Northport VA Medical Center

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

BACKGROUND: The goal of this study was to determine the relative contribution of system-related and cognitive components to diagnostic error and to develop a comprehensive working taxonomy. METHODS: One hundred cases of diagnostic error involving internists were identified through autopsy discrepancies, quality assurance activities, and voluntary reports. Each case was evaluated to identify system-related and cognitive factors underlying error using record reviews and, if possible, provider interviews. RESULTS: Ninety cases involved injury, including 33 deaths. The underlying contributions to error fell into 3 natural categories: "no fault," system-related, and cognitive. Seven cases reflected no-fault errors alone. In the remaining 93 cases, we identified 548 different system-related or cognitive factors (5.9 per case). System-related factors contributed to the diagnostic error in 65% of the cases and cognitive factors in 74%. The most common system-related factors involved problems with policies and procedures, inefficient processes, teamwork, and communication. The most common cognitive problems involved faulty synthesis. Premature closure, ie, the failure to continue considering reasonable alternatives after an initial diagnosis was reached, was the single most common cause. Other common causes included faulty context generation, misjudging the salience of findings, faulty perception, and errors arising from the use of heuristics. Faulty or inadequate knowledge was uncommon. CONCLUSIONS: Diagnostic error is commonly multifactorial in origin, typically involving both system-related and cognitive factors. The results identify the dominant problems that should be targeted for additional research and early reduction; they also further the development of a comprehensive taxonomy for classifying diagnostic errors.

BACKGROUND: Coronary-artery bypass grafting (CABG) has traditionally been performed with the use of cardiopulmonary bypass (on-pump CABG). CABG without cardiopulmonary bypass (off-pump CABG) might reduce the number of complications related to the heart-lung machine. METHODS: We randomly assigned 2203 patients scheduled for urgent or elective CABG to either on-pump or off-pump procedures. The primary short-term end point was a composite of death or complications (reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure) before discharge or within 30 days after surgery. The primary long-term end point was a composite of death from any cause, a repeat revascularization procedure, or a nonfatal myocardial infarction within 1 year after surgery. Secondary end points included the completeness of revascularization, graft patency at 1 year, neuropsychological outcomes, and the use of major resources. RESULTS: There was no significant difference between off-pump and on-pump CABG in the rate of the 30-day composite outcome (7.0% and 5.6%, respectively; P=0.19). The rate of the 1-year composite outcome was higher for off-pump than for on-pump CABG (9.9% vs. 7.4%, P=0.04). The proportion of patients with fewer grafts completed than originally planned was higher with off-pump CABG than with on-pump CABG (17.8% vs. 11.1%, P<0.001). Follow-up angiograms in 1371 patients who underwent 4093 grafts revealed that the overall rate of graft patency was lower in the off-pump group than in the on-pump group (82.6% vs. 87.8%, P<0.01). There were no treatment-based differences in neuropsychological outcomes or short-term use of major resources. CONCLUSIONS: At 1 year of follow-up, patients in the off-pump group had worse composite outcomes and poorer graft patency than did patients in the on-pump group. No significant differences between the techniques were found in neuropsychological outcomes or use of major resources. (ClinicalTrials.gov number, NCT00032630.).

A consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that "Sarcopenia, ie, reduced muscle mass, with limited mobility" should be considered an important clinical entity and that most older persons should be screened for this condition. "Sarcopenia with limited mobility" is defined as a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a 6-minute walk, and who has a lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group. The limitation in mobility should not clearly be a result of otherwise defined specific diseases of muscle, peripheral vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia. Clinically significant interventions are defined as an increase in the 6-minute walk of at least 50 meters or an increase of walking speed of at least 0.1 m/s.

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

In vitro cellular responses of osteoblast-like cells were studied on titanium surfaces with different surface morphologies. Surface profilometry was used to determine whether rough or smooth surfaces with regular or irregular morphologies can be produced by conventional fabrication techniques. Significantly higher levels of cellular attachment were found using rough, sandblasted surfaces with irregular morphologies. These results correlate with recent in vivo findings and suggest that implants should be prepared with roughened surfaces at bony contact areas.

Candidiasis can be present as a cutaneous, mucosal or deep-seated organ infection, which is caused by more than 20 types of Candida sp., with C. albicans being the most common. These are pathogenic yeast and are usually present in the normal microbiome. High-risk individuals are patients of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), organ transplant, and diabetes. During infection, pathogens can adhere to complement receptors and various extracellular matrix proteins in the oral and vaginal cavity. Oral and vaginal Candidiasis results from the overgrowth of Candida sp. in the hosts, causing penetration of the oral and vaginal tissues. Symptoms include white patches in the mouth, tongue, throat, and itchiness or burning of genitalia. Diagnosis involves visual examination, microscopic analysis, or culturing. These infections are treated with a variety of antifungals that target different biosynthetic pathways of the pathogen. For example, echinochandins target cell wall biosynthesis, while allylamines, azoles, and morpholines target ergosterol biosynthesis, and 5-Flucytosine (5FC) targets nucleic acid biosynthesis. Azoles are commonly used in therapeutics, however, because of its fungistatic nature, Candida sp. evolve azole resistance. Besides azoles, Candida sp. also acquire resistance to polyenes, echinochandins, and 5FC. This review discusses, in detail, the drug resistance mechanisms adapted by Candida sp.

Neurological complications from cocaine use are well recognized. We propose that chronic cocaine use can also cause clinically silent brain dysfunction. We investigated brain glucose metabolism with positron emission tomography (PET) and 2-deoxy-2[18F] fluoro-D-glucose (FDG) in 21 neurologically intact chronic cocaine abusers (C) and 18 normal controls (N). The cocaine abusers were tested 1-6 weeks after the last use of cocaine and seven were retested after a 3 month drug-free period. Global cerebral glucose metabolism was not significantly different between controls and cocaine abusers (N = 38.4 +/- 3, C = 36.5 +/- 5 mumol/100 g of tissue, min). However, cocaine abusers had significantly (P less than 0.05) lower metabolic activity in 16 of the 21 left frontal regions and 8 of the 21 right frontal regions. These decreases persisted after 3-4 months of detoxification and were correlated with the dose (P less than or equal to 0.01) and the years of cocaine use (P less than or equal to 0.05). This study shows reduced rates of frontal metabolism in neurologically intact cocaine abusers that persist even after 3-4 months of detoxification.

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function.

Many of the tumor-associated matrix metalloproteinases that are implicated in metastasis are produced by stromal fibroblasts within or surrounding the tumor in response to stimulation by factors produced by tumor cells. In this study we transfected Chinese hamster ovary cells with putative cDNA for human extracellular matrix metalloproteinase inducer (EMMPRIN), a transmembrane glycoprotein that is attached to the surface of many types of malignant human tumor cells and that has previously been implicated in stimulation of matrix metalloproteinase production in fibroblasts. We show that these transfected cells synthesize EMMPRIN that is extensively post-translationally processed; this recombinant EMMPRIN stimulates human fibroblast production of interstitial collagenase, stromelysin-1, and gelatinase A (72-kDa type IV collagenase). We propose that EMMPRIN regulates matrix metalloproteinase production during tumor invasion and other processes involving tissue remodeling. Many of the tumor-associated matrix metalloproteinases that are implicated in metastasis are produced by stromal fibroblasts within or surrounding the tumor in response to stimulation by factors produced by tumor cells. In this study we transfected Chinese hamster ovary cells with putative cDNA for human extracellular matrix metalloproteinase inducer (EMMPRIN), a transmembrane glycoprotein that is attached to the surface of many types of malignant human tumor cells and that has previously been implicated in stimulation of matrix metalloproteinase production in fibroblasts. We show that these transfected cells synthesize EMMPRIN that is extensively post-translationally processed; this recombinant EMMPRIN stimulates human fibroblast production of interstitial collagenase, stromelysin-1, and gelatinase A (72-kDa type IV collagenase). We propose that EMMPRIN regulates matrix metalloproteinase production during tumor invasion and other processes involving tissue remodeling.

Hantaviruses replicate primarily in the vascular endothelium and cause two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In this report, we demonstrate that the cellular entry of HFRS-associated hantaviruses is facilitated by specific integrins expressed on platelets, endothelial cells, and macrophages. Infection of human umbilical vein endothelial cells and Vero E6 cells by the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala (PUU) is inhibited by antibodies to alphavbeta3 integrins and by the integrin ligand vitronectin. The cellular entry of HTN, SEO, and PUU viruses, but not the nonpathogenic Prospect Hill (PH) hantavirus (i.e., a virus with no associated human disease), was also mediated by introducting recombinant alphaIIbbeta3 or alphavbeta3 integrins into beta3-integrin-deficient CHO cells. In addition, PH infectivity was not inhibited by alphavbeta3-specific sera or vitronectin but was blocked by alpha5beta1-specific sera and the integrin ligand fibronectin. RGD tripeptides, which are required for many integrin-ligand interactions, are absent from all hantavirus G1 and G2 surface glycoproteins, and GRGDSP peptides did not inhibit hantavirus infectivity. Further, a mouse-human hybrid beta3 integrin-specific Fab fragment, c7E3 (ReoPro), also inhibited the infectivity of HTN, SEO, and PUU as well as HPS-associated hantaviruses, Sin Nombre (SN) and New York-1 (NY-1). These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses enter cells via beta3 integrins, which are present on the surfaces of platelets, endothelial cells, and macrophages. Since beta3 integrins regulate vascular permeability and platelet function, these findings also correlate beta3 integrin usage with common elements of hantavirus pathogenesis.

BACKGROUND: Coronary-artery bypass grafting (CABG) surgery may be performed either with cardiopulmonary bypass (on pump) or without cardiopulmonary bypass (off pump). We report the 5-year clinical outcomes in patients who had been included in the Veterans Affairs trial of on-pump versus off-pump CABG. METHODS: From February 2002 through June 2007, we randomly assigned 2203 patients at 18 medical centers to undergo either on-pump or off-pump CABG, with 1-year assessments completed by May 2008. The two primary 5-year outcomes were death from any cause and a composite outcome of major adverse cardiovascular events, defined as death from any cause, repeat revascularization (CABG or percutaneous coronary intervention), or nonfatal myocardial infarction. Secondary 5-year outcomes included death from cardiac causes, repeat revascularization, and nonfatal myocardial infarction. Primary outcomes were assessed at a P value of 0.05 or less, and secondary outcomes at a P value of 0.01 or less. RESULTS: The rate of death at 5 years was 15.2% in the off-pump group versus 11.9% in the on-pump group (relative risk, 1.28; 95% confidence interval [CI], 1.03 to 1.58; P=0.02). The rate of major adverse cardiovascular events at 5 years was 31.0% in the off-pump group versus 27.1% in the on-pump group (relative risk, 1.14; 95% CI, 1.00 to 1.30; P=0.046). For the 5-year secondary outcomes, no significant differences were observed: for nonfatal myocardial infarction, the rate was 12.1% in the off-pump group and 9.6% in the on-pump group (P=0.05); for death from cardiac causes, the rate was 6.3% and 5.3%, respectively (P=0.29); for repeat revascularization, the rate was 13.1% and 11.9%, respectively (P=0.39); and for repeat CABG, the rate was 1.4% and 0.5%, respectively (P=0.02). CONCLUSIONS: In this randomized trial, off-pump CABG led to lower rates of 5-year survival and event-free survival than on-pump CABG. (Funded by the Department of Veterans Affairs Office of Research and Development Cooperative Studies Program and others; ROOBY-FS ClinicalTrials.gov number, NCT01924442 .).

Overproduction of matrix metalloproteinases (MMPs) is a common characteristic of metastatic cancer cells. Since MMPs can be identified in plasma, we proposed that enhanced MMP-9 secretion by invasive cancer cells may be detected by plasma assay. To this end, we developed a specific sandwich enzyme-linked immunosorbent assay which uses two mouse monoclonal antibodies to human M(r) 92,000 type IV collagenase (MMP-9). The plasma concentration of MMP-9 (mean +/- SD) in 60 healthy subjects (9 +/- 11 ng/ml), 136 patients without cancer, and 179 patients with cancer of the lung, genitourinary tract, or lymphomas-leukemias did not differ significantly. In contrast, plasma MMP-9 was significantly increased (P < 0.01) in 122 patients with gastrointestinal tract cancer and breast cancer (18 +/- 23 and 21 +/- 22 ng/ml, respectively). Whereas carcinoembryonic antigen levels were significantly increased in patients with stage IV gastrointestinal cancer, MMP-9 concentrations were not significantly increased in patients with metastatic disease as compared to those with nonmetastatic cancer. Combining both assays improves sensitivity of detection of colon cancer. MMP-9 was also significantly increased during pregnancy which is consistent with the extensive ongoing tissue remodeling and the leaching of the tissue proteinase into plasma.

The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.

This review considers the feasibility of reducing or eliminating the three major categories of diagnostic errors in medicine: "No-fault errors" occur when the disease is silent, presents atypically, or mimics something more common. These errors will inevitably decline as medical science advances, new syndromes are identified, and diseases can be detected more accurately or at earlier stages. These errors can never be eradicated, unfortunately, because new diseases emerge, tests are never perfect, patients are sometimes noncompliant, and physicians will inevitably, at times, choose the most likely diagnosis over the correct one, illustrating the concept of necessary fallibility and the probabilistic nature of choosing a diagnosis. "System errors" play a role when diagnosis is delayed or missed because of latent imperfections in the health care system. These errors can be reduced by system improvements, but can never be eliminated because these improvements lag behind and degrade over time, and each new fix creates the opportunity for novel errors. Tradeoffs also guarantee system errors will persist, when resources are just shifted. "Cognitive errors" reflect misdiagnosis from faulty data collection or interpretation, flawed reasoning, or incomplete knowledge. The limitations of human processing and the inherent biases in using heuristics guarantee that these errors will persist. Opportunities exist, however, for improving the cognitive aspect of diagnosis by adopting system-level changes (e.g., second opinions, decision-support systems, enhanced access to specialists) and by training designed to improve cognition or cognitive awareness. Diagnostic error can be substantially reduced, but never eradicated.

It has been proposed that tissue inhibitor of metalloproteinase-2 (TIMP-2), in stoichiometric concentrations, serves as an intermediate in progelatinase A activation by binding to activated membrane type 1-matrix metalloproteinase 1 (MT1-MMP) on the plasma membrane. An MT1-MMP-independent cell surface receptor for TIMP-2 has also been postulated. To clarify TIMP-2 binding, we have performed 125I-TIMP-2 binding studies on transfected COS-1 cells and endothelial cells. Specific receptors for TIMP-2 were identified on COS-1 cells transfected with MT1-MMP cDNA, but not on vector-transfected cells. Treatment of MT1-MMP transfected COS-1 cells with a hydroxamic acid inhibitor of MMPs, CT-1746, but not an inactive stereoisomer, CT-1915, produced dose-dependent inhibition of specific TIMP-2 binding comparable with that noted with excess unlabeled TIMP-2. This result suggests that TIMP-2 binds to the zinc catalytic site of MT1-MMP. As demonstrated by the limited competition for binding of C-terminal deleted TIMP-2, the C-terminal domain of TIMP-2 participates in binding to MT1-MMP. Cross-linking studies followed by immunoprecipitation using antibodies to MT1-MMP were employed to identify 125I-TIMP-2.MT1-MMP complexes in MT1-MMP-transfected COS-1 cell membrane extracts. TIMP-2 receptors were also identified on concanavalin A-treated human umbilical vein endothelial cells; inhibition of TIMP-2 binding with CT-1746 was demonstrated.

Surgical specimens of malignant, supratentorial, astrocytic gliomas from 503 patients randomized on an RTOG-ECOG treatment protocol were examined by central pathologic review. The diagnosis of glioblastoma multiforme (GBM) was made only when one or more foci of coagulation necrosis involving astrocytic tumor cells were identified histologically. Malignant astrocytic neoplasms without necrosis were classified as astrocytoma with atypical or anaplastic features (AAF). The median survival stratifying for treatment for patients with GBM was eight months compared to 28 months for patients with AAF. In most cases the specimens were received with a Kernohan grade. On the basis of these grades, patients with astrocytoma Grade 3 had a median survival of ten months as compared to a median survival of nine months for those with astrocytoma Grade 4. Observations demonstrate that necrosis is a reliable, decisive prognostic factor associated with malignant, supratentorial, astrocytic gliomas. The Kernohan system is of limited value in assessing prognosis for this group of tumors.

Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.

Emmprin (basigin;CD147) is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily and is highly enriched on the surface of malignant tumour cells. Emmprin is involved in numerous physiological and pathological systems and exhibits several molecular and cellular characteristics, but a major function of emmprin is stimulation of synthesis of several matrix metalloproteinases. In tumours, emmprin most likely stimulates matrix metalloproteinase production in stromal fibroblasts and endothelial cells as well as in tumour cells themselves by a mechanism involving homophilic interactions between emmprin molecules on apposing cells or on neighbouring cells after membrane vesicle shedding. Membrane-associated cofactors, including caveolin-1 and annexin II, regulate emmprin activity. Emmprin induces angiogenesis via stimulation of VEGF production, invasiveness via stimulation of matrix metalloproteinase production and multidrug resistance via hyaluronan-mediated up-regulation of ErbB2 signaling and cell survival pathway activities. Although the detailed mechanisms whereby it regulates these numerous phenomena are not yet known, it is clear that emmprin is a major mediator of malignant cell behavior.

The balance between production and activation of MMPs and their inhibition by TIMPs is a crucial aspect of cancer invasion and metastasis. On the basis of the concept that MMPs synthesized in tissues seep into the bloodstream, we have examined MMP levels in the plasma of patients with cancer. In colorectal, breast, prostate, and bladder cancer, most patients with aggressive disease have increased plasma levels of gelatinase B. In patients with advanced colorectal cancer, high levels of either gelatinase B or TIMP complex were associated with shortened survival. We propose that these assays may be clinically useful in characterizing metastatic potential in selected kinds of cancer. In rheumatoid arthritis and systemic lupus erythematosus (SLE), serum and plasma levels of stromelysin-1 were approximately 3-5-fold increased. Fluctuating serum stromelysin-1 levels in SLE did not correspond with change in disease activity. In SLE, stromelysin-1 may be a component of the chronic tissue repair process rather than being responsible for inciting tissue damage. On the basis of these observations, we conclude that measurement of plasma/serum MMP and TIMP levels may provide important data for selecting and following patients considered for treatment with drugs that interfere with MMP activity.