Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat.

BACKGROUND: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). SUBJECTS AND METHODS: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. RESULTS: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10(-6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10(-7)), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 × 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10(-8) to 1.13 × 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. CONCLUSIONS: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

Brucellosis in a renal transplant recipient.

Brucellosis is one of the most common systemic zoonotic diseases transmitted by consumption of unpasteurized dairy products or by occupational contact with infected animals. Brucellosis is rare in renal transplant recipients. Only 3 cases have been reported in the literature. We report a case of brucellosis with hematologic and hepatobiliary complications in a patient 3 years after renal transplantation. The mean time from transplantation to the diagnosis of brucellosis in these 4 reported patients was 5.1 years (range 17 months to 13 years). All patients had fever and constitutional symptoms, and all attained clinical cure after combination antibiotic therapy. Given the small number of patients, further study is needed to identify the characteristics of brucellosis in renal transplant recipients. Drug interactions and acute renal failure developed in our patient during antibiotic treatment. Therefore, we should monitor the levels of immunosuppressive agents frequently. Several studies have shown in vitro susceptibilities of Brucella melitensis to tigecycline. In our patient, fever finally subsided after tigecycline administration. The minimum inhibitory concentration of tigecycline using Etest was 0.094 µg/mL. Tigecycline may be a potential option for treatment of brucellosis in the setting of transplantation.

Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development.

The B lymphocyte-induced maturation protein (Blimp-1) upregulates the expression of syndecan-1 and J chain and represses that of c-myc. We have transfected Blimp-1 into two sublines of the BCL1 B cell lymphoma that represent distinct stages of B cell development in secondary lymphoid tissues. After interleukin (IL)-2 and IL-5 stimulation, the BCL1 3B3 cells differentiate into centrocyte-like cells, whereas the BCL1 5B1b cells blast and appear to be blocked at the centroblast stage. This blasting effect and the increase in IgM secretion that follows it can be blocked by a dominant negative form of Blimp-1. At the same time, the ectopic expression of Blimp-1 in these partially activated cells induces an apoptotic response that also can be suppressed by the same dominant negative protein. A similar effect was noticed when Blimp-1 was expressed in the mature L10A and the immature WEHI-231 lines, indicating this may be a general effect at earlier stages of the B cell development, and distinct from the ability of Blimp-1 to induce maturation in late stages of differentiation. Truncation mutants indicate that the induction of the apoptotic response relies mainly on 69 amino acids within Blimp-1's proline-rich domain. We propose that Blimp-1 expression defines a checkpoint beyond which fully activated B cells proceed to the plasma cell stage, whereas immature and partially activated cells are eliminated at this point.

Calcitonin promotes outgrowth of trophoblast cells on endometrial epithelial cells: involvement of calcium mobilization and protein kinase C activation.

Embryo implantation is a complex process that requires coordinated trophoblast-endometrial interactions. During implantation, trophoblast cells of the attached blastocyst penetrate the luminal epithelium of the endometrium before invasion into the endometrial stroma. Previous studies demonstrated that calcitonin was actively secreted by rat and human endometrial epithelial cells (EEC) during the implantation window and targeted disruption of endometrial calcitonin expression dramatically decreased embryo implantation rates; however, the role and signal transduction of calcitonin in trophoblast-endometrial interactions remained unclear and are therefore examined in this study. BeWo trophoblast and RL95-2 EEC lines were used because they preserve many properties of their respective normal tissues. We co-cultured BeWo trophoblast spheroids with RL95-2 EEC monolayers to mimic the blastocyst-endometrial interaction, and found that most spheroids quickly attached to EEC monolayers and then progressively expanded, with marked displacement of EEC adjacent to the outgrowing trophoblast cells. Interestingly, pretreatment of EEC monolayers with calcitonin before the addition of spheroids significantly enhanced trophoblast expansion on EEC monolayers. Cytosolic calcium (Ca(2+)) levels in EEC increased rapidly upon exposure to calcitonin, and blockade of Ca(2+) release by BAPTA-AM effectively prevented the promoting effect of calcitonin on trophoblast expansion on EEC. The Ca(2+)-dependent protein kinase C (PKC) was also activated in EEC after calcitonin treatment, and the PKC inhibitors staurosporine and calphostin C could completely abolish calcitonin-induced augmentation of trophoblast expansion on EEC. Our results suggest that calcitonin promotes trophoblastic displacement of EEC through calcium mobilization and PKC activation, thereby facilitating embryo implantation.

Anti-fas activating antibody enhances trophoblast outgrowth on endometrial epithelial cells by induction of P38 MAPK/JNK-mediated apoptosis.

In species with hemochorial placentation, such as the mouse and human, trophoblast cells of the implanting blastocyst induce apoptosis and displace endometrial epithelial cells (EEC) to cross the luminal epithelium of the endometrium. Since Fas and Fas ligand (FasL) are expressed in EEC and trophoblast cells respectively and mitogen-activated protein kinases (MAPKs) mediate Fas-induced apoptosis, the roles of Fas/FasL and MAPK signaling in trophoblast-EEC interactions were studied. By co-culturing BeWo trophoblast spheroids with RL95-2 EEC monolayers to mimic blastocyst-endometrial interactions, we found that trophoblast spheroid outgrowth on EEC was significantly enhanced by anti-Fas activating antibody. Since anti-Fas activating antibody had no effect on spheroid expansion on EEC-free culture surfaces, its enhancing effect on spheroid outgrowth on EEC may be mediated by acting on EEC to facilitate trophoblast-induced EEC apoptosis and displacement. Valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (VAD-FMK) staining showed that the percentage of apoptotic EEC at the spheroid-EEC interface was markedly increased by anti-Fas activating antibody. Moreover, the pancaspase inhibitor benzyloxycarbonyl-VAD-FMK was able to suppress the enhancing effect of anti-Fas activating antibody on spheroid expansion on EEC. Upon anti-Fas activating antibody stimulation, both p38 MAPK and c-Jun NH(2)-terminal kinase (JNK) were activated. Furthermore, the anti-Fas activating antibody-enhanced EEC apoptosis and spheroid expansion on EEC were significantly inhibited by the p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125. Our results establish that anti-Fas activating antibody could activate p38 MAPK and JNK to induce EEC apoptosis, thereby promoting trophoblast outgrowth on EEC.

Activation and retrograde transport of protein kinase G in rat nociceptive neurons after nerve injury and inflammation.

Nerve injury elicits both universal and limited responses. Among the former is regenerative growth, which occurs in most peripheral neurons, and among the latter is the long-term hyperexcitability that appears selectively in nociceptive sensory neurons. Since positive injury signals communicate information from the site of an injury to the cell body, we hypothesize that a nerve injury activates both universal and limited positive injury signals. Studies in Aplysia indicate that protein kinase G is a limited signal that is responsible for the induction of long-term hyperexcitability. Given that long-term hyperexcitability contributes to chronic pain after axotomy in rodent neuropathic pain models, we investigated its underlying basis in the rat peripheral nervous system. Using biochemical assays, Western blots, and immunocytochemistry we found that the Type 1alpha protein kinase G is the predominant isoform in the rat periphery. It is present primarily in axons and cell bodies of nociceptive neurons, including populations that are isolectin B4-positive, isolectin B4-negative, and those that express transient receptor potential vanilloid receptor-1. Surprisingly, protein kinase G is not present in the facial nerve, which overwhelmingly contains axons of motor neurons. Crushing the sciatic nerve or a cutaneous sensory nerve activates protein kinase G in axons and results in its retrograde transport to the neuronal somata in the DRG. Preventing the activation of protein kinase G by injecting Rp-8-pCPT-cGMPS into the crush site abolished the transport. The protein kinase A inhibitor Rp-8-pCPT-cAMPS had no effect. Extracellular signal-related kinases 42/44 are also activated and transported after nerve crush, but in both motor and sensory axons. Chronic pain has been linked to long-term hyperexcitability following a nerve inflammation in several rodent models. We therefore injected complete Freund's adjuvant into the hindpaw to induce an inflammation and found that protein kinase G was activated in the sural nerve and transported to the DRG. In contrast, the extracellular signal-related kinases in the sensory axons were not activated by the complete Freund's adjuvant. These studies support the idea that the extracellular signal-related kinases are universal positive axonal signals and that protein kinase G is a limited positive axonal signal. They also establish the association between protein kinase G, the induction of long-term hyperexcitability, and chronic pain in rodents.

Nitric oxide (.NO)-induced mitochondrial injury among chicken .NO-generating and target leukocytes.

In an analysis of nitric oxide (.NO) production and toxicity, chicken macrophage-generated .NO inhibited mitochondrial activity in both .NO-producing macrophages themselves and lymphoid tumor targets. However, differences in targeting of mitochondrial toxicity were observed among these cells. Two chicken macrophage cell lines, HD11 and MQ-NCSU, produced .NO (measured as nitrite) dependent upon concentrations of L-arginine and bacterial endotoxin (lipopolysaccharide). Mitochondrial activity was negatively correlated with the amount of .NO produced. Using a modified MTT assay, .NO induced suppression in two mitochondrial complexes. Mitochondrial activity was significantly suppressed among HD11 cells receiving LPS alone (complex I, 63.0 +/- 5.5% suppression; complex II, 27.9 +/- 5.2%). In contrast, mitochondrial activities in samples receiving LPS plus inhibitor, NG-nitro-L-arginine methyl ester (NAME; 5 mM) or 2,4-diamino-6-hydroxypyrimidine (DAHP; 5 mM), were not significantly different from control values. When HD11 macrophages were cocultured with lymphoblastoid tumor targets, RECC-CU60 (T cell) or LSCC-RP9 (B cell), adding LPS (1 microgram/ml), tumor cell mitochondrial activity was significantly suppressed. In the generator macrophages, complex I was more suppressed than complex II, whereas in lymphoid targets no such difference was observed. These results indicate that .NO inhibits complex I and II mitochondrial activity but that differential targeting can occur among chicken leukocyte populations.

L-arginine-dependent production of a reactive nitrogen intermediate by macrophages of a uricotelic species.

L-arginine-dependent production of reactive nitrogen intermediates (RNIs: nitric oxide, nitrite, and nitrate) by mammalian macrophages has been proposed to occur via an L-arginine oxidative deimination pathway and is known to be responsible for certain antineoplastic and antimicrobial effector functions. The present study represents the first examination of this pathway in a non-mammalian vertebrate. Because chickens, unlike mammals, lack a urea cycle and are incapable of de novo synthesis of L-arginine, the possible existence of an avian macrophage pathway for production of RNIs is questionable. We have defined conditions under which chicken macrophages are able to produce nitrite. Sephadex-elicited chicken peritoneal macrophages required a bacterial lipopolysaccharide (LPS from Escherichia coli) signal to produce nitrite during 24 hour cultures in the presence of L-arginine. As little as 5 ng/ml LPS resulted in significant nitrite production in culture. The relationship of nitrite production to both LPS and L-arginine levels was dose-dependent. D-arginine was unable to substitute for L-arginine but also produced no inhibitory effect. In contrast, L-NG-monomethyl arginine showed a significant inhibitory effect on nitrite production. A virus-transformed chicken macrophage cell line, HD11, also produced nitrite in a dose-dependent manner relative to both LPS and L-arginine concentration. Concentrations as low as 5 ng/ml LPS and 0.1 mM L-arginine resulted in significant nitrite production, while maximum levels of nitrite production were obtained using greater than or equal to 0.5 micrograms/ml LPS and greater than or equal to 0.4 mM L-arginine. These results indicate that chicken macrophages can produce RNIs. This production is dependent upon activation and is influenced by local L-arginine concentration. Moreover, because the chicken does not possess the ability to synthesize arginine and has an absolute nutritional requirement for this amino acid, the chicken represents a highly controllable system to examine the in vivo effects of L-arginine on macrophage-related immune functions.

Nitric oxide enhances the growth of U937 human leukemic cells through a cyclooxygenase-mediated pathway.

The mechanisms of exogenous nitric oxide (NO)-enhanced growth of the U937 human myeloid leukemic cells were examined using sodium nitroprusside (SNP) as a NO donor. Treatment with 0.1 mM SNP for 72 h caused a 45 +/- 2% increase in U937 cell growth with significantly increased S/G2+M-phase and decreased G0/G1-phase of the cell cycle. The growth-enhancing effect of SNP was blocked by indomethacin, a cyclooxygenase inhibitor, but not by H7, a broad spectrum kinase inhibitor, or PD98059, a mitogen-activated protein kinase inhibitor. SNP treatment resulted in a dose-dependent increase in prostaglandin E2 (PGE2) production. Furthermore, the addition of exogenous PGE2 not only enhanced U937 cell growth but restored the indomethacin-inhibited mitogenic effect of SNP. We suggest that NO can enhance cell growth through activating the cyclooxygenase pathway and that PGE2 may be an effector molecule for NO-regulated cell proliferation. Our data provide a mechanistic insight into the regulatory role of NO in myelopoiesis.

The Patient State Index is well balanced for propofol sedation.

BACKGROUND: The SEDLine™ monitor derived patient state index (PSI) is used to follow the depth of sedation. The demand for propofol sedation by anesthesiologists or non-anesthesiologists is increasing, and there are only a few studies addressing the relationship between PSI and propofol sedation. We aimed to investigate the ability of PSI index to identify the correct level of sedation of our patients during induction to anesthesia with target-controlled infusions of propofol. METHODS: Twenty patients were enrolled in this study. The target effect site concentration of propofol was set at 1.5 µg/ml followed by increments of 0.5 µg/ml every five minutes. The PSI values and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale were recorded every twenty-five seconds during the infusion of propofol. Patients were considered losing verbal responsiveness at MOAA/S scale ≤ 2. Also, blood pressure, heart rate, and oxygen saturation were recorded every five minutes. RESULTS: The PSI values corresponding to the sedation of various depths (MOAA/S scales) and alertness with verbal response were significantly different (p <0.001). We observed a good correlation of the PSI values to the decreasing MOAA/S scale (r =0.87667). CONCLUSIONS: The PSI index is well correlated with MOAA/S scale and effectively distinguishes the level of sedation during propofol infusion. Hippokratia 2015; 19 (3): 235-238.

Use of two reverse transcriptases eliminates false-positive results in differential display.

The selection of false-positive clones in differential display PCR (DDRT-PCR) represents a formidable drawback to this otherwise powerful technique of detecting subtle differences between cell types. DDRT-PCR performed with cDNAs generated by two different reverse transcriptases from the same RNA doubles the total number of reactions; nevertheless, false-positive clones arising from small differences between RNA preparations are easily distinguished from differentially expressed transcripts.

Tetrandrine ameliorates ischaemia-reperfusion injury of rat myocardium through inhibition of neutrophil priming and activation.

1. We have previously shown that tetrandrine (TTD), a bisbenzyltetrahydroiosquinoline isolated from the Chinese herb Stephania tetrandra, inhibits neutrophil adhesion, Mac-1 expression, and reactive oxygen species (ROS) production. To examine whether inhibition of neutrophil function may confer upon TTD the ability to prevent myocardial ischaemia-reperfusion (MI/R) injury, experiments were performed on rats subjected to coronary ligation followed by reperfusion for induction of MI/R injury. 2. Intravenous administration of TTD (0.1 and 1.0 mg kg-1) 15 min prior to coronary ligation completely prevented MI/R-associated mortality. TTD pretreatment also significantly reduced MI/R-induced ventricular tachyarrhythmia, myocardial infarct size, and neutrophil infiltration. 3. However, TTD pretreatment did not influence mean arterial blood pressure, heart rate, or product of pressure-rate, indicating that TTD extenuated MI/R through mechanisms independent of modulating haemodynamics or myocardial oxygen demand. 4. Peripheral blood neutrophils were isolated for ex vivo examination of shape change and Mac-1 upregulation of neutrophils, two sensitive indicators of proinflammatory priming, as well as N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced adhesion and ROS production, parameters commonly used for the assessment of neutrophil activation. 5. Neutrophils from MI/R animals showed significant shape change and Mac-1 upregulation, both of which were prevented by TTD-pretreatments. On the other hand, fMLP-induced adhesion and ROS production of neutrophils were markedly enhanced by MI/R but diminished in TTD-pretreated animals. 6. These data suggest that the protective effect of TTD against MI/R injury can be accounted for by inhibition of neutrophil priming and activation, thereby abolishing subsequent infiltration and ROS production that cause MI/R injury.

Selectively enriched mRNAs in rat synaptoneurosomes.

Differential display was used to identify synapse-enriched mRNAs. Of 15 mRNAs initially identified, all were found in multiple synaptoneurosome preparations; 58% were subsequently shown to be enriched in all the preparations by Northern blotting and semiquantitative RT-PCR. RNAs involved in signal transduction, vesicle trafficking, lipid modification and cell shape and remodeling were among these messages. Tip60a mRNA, recently found to associate with the fragile X mental retardation protein, was also identified. These data demonstrate the diversity of the local message pool at synapses.

Magnolol inhibits Mac-1 (CD11b/CD18)-dependent neutrophil adhesion: relationship with its antioxidant effect.

Magnolol, a phenolic compound isolated from a Chinese herbal drug, Magnolia officinalis, has been shown to protect rat heart from ischemia/reperfusion injury. Neutrophil adhesion plays a crucial process during this inflammatory response. To evaluate whether magnolol prevents ischemia/reperfusion injury by inhibiting neutrophil adhesion, we determined whether magnolol can inhibit adhesion of phorbol-12-myristate-13-acetate (PMA)-activated human neutrophils to a fibrinogen-coated surface in a dose-dependent manner. Using flow cytometric analysis, we observed that magnolol pretreatment (10 min at 37 degrees C) diminished PMA (100 ng/ml)-induced Mac-1 upregulation. PMA also induced rapid intracellular accumulation of superoxide (O2-.) and hydrogen peroxide (H2O2) in neutrophils; magnolol pretreatment attenuated the accumulation of these two substances. Inhibition of reactive oxygen species by superoxide dismutase and/or catalase, which decompose O2-. and H2O2, respectively, also abolished Mac-1 upregulation and neutrophil adhesion. We conclude that magnolol inhibits neutrophil adhesion and that this can account for its anti-ischemia/reperfusion injury effect. We propose that the inhibitory effect of magnolol on neutrophil adhesion to the extracellular matrix is mediated, at least in part, by inhibition of the accumulation of reactive oxygen species, which in turn suppresses the upregulation of Mac-1 that is essential for neutrophil adhesion.

Oxidative stress is insignificant in N1S1-transplanted hepatoma despite markedly declined activities of the antioxidant enzymes.

It has been proposed that persistent oxidative stress accounts for the increased levels of DNA damage in cancer tissues. We have examined the profile of anti-oxidant enzymes in a transplanted hepatic tumor model by injecting N1S1 rat hepatoma cells into the liver of Sprague-Dawley rats. The transplanted N1S1 tumors displayed characteristics resembling human hepatocellular carcinoma. The immunoreactivities of catalase (CAT), manganese-superoxide dismutase (Mn SOD), copper/zinc-SOD (Cu/Zn SOD), and glutathione peroxidase (GPx) were found to decrease significantly. The enzyme activity in tumors decreased 26.2-, 4.2-, 4.5-, and 5.4-fold for CAT, Mn SOD, Cu/Zn SOD, and GPx, respectively, relative to those in normal liver tissue from the same animals. In contrast, the mRNA levels of CAT and GPx in tumors decreased only 5- and 2-fold, respectively, and the mRNA levels of Cu/Zn SOD and Mn SOD showed either no change or an increase as compared to those of normal liver tissue. The contents of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and thiobarbituric acid-reactive substances (TBARS) were comparable to those of normal controls. Furthermore, mitochondrial production of superoxide in tumors was 4 times lower than that in normal tissues. In conclusion, the data indicate that the reduced activities of anti-oxidant enzymes in the N1S1 tumor did not cause significant oxidative stress.

Multiple inhibitory actions of the paramedian reticular nucleus--effects on blood pressure and motor activities in rats.

The paramedian reticular nucleus (PRN) is a triangle midline structure located in the caudal medulla. Electrophysiological and biochemical evidence has suggested that PRN is an important depressor area, and it regulates various cardiovascular functions. The present results have demonstrated that PRN also plays an inhibitory role in a variety of behavioral functions. Lesions of this nucleus produced augmentations of many behavioral measures including: locomotor activity, clockwise and anti-clockwise turnings, as well as stereotyped behavior in rats. It also produced an increased and a more randomized pattern of locomotion. Destructions of the area of nucleus of solitary tract, which affects bradycardia and sometimes hypotension; as well as the midbrain reticular formation, which does not show any cardiovascular responses, yielded much less significant effects. These results confirm previous physiological findings from our laboratory and further suggest that PRN is a unique and independent area which exerts multiple inhibitory actions upon various physiological and behavioral functions in animals.

Profiles of chicken macrophage effector functions.

In contrast to the mammalian system, avian species lack the so-called "resident" or "harvestable" macrophage population in the abdominal exudate. However, macrophages can be recruited into the chicken's abdominal cavity (presumably from the blood monocyte pool) if an inflammatory agent such as Sephadex is injected. The kinetics of inflammatory cell recruitment in terms of time, cell type, and state of activation to perform a particular effector function is currently an active area of research. This report will provide information on several chicken macrophage effector functions, including in vivo chemotaxis, phagocytosis, bacterial uptake and killing, biosynthesis of nitric oxide and various enzymes, and monokines such as interleukin-1 and granulocyte colony-stimulating factor.

Genome-wide meta-analyses of smoking behaviors in African Americans.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

The association of clinical findings and exposure profiles with melamine associated nephrolithiasis.

BACKGROUND: Little is known about the exposure profiles of melamine in children. We evaluated the association of clinical findings, exposure patterns and biomarkers with nephrolithiasis in children with potential exposure to melamine. METHODS: A case-control study was conducted in children aged 0-16 years with potential exposure to contaminated dairy products. Cases were defined as nephrolithiasis detected by renal ultrasonography. On the basis of different brands of contaminated dairy products consumed, subjects were classified into high exposure, low exposure and control groups with estimated melamine exposure levels of higher than 2.5 ppm, 0.05-2.5 ppm and lower than detection limits <0.05 ppm. We measured urine melamine for those with nephrolithiasis and age-matched and gender-matched controls within the subset of the study population. RESULTS: The duration of consumption of contaminated products was longer in children with nephrolithiasis in the high exposure group than in controls (median (IQR) 12.0 (3.3-24.0) vs 6.0 (4.0-7.0) months; p = 0.048). High melamine exposure levels were significantly associated with nephrolithiasis (OR 61.04 (95% CI 12.73 to 292.84)). The risk was found to increase with estimate melamine exposure levels (p for trend <0.001). Two among 10 affected subjects with nephrolithiasis showed elevated urine melamine levels. In comparison, levels of all 20 controls were lower than the detection limit. CONCLUSIONS: The risk of melamine-associated nephrolithiasis was related to duration of consumption of contaminated products and estimated melamine exposure levels. Though urine melamine was not a sensitive test, it might serve as an exposure biomarker in melamine-associated nephrolithiasis.