PM2.5-Bound Organophosphate Flame Retardants in Hong Kong: Occurrence, Origins, and Source-Specific Health Risks.

Organophosphate flame retardants (OPFRs) are emerging organic pollutants in PM2.5, which have caused significant public health concerns in recent years, given their potential carcinogenic and neurotoxic effects. However, studies on the sources, occurrence, and health risk assessment of PM2.5-bound OPFRs in Hong Kong are lacking. To address this knowledge gap, we characterized 13 OPFRs in one-year PM2.5 samples using gas chromatography-atmospheric pressure chemical ionization tandem mass spectrometry. Our findings showed that OPFRs were present at a median concentration of 4978 pg m-3 (ranging from 1924 to 8481 pg m-3), with chlorinated OPFRs dominating and accounting for 82.7% of the total OPFRs. Using characteristic source markers and positive matrix factorization, we identified one secondary formation and five primary sources of OPFRs. Over 94.0% of PM2.5-bound OPFRs in Hong Kong were primarily emitted, with plastic processing and waste disposal being the leading source (61.0%), followed by marine vessels (14.1%). The contributions of these two sources to OPFRs were more pronounced on days influenced by local pollution emissions (91.9%) than on days affected by regional pollution (44.2%). Our assessment of health risks associated with human exposure to PM2.5-bound OPFRs indicated a low-risk level. However, further source-specific health risk assessment revealed relatively high noncarcinogenic and carcinogenic risks from chlorinated OPFRs emitted from plastic processing and waste disposal, suggesting a need for more stringent emission control of OPFRs from these sources in Hong Kong.

Interleukins 4 and 21 Protect Anti-IgM Induced Cell Death in Ramos B Cells: Implication for Autoimmune Diseases.

Interleukins 4 (IL-4) and 21 (IL-21) belong to the common gamma chain cytokine family which are highly involved in the progression of autoimmune diseases. While IL-4 is well known to be involved in the suppression of apoptosis of autoreactive B cells, the role played by IL-21 remains unclear. In the current study, we activated the human Burkitt's lymphoma Ramos B cells with anti-IgM to mimic B cell hyperactivation observed in patients of autoimmune diseases. Consistent with other reported findings, anti-IgM led to the downregulation of proteins involved in B cell survival and proliferation, as well as the activation of caspase 3 activity and DNA damage, resulting in apoptotic cell death after 48-hour treatment. Although both IL-4 and IL-21 reversed anti-IgM-induced apoptosis and cell cycle arrest, they did so via different mechanisms: while IL-4 could directly suppress anti-IgM-induced caspase 3 activation and marker indicative of DNA damage, IL-21 could induce B cell proliferation in the presence of anti-IgM. Importantly, IL-21 also suppressed activation induced cell death in human primary B cells. Pre-treatment with clinically validated JAK inhibitors completely reversed the effects of IL-4 and IL-21 to rescue anti-IgM induced cell death and DNA damage. The results indicate the underlying mechanisms of how IL-4 and IL-21 differentially promote survival of hyperactivated B cells and provide hints to treat autoimmune diseases.

In Vivo Genome-Wide CRISPR Activation Screening Identifies Functionally Important Long Noncoding RNAs in Hepatocellular Carcinoma.

BACKGROUND & AIMS: Long noncoding RNAs (lncRNAs) are found to have profound impacts on diverse cellular processes. Although high-throughput sequencing studies have shown the differential lncRNA expression profiles between hepatocellular carcinoma (HCC) and nontumor livers, the functional impacts of lncRNAs on HCC development await further investigation. Herein, we sought to address the functional roles of lncRNAs in HCC pathogenesis by in vivo functional screening. METHODS: We performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/dead CRISPR-associated protein 9 (dCas9) lncRNA activation screening in HCC xenografts. We characterized the clinical relevance of positively selected lncRNAs using transcriptomic data sets. We used CRISPR-based gene activation and knockdown approaches to show the functional roles of positively selected lncRNAs including Cancer Susceptibility 11 (CASC11) in HCC. RNA sequencing and chromatin isolation by RNA purification sequencing were used to investigate the molecular mechanisms of CASC11 in HCC progression. RESULTS: The in vivo functional screening identified 1603 positively selected lncRNAs, 538 of which were overexpressed in HCC patients. Systematic transcriptomic data analysis and clinical investigation showed that patients with high expression of these lncRNA candidates correlated with aggressive tumor behaviors. Overexpression of these lncRNAs aggravated HCC cell growth. Detailed characterization of a lncRNA candidate, CASC11, showed its pivotal role in cell proliferation and tumor growth. Mechanistically, chromatin isolation by RNA purification sequencing showed that CASC11 was bound to the CASC11/MYC proto-oncogene shared promoter region on chromosome 8q24. CASC11 modulated the transcriptional activity of MYC in a cis-regulatory manner, which affected the expression of MYC downstream target genes, consequently promoting G1/S progression. CONCLUSIONS: Our study showed the power of in vivo CRISPR screening, which comprehensively investigated the functionality of lncRNAs in HCC progression, providing a rationale for targeting these lncRNAs clinically.

Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer.

Hypoxia, low oxygen (O2), is a key feature of all solid cancers, including hepatocellular carcinoma (HCC). Genome-wide CRISPR-Cas9 knockout library screening is used to identify reliable therapeutic targets responsible for hypoxic survival in HCC. We find that protein-tyrosine phosphatase mitochondrial 1 (PTPMT1), an important enzyme for cardiolipin (CL) synthesis, is the most significant gene and ranks just after hypoxia-inducible factor (HIF)-1α and HIF-1ß as crucial to hypoxic survival. CL constitutes the mitochondrial membrane and ensures the proper assembly of electron transport chain (ETC) complexes for efficient electron transfer in respiration. ETC becomes highly unstable during hypoxia. Knockout of PTPMT1 stops the maturation of CL and impairs the assembly of ETC complexes, leading to further electron leakage and ROS accumulation at ETC in hypoxia. Excitingly, HCC cells, especially under hypoxic conditions, show great sensitivity toward PTPMT1 inhibitor alexidine dihydrochloride (AD). This study unravels the protective roles of PTPMT1 in hypoxic survival and cancer development.

Secretome from hypoxia-conditioned adipose-derived mesenchymal stem cells promotes the healing of gastric mucosal injury in a rodent model.

Studies have indicated that the definitive engraftment and transdifferentiation potential of stem cells do not seem crucial for its property of tissue repair. Our previous study showed that transplantation of adipose-derived mesenchymal stem cells (ADMSCs) enhanced the healing of sutured gastric perforation. This study aimed to investigate the paracrine role of ADMSCs in the experimental gastric mucosal injury. Normoxia-conditioned medium (Nor CM) and hypoxia (HPO) CM were obtained after culturing ADMSCs in 20% O2 and 5% O2 for 48h. Cell migration, proliferation, viability, and angiogenesis in vitro were significantly enhanced upon incubation with CM, especially the HPO CM. Experiments in vivo using a rodent model of gastric ulcer demonstrated that HPO CM treatment significantly accelerated wound healing by suppressing inflammation and promoting neovascularization and re-epithelization. Meanwhile, the infusion of HPO CM activated the COX2-PGE2 axis both in vitro and in vivo. And the upregulation of COX2 was further dependent on the activation of ErK1/2-MAPK pathway. In addition, vascular endothelial growth factor, tissue inhibitors of metalloproteinases-1, and chemokine (C-C motif) ligand 20 (CCL-20) were analyzed as being highly abundant factors secreted by ADMSCs under hypoxic condition. Notably, the blockade of CCL-20 abrogated the HPO CM-induced COX2 signaling in the primary gastric mucosal epithelial cells, while incubation with recombinant CCL-20 increased the expression of COX2. In conclusion, the secretome from hypoxia-conditioned ADMSCs facilitates the repair of gastric mucosal injury through the enhancement of angiogenesis and re-epithelization, as well as the activation of COX2-PGE2 axis with a paracrine activity involving CCL-20 factor.

Varieties, production, composition and health benefits of vinegars: A review.

Vinegars are liquid products produced from the alcoholic and subsequent acetous fermentation of carbohydrate sources. They have been used as remedies in many cultures and have been reported to provide beneficial health effects when consumed regularly. Such benefits are due to various types of polyphenols, micronutrients and other bioactive compounds found in vinegars that contribute to their pharmacological effects, among them, antimicrobial, antidiabetic, antioxidative, antiobesity and antihypertensive effects. There are many types of vinegars worldwide, including black vinegar, rice vinegar, balsamic vinegar and white wine vinegar. All these vinegars are produced using different raw materials, yeast strains and fermentation procedures, thus giving them their own unique tastes and flavours. The main volatile compound in vinegar is acetic acid, which gives vinegar its strong, sour aroma and flavour. Other volatile compounds present in vinegars are mainly alcohols, acids, esters, aldehydes and ketones. The diversity of vinegars allows extensive applications in food.

Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

The aqueous extract of rhizome of Gastrodia elata Blume attenuates locomotor defect and inflammation after traumatic brain injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism. MATERIALS AND METHODS: Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7. RESULTS: GE treatment significantly improved the impaired locomotor functions induced by TBI. GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed. CONCLUSIONS: GE treatment attenuated the locomotor deficit caused by TBI. The anti-inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain.

Non-Neuronal Cells Are Required to Mediate the Effects of Neuroinflammation: Results from a Neuron-Enriched Culture System.

Chronic inflammation is associated with activated microglia and reactive astrocytes and plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's. Both in vivo and in vitro studies have demonstrated that inflammatory cytokine responses to immune challenges contribute to neuronal death during neurodegeneration. In order to investigate the role of glial cells in this phenomenon, we developed a modified method to remove the non-neuronal cells in primary cultures of E16.5 mouse cortex. We modified previously reported methods as we found that a brief treatment with the thymidine analog, 5-fluorodeoxyuridine (FdU), is sufficient to substantially deplete dividing non-neuronal cells in primary cultures. Cell cycle and glial markers confirm the loss of ~99% of all microglia, astrocytes and oligodendrocyte precursor cells (OPCs). More importantly, under this milder treatment, the neurons suffered neither cell loss nor any morphological defects up to 2.5 weeks later; both pre- and post-synaptic markers were retained. Further, neurons in FdU-treated cultures remained responsive to excitotoxicity induced by glutamate application. The immunobiology of the FdU culture, however, was significantly changed. Compared with mixed culture, the protein levels of NFκB p65 and the gene expression of several cytokine receptors were altered. Individual cytokines or conditioned medium from ß-amyloid-stimulated THP-1 cells that were, potent neurotoxins in normal, mixed cultures, were virtually inactive in the absence of glial cells. The results highlight the importance of our glial-depleted culture system and identifies and offer unexpected insights into the complexity of -brain neuroinflammation.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension.

AIMS: To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. METHODS AND RESULTS: A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were -28, -27, -27, and -28%; and in apolipoprotein B -29, -28, -30, and -31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6-12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. CONCLUSION: Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. CLINICALTRIALS.GOV: NCT00694109.

The interaction of the atm genotype with inflammation and oxidative stress.

In ataxia-telangiectasia (A-T) the death of neurons is associated with the loss of neuronal cell cycle control. In most Atm(-/-) mouse models, however, these cell cycle anomalies are present but the phenotype of neuronal cell loss found in humans is not. Mouse Atm(-/-) neurons re-enter a cell cycle and replicate their DNA, but they do not die--even months after initiating the cycle. In the current study, we explore whether systemic inflammation or hypoxia-induced oxidative stress can serve as second stressors that can promote cell death in ATM-deficient neurons. We find that after either immune or hypoxic challenge, the levels of cell cycle proteins--PCNA, cyclin A and cyclin B--are significantly elevated in cerebellar Purkinje cells. Both the number of cells that express cell cycle proteins as well as the intensity of the expression levels in each cell is increased in the stressed animals. The cell cycle-positive neurons also increasingly express cell death markers such as activated caspase-3, γ-H2AX and TUNEL staining. Interestingly, nuclear HDAC4 localization is also enhanced in Atm(-/-) Purkinje neurons after the immune challenge suggesting that both genetic and epigenetic changes in Atm(-/-) mice respond to environmental challenges. Our findings support the hypothesis that multiple insults are needed to drive even genetically vulnerable neurons to die a cell cycle-related cell death and point to either inflammation or oxidative stressors as potential contributors to the A-T disease process.

Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: This study sought to examine the efficacy and safety of mipomersen for reducing atherogenic lipids and lipoproteins in patients with hypercholesterolemia. BACKGROUND: Many patients on lipid-lowering therapies remain unable to achieve target low-density lipoprotein (LDL) cholesterol levels. Mipomersen, an antisense oligonucleotide inhibitor of apolipoprotein B, reduces LDL cholesterol and atherogenic lipoproteins. METHODS: This randomized, double-blind, multicenter study enrolled 158 patients with baseline LDL cholesterol levels ≥100 mg/dl with, or at high risk for, coronary heart disease who were receiving maximally tolerated lipid-lowering therapy. Patients received weekly subcutaneous mipomersen 200 mg (n = 105) or placebo (n = 52) for 26 weeks, with a 24-week follow-up period. Randomization was stratified by type 2 diabetes status. RESULTS: Sixty mipomersen and 44 placebo patients completed treatment. Mean baseline LDL cholesterol levels were 122.7 and 122.6 mg/dl in the placebo and mipomersen patients, respectively. Mipomersen reduced LDL cholesterol by -36.9% compared with placebo at -4.5% (p < 0.001). Target LDL cholesterol <100 mg/dl was attained in 76% of mipomersen and 38% of placebo patients. Mipomersen also significantly reduced apolipoprotein B (-38%) and lipoprotein(a) (-24%) (p < 0.001). Common adverse events included injection site reactions (78% with mipomersen, 31% with placebo) and flu-like symptoms (34% with mipomersen, 21% with placebo). Elevations in transaminases and liver fat also occurred in some patients, and these levels returned toward baseline after treatment cessation. CONCLUSIONS: Mipomersen significantly reduced LDL cholesterol, apolipoprotein B, and lipoprotein(a) in patients with hypercholesterolemia with, or at risk for, coronary heart disease not controlled by existing therapies. (Safety and Efficacy of Mipomersen [ISIS 301012] as Add-On Therapy in High Risk Hypercholesterolemic Patients; NCT00770146).

Applications of exogenous mesenchymal stem cells and low intensity pulsed ultrasound enhance fracture healing in rat model.

The present study aimed to investigate the effects of combined treatment of exogenous mesenchymal stem cells (MSCs) and low intensity pulsed ultrasound (LIPUS) on fracture healing by comparing LIPUS-MSC, MSC and control (CTL) groups. Radiography and quantitative callus width/area demonstrated that the MSC-LIPUS group had the best healing, MSC group the second and CTL group the poorest with significant differences among each at different time points. Micro-CT data supported that MSC-LIPUS had the highest bone volume/tissue volume. Histomorphometry showed a significantly faster remodeling in late phase in MSC-LIPUS and MSC groups. These indicated that the combined treatment of MSCs and LIPUS was beneficial to fracture healing. Regenerative power and homing ability of MSCs were shown by promotion in fracture healing and locally found green fluorescent protein (GFP)-labeled MSCs at fracture calluses. This evidence reflects that co-treatment of MSCs and LIPUS may be developed as an intervention for delayed union or nonunion.

Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. METHODS AND RESULTS: This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (-28.0% [-34.0% to -22.1%] compared with 5.2% [-0.5% to 10.9%] increase with placebo; P<0.001). Mipomersen significantly reduced apolipoprotein B (-26.3%), total cholesterol (-19.4%), and lipoprotein(a) (-21.1%) compared with placebo (all P<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001). CONCLUSIONS: Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00706849.

Purification of the extra-cellular domain of Nipah virus glycoprotein produced in Escherichia coli and possible application in diagnosis.

The glycoprotein (G) of Nipah virus (NiV) is important for virus infectivity and induction of the protective immunity. In this study, the extra-cellular domain of NiV G protein was fused with hexahistidine residues at its N-terminal end and expressed in Escherichia coli. The expression under transcriptional regulation of T7 promoter yielded insoluble protein aggregates in the form of inclusion bodies. The inclusion bodies were solubilized with 8 M urea and the protein was purified to homogeneity under denaturing conditions using nickel-nitrilotriacetic acid (Ni-NTA) affinity chromatography. The denatured protein was renatured by gradual removal of the urea. Light scattering analysis of the purified protein showed primarily monodispersity. The purified protein showed significant reactivity with the antibodies present in the sera of NiV-infected swine, as demonstrated in Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Taken together, the data indicate the potential usefulness of the purified G protein for structural or functional studies and the development of immunoassay for detection of the NiV antibodies.

Comparison of one-year outcomes following coronary artery stenting in diabetic versus nondiabetic patients (from the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy [ESPRIT] Trial).

For patients undergoing nonurgent coronary stent implantation, blockade of the glycoprotein IIb/IIIa receptor with eptifibatide reduces the incidence of ischemic complications. We evaluated the interaction of eptifibatide with diabetes in patients who underwent this procedure by analyzing the 1-year outcomes of those enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (466 diabetic and 1,595 nondiabetic patients). At 1 year, the composite end point of death, myocardial infarction (MI), or target vessel revascuarlization (TVR) was higher in diabetic patients (24.5% vs 18.4%; p = 0.008). At 1 year, eptifibatide had a similar effect on the composite end point of death, MI, or TVR in diabetic (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.49 to 1.04) and nondiabetic patients (HR 0.80, 95% CI 0.63 to 0.99). A similar treatment effect was also seen on death or MI in both groups. The 1-year mortality rate for diabetic patients assigned to placebo was 3.5% versus 1.3% for patients receiving eptifibatide (HR 0.37, 95% CI 0.10 to 1.41); the latter rate was similar to the mortality rate of 1.4% for nondiabetic patients in the eptifibatide group. However, eptifibatide did not have a significant effect on TVR in diabetic patients (HR 0.90, 95% CI 0.57 to 1.41). Our data suggest that treatment with eptifibatide is associated with a similar relative reduction in adverse ischemic complications in diabetic and nondiabetic patients undergoing coronary stent implantation. There is no evidence of a statistical interaction in the treatment effect of eptifibatide between patients with and without diabetes.