Robert Hunter

TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte alpha-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1-/- mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1-/- mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1-/- mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.

Differences in prescription of antiretroviral therapy in a large cohort of HIV-infected patients.

The objective of this study was to determine factors associated with prescription of highly active antiretroviral therapy (HAART). The authors observed 9530 patients eligible for antiretroviral therapy (ART) in more than 100 hospitals and clinics in 10 US cities. Multiple logistic regression analysis was used to assess factors associated with HAART prescription, stratifying patients by no history versus history of ART to assess the association between prescription and CD4, viral load, and outpatient visits. Overall, female gender (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.60–0.76) and alcoholism (OR, 0.85; 95% CI, 0.74–0.99) were associated with decreased likelihood of HAART prescription. Enrollment at a private facility (OR, 1.33; 95% CI, 1.14–1.56), heterosexual exposure (OR, 1.34; 95% CI, 1.13–1.58), and Hispanic ethnicity (OR, 1.19; 95% CI, 1.04–1.37) were associated with prescription. For patients with no history of prescribed ART, CD4 <500 cells/&mgr;L (OR, 3.94; 95% CI, 2.02–7.66), and high viral load were associated with increased likelihood of prescription; for patients with history of ART prescription, those whose outpatient visits averaged ≥2 per 6-month interval (OR, 1.30; 95% CI, 1.10–1.54) were more likely and those with high viral load were less likely to be prescribed HAART (OR, 0.50; 95% CI, 0.44–0.56). The authors found differences in HAART prescription by gender, race, exposure mode, alcoholism, and provider type for all patients, by CD4 and viral load for patients with no history of ART prescription, and by average number of outpatient visits and viral load for patients with history of ART prescription.

The shape of the HIV/AIDS epidemic in Puerto Rico

This study presents information on AIDS patients in Puerto Rico, including their general sociodemographic profile, some risk-related parameters, characteristics of vulnerable groups, and elements of the clinical spectrum of the disease. Data were analyzed from the Puerto Rico AIDS Surveillance Program and available studies about the HIV/AIDS epidemic in Puerto Rico. A total of 23,089 AIDS cases was reported to the Puerto Rico AIDS Surveillance Program from January 1981 through February 1999. The HIV/AIDS epidemic has affected mostly males and females between the ages of 30 and 49, though cases have also been reported for other age groups. The cumulative proportion of persons with AIDS who are women has increased tremendously, from 11.4% for the 1981-1986 period to 21.6% for the entire 1981-1999 period. In Puerto Rico the category of injecting drug users (IDUs) accounts for the majority of the AIDS cases (52%), followed by heterosexual contact (22%), and men who have sex with men (17%). The three main diagnoses for AIDS on the island are wasting syndrome (30.7%); esophageal, bronchial, and lung candidiasis (29.4%); and Pneumocystis carinii pneumonia (26.8%). According to 1994 vital statistics for Puerto Rico, AIDS was the fourth-leading cause of death. The overall reported AIDS mortality rate was 42.0 per 100,000 persons, with the rate for males, 67.8, much higher than it was for females, 17.4. AIDS is the first cause of death among persons between 30 and 39 years old. Intense efforts are needed to better understand the epidemic in Puerto Rico and its biology, social and family impacts, and financial costs.

Soluble TLT-1 modulates platelet-endothelial cell interactions and actin polymerization.

Triggering receptor expressed on myeloid cells (TREM) like transcript-1 (TLT-1) is a membrane protein receptor found in α-granules of platelets and megakaryocytes. Upon platelet activation TLT-1 is rapidly brought to the surface of platelets. Recently, we demonstrated that activated platelets release a soluble form of TLT-1 (sTLT-1) that is found in serum but not in the plasma of healthy individuals and can enhance platelet aggregation in vitro. Furthermore, evaluation of patients diagnosed with inflammatory diseases, such as sepsis, show that these patients have significantly elevated levels of sTLT-1 in their blood. Accordingly, mice deficient in TLT-1 are predisposed to bleeding in response to an inflammatory challenge; however, the mechanism of TLT-1 function remains unknown. In this investigation, we demonstrate an increase in the amount of platelets that adhere to endothelial cell monolayers in the presence of recombinant sTLT-1 (rsTLT-1). Additionally, we present evidence that rsTLT-1 increases platelet adherence to glass slides by stimulating actin polymerization in platelets, as determined by increased staining of rodamine phalloidin. These results suggest that during inflammation, sTLT-1 may mediate hemostasis by enhancing actin polymerization, resulting in increased platelet aggregation and adherence to the endothelium.

Efficacy of a food safety comic book on knowledge and self-reported behavior for persons living with AIDS.

Introduction Persons living with AIDS are highly vulnerable to foodborne enteric infections with the potential for substantial morbidity and mortality. Educational materials about foodborne enteric infections intended for this immunocompromised population have not been assessed for their efficacy in improving knowledge or encouraging behavior change. Methods/Results AIDS patients in four healthcare facilities in Chicago, New Orleans, and Puerto Rico were recruited using fliers and word of mouth to healthcare providers. Those who contacted research staff were interviewed to determine food safety knowledge gaps and risky behaviors. A food safety educational comic book that targeted knowledge gaps was created, piloted, and provided to these patients who were instructed to read it and return at least 2 weeks later for a follow-up interview. The overall food safety score was determined by the number of the 26 knowledge/belief/behavior questions from the survey answered correctly. Among 150 patients who participated in both the baseline and follow-up questionnaire, the intervention resulted in a substantial increase in the food safety score (baseline 59%, post-intervention 81%, p<0.001). The intervention produced a significant increase in all the food safety knowledge, belief, and behavior items that comprised the food safety score. Many of these increases were from baseline knowledge below 80 percent to well above 90%. Most (85%) of the patients stated they made a change to their behavior since receiving the educational booklet. Conclusion This comic book format intervention to educate persons living with AIDS was highly effective. Future studies should examine to what extent long-term behavioral changes result.

Levels of soluble TREM-like transcript 1 in patients presenting to the emergency department with chest pain.

Objective: Recent studies suggest that the soluble triggering receptor expressed on myeloid cells-like transcript 1 (sTLT-1) facilitate atherothrombosis. Therefore, we evaluated sTLT-1 as a functional measure of atherothrombosis in acute coronary syndrome (ACS). Methods: Levels of sTLT-1 were determined by enzyme-linked immunosorbent assay on plasma from patients with potential ACS and compared with an age-matched control group with similar risk factors for cardiovascular disease. Results: Of 53 patients enrolled, 19 patients were undergoing ACS (15 unstable angina, 2 non–ST-segment elevated myocardial infarction, and 2 ST-segment elevated myocardial infarction), 5 patients were found with noncardiac chest pain, and 29 were in the control group. The mean plasma sTLT-1 values in the ACS group were 4.644 ng/mL ± 1.277 standard error of the mean (SEM), in the noncardiac chest pain group were 0.708 ng/mL ± 0.427 SEM, and in the control group were 1.007 ng/mL ± 0.098 SEM. Conclusion: A statistically significant difference exists between patients experiencing cardiogenic chest pain versus controls (P < .05), suggesting sTLT-1 as a potential tool for understanding atherothrombosis in ACS.

TLT-1 is a Prognostic Indicator in ALI/ARDS and Prevents Tissue Damage in the Lungs in a Mouse model

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (P < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor (P < .0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition, and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73 ± 24.75% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (P ≤ .001) and tissue damage by 25% (P ≤ .001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS.