Characteristics of long-term survivors of brain metastases from lung cancer

Background and aim

Long-term survival of lung cancer patients with brain metastases (BM) is very rare. Our aim is to report the characteristics of patients who survived for at least three years after a BM diagnosis.

Materials and methods

Nineteen lung cancer patients who had survived ≥3 years after a BM diagnosis were identified in our database. Seven (37%) had undergone whole-brain radiotherapy (WBRT) only, five (26%) BM surgery + WBRT, three (16%) BM surgery + WBRT + BM radiosurgery, and four (21%) no WBRT (one, surgery; one, radiosurgery; two, BM surgery + radiosurgery). Their characteristics were compared with historical data for 322 lung cancer patients with BM (control group, CG), who had received WBRT between 1986 and 1997.

Results

Median survival from BM in long survivors group was 73 months (in CG – 4 months). Characteristics comparison: median age 55 vs. 58 (CG), p = 0.16; female sex 68% vs. 28% (CG), p = 0.003; RTOG/RPA class 1 – 75% vs. 13% (CG), p = 0.00001; adenocarcinoma histology 84% vs. 24% (CG), p < 0.00001; control of primary tumor 95% vs. 27% (CG), p < 0.00001; extracranial metastases 0 vs. 26% (CG), p = 0.01; single BM 63% vs. 9% (CG), p = 0.00001; surgery of BM 53% vs. 14% (CG), p = 0.00001.

Conclusions

Beside prognostic factors already recognized as favorable in patients with BM, the adenocarcinoma histology and female sex were prevalent in long-term survivors of BM from lung cancer.     

Safety and quality of some chicken meat products in Al-Ahsa markets-Saudi Arabia

One hundred samples of 10 poultry meat products were collected from AL-Ahsa markets (Kingdom of Saudi Arabia). The samples were ranked from carcass cuts (chilled, frozen, fillet and thigh) to minced meat or further processed products as burger, nuggets, frankfurter and meat paste loaf. Samples were collected in triplicate for sensory, chemical and microbiological analysis to assure their quality and safety.The obtained results revealed variation in chemical composition; some products with high fat percentage had a high thiobarbituric acid value, which resulted in the appearance of an unacceptable flavor.Bacteriological analysis revealed that the mean total bacterial count was ranged from 2.7 × 10⁴ cfu/g for nuggets^A to 3.3 × 10⁷ cfu/g for burger^B and the other products in the range of 10⁵–10⁶ cfu/g. While Staphylococcus aureus mean count ranged from less than 10² cfu/g for all samples, accept 10⁴ and 10⁶ cfu/g for mince^B and frankfurter samples, respectively. Escherichia coli isolated from 70% of the samples and Salmonella arizona was isolated at once from thigh samples. Thirty percentages of samples not comply with Saudi Standards due to sensory unacceptability and 21% of samples nonconforming with bacteriological specifications.     

Gender-specific genetic associations of polymorphisms in ACE,AKR1C2, FTO and MMP2 with weight gain over a 10-year period

Weight gain, when it leads to overweight or obesity, is nowadays one of the major health problems. ACE, FTO, AKR1C2, TIMP4 and MMP2 genes have been implicated in previous studies on weight regulation. This study investigated the contribution of polymorphisms in these five candidate genes to the risk of weight gain over a 10-year time period. Two groups were selected from participants of the Doetinchem cohort study who were followed over a 10-year period: A stable weight group (±2 kg/10 year; n = 259) and a weight gainers group who increased their body weight by roughly 10 % (>8 kg/10 year; n = 237). Starting BMI was between 20 and 35 kg/m² and baseline age between 20 and 45 years. Selected SNPs and insert/deletion in candidate genes were measured in each group. In men, the allelic distribution of FTO rs9939609 (χ²p = 0.005), ACE rs4340 (χ²p = 0.006) and AKR1C2 rs12249281 (χ²p = 0.019) differed between the weight stable and weight gainers group. Interaction between FTO rs9939609 and ACE rs4340 was observed. In women, the allelic distribution of MMP2 rs1132896 differed between the weight stable and weight gainers group (χ²p = 0.00001). The A-allele of FTO was associated with a 1.99× higher risk of gaining weight in men (OR 1.99, p = 0.020), while in women, the C-allele of MMP2 was associated with a 2.50× higher risk of weight gain (OR 2.50, p = 0.001) over the 10-year period. We found that FTO in men and MMP2 in women are associated with weight gain over a 10-year follow-up period.

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Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting

Background

Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.

Methods

A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009–August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions.

Results

TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08–0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4⁺ count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03–1.96) per 50 cells/µL drop in CD4⁺ count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45–15.87).

Interpretation

Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.     

The omega-3 fatty acid docosahexaenoic acid favorably modulates the inflammatory pathways and macrophage polarization within aorta of LDLR?/? mice

The omega-3 fatty acid docosahexaenoic acid (DHA) has potent anti-atherogenic properties but its mechanisms of action at the vascular level remain poorly explored. Knowing the broad range of molecular targets of omega-3 fatty acids, microarray analysis was used to open-mindedly evaluate the effects of DHA on aorta gene expression in LDLR^−/− mice and better understand its local anti-atherogenic action. Mice were fed an atherogenic diet and received daily oral gavages with oils rich in oleic acid or DHA. Bioinformatics analysis of microarray data first identified inflammation and innate immunity as processes the most affected by DHA supplementation within aorta. More precisely, several down-regulated genes were associated with the inflammatory functions of macrophages (e.g., CCL5 and CCR7), cell movement (e.g., ICAM-2, SELP, and PECAM-1), and the major histocompatibility complex (e.g., HLA-DQA1 and HLA-DRB1). Interestingly, several genes were identified as specific biomarkers of macrophage polarization, and their changes suggested a preferential orientation toward a M2 reparative phenotype. This observation was supported by the upstream regulator analysis highlighting the involvement of three main regulators of macrophage polarization, namely PPARγ (z-score = 2.367, p = 1.50 × 10⁻¹³), INFγ (z-score = −2.797, p = 2.81 × 10⁻¹⁴), and NFκB (z-score = 2.360, p = 6.32 × 10⁻⁹). Moreover, immunohistological analysis of aortic root revealed an increased abundance of Arg1 (+111 %, p = 0.01), a specific biomarker of M2 macrophage. The present study showed for the first time that DHA supplementation during atherogenesis is associated with protective modulation of inflammation and innate immunity pathways within aorta putatively through the orientation of plaque macrophages toward a M2 reparative phenotype.

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The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels

The Ile148Met (rs738409, G-allele) in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) associates with liver fat content and may lead to loss-of-function (hydrolysis) or gain-of-function (CoA-dependent lysophosphatidic acid acyltransferase) defects. PNPLA3 is up-regulated by dietary carbohydrates, and interactions between rs738409 and carbohydrates, and sugar and ω6:ω3-polyunsaturated fatty acid (PUFA) ratio on hepatic fat accumulation have been reported. We examined interaction between rs738409 and overweight, and between rs738409 and dietary intakes (carbohydrates, sucrose and ω6:ω3-PUFA ratio), on fasting triglyceride levels. From the Malmo Diet and Cancer Study-Cardiovascular Cohort, 4,827 individuals without diabetes aged 58 ± 6 years, 2,346 with BMI ≤ 25 kg/m² and 2,478 with BMI > 25 kg/m², were included in cross-sectional analyses. Dietary data were collected by a modified diet history method. Overweight modified the association between rs738409 and fasting triglyceride levels (P_interaction = 0.003). G-allele associated with lower triglycerides only among overweight individuals (P = 0.01). Nominally, significant interaction on triglyceride levels was observed between rs738409 and sucrose among normal-weight individuals (P_interaction = 0.03). G-allele associated with lower triglycerides among overweight individuals in the lowest tertiles of carbohydrate and ω6:ω3-PUFA ratio (P = 0.04 and P = 0.001) and with higher triglycerides among normal-weight individuals in the highest tertile of sucrose (P = 0.001). We conclude that overweight and dietary sucrose may modify the association between rs738409 and fasting triglyceride levels.

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Zinc-induced upregulation of metallothionein (MT)-2A is predicted by gene expression of zinc transporters in healthy adults

The usefulness of zinc transporter and metallothionein (MT) gene expressions to detect changes in zinc intake remains unclear. This pilot study aimed to determine the effects of zinc supplementation on zinc transporter and MT gene expressions in humans. Healthy adults (n = 39) were randomised to zinc treatment (ZT), receiving 22 mg Zn/day (n = 19), or no treatment (NT) (n = 20). Blood samples were collected on Days 0, 2, 7, 14, and 21. Plasma zinc and serum C-reactive protein concentrations were analysed. Gene expression of zinc transporters and MT in peripheral blood mononuclear cells was analysed using real-time PCR. Using repeated-measures ANOVA, MT-2A gene expression and fold change were found to be higher in the ZT group (P = 0.025 and P = 0.016, respectively) compared to the NT group, specifically at Day 2 (40 ± 18 % increase from baseline, P = 0.011), despite no significant increase in plasma zinc concentration. In a multiple regression model exploring the changes in gene expressions between Days 0 and 21, the change in MT-2A gene expression was correlated with changes in all zinc transporter expressions (r² = 0.54, P = 0.029); the change in ZIP1 expression emerged as a univariate predictor (P = 0.003). Dietary zinc intake was predictive of zinc transporter and MT expressions (P = 0.030). Physical activity level was positively correlated with baseline ZIP7 expression (r = 0.36, P = 0.029). The present study shows that MT-2A expression is related to changing expression of zinc transporter genes, specifically ZIP1, in response to zinc supplementation. The current report adds to our understanding of MT in the coordinated nature of cellular zinc homeostasis.

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Camera trap reveals the co‐occurrence patterns of two sympatric muntjac species in southern Anhui Province,China: No spatial segregation

The competitive relationship and coexistence pattern among close related species have long been one of the hot issues in ecological research. Interspecies interactions can exert important influences on the local distribution of rare species. Black muntjac Muntiacus crinifrons is an endemic species to eastern China, currently restricted to limited regions. In contrast, Chinese muntjac Muntiacus reevesi is the most common and widespread deer in southern China. Both species co‐occur in southern Anhui and western Zhejiang Province. Little is known about the interaction of these two sympatric‐related species. In this study, to investigate the site use determinants and co‐occurrence pattern of the two sympatric muntjac species, we conducted a camera trap survey across about 250 km² in mountainous area of southern Anhui Province, China. We adopted a multistep approach to incorporate habitat preferences while modeling occupancy and detection. We found that the two species did not separate along elevation gradient (range from 400 m to 1,400 m) as described in previous studies. Results of single‐species occupancy models indicated that elevation had positive effects on the site use of both species, while slope had an opposite influence on their site use. Positive effects of elevation on the site use implied that both species try to avoid human interference at low elevations. Significant negative effect of slope on the site use of black muntjac suggested that the species prefer habitat with gentle slope and avoided steep. Co‐occurrence models and species interaction factors provided evidence that the two muntjac species had an independent occupancy (ψ ^{BM CM} = ψ ^{BM cm}, SIF = 1) and exhibited a positive species interaction in detection probability (p ^BM < r ^{BM CM}). Combined with the results of previous studies, we suggested that it was fine differentiation in microhabitats and food resources utilization rather spatial or temporal segregation that allowed the two species co‐occurrence. The site use determinants revealed in our study would be useful for the habitat conservation and restoration for the rare black muntjac, and the co‐occurrence pattern of the two sympatric muntjac species could provide useful information for deep understanding of the coexistence mechanism among forest‐dwelling ungulates.     

Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

Isoniazid represents a first-line anti-tuberculosis medication in prevention and treatment. This prodrug is activated by a mycobacterial catalase-peroxidase enzyme called KatG in Mycobacterium tuberculosis), thereby inhibiting the synthesis of mycolic acid, required for the mycobacterial cell wall. Moreover, isoniazid activation by KatG produces some radical species (e.g., nitrogen monoxide), that display anti-mycobacterial activity. Remarkably, the ability of mycobacteria to persist in vivo in the presence of reactive nitrogen and oxygen species implies the presence in these bacteria of (pseudo-)enzymatic detoxification systems, including truncated hemoglobins (trHbs). Here, we report that isoniazid binds reversibly to ferric and ferrous M. tuberculosis trHb type N (or group I; Mt-trHbN(III) and Mt-trHbN(II), respectively) with a simple bimolecular process, which perturbs the heme-based spectroscopic properties. Values of thermodynamic and kinetic parameters for isoniazid binding to Mt-trHbN(III) and Mt-trHbN(II) are K = (1.1±0.1)×10⁻⁴ M, k _on = (5.3±0.6)×10³ M⁻¹ s⁻¹ and k _off = (4.6±0.5)×10⁻¹ s⁻¹; and D = (1.2±0.2)×10⁻³ M, d _on = (1.3±0.4)×10³ M⁻¹ s⁻¹, and d _off = 1.5±0.4 s⁻¹, respectively, at pH 7.0 and 20.0°C. Accordingly, isoniazid inhibits competitively azide binding to Mt-trHbN(III) and Mt-trHbN(III)-catalyzed peroxynitrite isomerization. Moreover, isoniazid inhibits Mt-trHbN(II) oxygenation and carbonylation. Although the structure of the Mt-trHbN-isoniazid complex is not available, here we show by docking simulation that isoniazid binding to the heme-Fe atom indeed may take place. These data suggest a direct role of isoniazid to impair fundamental functions of mycobacteria, e.g. scavenging of reactive nitrogen and oxygen species, and metabolism.     

Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine

Liposomal encapsulated cytarabine (DepoCyte^®, Mundipharma GmbH, Limburg/Lahn, Germany) is a slow-release formulation of conventional cytarabine. It is licensed for intrathecal use in patients with lymphomatous and leukemic meningitis. DepoCyte^® obtained superior response rates, improved patient quality of life and improved the time to neurological progression in a randomized albeit small clinical trial. In this review we briefly summarize the clinical data and discuss them in light of clinical problems and possible treatment scenarios.     

Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup’ik people

n-3 Polyunsaturated fatty acids (n-3 PUFAs) have anti-obesity effects that may modulate risk of obesity, in part, through interactions with genetic factors. Genome-wide association studies (GWAS) have identified genetic variants associated with body mass index (BMI); however, the extent to which these variants influence adiposity through interactions with n-3 PUFAs remains unknown. We evaluated 10 highly replicated obesity GWAS single nucleotide polymorphisms (SNPs) for individual and cumulative associations with adiposity phenotypes in a cross-sectional sample of Yup’ik people (n = 1,073) and evaluated whether genetic associations with obesity were modulated by n-3 PUFA intake. A genetic risk score (GRS) was calculated by adding the BMI-increasing alleles across all 10 SNPs. Dietary intake of n-3 PUFAs was estimated using nitrogen stable isotope ratio (δ¹⁵N) of red blood cells, and genotype–phenotype analyses were tested in linear models accounting for familial correlations. GRS was positively associated with BMI (p = 0.012), PBF (p = 0.022), ThC (p = 0.025), and waist circumference (p = 0.038). The variance in adiposity phenotypes explained by the GRS included BMI (0.7 %), PBF (0.3 %), ThC (0.7 %), and WC (0.5 %). GRS interactions with n-3 PUFAs modified the association with adiposity and accounted for more than twice the phenotypic variation (~1–2 %), relative to GRS associations alone. Obesity GWAS SNPs contribute to adiposity in this study population of Yup’ik people and interactions with n-3 PUFA intake potentiated the risk of fat accumulation among individuals with high obesity GRS. These data suggest the anti-obesity effects of n-3 PUFAs among Yup’ik people may, in part, be dependent upon an individual’s genetic predisposition to obesity.

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A proteomic profile of synoviocyte lesions microdissected from formalin-fixed paraffin-embedded synovial tissues of rheumatoid arthritis

Background

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints. Early intervention followed by early diagnosis can result in disease remission; however, both early stage diagnosis and provision of effective treatment have been impeded by the heterogeneity of RA, which details of pathological mechanism are unclear. Regardless of numerous investigations of RA by means of genomic and proteomic approaches, proteins interplaying in RA synovial tissues that contain various types of synoviocytes, are not yet sufficiently understood. Hence we have conducted an HPLC/mass spectrometry-based exploratory proteomic analysis focusing on synoviocyte lesions laser-microdissected (LMD) from formalin-fixed paraffin-embedded (FFPE) synovial tissues (RA, n = 15; OA, n = 5), where those of Osteoarthritis (OA) were used as the control.

Results

A total of 508 proteins were identified from the RA and OA groups. With the semi-quantitative comparisons, the spectral index (SpI), log2 protein ratio (R_SC) based on spectral counting, and statistical G-test, 98 proteins were found to be significant (pair-wise p < 0.05) to the RA synovial tissues. These include stromelysin-1 (MMP3), proteins S100-A8 and S100-A9, plastin-2, galectin-3, calreticulin, cathepsin Z, HLA-A, HLA-DRB1, ferritin, neutrophil defensin 1, CD14, MMP9 etc.

Conclusions

Our results confirmed the involvement of known RA biomarkers such as stromelysin-1 (MMP3) and proteins S100-A8 and S100-A9, and also that of leukocyte antigens such as HLA-DRB1. Network analyses of protein–protein interaction for those proteins significant to RA revealed a dominant participation of ribosome pathway (p = 5.91 × 10⁻⁴⁵), and, interestingly, the associations of the p53 signaling (p = 2.34 × 10⁻⁵). An involvement of proteins including CD14, S100-A8/S100-A9 seems to suggest an activation of the NF-kB/MAPK signaling pathway. Our strategy of laser-microdissected FFPE-tissue proteomic analysis in Rheumatoid Arthritis thus demonstrated its technical feasibility in profiling proteins expressed in synovial tissues, which may play important roles in the RA pathogenesis.

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Effects on metabolic markers are modified by PPARG2 and COX2 polymorphisms in infants randomized to fish oil

Long-chain n-3 fatty acids (n-3 LCPUFA) improve blood pressure (BP) and lipid profile in adults and improve insulin sensitivity in rodents. We have previously shown that n-3 LCPUFA reduces BP and plasma triacylglycerol (TAG) in infants. Few studies have found effects on glucose homeostasis in humans. We explored possible effect modification by FADS, PPARG2, and COX2 genotypes to support potential effects of n-3 LCPUFA on metabolic markers in infants. Danish infants (133) were randomly allocated to daily supplementation with a teaspoon (~5 mL/day) of fish oil (FO) or sunflower oil (SO) from 9 to 18 months of age. Before and after the intervention, we assessed BP, erythrocyte n-3 LCPUFA, plasma lipid profile, insulin, and glucose in addition to functional single nucleotide polymorphisms in FADS, PPARG2, and COX2. At 18 months, plasma TAG was lower in the FO compared with SO group (p = 0.014). This effect was modified by PPARG2-Pro12Ala, as TAG only decreased among heterozygotes. FO supplemented PPARG2 Pro12Ala heterozygotes also had decreased plasma glucose compared with the SO group (p = 0.043). The effect of FO on mean arterial BP at 18 months was gender dependent (p = 0.020) and reduced in boys only (p = 0.028). Diastolic BP was, however, lower among all FO supplemented homozygous COX2-T8473C variant allele carriers compared with the SO group (p = 0.001). In conclusion, our results confirm that FO supplementation in late infancy reduces TAG and BP and indicates that the effects are mediated via peroxisome proliferator-activated receptor-γ and cyclooxygenase-2. Furthermore, FO reduced plasma glucose only in PPARG2 heterozygotes.

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Real-life use of vitamin D3-fortified bread and milk during a winter season: the effects of CYP2R1 and GC genes on 25-hydroxyvitamin D concentrations in Danish families,the VitmaD study

Common genetic variants rs10741657 and rs10766197 in CYP2R1 and rs4588 and rs842999 in GC and a combined genetic risk score (GRS) of these four variants influence late summer 25-hydroxyvitamin D (25(OH)D) concentrations. The objectives were to identify those who are most at risk of developing low vitamin D status during winter and to assess whether vitamin D₃-fortified bread and milk will increase 25(OH)D concentrations in those with genetically determined low 25(OH)D concentrations at late summer. We used data from the VitmaD study. Participants were allocated to either vitamin D₃-fortified bread and milk or non-fortified bread and milk during winter. In the fortification group, CYP2R1 (rs10741657) and GC (rs4588 and rs842999) were statistically significantly associated with winter 25(OH)D concentrations and CYP2R1 (rs10766197) was borderline significant. There was a negative linear trend between 25(OH)D concentrations and carriage of 0–8 risk alleles (p < 0.0001). No association was found for the control group (p = 0.1428). There was a significant positive linear relationship between different quintiles of total vitamin D intake and the increase in 25(OH)D concentrations among carriers of 0–2 (p = 0.0012), 3 (p = 0.0001), 4 (p = 0.0118) or 5 (p = 0.0029) risk alleles, but not among carriers of 6–8 risk alleles (p = 0.1051). Carriers of a high GRS were more prone to be vitamin D deficient compared to carriers of a low GRS. Furthermore, rs4588-AA carriers have a low but very stable 25(OH)D concentration, and interestingly, also low PTH level.

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Identification of novel susceptibility loci for non‐syndromic cleft lip with or without cleft palate

Although several genome‐wide association studies (GWAS) of non‐syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in‐depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case‐parent trios and another in‐house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3’ of SERTAD4, P = 6.44 × 10⁻¹⁴; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10⁻¹³ and 2.80 × 10⁻¹¹, respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10⁻⁶; rs2095293: intron of NR6A1, P = 2.98 × 10⁻⁵). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10⁻¹⁶). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down‐regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population.     

Polymorphism in miR-31 and miR-584 binding site in the angiotensinogen gene differentially influences body fat distribution in both sexes

Angiotensinogen (AGT), its active fragments and microRNA-31 (miR-31) play an important role in adipocyte differentiation. AGT contains a miR-31 polymorphic binding site. We hypothesize that the rs7079 polymorphism in the miR-31/584 binding site of the AGT gene could influence body fat distribution. A total of 751 subjects (195 men, 556 women) were enrolled in the study. The rs7079 genotypes were determined by qRT-PCR. Anthropometric measurements were taken on all subjects, who were subsequently divided into two groups: obese (>30 kg m⁻²) and non-obese (<30 kg m⁻²). Linear regression models were created to determine the contributions of sex, obesity status and rs7079 to all measured parameters. Adding the rs7079 genotype significantly contributed to the linear regression model for waist circumference (p = 0.013), hip circumference (p = 0.018) and supraspinal skin-fold thickness (p = 1 × 10⁻³). Differences between sexes and between the obese and non-obese groups were observed. Waist circumference was lower in men carrying the A allele (p = 0.022); hip circumference was higher only in obese women carrying the A allele (p = 0.015). While men carrying the A allele had lower supraspinal skin-fold thickness (p = 0.022), this parameter was found to be higher in A allele carrying women (p = 3 × 10⁻³). The higher total sum of skin-fold thickness in A allele carrying women was restricted to obese individuals (p = 0.028). The presence of the A allele was associated with both lower tricipital skin-fold thickness in non-obese women (p = 0.023) and a trend of higher thickness in non-obese men (p = 0.065). Significant associations of rs7079 in the AGT gene and body fat distribution were observed. The distribution followed opposing patterns in both sexes.     

ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement

Fish oil supplementation provides an inconsistent degree of protection from cardiovascular disease (CVD), which may be attributed to genetic variation. Single nucleotide polymorphisms (SNPs) in the elongation-of-very-long-chain-fatty-acids-2 (ELOVL2) gene have been strongly associated with plasma proportions of n-3 long-chain polyunsaturated fatty acids (LC-PUFA). We investigated the effect of genotype interaction with fish oil dosage on plasma n-3 LC-PUFA proportions in a parallel double-blind controlled trial, involving 367 subjects randomised to treatment with 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1.51:1) or olive oil placebo for 6 months. We genotyped 310 subjects for ELOVL2 gene SNPs rs3734398, rs2236212 and rs953413. At baseline, carriers of all minor alleles had lower proportions of plasma DHA than non-carriers (P = 0.021–0.030). Interaction between genotype and treatment was a significant determinant of plasma EPA (P < 0.0001) and DHA (P = 0.004–0.032). After the 1.8 g/day dose, carriers of ELOVL2 SNP minor alleles had approximately 30 % higher proportions of EPA (P = 0.002–0.004) and 9 % higher DHA (P = 0.013–0.017) than non-carriers. Minor allele carriers could therefore particularly benefit from a high intake of EPA and DHA in maintaining high levels of plasma n-3 PUFA conducive to protection from CVD.

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Thermus parvatiensis RLT sp. nov., Isolated from a Hot Water Spring,Located Atop the Himalayan Ranges at Manikaran,India

A Gram negative, yellow pigmented, rod shaped bacterium designated as RL^T was isolated from a hot water spring (90–98 °C) located at Manikaran in Northern India. The isolate grows at 60–80 °C (optimum, 70 °C) and at pH 7.0–9.0 (optimum pH 7.2). Phylogenetic analysis of 16S rRNA gene sequences and levels of DNA–DNA relatedness together indicate that the new isolate represents a novel species of the genus Thermus with closest affinity to Thermus thermophilus HB8^T (99.5 %) followed by Thermus arciformis (96.4 %). A comparative analysis of partial sequences of housekeeping genes (HKG) further revealed that strain RL^T is a novel species belonging to the genus Thermus. The melting G+C content of strain RL^T was calculated as 68.7 mol%. The DNA–DNA relatedness value of strain RL^T with its nearest neighbours (>97 %) was found to be less than 70 % indicating that strain RL^T represents a novel species of the genus Thermus. MK-8 was the predominant respiratory quinone. The presence of characteristic phospholipid and glycolipid further confirmed that strain RL^T belongs to the genus Thermus. The predominant fatty acids of strain RL^T were iso-C_17:0 (23.67 %) and iso-C_15:0 (24.50 %). The results obtained after DNA–DNA hybridization, biochemical and physiological tests clearly distinguished strain RL^T from its closely related species. Thus, strain RL^T represents a novel species of the genus Thermus for which the name Thermus parvatiensis is proposed (=DSM 21745^T= MTCC 8932^T).

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Genetic predisposition scores for dyslipidaemia influence plasma lipid concentrations at baseline,but not the changes after controlled intake of n-3 polyunsaturated fatty acids

Inconsistent effects of fish oil supplementation on plasma lipids may be influenced by genetic variation. We investigated 12 single nucleotide polymorphisms (SNPs) associated with dyslipidaemia in genome-wide association studies, in 310 participants randomised to treatment with placebo or 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) (1.51:1) in a 12-month parallel controlled trial. Effects of risk alleles were assessed as trait-specific genetic predisposition scores (GPS) and singly. GPS were positively associated with baseline concentrations of plasma total cholesterol, low-density-lipoprotein cholesterol and triglyceride (TG) and negatively with high-density-lipoprotein cholesterol. The TG-GPS was associated with 0.210 mmol/L higher TG per risk allele (P < 0.0001), but no effects of single TG SNPs were significant at baseline. After treatment with EPA and DHA, TG-GPS was associated with 0.023 mmol/L lower TG per risk allele (P = 0.72). No interactions between GPS and treatment were significant; however, FADS1 SNP rs174546 C/T interaction with treatment was a significant determinant of plasma TG concentration (P = 0.047, n = 267). Concentration differed between genotype groups after the 1.8 g/day dose (P = 0.026), decreasing by 3.5 (95 % CI −15.1 to 8.2) % in non-carriers of the risk T-allele (n = 30) and by 21.6 (95 % CI −32.1 to −11.2) % in carriers (n = 37), who showed a highly significant difference between treatments (P = 0.007). Carriers of the FADS1 rs174546 risk allele could benefit from a high intake of EPA and DHA in normalising plasma TG.

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Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells

Identification of genetic variants associated with glucocorticoids (GC) sensitivity of leukaemia cells may provide insight into potential drug targets and tailored therapy. In the present study, within 72 leukaemic cell lines derived from Japanese patients with B‐cell precursor acute lymphoblastic leukaemia (ALL), we conducted genome‐wide genotyping of single nucleotide polymorphisms (SNP) and attempted to identify genetic variants associated with GC sensitivity and NR3C1 (GC receptor) gene expression. IC50 measures for prednisolone (Pred) and dexamethasone (Dex) were available using an alamarBlue cell viability assay. IC50 values of Pred showed the strongest association with rs904419 (P = 4.34 × 10⁻⁸), located between the FRMD4B and MITF genes. The median IC50 values of prednisolone for cell lines with rs904419 AA (n = 13), AG (n = 31) and GG (n = 28) genotypes were 0.089, 0.139 and 297 µmol/L, respectively. For dexamethasone sensitivity, suggestive association was observed for SNP rs2306888 (P = 1.43 × 10⁻⁶), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10⁻⁸), located in the PLEKHA8 gene. These genetic variants may affect GC sensitivity of ALL cells and may give rise to opportunities in personalized medicine for effective and safe chemotherapy in ALL patients.