeta chain. We were interested to determine whether a similar abnormality existed in TILs from human colorectal hepatic metastasis (CHM) and, if so, whether correcting the abnormality in vitro would restore anti-tumour activity and provide support for the development of immunotherapy for colorectal hepatic metastases. Twelve of 19 TILs from colorectal hepatic metastases were successfully expanded in vitro in high-dose recombinant interleukin 2 (rlL-2) and their specific anti-tumour cytolytic activity was determined. CD3-positive (CD3+) TILs were HLA-Drhigh and CD69high, suggesting that they had been activated by exposure to antigen but expressed low levels of CD25, CD71 and the nuclear proliferation antigen Ki-67. Furthermore, they showed reduced expression of CD3-zeta compared with autologous peripheral blood T cells (PBTs) and failed to proliferate in the absence of high-dose rIL-2. Expansion of TILs in rIL-2 resulted in restoration of CD3-zeta expression and the ability to lyse K562 and Daudi cells but not autologous tumour cells. The absence of autologous tumour-specific cytolytic T-cell (CTL) activity may be due to the poor immunogenicity of colorectal tumour cells, which we found expressed only low levels of MHC I antigens and CD54 and failed to express MHC II antigens or the co-stimulatory molecules CD80, CD86 or CD106. The inability of rIL-2 to generate tumour-specific CTLs despite restoration of CD3-zeta expression and the presence of an intact lytic mechanism suggests that successful immunotherapy may require the development of strategies to increase the immunogenicity of this tumour.

Adult↗
PubMed1997

Chemokines: leucocyte recruitment and activation cytokines.

Chemokines are a family of structurally related proteins that share the ability to induce migration of specific subsets of leucocytes. These specialised cytokines play a critical part in the generation of cellular inflammation, both in the protective responses to invading pathogens and in the pathological processes associated with infection and immune-mediated diseases. Chemokines are more than simple chemotactic factors, since they are also implicated in leucocyte activation, angiogenesis, and antimicrobial functions, including a protective role in HIV infection. These molecules provide potentially valuable targets for therapeutic intervention in a wide range of diseases.

Chemokines↗
PubMed1997

Holmium:YAG laser and pulsed dye laser: a cost comparison.

BACKGROUND AND OBJECTIVE: This study was designed to evaluate the relative cost effectiveness of the Holmium:YAG laser and the pulsed dye laser for the treatment of ureteral calculi. Cost containment is a priority for every health care facility. As a result, the staff of the Lutheran Medical Center (Wheat Ridge, CO) looked at alternative ways to provide quality laser treatment of ureteral stones. As part of our study, the laser committee offered the Holmium:YAG laser to urologists for ureteral lithotripsy. Previously, the pulsed dye laser was rented for ureteral calculi on a per case basis at $1,500. A hospital processing fee was added to this cost, resulting in a total charge of $1,638 to the patient. Our organization owns a Holmium:YAG laser and uses it primarily in orthopedics. STUDY DESIGN/MATERIALS AND METHODS: Two ureteral lithotripsy cases were performed and compared. One case used the Holmium:YAG for ureteral lithotripsy; the other procedure used the pulsed dye laser. A cost analysis was performed after the procedures. RESULTS: The data indicated a significant difference in cost between the two lasers. Approximately $1,000 was eliminated when using the Holmium:YAG laser. CONCLUSION: A cost savings of $15,000 per year would be realized if 15 cases were performed. The Holmium:YAG laser also can be used on cystine calculi, a procedure for which the pulsed dye laser is ineffective. The potential for ureteral injury exists. When using the Holmium:YAG laser, appropriate training is required. Due to this risk, not all urologists will use the Holmium:YAG laser. We also found a positive correlation between the proficiency of the urologists' laser skills and overall cost effectiveness.

Cost Savings↗