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Biomedical subjects

Michael Laposata

Publications and source records attributed to Michael Laposata.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation.

CONTEXT: Leptin is a nutritionally regulated adipocyte-derived cytokine. Previous studies in obese patients have demonstrated increased inflammatory markers and increased platelet aggregation in association with leptin. However, the effects of leptin administration on markers of inflammation and platelet aggregation in a human model of undernutrition have not previously been studied. OBJECTIVE: The objective of the study was to investigate markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation and increased leptin sensitivity. DESIGN: This study was a randomized, placebo-controlled study conducted between November 2002 and November 2003. SETTING: The study was conducted at an inpatient care setting at the General Clinical Research Center. PARTICIPANTS: Twenty healthy, young (18-35 yr old), normal-weight (body mass index, 20-26 kg/m2) women were recruited from local advertisements. No subjects withdrew due to adverse effects. INTERVENTION: The effects of physiological recombinant methionyl human leptin or identical placebo administration were investigated over a 4-d fast. MAIN OUTCOME MEASURES: The primary outcome measures for this study were C-reactive protein (CRP) and indices of platelet activity. RESULTS: Leptin administration prevented the fasting-induced decline in leptin (P < 0.05 vs. placebo at each time point). Leptin administration increased CRP (6.3 +/- 2.4 vs. 0.7 +/- 0.3 mg/liter; P = 0.04), circulating P-selectin (11.6 +/- 10.2 vs. -28.9 +/- 15.6 ng/ml; P = 0.04), and induction of platelet aggregation (5.8 +/- 2.6 vs. -2.7 +/- 2.9%, P = 0.04, percent maximum platelet aggregation) relative to placebo administration (change in leptin vs. change in placebo, respectively, for each variable). Leptin tended to increase serum amyloid A [0.1 +/- 0.2 vs. -0.3 +/- 0.1 log10 (ng/ml); P = 0.07], and the changes in serum amyloid A and CRP were highly correlated (r = 0.83; P < 0.0001). No changes in TNFalpha, IL-6, IL-10, plasminogen activator inhibitor-1, haptoglobin, intercellular adhesion molecule, or vascular cell adhesion molecule were seen between the groups. CONCLUSIONS: Our data provide evidence that physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation.

Adult↗
PubMed2005

Comparison of serum fatty acid ethyl esters and urinary 5-hydroxytryptophol as biochemical markers of recent ethanol consumption.

AIMS: To examine the effects of an acute dose of ethanol on serum fatty acid ethyl esters (FAEEs) concentration and urinary 5-hydroxytryptophol (5-HTOL)/5-hydroxyindole-3-acetic acid (5-HIAA) ratio. METHODS: Sixteen (14 male, 2 female) heavy alcohol drinkers were tested in a single, 2-day long session. Six participants received 1.5 g/l of ethanol/l of body water (approximately 0.75 g/kg of body weight, low dose group: LD) and 10 participants received 2.0 g/l of ethanol ( approximately 1.0 g/kg of body weight, high dose group: HD) in four divided doses every 20 min. Blood, urine, and breath samples were collected repeatedly over 36 h following the ingestion of ethanol and were analyzed for the presence of FAEE, 5-HTOL/5-HIAA, and ethanol, respectively. Serum gamma-glutamyltransferase (GGT), a marker of chronic ethanol use, was also included. RESULTS: The breath ethanol level peaked approximately 1 h after the last dose, at 95 and 120 mg/dl for the LD and HD groups, respectively. The mean ratio of urinary 5-HTOL/5-HIAA was significantly elevated 5 and 9 h after ethanol administration, but returned to baseline 13 h after ethanol administration. This ratio was twice as high for the HD group compared with the LD group. Serum levels of FAEEs were significantly elevated at 5 h, but not 13 h after ethanol administration. There were no time-dependent changes in serum GGT levels. CONCLUSIONS: Measuring the levels of FAEE and 5-HTOL/5-HIAA ratio provides a convenient method to detect recent, particularly binge-type, ethanol use, but these measures may have limited applicability in detecting ethanol use in traditional clinical trial settings.

Adult↗
PubMed2005

Platelet activation in cystic fibrosis.

Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E(1) (PGE(1)). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF.

Adenylyl Cyclases↗
PubMed2005

Fatty acid methyl esters are detectable in the plasma and their presence correlates with liver dysfunction.

BACKGROUND: Methanol is a component of certain alcoholic beverages and is also an endogenously formed product. On this basis, we have proposed that methanol may promote synthesis of fatty acid methyl esters (FAMEs) in the same way that ethanol promotes fatty acid ethyl ester (FAEE) synthesis. We tested the hypothesis that FAMEs appear in the blood after ethanol intake. METHODS: Patient plasma samples obtained from our laboratory (n=78) were grouped according to blood ethanol concentrations (intoxicated, blood ethanol >800 mg/l) and non-intoxicated. These samples were further subdivided into groups based on whether the patient had normal or abnormal liver function tests (abnormal, defined as > or =1 abnormality of plasma alanine and aspartate aminotransferase, albumin, total bilirubin, and alkaline phosphatase). A separate set of plasma samples were also divided into normal and abnormal groups based on pancreatic function tests (amylase and lipase). There were no patients with detectable ethanol in this group. Patients with abnormalities in pancreatic function tests were included upon recognition of endogenously produced FAMEs by patients with liver function test abnormalities. FAMEs were extracted from plasma and individual species of FAMEs quantified by gas chromatography-mass spectrometry (GC/MS). RESULTS: Increased concentrations of FAME were found in patient samples with evidence of liver dysfunction, regardless of whether or not they were intoxicated (n=21, p=0.01). No significant differences in plasma FAME concentrations were found between patients with normal (n=15) versus abnormal pancreatic function tests (n=22, p=0.72). CONCLUSIONS: The presence of FAMEs in human plasma may be related to the existence of liver disease, and not to blood ethanol concentrations or pancreatic dysfunction. The metabolic pathways associated with FAME production in patients with impaired liver function remain to be identified.

Esters↗
PubMed2005

Ethanol administration to cystic fibrosis knockout mice results in increased fatty acid ethyl ester production.

BACKGROUND: Fatty acid ethyl esters (FAEE) are nonoxidative ethanol metabolites shown to produce toxic effects in the liver and pancreas in vivo and in vitro. Because alcohol-induced chronic pancreatitis is associated with mutations in the gene responsible for cystic fibrosis (CFTR), we hypothesized that CFTR dysfunction leads to increased levels of these toxic nonoxidative ethanol metabolites following alcohol administration. METHODS: Cystic fibrosis (CF) and wild-type (WT) mice were injected intraperitoneally with 1, 2, or 3 g/kg of 50% ethanol. Mice were sacrificed and the liver and pancreas removed for FAEE analysis. RESULTS: The mean FAEE concentration (pmol/g) detected in the liver of cftr mice following injection with 2 g/kg of ethanol was significantly greater than the amount detected in WT (p < 0.005). A similar trend in FAEE concentration was seen in the pancreas, but the difference was not statistically different. In both the liver and pancreas, analysis of individual FAEE species demonstrated a selective increase in ethyl oleate. CONCLUSION: These data show an association between CFTR dysfunction and qualitative and quantitative changes in FAEE in liver and pancreas upon ethanol exposure.

Animals↗
PubMed2005

Aspirin resistance: moving forward with multiple definitions, different assays, and a clinical imperative.

Many patients are treated with aspirin to prevent a serious vascular event, most notably myocardial infarction and stroke. A growing number of studies have been appearing in the literature that indicate a significant fraction of aspirin-treated patients may be resistant to the antiplatelet effects of the drug. Resistance to aspirin may be related to the concomitant ingestion of aspirin and nonsteroidal anti-inflammatory drugs, which impairs the aspirin effect, or to more complex situations, such as metabolic defects that diminish the therapeutic effect of aspirin. The incidence of aspirin resistance is unknown, but it may approach 20% to 30%. The diagnosis of aspirin resistance has been evaluated using multiple assays, and because there are multiple assays, this has resulted in multiple definitions for aspirin resistance. This review considers aspirin resistance at a time when there is confusion about the definition, and the clinical assay to best assess it, because there is a clinical imperative to know now which patients taking aspirin are not receiving a therapeutic effect.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Effects of alcohol on hemostasis.

Several epidemiologic studies have shown that moderate intake of alcohol is associated with a lower risk of cardiovascular disease (CVD), but the mechanism is not fully elucidated. One of the proposed mechanisms of the protective effect of moderate alcohol intake is its beneficial effect on hemostasis. The aim of this review is to summarize the effect of ethanol intake on platelet aggregation and activation, coagulation factors including von Willebrand factor (vWF), and the fibrinolytic system. With regard to the effect of alcohol on platelet function, evidence in the literature suggests both platelet activation and platelet inhibition by ethanol. A unifying hypothesis is that platelets are partially activated by ethanol, with partial degranulation allowing for continued circulation of platelets with impaired function. Evidence also exists showing that ethanol intake decreases fibrinogen, factor VII, and vWF levels. In addition, alcohol intake has been found to increase fibrinolysis by increasing tissue plasminogen activator activity. The effect of ethanol on platelets, coagulation factors, and the fibrinolytic system is likely to contribute to protection against CVD.

Cerebrovascular Disorders↗
PubMed2005

Children with signs of abuse: when is it not child abuse?

Child abuse is a problem that is frequently underdiagnosed. Recognition that underdiagnosis of abuse exists has produced a high zeal for identifying cases of child abuse, which has inevitably produced cases of overdiagnosis. Overdiagnosis of child abuse is as catastrophic as underdiagnosis. In this case, a family member is often accused of injuring or killing a child at a time when the loss is felt most deeply. This review focuses on 1 specific presentation of child abuse--the child with bruises and bleeding. Many children and adults have coagulation or vascular disorders that predispose them to bruise or bleed excessively with minor trauma. It is very easy for a health care worker to presume that bruising and bleeding is associated with trauma, because the coagulopathies that may explain the findings are often poorly understood. The clinical cases reviewed in this article show the need for an extremely thorough analysis for an underlying bleeding disorder in the bruised or bleeding child being evaluated as a possible victim of child abuse.

Blood Coagulation Disorders↗
PubMed2004

Association of cystic fibrosis with abnormalities in fatty acid metabolism.

BACKGROUND: Patients with cystic fibrosis have altered levels of plasma fatty acids. We previously demonstrated that arachidonic acid levels are increased and docosahexaenoic acid levels are decreased in affected tissues from cystic fibrosis-knockout mice. In this study we determined whether humans with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have a similar fatty acid defect in tissues expressing CFTR. METHODS: Fatty acids from nasal- and rectal-biopsy specimens, nasal epithelial scrapings, and plasma were analyzed from 38 subjects with cystic fibrosis and compared with results in 13 obligate heterozygotes, 24 healthy controls, 11 subjects with inflammatory bowel disease, 9 subjects with upper respiratory tract infection, and 16 subjects with asthma. RESULTS: The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects. In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease in docosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acid was increased in subjects with cystic fibrosis (P<0.001), as compared with healthy controls, with values in obligate heterozygotes intermediate between these two groups (P<0.001). The ratio was not increased in subjects with inflammatory bowel disease. Subjects with asthma and those with upper respiratory tract infection had values intermediate between those in subjects with cystic fibrosis and those in healthy control subjects. CONCLUSIONS: These data indicate that alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.

Arachidonic Acid↗
PubMed2004

Oral docosahexaenoic acid given to pregnant mice increases the amount of surfactant in lung and amniotic fluid in preterm fetuses.

OBJECTIVE: Our purpose was to determine whether docosahexaenoic acid increased surfactant production, as reflected by increased dipalmitoyl phosphatidylcholine, in mouse fetal lung and amniotic fluid. STUDY DESIGN: On day 9.5 of gestation, pregnant mice were given docosahexaenoic acid orally at 0, 5, 10, or 20 mg per day and were killed at day 16.5 (preterm) and day 19.5 (term) of gestation. Dipalmitoyl phosphatidylcholine was measured in fetal lung homogenates and amniotic fluid by high-performance thin-layer chromatography. RESULTS: Dipalmitoyl phosphatidylcholine values in lung were 0.22 +/- 0.27 microg/mg of total protein in preterm versus 1.96 +/- 0.57 microg/mg in term control fetuses. Pretreatment with 5, 10, or 20 mg docosahexaenoic acid increased dipalmitoyl phosphatidylcholine levels in preterm fetuses to 1.20 +/- 0.75, 1.60 +/- 0.67, and 3.28 +/- 0.44 microg/mg of protein, respectively. A similar trend was observed in amniotic fluid in which dipalmitoyl phosphatidylcholine levels were 1.86 +/- 3.70 microg/mL in preterm fetuses at baseline and increased to 7.81 +/- 1.21, 16.83 +/- 1.62 and 22.72 +/- 3.44 microg/mL after pretreatment for 7 days with 5, 10, and 20 mg docosahexaenoic acid (P<.05 compared to untreated mice). Dipalmitoyl phosphatidylcholine levels in amniotic fluid were 24.46 +/- 10.3 microg/mL in term control mice. CONCLUSION: The oral administration of docosahexaenoic acid to pregnant mice during pregnancy can induce dipalmitoyl phosphatidylcholine production and secretion, which is the major lipid component of surfactant.

Administration, Oral↗
PubMed2004

Prothrombin gene mutation G20210A, homocysteine, antiphospholipid antibodies and other hypercoagulable states in ocular thrombosis.

The purpose of the present study was to determine whether using an extended panel of laboratory tests increases the detection of a hypercoagulable state in patients with ocular thromboses. Twenty consecutive patients with ocular thromboses (vein, artery, or choriocapillaris occlusions) underwent testing for activated protein C resistance/factor V Leiden, prothrombin G20210A, lupus anticoagulant, anticardiolipin antibodies, hyperhomocysteinemia, and deficiencies of protein C, protein S, and antithrombin. For each patient, we selected two age-matched and gender-matched individuals without ocular thromboses as controls. Sixteen of the 20 patients (80%) had one or more laboratory tests that supported a hypercoagulable condition. Prothrombin G20210A (P < 0.02) and hyperhomocysteinemia (P < 0.0006) were significantly more frequent in ocular thrombosis patients compared with controls. The most common condition was antiphospholipid antibody syndrome, present in 40% of patients (confirmed by repeat testing at least 6 weeks later), but this did not reach statistical significance compared with the controls. No patients with ocular thromboses had hereditary abnormalities of protein S, protein C, or antithrombin. In conclusion, an extended panel of laboratory tests improved the detection of a hypercoagulable state in ocular thromboses. Testing for homocysteine, antiphospholipid antibodies, and the prothrombin G20210A mutation should be considered in patients with ocular thromboses.

Activated Protein C Resistance↗
PubMed2004

Physician survey of a laboratory medicine interpretive service and evaluation of the influence of interpretations on laboratory test ordering.

CONTEXT: Complex coagulation test panels ordered by clinicians are typically reported to clinicians without a patient-specific interpretive paragraph. OBJECTIVES: To survey clinicians regarding pathologist-generated interpretations of complex laboratory testing panels and to assess the ability of the interpretations to educate test orderers. DESIGN: Surveys were conducted of physicians ordering complex coagulation laboratory testing that included narrative interpretation. Evaluation of order requisitions was performed to assess the interpretation's influence on ordering practices. SETTING: Physicians ordering coagulation testing at a large academic medical center hospital in Boston, Mass, and physicians from outside hospitals using the academic medical center as a reference laboratory for coagulation testing. OUTCOME MEASURES: Physician surveys and evaluation of laboratory requisition slips. RESULTS: In nearly 80% of responses, the ordering clinicians perceived that the interpretive comments saved them time and improved the diagnostic process. Moreover, the interpretations were perceived by ordering clinicians to help prevent a misdiagnosis or otherwise impact the differential diagnosis in approximately 70% of responses. In addition, interpretations appeared to be able to train the ordering clinicians as to the standard ordering practices. CONCLUSIONS: The results demonstrate physician satisfaction with an innovative information delivery approach that provides laboratory diagnostic interpretation and test-ordering education to clinicians in the context of their daily workflow.

Academic Medical Centers↗
PubMed2003

Red blood cell fatty acid ethyl esters: a significant component of fatty acid ethyl esters in the blood.

Although alcohol abuse is known to cause an array of ethanol-induced red blood cell (RBC) abnormalities, the underlying molecular mechanisms remain poorly understood. Fatty acid ethyl esters (FAEEs) are toxic, nonoxidative ethanol metabolites that have been found in blood, plasma, and tissues. Because FAEEs have been shown to be incorporated into phospholipid bilayers, we conducted a controlled ethanol intake study to test the hypothesis that FAEEs accumulate and persist within RBCs following ethanol ingestion. We demonstrated that RBC FAEEs account for approximately 5% to 20% of total whole-blood FAEEs, and that the fatty acid composition of FAEEs in RBCs and plasma are different and vary differently over time. These data indicate that a significant percentage of FAEEs in the blood is associated with RBCs and that the metabolism of RBC FAEEs and that of plasma FAEEs (bound to albumin or lipoproteins) are largely independent.

Adult↗
PubMed2003

Fatty acid ethyl esters: toxic non-oxidative metabolites of ethanol and markers of ethanol intake.

This report describes the biochemistry of fatty acid ethyl esters (FAEE), non-oxidative metabolites of ethanol, and their clinical significance. We review information regarding the enzymes responsible for FAEE synthesis and degradation, and the mechanisms involved with the intracellular and extracellular transport of FAEE and FAEE-mediated cytotoxicity. Also a summary of reports on the emerging clinical significance and diagnostic utility of FAEE as short and long-term markers of alcohol consumption, and the methodological aspects of FAEE assessment is included.

Alcohol Drinking↗
PubMed2003

Stearic acid stimulates FA ethyl ester synthesis in HepG2 cells exposed to ethanol.

FA ethyl esters (FAEE) are nonoxidative metabolites of ethanol produced by the esterification of FA and ethanol. FAEE have been implicated as mediators of ethanol-induced organ damage in vivo and in vitro, and are markers of ethanol intake. Upon ethanol intake, FAEE are synthesized in the liver and pancreas in significant quantities. There is limited information on the stimulation of FAEE synthesis upon addition of exogenous FA in vitro. HepG2 cells were incubated with ethanol alone, ethanol with 25 microM linoleate, and ethanol with 25 microM stearate. The amount of FAEE in human hepatoblastoma (HepG2) cells was determined 1-3 h after ethanol and FA addition. Stearate increased the FAEE concentration in HepG2 cells when incubated with the cells for 1 h, whereas linoleate did not increase the cellular FAEE concentration at any time. Ethyl palmitate, ethyl stearate, and ethyl oleate were the predominant FAEE species identified in all cases, independent of the specific supplemental FA added to the medium.

Carcinoma, Hepatocellular↗
PubMed2003

Antiphospholipid antibody syndrome in a six-year-old female patient.

PURPOSE: To report the first instance of primary antiphospholipid antibody (APA) syndrome in an otherwise healthy 6-year-old female patient with retinal venous thromboses. DESIGN: Observational case report. METHODS: A 6-year-old girl with poor vision in the left eye and preretinal hemorrhage underwent testing for infectious, autoimmune and embolic disease, diabetes, and hypertension. Testing for factor V Leiden and prothrombin G20210A mutations, homocysteine, anticardiolipin antibodies (ACAs), lupus anticoagulant, and functional assays for protein S, protein C, and antithrombin III were performed to detect a hypercoagulable state. No IRB approval was necessary. RESULTS: Only a positive lupus anticoagulant and moderately elevated ACA IgG were found. The ACA IgG was moderately elevated on repeat testing 18 months later. Laser to nonperfused retina caused some regression of retinal neovascularization. Aspirin was recommended to reduce the risk of future thromboses. CONCLUSIONS: Although uncommon, retinovascular thrombosis in children can occur in APA syndrome. Testing for ACA and lupus anticoagulant should be considered.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Assessment of the stability of dalteparin sodium in prepared syringes for up to thirty days: an in vitro study.

BACKGROUND: If a low-molecular-weight heparin (LMWH) injectable formulation maintains its stability for up to 30 days, substantial cost reductions in hospital stay could be achieved with its use on an outpatient basis in patients who might otherwise be treated with IV heparin as inpatients. OBJECTIVE: This study was designed to assess the stability for up to 30 days of injectable solutions of the LMWH dalteparin sodium when repackaged in plastic syringes. METHODS: In the first part of the study, 1-mL and 3-mL plastic syringes were filled with the contents of a 10,000-IU/mL dalteparin ampule or a 25,000-IU/mL dalteparin multidose vial. In a separate part of the study, 1-mL and 3-mL syringes were filled with doses of 7500 IU and 10,000 IU, respectively, from a 10,000-IU/mL multidose vial. After the syringes were brought to room temperature or 4 degrees C, the stability of dalteparin was assessed over 30 days by measuring anti-factor Xa levels. RESULTS: No significant loss of dalteparin activity was found for up to 30 days in the syringes after storage at room temperature or 4 degrees C. The solutions retained anti-factor Xa activity at room temperature and under refrigeration. CONCLUSION: Dalteparin is stable for up to 30 days when stored at room temperature or 4 degrees C. The findings suggest that preparation of a postdischarge supply of dalteparin is feasible, contributing to more convenient and effective management of outpatients at risk for thrombotic complications.

Anticoagulants↗