Biomedical subjects

Louis M Fink

Publications and source records attributed to Louis M Fink.

12 recordsLinked to original sources

PubMed2006

Comparison of mortality rates in statin users versus nonstatin users in a United States veteran population.

Statins have been shown to be effective in reducing cardiovascular events and overall mortality in primary and secondary prevention trials. This study was designed to examine the effect of statin use on overall death. Cross-sectional data were obtained from the Department of Veterans Affairs Veterans Integrated Service Network 16 database for approximately 1.5 million veterans followed up in 10 hospitals in the southern United States. Statins were prescribed more often to elderly subjects with a history of coronary artery disease, hypertension, diabetes mellitus, current smoking, and using cardiovascular drugs (beta blockers, aspirin, angiotensin-converting enzyme inhibitors, and calcium channel blockers). The predictors of death were, as expected, cancer, diabetes mellitus, the use of cardiac drugs, and age. Importantly, using statins showed a highly significant negative association with death (odds ratio 0.54, 95% confidence interval 0.42 to 0.69, p <0.0001), even after adjustment for all other variables. Overall, the mean age at death among statin users was 2 years older than among nonstatin users, despite statin users being at a higher risk of death. In conclusion, the results of this study have shown that using statins is a potent life-saving strategy. The benefit observed in this study is unique because almost 1/2 the patients were >or=70 years of age when statin therapy was initiated.

Adrenergic beta-Antagonists↗

PubMed2006

Comparative expression profiling in primary and immortalized endothelial cells: changes in gene expression in response to hydroxy methylglutaryl-coenzyme A reductase inhibition.

Immortalized cell lines offer significant logistical advantages over primary cells when used for in-vitro studies. Immortalized cells may, however, exhibit important differences relative to their primary cell counterparts. In this study, microarrays were used to make a genome-wide comparison between primary human umbilical vein endothelial cells (HUVECs) and EA.hy926, an immortalized HUVEC cell line, in their baseline properties and in their response to inhibition of the mevalonate pathway with an inhibitor of hydroxy methylglutaryl-coenzyme A reductase (statin). HUVECs and EA.hy926 were incubated with control medium, atorvastatin, mevalonate, or a combination of atorvastatin and mevalonate for 24 h. Gene expression profiles were obtained in duplicates using Affymetrix Human Genome U133A 2.0 arrays (Santa Clara, California, USA). Probe-sets were selected according to the following criteria: a twofold or greater increase/decrease in atorvastatin-treated cells compared with untreated cells; a twofold or greater reversal of the effect of atorvastatin by combined treatment with atorvastatin and mevalonate; no significant change in gene expression in cells treated with mevalonate alone compared with untreated cells. Most genes that were expressed by untreated HUVECs, were also expressed by untreated EA.hy926 cells. EA.hy926 cells, however, constitutively expressed a large number of additional genes, many of which were related to cell cycle control and apoptosis. Atorvastatin induced differential expression (> or = twofold) of 103 genes in HUVECs (10 up, 93 down) and 466 genes in EA.hy926 cells (198 up, 268 down). Applying the above selection criteria, thrombomodulin and tissue plasminogen activator were up-regulated in both cell types, whereas, connective tissue growth factor, thrombospondin-1, and cysteine-rich angiogenic inducer 61 were down-regulated. In conclusion, EA.hy926 cells retain most of the characteristics of endothelial cells under baseline conditions as well as after treatment with atorvastatin. It is necessary, however, to carefully select and validate changes in genes that are the focus of studies when using EA.hy926 cells. While this cell line is highly useful in studies on some genes, including genes encoding molecules involved in regulating thrombohemorrhagic homeostasis, they appear to be less suited for studies focused on other genes, particularly those involved in the regulation of cell proliferation and apoptosis.

Apoptosis↗

PubMed2005

Modulation of the intestinal response to ionizing radiation by anticoagulant and non-anticoagulant heparins.

Endothelial dysfunction is involved in radiation responses in many normal tissues, including intestine. Endothelium-directed interventions ameliorate intestinal radiation injury (radiation enteropathy) in animal models, and anecdotal reports also suggest a beneficial effect of heparin. This study assessed low molecular weight heparin as an intestinal radiation response modifier. Rats underwent localized small bowel irradiation. Groups of rats were treated with saline, nadroparin (3 mg/kg/d), or a non-anticoagulant heparin (SR80258, 3 mg/kg/d), from 3 days before to 2 weeks after irradiation. The intestinal radiation response was assessed 2 weeks and 6 weeks after irradiation using quantitative histology; morphometry, and cellular and molecular end-points. Compared to vehicle-treated controls, nadroparin significantly exacerbated structural radiation injury, neutrophil infiltration, and TGFbeta and collagen I immunoreactivity levels 2 weeks after irradiation. SR80258 was associated with increased TGFbeta levels, but the other parameters did not reach statistical significance. At 6 weeks, structural, cellular, and molecular injury was similar in the three experimental groups. Heparin, in contrast to antiplatelet agents and direct thrombin inhibitors, does not ameliorate, but exacerbates acute intestinal radiation toxicity. These data underscore the importance of heparin as an inhibitor of physiological anti-inflammatory mechanisms during tissue injury, as well as the non-anticoagulant effects of heparin. Moreover, these data may have implications for the use of heparin during radiation therapy.

Animals↗

PubMed2004

Infrared imaging of subcutaneous veins.

BACKGROUND AND OBJECTIVES: Imaging of subcutaneous veins is important in many applications, such as gaining venous access and vascular surgery. Despite a long history of medical infrared (IR) photography and imaging, this technique is not widely used for this purpose. Here we revisited and explored the capability of near-IR imaging to visualize subcutaneous structures, with a focus on diagnostics of superficial veins. STUDY DESIGN/MATERIALS AND METHODS: An IR device comprising a head-mounted IR LED array (880 nm), a small conventional CCD camera (Toshiba Ik-mui, Tokyo, Japan), virtual-reality optics, polarizers, filters, and diffusers was used in vivo to obtain images of different subcutaneous structures. The same device was used to estimate the IR image quality as a function of wavelength produced by a tunable xenon lamp-based monochrometer in the range of 500-1,000 nm and continuous-wave Nd:YAG (1.06 microm) and diode (805 nm) lasers. RESULTS: The various modes of optical illumination were compared in vivo. Contrast of the IR images in the reflectance mode was measured in the near-IR spectral range of 650-1,060 nm. Using the LED array, various IR images were obtained in vivo, including images of vein structure in a pigmented, fatty forearm, varicose leg veins, and vascular lesions of the tongue. CONCLUSION: Imaging in the near-IR range (880-930 nm) provides relatively good contrast of subcutaneous veins, underscoring its value for diagnosis. This technique has the potential for the diagnosis of varicose veins with a diameter of 0.5-2 mm at a depth of 1-3 mm, guidance of venous access, podiatry, phlebotomy, injection sclerotherapy, and control of laser interstitial therapy.

Forearm↗

PubMed2004

Radiation injury and the protein C pathway.

OBJECTIVE: To summarize current knowledge regarding the role of the thrombomodulin (TM)-protein C system in acute and chronic radiation responses in normal tissues. DATA SOURCE: Studies published in the biomedical literature during the past three decades and cited in PubMed and unpublished clinical and laboratory data from our own research program. STUDY SUMMARY: The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. Microvascular injury is a prominent feature of normal tissue radiation injury and plays a critical role in both acute (inflammatory) and chronic (fibrotic) radiation responses. Evidence from our own and other laboratories strongly suggests that dysfunction of the TM-protein C system plays a key role in the pathogenesis of radiation-induced injury to normal tissue. Exposure of normal tissues to ionizing radiation causes a pronounced, sustained deficiency of endothelial TM. This is likely to be due to a combination of initial inactivation of TM by reactive oxygen species, reduced transcription of TM, and release of TM into the circulation. Deficient levels of endothelial TM cause loss of local vascular thrombo-resistance, excessive activation of protease-activated receptor-1 by thrombin, and insufficient activation of protein C. These changes are presumed to be critically involved in many aspects of acute radiation toxicity and in sustaining the fibroproliferative processes that lead to chronic radiation-induced organ dysfunction and clinical complications. CONCLUSION: Injury of vascular endothelium may be key to the acute responses of normal tissues to ionizing radiation and to the progressive nature of chronic radiation fibrosis. Restitution of the TM-protein C pathway is an appealing strategy by which to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.

Endothelium↗

PubMed2004

Recombinant factor VIIa in the treatment of bleeding.

Recombinant factor VIIa (rFVIIa) has become available for treating people with hemophilia with inhibitors who experience bleeding or require surgery. It has become apparent that rFVIIa is useful in controlling bleeding in a variety of clinical situations. This review attempts to collate and summarize the nonhemophilia applications of rFVIIa. The theoretical mechanism for the coagulation and hemostatic effects of rFVIIa are discussed. The dosage and clinical administration are described. The potential uses for patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, von Willebrand disease, and other bleeding disorders are reviewed. The use of rFVIIa is evolving, and the indications, dosage, and precautions or contraindications need to be further described and defined. It is an expensive therapy and needs to be prescribed judiciously. This review is meant to be an introduction to this new hemostatic reagent. The uses for rFVIIa will evolve as more studies are published.

Acute Disease↗

PubMed2003

Insulin sensitivity and plasma homocysteine concentrations in non-diabetic obese and normal weight subjects.

OBJECTIVE: To determine whether plasma homocysteine (tHcy) levels were related to insulin resistance and obesity in subjects without diabetes or vascular disease. RESEARCH DESIGN AND METHODS: We studied correlates of plasma tHcy in 26 subjects covering a wide spectrum of obesity and insulin sensitivity (S(I)). The measurement of in vivo insulin sensitivity was performed using the minimal model analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT). RESULTS: There was no relationship between tHcy and body mass index. There was a significant relationship between plasma tHcy and S(I) (r=0.53, P=0.006), demonstrating that the more insulin sensitive subjects had higher levels of tHcy. On log transformation of the plasma insulin values, log insulin correlated negatively with plasma tHcy (r=-0.47; P=0.02). None of the subjects were deficient in vitamin B(12) and folate. Plasma vitamin B(12) was significantly related to plasma tHcy (r=-0.44, P=0.017), although we found no significant relationship between plasma folate and tHcy (r=-0.21, P=0.27). S(I) correlated significantly with vitamin B(12) (r=0.4, P=0.045) whereas, we found no significant relationship between S(I) and plasma folate (r=0.27, P=0.2). On multiple linear regression using tHcy as the dependent variable, S(I) and vitamin B(12) remained significant predictors of plasma tHcy, whereas, age and plasma folate were not predictors of tHcy. CONCLUSIONS: We conclude that in vitamin replete lean and obese individuals, insulin sensitivity correlates significantly with plasma tHcy. This relationship may need to be considered when evaluating the role of plasma homocysteine as a risk factor in patients with obesity and type 2 diabetes.

Adult↗

PubMed2003

Statins increase thrombomodulin expression and function in human endothelial cells by a nitric oxide-dependent mechanism and counteract tumor necrosis factor alpha-induced thrombomodulin downregulation.

Expression of functionally active thrombomodulin (TM) on the luminal surface of endothelial cells is critical for vascular thromboresistance. TM maintains thrombohemorrhagic homeostasis by forming a complex with thrombin, which subsequently loses its procoagulant properties and instead activates protein C. Acquired deficiency of endothelial TM is of particular pathophysiological significance in sepsis and related disorders. We show here that two different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), atorvastatin and simvastatin, strongly increase the expression and functional activity of TM in human umbilical vein endothelial cells, human coronary artery endothelial cells, and EA.hy926 endothelial cells. The increase in endothelial TM conferred by statin was prevented by the addition of mevalonic acid, geranylgeranyl-pyrophosphate, and nitric oxide scavenger, and was mimicked by the addition of a specific inhibitor of geranylgeranyl transferase, as well as by nitric oxide donors. Moreover, statin counteracted tumor necrosis factor alpha-induced downregulation of endothelial cell TM. The increase in endothelial cell TM activity in response to statin constitutes a novel pleiotropic (non-lipid-related) effect of these commonly used compounds, and may be of clinical significance in disorders where deficient endothelial TM and protein C activation play a pathophysiological role.

Anticholesteremic Agents↗

PubMed2002

Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats.

Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be an important factor in adverse cardiac remodeling in hypertension. Specifically, convergence of myocardial and vascular alterations promoted by Hhe and hypertension may exacerbate cardiac remodeling and myocardial dysfunction. We studied male spontaneously hypertensive rats fed one of three diets: control, intermediate Hhe inducing, or severe Hhe inducing. After 10 wk of dietary intervention, cardiac function was assessed in vitro, and cardiac and coronary arteriolar remodeling were monitored by histomorphometric, immunohistochemical, and biochemical techniques. Results showed that Hhe induced diastolic dysfunction, as characterized by the diastolic pressure-volume curve, without significant changes in baseline systolic function. Perivascular collagen levels were increased by Hhe, and there was an increase in left ventricular hydroxyproline levels. Myocyte size was not affected. Coronary arteriolar wall thickness increased with Hhe due to smooth muscle hyperplasia. Mast cells increased in parallel with Hhe and collagen accumulation. In summary, 10 wk of Hhe caused coronary arteriolar remodeling, myocardial collagen deposition, and diastolic dysfunction in hypertensive rats.

Animals↗

PubMed2002

Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1 in irradiated rat intestine: possible link between endothelial dysfunction and chronic radiation fibrosis.

Microvascular injury is believed to be mechanistically involved in radiation fibrosis, but direct molecular links between endothelial dysfunction and radiation fibrosis have not been established in vivo. We examined radiation-induced changes in endothelial thrombomodulin (TM) and protease-activated receptor-1 (PAR-1) in irradiated intestine, and their relationship to structural, cellular, and molecular aspects of radiation injury. Rat small intestine was locally exposed to fractionated X-radiation. Structural injury was assessed 24 hours and 2, 6, and 26 weeks after the last radiation fraction using quantitative histology and morphometry. TM, neutrophils, transforming growth factor-beta, and collagens I and III were assessed by quantitative immunohistochemistry. PAR-1 protein was localized immunohistochemically, and cells expressing TM or PAR-1 transcript were identified by in situ hybridization. Steady-state PAR-1 mRNA levels in intestinal smooth muscle were determined using laser capture microdissection and competitive reverse transcriptase-polymerase chain reaction. Radiation caused a sustained, dose-dependent decrease in microvascular TM. The number of TM-positive vessels correlated with all parameters of radiation enteropathy and, after adjusting for radiation dose and observation time in a statistical model, remained independently associated with neutrophil infiltration, intestinal wall thickening, and collagen I accumulation. PAR-1 immunoreactivity and transcript increased in vascular and intestinal smooth muscle cells in irradiated intestine. PAR-1 mRNA increased twofold in irradiated intestinal smooth muscle. Intestinal irradiation up-regulates PAR-1 and causes a dose-dependent, sustained deficiency of microvascular TM that is independently associated with the severity of radiation toxicity. Interventions aimed at preserving or restoring endothelial TM or blocking PAR-1 should be explored as strategies to increase the therapeutic ratio in clinical radiation therapy.

Animals↗

PubMed2002

Pathologists in a teaching institution assess the value of the autopsy.

CONTEXT: With the advent of modern diagnostic technology, use of the autopsy as a means of assessing diagnostic accuracy has declined precipitously. Interestingly, during the same period, the rate of misdiagnosis found at autopsy has not changed. OBJECTIVES: To ascertain why an autopsy was requested, whether or not questions asked by clinicians were specifically addressed, and what types of misdiagnoses were found. DESIGN: One hundred forty-two consecutive autopsy records from the University of Arkansas for Medical Sciences Hospital were reviewed. In the same period, 715 deaths occurred, giving an overall autopsy rate of 20.14%. RESULTS: Of the 125 autopsies in which the problem-oriented autopsy request was available for review, a reason for the autopsy was given in only 69 cases (55%). One hundred three clinical questions were asked, and of these, 81 were specifically addressed in the final anatomic diagnosis, 10 were addressed in some part of the autopsy report but not in the final anatomic diagnosis, 10 were not addressed at all, and 2 could not be answered by the autopsy. Sixty-one autopsies revealed 81 misdiagnoses: 47 class I (missed major diagnosis that, if detected before death, could have led to a change in management that might have resulted in cure or prolonged survival) and 34 class II misdiagnoses (missed major diagnosis in which antemortem detection would have not led to a change in management). CONCLUSIONS: The autopsy continues to be a vital part of medical education and quality assurance. It is important for the clinician to provide a clinical summary and specific clinical questions to be addressed or to speak directly with the pathologist and for the pathologist to provide answers that are easily accessible within the autopsy report. In this way, a problem-oriented autopsy can be performed based on questions raised by the clinician and the pathologist as a result of the gross dissection and microscopic evaluation.

Adolescent↗

PubMed2002

Short-term inhibition of ADP-induced platelet aggregation by clopidogrel ameliorates radiation-induced toxicity in rat small intestine.

Endothelial dysfunction and increased platelet aggregation may be involved in the pathogenesis of normal tissue radiation toxicity. This study assessed clopidogrel, an inhibitor of ADP-induced platelet aggregation, as a modulator of intestinal radiation injury (radiation enteropathy). Rat small intestine was exposed to 21 Gy X-radiation. Clopidogrel (20 mg/kg/day) or vehicle was administered from 2 days before to 10 days after irradiation. Structural radiation injury, neutrophil infiltration, smooth muscle cell proliferation, collagen content, and TGF-beta1 expression were assessed 2 weeks (early phase) and 26 weeks (delayed phase) after irradiation, using quantitative histology and immunohistochemistry, morphometry, and real-time fluorogenic probe RT-PCR. Irradiated intestine exhibited significant histopathologic injury, reduced mucosal surface area, vascular sclerosis, intestinal wall fibrosis, increased collagen content, and increased TGF-beta1 expression. Clopidogrel reduced ADP-induced platelet aggregation by 93% and significantly attenuated the severity of post-radiation vascular sclerosis (p = 0.004 and p = 0.02) and the loss of mucosal surface area (p = 0.0008 and p = 0.003) at both 2 and 26 weeks. Clopidogrel also ameliorated overall histopathologic injury (p = 0.02), relative intestinal collagen content (p = 0.03), and collagen III immunoreactivity levels 2 weeks after irradiation, and caused a borderline reduction in the radiation-induced increase in extracellular matrix-associated TGF-beta immunoreactivity at 26 weeks (p = 0.04). The effects of clopidogrel on steady-state TGF-beta1 mRNA levels and neutrophil infiltration were not statistically significant. Short-term clopidogrel administration affords protection against early and, to a lesser extent, delayed radiation enteropathy. Modulation of platelet aggregation should be subject to further studies as a potential method to increase safety and efficacy of radiation therapy.

Adenosine Diphosphate↗