Ultrasonographic findings in nevus lipomatosus cutaneous superficialis: What differentiates this tumor from other soft tissue tumors?

Nevus lipomatosus cutaneous superficialis is a rare, benign hamartoma characterized by mature adipocyte proliferation in the dermis. It is frequently difficult to distinguish clinically from soft tissue tumors, including lipoma, neurofibroma, venous malformation, and angiolipoma. Notably, the classical form, which shows multiple and sometimes enlarged nodules, is difficult to differentiate from liposarcoma based on clinical examination, computed tomography, and magnetic resonance imaging findings. Therefore, to ascertain the utility of ultrasonography in diagnosing nevus lipomatosus cutaneous superficialis, sonographic examinations were performed on eight patients with nevus lipomatosus cutaneous superficialis. All patients had ill-defined hyperechoic masses in the dermis or from the dermis to the subcutis, and the posterior echoes were attenuated in seven patients. Color Doppler sonography revealed no blood flow to the lesions. Ultrasound images were created using the reflections of ultrasound waves at interfaces with different acoustic impedances. Therefore, it is assumed that, in nevus lipomatosus cutaneous superficialis, the ultrasound beam is scattered by ectopic mature adipocytes intermingled with collagen bundles, which are shown as hyperechoic masses. Furthermore, the scattering of the ultrasound beam is thought to reduce tissue penetration, which may attenuate the posterior echo.

Longer time to extubation after general anesthesia with desflurane in patients with obstructive respiratory dysfunction: a retrospective study.

BACKGROUND: The prospect of patients with obstructive respiratory dysfunction undergoing surgery has increased with the growth in the elderly population; however, there have been few investigations about the recovery profile from volatile anesthesia. This study aimed to investigate the impact of obstructive respiratory dysfunction on recovery from desflurane anesthesia. METHODS: A retrospective cohort study included patients who underwent orthopedic lower limb surgery between September 2018 and March 2020. Patients were divided into two groups: those whose preoperative forced expiratory volume in 1 s/forced vital capacity ratio was <70% (obstructive respiratory dysfunction group, n = 180) or ≥70% (control group, n = 45). Time from discontinuation of desflurane to extubation (extubation time) was compared between the two groups. Univariate and multivariable Cox regression models were used to compare odds ratios for prolonged extubation (≥10 min). RESULTS: A total of 45 patients with obstructive respiratory dysfunction and 180 control patients were eligible for analysis. Extubation time was significantly longer in patients in the obstructive respiratory dysfunction group than those in the control group. In the multivariable Cox model, male sex (HR = 2.00, 95% CI 1.12-3.57; P = 0.020) and obstructive respiratory dysfunction (HR = 2.07, 95% CI 1.05-4.08; P = 0.036) were associated with prolonged extubation. CONCLUSIONS: This retrospective study indicated that extubation time was longer in patients with obstructive respiratory function than in patients without obstructive respiratory function. Male sex and obstructive respiratory function were factors that contributed to extubation time.

Real-World Effectiveness of Ramelteon and Suvorexant for Delirium Prevention in 948 Patients With Delirium Risk Factors.

OBJECTIVE: The aim of this study was to examine the effectiveness of ramelteon and suvorexant for delirium prevention in real-world practice. It explored whether ramelteon and/or suvorexant would affect delirium prevention among both patients at risk for but without delirium (patients at risk) and those with delirium the night before a consultation. METHODS: This multicenter, prospective, observational study was conducted by trained psychiatrists at consultation-liaison psychiatric services from October 1, 2017, to October 7, 2018. Patients who were aged 65 years or older and hospitalized because of acute diseases or elective surgery, had risk factors for delirium, and had insomnia or delirium on the night before the consultation were prescribed ramelteon and/or suvorexant. The decision to take medication was left to the discretion of each patient. The primary outcome was incidence of delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, during the first 7 days. RESULTS: Among 526 patients at risk, those taking ramelteon and/or suvorexant developed delirium significantly less frequently than those who did not, after control for the effects of risk factors on the estimate of an independent association between the effects of ramelteon and/or suvorexant and the outcome of developing delirium (15.7% vs 24.0%; odds ratio [OR] = 0.48;, 95% CI, 0.29-0.80; P = .005). Similar results were found among 422 patients with delirium (39.9% vs 66.3%; OR = 0.36; 95% CI, 0.22-0.59; P < .0001). CONCLUSIONS: Ramelteon and suvorexant appear to be effective for delirium prevention in real-world practice.

Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse.

It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30-month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by aging-related stress and may control aging phenotype.

Acid hydrolysis reveals a low but constant level of pheomelanin in human black to brown hair.

We previously reported a constant ratio of the benzothiazole pheomelanin marker thiazole-2,4,5-tricarboxylic acid (TTCA) to the eumelanin marker pyrrole-2,3,5-tricarboxylic acid (PTCA) in eumelanic, black human hair. A constant level (20%-25%) of benzothiazole-type pheomelanin was recently demonstrated in human skin with varying concentrations of melanin. Therefore, in this study, we aimed to investigate the origin of pheomelanin markers in black to brown human hair by developing a method to remove protein components from hair by heating with 6 M HCl at 110°C for 16 hr. For comparison, synthetic melanins were prepared by oxidizing mixtures of varying ratios of dopa and cysteine with tyrosinase. Hair melanins and synthetic melanins were subjected to acid hydrolysis followed by alkaline H2 O2 oxidation. The results show that the hydrolysis leads to decarboxylation of the 5,6-di-hydroxyindole-2-carboxylic acid moiety in eumelanin and the benzothiazole moiety in pheomelanin and that eumelanic human hair contains 11%-17% benzothiazole-type pheomelanin.

Chemical analysis of constitutive pigmentation of human epidermis reveals constant eumelanin to pheomelanin ratio.

The skin constitutive pigmentation is given by the amount of melanin pigment, its relative composition (eu/pheomelanin) and distribution within the epidermis, and is largely responsible for the sensitivity to UV exposure. Nevertheless, a precise knowledge of melanins in human skin is lacking. We characterized the melanin content of human breast skin samples with variable pigmentations rigorously classified through the Individual Typology Angle (ITA) by image analysis, spectrophotometry after solubilization with Soluene-350 and high-performance liquid chromatography (HPLC) after chemical degradation. ITA and total melanin content were found correlated, ITA and PTCA (degradation product of DHICA melanin), and TTCA (degradation product of benzothiazole-type pheomelanin) as well but not 4-AHP (degradation product of benzothiazine-type pheomelanin). Results revealed that human epidermis comprises approximately 74% of eumelanin and 26% pheomelanin, regardless of the degree of pigmentation. They also confirm the low content of photoprotective eumelanin among lighter skins thereby explaining the higher sensitivity toward UV exposure.

Tyrosinase-catalyzed metabolism of rhododendrol (RD) in B16 melanoma cells: production of RD-pheomelanin and covalent binding with thiol proteins.

RS-4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD) was reported to induce leukoderma of the skin. To explore the mechanism underlying that effect, we previously showed that oxidation of RD with mushroom tyrosinase produces RD-quinone, which is converted to secondary quinone products, and we suggested that those quinones are cytotoxic because they bind to cellular proteins and produce reactive oxygen species. We then confirmed that human tyrosinase can oxidize both enantiomers of RD. In this study, we examined the metabolism of RD in B16F1 melanoma cells in vitro. Using 4-amino-3-hydroxy-n-butylbenzene as a specific indicator, we detected moderate levels of RD-pheomelanin in B16F1 cells exposed to 0.3 to 0.5 mM RD for 72 h. We also confirmed the covalent binding of RD-quinone to non-protein thiols and proteins through cysteinyl residues. The covalent binding of RD-quinone to proteins was 20- to 30-fold greater than dopaquinone. These results suggest that the tyrosinase-induced metabolism of RD causes melanocyte toxicity.

Photoaging of human retinal pigment epithelium is accompanied by oxidative modifications of its eumelanin.

Although photodegradation of the retinal pigment epithelium (RPE) melanin may contribute to the etiology of age-related macular degeneration, the molecular mechanisms of this phenomenon and the structural changes of the modified melanin remain unknown. Recently, we found that the ratio of pyrrole-2,3,4,5-tetracarboxylic acid (PTeCA) to pyrrole-2,3,5-tricarboxylic acid (PTCA) is a marker for the heat-induced cross-linking of eumelanin. In this study, we examined UVA-induced changes in synthetic eumelanins to confirm the usefulness of the PTeCA/PTCA ratio as an indicator of photo-oxidation and compared changes in various melanin markers and their ratios in human melanocytes exposed to UVA, in isolated bovine RPE melanosomes exposed to strong blue light and in human RPE cells from donors of various ages. The results indicate that the PTeCA/PTCA ratio is a sensitive marker for the oxidation of eumelanin exposed to UVA or blue light and that eumelanin and pheomelanin in human RPE cells undergo extensive structural modifications due to the life-long exposure to blue light.

UVA-induced oxidative degradation of melanins: fission of indole moiety in eumelanin and conversion to benzothiazole moiety in pheomelanin.

Eumelanin is photoprotective while pheomelanin is phototoxic to pigmented tissues. Ultraviolet A (UVA)-induced tanning seems to result from the photooxidation of pre-existing melanin and contributes no photoprotection. However, data available for melanin biodegradation remain limited. In this study, we first examined photodegradation of eumelanin and pheomelanin in human black hairs and found that the ratio of Free (formed by peroxidation in situ) to Total (after hydrogen peroxide oxidation) pyrrole-2,3,5-tricarboxylic acid (PTCA) increases with hair aging, indicating fission of the dihydroxyindole moiety. In red hair, the ratio of thiazole-2,4,5-tricarboxylic acid (TTCA) to 4-amino-3-hydroxyphenylalanine (4-AHP) increases with aging, indicating the conversion from benzothiazine to benzothiazole moiety. These photodegradation of melanins were confirmed by UVA (not UVB) irradiation of melanins from mice and human hairs and synthetic eumelanin and pheomelanin. These results show that both eumelanin and pheomelanin degrade by UVA and that Free/Total PTCA and TTCA/4-AHP ratios serve as sensitive indicators of photodegradation.

Usefulness of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin in various tissue samples: application to chemical analysis of human hair melanins.

Eumelanin and pheomelanin in tissue samples can be specifically measured as the markers pyrrole-2,3,5-tricarboxylic acid (PTCA) and 4-amino-3-hydroxyphenylalanine after acidic permanganate oxidation and hydroiodic acid hydrolysis, respectively. Those degradation methods, although widely applied, are not easily performed in most laboratories. To overcome this difficulty, we developed alkaline H(2)O(2) oxidation in 1 M K(2)CO(3) that produces, in addition to the eumelanin marker PTCA, thiazole-2,4,5-tricarboxylic acid (TTCA) and thiazole-4,5-dicarboxylic acid (TDCA) as markers for pheomelanin and pyrrole-2,3-dicarboxylic acid (PDCA) as a marker for 5,6-dihydroxyindole-derived eumelanin. Those four degradation products can be easily separated by HPLC and analyzed with ultraviolet detection. The alkaline H(2)O(2) oxidation method is simple, reproducible and applicable to all pigmented tissues. Its application to characterize eumelanin and pheomelanin in human hair shows that PTCA and TTCA serve as specific markers for eumelanin and pheomelanin, respectively, although some caution is needed regarding the artificial production of TTCA from eumelanic tissue proteins.

Serum levels of 5-s-cysteinyldopa are correlated with skin colors in hemodialysis patients but not in peritoneal dialysis patients.

BACKGROUND: Diffuse hyperpigmentation is common in patients with chronic renal failure undergoing hemodialysis (HD) or peritoneal dialysis (PD). We previously reported that serum levels of 5-S-cysteinyldopa (5SCD, a pheomelanin precursor) and pheomelanin were significantly elevated in HD patients. METHODS: Skin color was assessed using a Mexameter that measures the melanin index (MI) and the erythema index (EI). The upper inner arms (non-sun-exposed site) and the foreheads (sun-exposed site) of HD and PD patients and control subjects were analyzed. RESULTS: MI values on the upper inner arms and on the foreheads of HD and PD patients were significantly higher than in controls. In HD patients, significant correlations were found for serum 5SCD levels with MI and EI on the upper inner arm, and for EI on the forehead. In PD patients, no such correlations were found. CONCLUSIONS: Hyperpigmentation in HD patients results partly from accumulation of pheomelanin in the skin.

Analysis of PPARalpha-dependent and PPARalpha-independent transcript regulation following fenofibrate treatment of human endothelial cells.

Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPARalpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. We have limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPARalpha-independent manner. In order to identify PPARalpha-dependently and PPARalpha-independently regulated transcripts, we generated microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARalpha. We also constructed dynamic Bayesian transcriptome networks to reveal PPARalpha-dependent and -independent pathways. Our transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARalpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARalpha-independent master-regulator of fenofibrate action in human endothelial cells.

Unraveling dynamic activities of autocrine pathways that control drug-response transcriptome networks.

Some drugs affect secretion of secreted proteins (e.g. cytokines) released from target cells, but it remains unclear whether these proteins act in an autocrine manner and directly effect the cells on which the drugs act. In this study, we propose a computational method for testing a biological hypothesis: there exist autocrine signaling pathways that are dynamically regulated by drug response transcriptome networks and control them simultaneously. If such pathways are identified, they could be useful for revealing drug mode-of-action and identifying novel drug targets. By the node-set separation method proposed, dynamic structural changes can be embedded in transcriptome networks that enable us to find master-regulator genes or critical paths at each observed time. We then combine the protein-protein interaction network with the estimated dynamic transcriptome network to discover drug-affected autocrine pathways if they exist. The statistical significance (p-values) of the pathways are evaluated by the meta-analysis technique. The dynamics of the interactions between the transcriptome networks and the signaling pathways will be shown in this framework. We illustrate our strategy by an application using anti-hyperlipidemia drug, Fenofibrate. From over one million protein-protein interaction pathways, we extracted significant 23 autocrine-like pathways with the Bonferroni correction, including VEGF-NRP1-GIPC1-PRKCA-PPARalpha, that is one of the most significant ones and contains PPARalpha, a target of Fenofibrate.

A comparative intervention trial on fish sauce fortified with NaFe-EDTA and FeSO4+citrate in iron deficiency anemic school children in Kampot, Cambodia.

BACKGROUND: Inhabitants of agrarian villages of rural Cambodia suffer from high prevalences of iron deficiency and anemia in the context of a monotonous diet. OBJECTIVE: To compare the efficacy and safety of placebo Khmer fish sauce to that of 10 mL of fish sauce containing 10 mg of iron, added to daily school meals either as NaFe-EDTA or as FeSO4+ citrate. METHODS: 140 students aged 6-21 years were enrolled in a double-blinded, placebo-controlled intervention trial. They were randomly allocated to one of three treatment groups, and followed for 21 weeks during which 114 school meals seasoned with 10 mL of fish sauce were consumed by each participant. Changes in the concentrations of hemoglobin (hb), serum ferritin (SF), and C-reactive protein (CRP) and in body weight and standing height were determined. Prevalences of vomiting, diarrhea, and acute respiratory infections were monitored weekly. RESULTS: Both iron-fortified fish sauces increased hb and SF concentrations significantly as compared to placebo. No significant differences were observed between FeSO4+citrate and NaFe-EDTA fortification, regarding mitigation of iron-deficiency anemia (IDA) or regarding CRP, growth, infections, or side-effects. CONCLUSIONS: Iron-fortified Khmer fish sauce added to Khmer food is a suitable vehicle for iron fortification in children and adolescents. FeSO4+citrate and NaFe-EDTA show equivalent efficacy and safety.

Pigmentation effects of solar-simulated radiation as compared with UVA and UVB radiation.

Different wavelengths of ultraviolet (UV) radiation elicit different responses in the skin. UVA induces immediate tanning and persistent pigment darkening through oxidation of pre-existing melanin or melanogenic precursors, while UVB induces delayed tanning which takes several days or longer to develop and requires activation of melanocytes. We compared the effects of a 2-week repetitive exposure of human skin to solar-simulated radiation (SSR), UVA or UVB at doses eliciting comparable levels of visible tanning and measured levels of melanins and melanin-related metabolites. Levels of eumelanin and pheomelanin were significantly higher in the order of SSR, UVB, UVA or unexposed control skin. Levels of free 5-S-cysteinyldopa (5SCD) were elevated about 4-fold in SSR- or UVB-exposed skin compared with UVA-exposed or control skin. Levels of protein-bound form of 5SCD tended to be higher in SSR- or UVB-exposed skin than in UVA-exposed or control skin. Total levels of 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) and 6H5MI2C were higher in SSR- than in UVB-exposed or control skin. These results show that SSR is more effective in promoting delayed tanning than UVB radiation alone, suggesting a synergistic effect of UVA radiation. Furthermore, free 5SCD may serve as a good marker of the effect of SSR and UVB.

Serum levels of pigmentation markers are elevated in patients undergoing hemodialysis.

BACKGROUND: Diffuse hyperpigmentation is common among patients with chronic renal failure undergoing hemodialysis (HD). We have examined serum levels of 5-S-cysteinyldopa (5SCD, a pheomelanin precursor), pheomelanin, eumelanin, and protein-bound (PB-) 3,4-dihydroxyphenylalanine (DOPA) and PB-5SCD in HD patients. METHODS: Pheomelanin and eumelanin were assayed by chemical degradation methods. RESULTS: Serum levels of free 5SCD in HD patients (n = 16) were 9-fold higher than in healthy controls (n = 16). Levels of pheomelanin in HD patients were 2.6-fold higher than in controls, while levels of eumelanin did not differ between HD patients and controls. Levels of PB-DOPA and PB-5SCD in HD patients were approximately 1.5-fold higher than in controls. Serum levels of free 5SCD were positively correlated to the duration of HD therapy. CONCLUSIONS: The high constitutive levels of free 5SCD, pheomelanin, and PB-DOPA in the blood may be deteriorating in HD patients through the production of reactive oxygen species.

Impact of lifestyle intervention on physical activity and diet of Japanese workers.

OBJECTIVE: To evaluate the effectiveness of the Life Style Modification Program for Physical Activity and Diet (LiSM-PAN) in comparison to a conventional healthcare program. METHOD: Subjects with risk factor(s) for chronic disease were allocated as a cluster to the LiSM group (n=92) or the Control group (n=85). The LiSM-PAN program consisted of counseling plus social and environment support, and the Control program consisted of written feedback for changing physical activity and dietary practice. Intervention was conducted for 6 months during 2001-2002 and with data analysis during 2003-2004 in Tokyo, Japan. The main outcomes were leisure time exercise energy expenditure (L.E.E.E.), maximum oxygen uptake (VO2max), dietary habits, body mass index (BMI), blood pressure, blood glucose, and lipid parameters. RESULTS: The LiSM group showed a significantly greater increase in L.E.E.E. than the Control group at the end of the intervention (mean inter-group difference: 400.6 kcal/week, 95% CI: 126.1, 675.0 kcal/week). No significant mean inter-group differences were observed in dietary habits. The LiSM group showed significantly greater decreases in BMI, systolic blood pressure, and LDL-cholesterol than the Control group. CONCLUSION: The LiSM-PAN program produced greater positive changes in L.E.E.E., dietary habits, and risk factors for cardiovascular diseases in high-risk middle-aged male workers compared to the Control program.

The use of NaFeEDTA-fortified fish sauce is an effective tool for controlling iron deficiency in women of childbearing age in rural Vietnam.

One cost-effective strategy for controlling iron deficiency is the fortification of staple foods or condiments with iron. We evaluated the effectiveness of fortifying fish sauce with NaFeEDTA for improving iron status in women of childbearing age in Vietnam in a double-blind intervention with randomization by village. All families in the selected villages were supplied with fish sauce that was either unfortified (Group C, 10 villages) or fortified with NaFeEDTA [9 mmol (500 mg) Fe/L, Group F, 11 villages] for 18 mo. The effect of fortification was assessed in the 576 women (n = 288/group) by measuring hemoglobin and serum ferritin (SF) at 6, 12, and 18 mo. Analysis of the group x time interaction using a repeated-measures test for each response demonstrated a significant effect of fortification on hemoglobin (P = 0.039) and log SF (P < 0.0001) in Group F with no significant changes in Group C. The prevalence of iron deficiency (SF < 12 microg/L) decreased from 22.3 to 4.0% and the prevalence of anemia (hemoglobin < 120 g/L) from 24.7 to 8.5% in Group F with no significant changes in Group C. NaFeEDTA fortification of fish sauce is an effective method for reducing the prevalence of iron deficiency in women in Vietnam.

APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica.

Genetic variation in the APOC3 and APOA5 genes has been associated with plasma triglyceride concentrations and may affect the risk of myocardial infarction (MI). To assess whether APOC3/A5 haplotypes are associated with risk of MI, we examined three single-nucleotide polymorphisms (SNPs) in APOC3 (3238C>G, -455T>C, and -482C>T) and six SNPs in the APOA5 gene (-1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C) in incident cases (n = 1,703) of a first nonfatal MI matched for gender, age, and area of residence with population-based controls (n = 1,703). Conditional logistic regression models, adjusted for potential environmental confounders, were used for analysis. The common APOC3*222 haplotype was more frequent in cases than in controls (17.4% and 13.7%, respectively, P < 0.001) and was associated with increased risk of MI [odds ratio (OR) = 1.27; 95% confidence interval (95% CI), 1.09, 1.48] compared with APOC3*111 wild-type haplotype. This association was independent of the APOA5 SNPs. Although the APOC3 3238G, APOA5 -1131C, APOA5 c.-3G, and APOA5 c.1259C alleles were associated with higher triglyceride plasma concentrations, these effects could not explain the associations with MI in this population. In summary, this study supports the hypothesis that haplotypes in the APOC3 gene but not in the APOA5 gene increase susceptibility to MI.