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Biomedical subjects

L M Fink

Publications and source records attributed to L M Fink.

At least 37 records · Page 2Linked to original sources
PubMed1998

Hyperhomocysteinemia increases intimal hyperplasia in a rat carotid endarterectomy model.

PURPOSE: This preliminary study investigated the ability to elevate the serum homocysteine (H[e]) levels and investigated the increases in postoperative neointimal hyperplasia (IH) in an environment with hyperhomocysteinemia and the resultant restenosis in a rat carotid endarterectomy (CEA) model. METHOD: The 9 rats for the control group were fed rat chow, and the 8 rats for the H(e) group were fed H(e)-supplemented rat chow for 2 weeks before and after CEA. The animals underwent anesthesia, and a left common CEA was performed. After 14 days, the serum H(e) levels were measured and the left carotid artery was harvested and elastin stained. Morphometric measurements were used to calculate the area of stenosis of the lumen. The mean and the standard deviation of the mean were determined. The 2 groups were compared with the Mann-Whitney test and a linear regression model. Three additional rats per group were studied, with carotid artery sectioning with double immunohistochemical staining for 5-bromodeoxyuridine (BrdU) and alpha-smooth muscle (alpha-SM) actin. RESULTS: The serum H(e) level in the H(e) group was 36.32 micromol/L +/- 15.28, and in the control group the level was 5.53 micromol/L +/- 2.06 (P =.0007). IH presented as percent lumen stenosis was 21.89% +/- 4.82% in the H(e) group and 4.82% +/- 1.64% in the control group (P =.0007). The linear regression model of the serum H(e) levels and the percent stenosis showed a linear relationship (r2 =.72). The alpha-SM actin staining revealed that nearly all of the cells in the IH area were of smooth muscle or myofibroblast origin and that 10.1% +/- 2.6% of the cells were stained for BrdU in the control group versus 23% +/- 7.1% in the H(e) group. Also, 9.3% +/- 2.6% of the cells in the IH area were stained for BrdU and for alpha-SM actin versus 19.1% +/- 5. 6% stained for both BrdU and alpha-SM actin in the H(e) group. CONCLUSION: This is the first study to examine IH after CEA and hyperhomocysteinemia in rats. The study shows that the elevation of serum H(e) levels can be obtained by feeding rats modified diets with added H(e). The consistent elevation of serum H(e) levels was associated with more than 4 times the amount of IH after a CEA in a rat model.

Animals↗
PubMed1998

Hyperhomocysteinemia and premature vascular occlusive disease.

Hyperhomocysteinemia has recently been identified as an independent risk factor for arterial and venous occlusive disease. In particular, hyperhomocysteinemia has been associated with premature vascular disease, and may act synergistically with other risk factors. Two young patients with severe premature vascular disease, one venous and one arterial, have significantly elevated homocysteine levels. In addition to appropriate anti-coagulant therapy, these patients receive B6 and folate vitamin therapy which normalizes the homocysteine levels. While this course of therapy is prudent, no prospective clinical trials have yet demonstrated that reduction of homocysteine levels correlates with a decreased cardiovascular risk.

Adult↗
PubMed1997

Is the loss of endothelial thrombomodulin involved in the mechanism of chronicity in late radiation enteropathy?

BACKGROUND AND PURPOSE: Radiation enteropathy is characterized by locally elevated levels of inflammatory and fibrogenic cytokines. Microvascular injury may sustain these alterations through persistent local hypercoagulopathy, platelet aggregation, leukocyte adhesion and release of biologically active mediators. This study assessed the relationship of endothelial thrombomodulin (TM), a key regulator of the protein C anticoagulant pathway and marker of endothelial function, with transforming growth factor beta (TGF-beta) immunoreactivity and morphologic alterations in radiation enteropathy. MATERIALS AND METHODS: Small bowel resection specimens from 9 patients with radiation enteropathy were analyzed by computerized quantitative immunohistochemistry using antibodies against TM, von Willebrand factor (vWF) and TGF-beta. Identical measurements were performed on intestinal resection specimens from otherwise healthy penetrating trauma victims and on archived small intestines. A previously validated image analysis technique was used to assess submucosal vessels for TM and vWF immunoreactivity, and the intestinal wall for total extracellular matrix-associated TGF-beta immunoreactivity. RESULTS: Specimens from irradiated patients showed prominent submucosal and subserosal thickening and fibrosis, and obliterative vasculopathy. Control specimens were histopathologically normal. Vascular density and vWF immunoreactivity were similar in radiation enteropathy patients and controls. The image-analysis techniques were highly reproducible, with correlation coefficients for repeated measurements ranging from 0.86 to 0.93. Radiation enteropathy specimens exhibited a highly significant reduction in the number and proportion of TM-positive submucosal vessels per unit area (P < 0.0001) and increased intestinal wall TGF-beta immunoreactivity (P = 0.002). CONCLUSIONS: These data support the theory that sustained endothelial dysfunction is involved in the molecular pathogenesis of radiation enteropathy, and point to TM as important in the chronic nature of radiation enteropathy and a potential target for prophylactic and therapeutic interventions.

Aged↗
PubMed1997

Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection.

The role of neutralizing antibodies in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood and was assessed by evaluating responses at different stages of infection. Undiluted sera from long-term nonprogressors (LTNP) had broad neutralizing antibodies against heterologous primary isolates and were more likely to neutralize the contemporaneous autologous isolate than were sera from short-term nonprogressors and progressors. In primary infection, envelope-specific IgG was detected before the initial decline in plasma viremia, but neutralizing antibodies developed more slowly. Here, neutralizing antibodies against strains SF-2 and MN were sometimes the first to be detected, but titers were low for at least 17 weeks from onset of symptoms. Neutralizing antibodies against the early autologous isolate were detected for 4 patients by 5-40 weeks but were undetectable in 2 additional patients for 27-45 weeks. The results indicate that neutralizing antibody responses are slow to develop during primary infection and are uniquely broad in LTNP.

CD4 Lymphocyte Count↗
PubMed1996

Young women with advanced aortoiliac occlusive disease: new insights.

We identified a group of 24 young (less than 50 years of age) women with isolated, premature atherosclerotic aortoiliac occlusive disease and attempted to identify distinguishing hemostatic characteristics. Most of these patients (62%) presented with acute thromboembolic events (blue toe syndrome, n = 6; macroemboli, n = 6; or aortoiliac thrombosis, n = 3). Aortoiliac reconstruction (aortoiliac endarterectomy, n = 10, aortobifurcation bypass grafts, n = 6; and percutaneous angioplasty, n = 4) was complicated by early thrombosis in 6 of 20 cases (30%), (1 of 10 endarterectomies, 4 of 6 bypass grafts, and 1 of 4 angioplasties). Fresh thrombus overlying an atherosclerotic plaque was a common finding at surgery. This observation and the relatively high incidence of thromboembolic events led us to hypothesize that a characteristic hemostatic profile might underlie the remarkably similar clinical presentations of these women. Levels of antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant), plasminogen activator inhibitor-1, fibrinogen, antithrombin III, protein C, protein S, plasminogen, prothrombin fragment F1 + 2, and D-dimer were determined for these young women and for 21 age-matched white female control subjects without vascular disease and nine white male patients with aortoiliac occlusive disease (mean 61 years, range 43 to 74 years). The incidence of anticardiolipin antibodies was 42% (8 of 19) in the female patients, which was significantly elevated (p = 0.028). The female (62.5%) and male (100%) patients had significantly elevated D-dimer levels (p < 0.001). Deficiencies of antithrombin III, protein C, and protein S were rare. A unique pattern of premature aortoiliac atherosclerosis exists in some young women. Intra-arterial thromboembolic events are common at presentation and complicate surgical management. The role of antiphospholipid antibodies remains uncertain.

Adult↗
PubMed1996

Hyperhomocysteinemia. An emerging and important risk factor for thromboembolic and cardiovascular disease.

Homocysteine is an important contributing factor to thrombosis, vascular injury, and vascular disease. Mechanisms for homocysteine-induced vascular disease include alterations in coagulation as well as endothelial cell and vessel wall injury. Hyperhomocysteinemia (HH[e]) can occur when homocysteine metabolism is altered by mutations in enzymes responsible for homocysteine metabolism. Characterization of these mutations identifies patient groups at risk for vascular disease. Treatment of HH(e) consists of vitamins and raises the possibility that some forms of vascular disease may be easily, safely, and inexpensively treated.

Cardiovascular Diseases↗
PubMed1996

Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors.

Serum antibodies from human immunodeficiency virus type 1 (HIV-1)-infected long-term non-progressors (LTNPs) and non-LTNPs were evaluated for virus neutralization and infection enhancement in vitro. Sera from LTNPs had higher average titers of neutralizing antibodies to HIV-1 strains IIIB and MN and more frequently neutralized primary isolates from progressors (14.9% vs. 1.3%, P = .002). Replication-competent HIV-1 was isolated from peripheral blood mononuclear cells and lymph nodes of 3 LTNPs. All viruses from LTNPs had a non-syncytium-inducing phenotype, were resistant to neutralization by autologous serum obtained at the time of virus isolation, and showed little evidence of a heightened sensitivity to neutralization by heterologous sera. Complement-mediated, antibody-dependent enhancement (C'-ADE) of HIV-1IIIB and primary isolates was equally prevalent for sera from LTNPs and non-LTNPs. Results indicate that LTNPs produce vigorous serum antibody responses and that long-term nonprogression is not associated with homologous neutralization or the absence of C'-ADE.

Adult↗
PubMed1994

Bacteriophage epitope libraries. The generation of specific binding proteins and peptides in vitro.

New concepts and methodologies that can be used to generate proteins, such as specific variable regions of immunoglobulins and other binding peptides in an in vitro selection system are reviewed. These technologies can also be used to alter the kinetics, affinity and avidity of various binding interactions. The nature of epitopes recognized by specific antibodies or receptors can be delineated using selected epitopes displayed on bacteriophages. The basic principles of the technology is predicted upon the belief that if one has a large enough variety of keys, one can open any given lock. The range of utility of these systems to generate new reagents will impact upon the development of new diagnostic and therapeutic reagents. This technology should allow for a much wider range of probes which may have increased binding capacity and allow the development of more sensitive assays with higher signal to noise ratios. These reagents can be produced more efficiently without the use of animals and will be used in diagnostic and experimental pathology. This brief review presents a concise description of the concepts and uses of this new technology. Selected references and reviews are given as sources for further details.

Animals↗
PubMed1994

Loss of heterozygosity and overexpression of p53 gene in human primary prostatic adenocarcinoma.

We have examined the loss of heterozygosity (LOH) of codon 72 and evaluated the overexpression of the tumor suppressor gene p53 in 43 primary human prostatic adenocarcinomas (PC). DNA from tumors and normal tissues were extracted from radical prostatectomy specimens. LOH was determined by restriction fragment length polymorphism analysis (RFLP) of the codon-specific endonuclease-digested polymerase chain reaction (PCR) products. Results showed 17 heterozygous cases (39%) among this patient group. Seven of the heterozygous cases displayed LOH. Six of the seven LOH cases were high-grade PCs with Gleason's combined score of > or = 7 and showed capsular invasion. One of the LOH cases, however, displayed an intermediate morphological score of 6 but also with evidence of capsular invasion. The 43 primary PCs were also examined for overexpression of p53 by a monoclonal antibody-mediated immunofluorescence reaction. Overexpression of nuclear p53 as detected by antibody was demonstrable only in tumors with combined morphological Grade > or = 7. No significant overexpression of p53 was noted in lower-grade tumors. In addition, 10 cases of benign prostatic hyperplasia (BPH) were evaluated for p53 expression. All 10 cases showed no detectable p53 overexpression.

Adenocarcinoma↗
PubMed1993

Thromboembolism in patients undergoing thoracotomy.

To determine the incidence of thromboembolism in relation to thoracotomy, 77 patients undergoing pulmonary resection were prospectively studied up to 30 days postoperatively for deep venous thrombosis and pulmonary embolism. Overall, 20 of 77 patients (26%) had thromboembolic events during their hospitalization. Four deep venous thromboses and 1 pulmonary embolism were detected in 5 of 77 patients preoperatively for an incidence of 6%. Postoperative thromboembolism was detected in 15 of 77 (19%): deep venous thrombosis in 11 (14%) and pulmonary embolism in 4 (5%). No postoperative thromboembolisms occurred in the 17 patients receiving preoperative aspirin or ibuprofen, whereas they did occur in 25% of the remainder (15/60). Thromboembolism after pulmonary resection was more frequent with bronchogenic carcinoma than with metastatic cancer or benign disease (15/59 [25%] versus 0/18 [0%]; p < 0.01), adenocarcinoma compared with other types of carcinoma (11/25 [44%] versus 4/34 [12%]; p < 0.0004), large primary lung cancer (> 3 cm in diameter) compared with smaller lesions (9/19 [47%] versus 6/40 [15%]; p < 0.0001), stage II compared with stage I (7/14 [50%] versus 7/34 [21%]; p < 0.04), and pneumonectomy or lobectomy compared with segmentectomy and wedge resection (14/49 [29%] versus 1/28 [4%]; p < 0.005). Three of 4 patients with thromboembolism detected preoperatively had operation within the previous year. Postoperative pulmonary embolism was fatal in 1 of 4 (25%) and accounted for the one death. These results suggest patients undergoing thoracotomy for lung cancer, especially adenocarcinoma, should be considered for thromboembolic prophylaxis.

Adenocarcinoma↗
PubMed1993

The application of a rapid D-dimer test in suspected pulmonary embolus.

A prospective, consecutive series of plasma D-dimer (D-D) using a rapid, sensitive, and semiquantitative latex agglutination test from 169 patients clinically suspected of having acute pulmonary embolus (PE) was performed to determine its clinical utility in acute PE. All patients had ventilation/perfusion (V/Q) scans and 20 patients (12%) subsequently had pulmonary arteriography (PAG). The 20 patients who subsequently had PAG were used to establish the predictive value(s). In 10 patients with normal D-D results, none had PE according to PAG. In 10 patients with abnormal D-D results, seven showed PE by PAG and three did not show PE by PAG. The sensitivity, specificity, positive predictive values, and negative predictive values of the plasma D-D tests for acute PE based on PAG were 1.00, 0.77, 0.70, and 1.00, respectively. In nine patients with indeterminate V/Q scans who had PAG, four had PE and the D-D result was abnormal. Five of these patients did not have PE and the D-D result was abnormal in three and normal in two. Seventeen patients had high-probability V/Q scans, all of whom had abnormal D-D results. Only one had PAG that showed PE in this group. A normal D-D result using a rapid latex agglutination method can effectively exclude the diagnosis of acute PE. The negative predictive value of the rapid latex agglutination method is as good as the more cumbersome enzyme-linked immunosorbent assay methods. An abnormal result is nonspecific and is not useful in the diagnosis of acute PE. While some "false positives" did occur, there were no false-negative results. The best use of the D-D test is in the examination of the patient with indeterminate V/Q studies. We conclude that the D-D test can rapidly provide information in determining whether a patient needs further angiographic studies.

Blood Coagulation Tests↗
PubMed1993

Thrombomodulin activity and localization.

An overview on the properties, actions and localization of thrombomodulin (TM) in situations of tissue injury and in selected tumors is presented. The localization and activity of TM after injury to vascular endothelium shows that following balloon catheter denudation of the endothelium of the rabbit aorta, the activity and immunohistochemical staining is markedly reduced. The functional and antigenic levels approach the control levels approximately one week after the initial injury. The results suggest that the neointimal smooth muscle cells express TM. This phenotypic plasticity of the neointimal smooth muscle cells may be important in conferring thrombo-resistance to the lumenal lining cells of vessels after injury. Studies are also reviewed on the use of soluble recombinant TM to prevent thrombosis after ligature of vessels in an experimental model. Further characterization on the immunohistochemical distribution of TM in normal tissues and tumors shows that staining with a monoclonal anti TM antibody can be very useful in separating mesotheliomas from pulmonary adenocarcinomas. These studies may lead to insights concerning the role of TM in tissue-injury-repair and tissue differentiation.

Adenocarcinoma↗
PubMed1993

Plasma D-dimer: a useful tool for evaluating suspected pulmonary embolus.

Although ventilation-perfusion lung scanning is widely used in evaluating patients with suspected pulmonary embolus, additional rapid screening tests are needed to supplement scintigraphy in patients in whom the scan is indeterminate or the scan results are discordant with clinical suspicion. D-dimer is a fibrin degradation product which should be elevated in the presence of intravascular coagulation. We prospectively studied patients referred for lung scanning by obtaining a plasma D-dimer latex agglutination assay at the time of the scan. Of 64 patients who had pulmonary angiography to confirm the diagnosis, 16 were positive for pulmonary embolus and only one had a normal D-dimer. The D-dimer was normal in 27 of 48 patients without embolus and elevated in 21. Although an elevated D-dimer level is a nonspecific finding, we conclude that a normal D-dimer is a good negative predictor for pulmonary embolus, with a negative predictive value of 0.97.

Enzyme-Linked Immunosorbent Assay↗
PubMed1992

Thermospray high-performance liquid chromatography/mass spectrometric determination of cyclosporins.

The cyclic undecapeptides cyclosporin (Csp) A, CspD and dihydro CspC (HCspC) were analyzed by high-performance liquid chromatography/thermospray-mass spectrometry (HPLC/TSP-MS) on line with a UV detector. Positive ion partial (1000-1300 u) mass spectra of these compounds could be obtained with 1-2 pmol injected on column. Mass spectra were characterized by signals corresponding to the [M+H] ions as well as fragment ions derived from the loss of 112 (CspA and CspD) or 44, 114 and 114 + 44 (HCspC) mass units from the parent ion. The same qualitative profile was observed for negative-ion acquisition where the ions were formed by proton abstraction. The application of the technique to the characterization of CspA and its major hydroxylated and dealkylated metabolites in human blood samples is presented.

Chromatography, High Pressure Liquid↗
PubMed1991

Antisperm antibody binding to human acrosin: a study of patients with unexplained infertility.

OBJECTIVE: Antisperm antibody binding to acrosin was investigated by Western Blotting. The clinical significance of this binding specificity was assessed in a 2-year clinical follow-up. DESIGN: Consecutive serum samples positive for antisperm antibodies by both enzyme-linked immunosorbent assay and immunobead testing were evaluated for acrosin-binding specificity. SETTING: The patients were followed in an outpatient setting by private infertility specialists. PATIENTS: Sixty-five consecutive infertile referral patients with positive antisperm antibody were evaluated. Clinical follow-up was obtained on 8 of 9 females with evidence of antibody binding to acrosin and 19 of 26 females with no specific binding to acrosin. INTERVENTIONS: Prednisone therapy was given during six courses of intrauterine insemination with husband's sperm. All treatment decisions were made by private physicians independent of the acrosin-binding result. MAIN OUTCOME MEASURES: Pregnancy status was obtained as part of a 2-year follow-up. RESULTS: Acrosin-binding specificity was demonstrated in 10 (15%) of the 65 patients. Two of the 8 women (25%) with antibody binding to acrosin and 6 of the 19 women (32%) with antisperm antibodies but no specific binding to acrosin delivered normal children. CONCLUSIONS: Although antibody-binding specificity to acrosin could be demonstrated, a 2-year clinical follow-up showed no difference in pregnancy rates when compared with women with antisperm antibodies showing no binding specificity to acrosin.

Acrosin↗
PubMed1991

Rapid preparation of plasma for coagulation testing.

Currently recommended minimum centrifugation of whole blood to produce platelet-poor plasma for routine coagulation assays is 1000g relative centrifugal force for 10 minutes. Many clinical laboratories centrifuge blood for routine coagulation assays from 500g to 2000g, with spin times varying from 20 to 5 minutes. Ninety blood samples, routinely submitted to our coagulation laboratory, were prospectively assayed simultaneously for the prothrombin time, activated partial thromboplastin time, and fibrinogen level, comparing centrifugation at 11,000g for 2 minutes with centrifugation at 1000g for 10 minutes. Routine and readily available equipment and supplies were used. Platelet counts were performed on the supernatant plasma in each sample to determine the efficacy of platelet depletion. Excellent correlation of methods was observed for the prothrombin time, activated partial thromboplastin time, and fibrinogen level. Platelet counts on the plasma supernatant showed no significant difference between the two centrifugation methods. We concluded that high-speed centrifugation at 11,000g with a shortened spin time of 2 minutes and with the use of routinely available equipment and supplies can significantly decrease the specimen preparation time for routine coagulation testing.

Blood↗