FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness

Background

A common single nucleotide polymorphism (SNP) of FTO (rs9939609, T/A) is associated with total body fatness. We investigated the association of this SNP with abdominal and peripheral fatness and obesity-related metabolic traits in middle-aged men through a broad range of fatness present already in adolescence.

Methodology/Principal Findings

Obese young Danish men (n = 753, BMI≥31.0 kg/m²) and a randomly selected group (n = 879) from the same population were examined in three surveys (mean age 35, 46 and 49 years, respectively). The traits included anthropometrics, body composition, oral glucose tolerance test, blood lipids, blood pressure, fibrinogen and aspartate aminotransferase. Logistic regression analysis was used to assess the age-adjusted association between the phenotypes and the odds ratios for the FTO rs9939609 (TT and TA genotype versus the AA genotype), for anthropometrics and body composition estimated per unit z-score. BMI was strongly associated with the AA genotype in all three surveys: OR = 1.17, p = 1.1*10⁻⁶, OR = 1.20, p = 1.7*10⁻⁷, OR = 1.17, p = 3.4*10⁻³, respectively. Fat body mass index was also associated with the AA genotype (OR = 1.21, p = 4.6*10⁻⁷ and OR = 1.21, p = 1.0*10⁻³). Increased abdominal fatness was associated with the AA genotype when measured as waist circumference (OR = 1.21, p = 2.2*10⁻⁶ and OR = 1.19, p = 5.9*10⁻³), sagittal abdominal diameter (OR = 1.17, p = 1.3*10⁻⁴ and OR = 1.18, p = 0.011) and intra-abdominal adipose tissue (OR = 1.21, p = 0.005). Increased peripheral fatness measured as hip circumference (OR = 1.19, p = 1.3*10⁻⁵ and OR = 1.18, p = 0.004) and lower body fat mass (OR = 1.26, p = 0.002) was associated with the AA genotype. The AA genotype was significantly associated with decreased Stumvoll insulin sensitivity index (OR = 0.93, p = 0.02) and with decreased non-fasting plasma HDL-cholesterol (OR = 0.57, p = 0.037), but not with any other of the metabolic traits. However, all significant results for both body fat distribution and metabolic traits were explained by a mediating effect of total fat mass.

Conclusion

The association of the examined FTO SNP to general fatness throughout the range of fatness was confirmed, and this association explains the relation between the SNP and body fat distribution and decreased insulin sensitivity and HDL-cholesterol. The SNP was not significantly associated with other metabolic traits suggesting that they are not derived from the general accumulation of body fat.     

AA-amyloidosis can be transferred by peripheral blood monocytes

Spongiform encephalopathies have been reported to be transmitted by blood transfusion even prior to the clinical onset. Experimental AA-amyloidosis shows similarities with prion disease and amyloid-containing organ-extracts can prime a recipient for the disease. In this systemic form of amyloidosis N-terminal fragments of the acute-phase reactant apolipoprotein serum amyloid A are the main amyloid protein. Initial amyloid deposits appear in the perifollicular region of the spleen, followed by deposits in the liver. We used the established murine model and induced AA-amyloidosis in NMRI mice by intravenous injections of purified amyloid fibrils ('amyloid enhancing factor') combined with inflammatory challenge (silver nitrate subcutaneously). Blood plasma and peripheral blood monocytes were isolated, sonicated and re-injected into new recipients followed by an inflammatory challenge during a three week period. When the animals were sacrificed presence of amyloid was analyzed in spleen sections after Congo red staining. Our result shows that some of the peripheral blood monocytes, isolated from animals with detectable amyloid, contained amyloid-seed that primed for AA-amyloid. The seeding material seems to have been phagocytosed by the cells since the AA-precursor (SAA1) was found not be expressed by the monocytes. Plasma recovered from mice with AA amyloidosis lacked seeding capacity. Amyloid enhancing activity can reside in monocytes recovered from mice with AA-amyloidosis and in a prion-like way trigger amyloid formation in conjunction with an inflammatory disorder. Human AA-amyloidosis resembles the murine form and every individual is expected to be exposed to conditions that initiate production of the acute-phase reactant. The monocyte-transfer mechanism should be eligible for the human disease and we point out blood transfusion as a putative route for transfer of amyloidosis.     

A single CD8+ T cell epitope sets the long-term latent load of a murid herpesvirus

The pathogenesis of persistent viral infections depends critically on long-term viral loads. Yet what determines these loads is largely unknown. Here, we show that a single CD8+ T cell epitope sets the long-term latent load of a lymphotropic gamma-herpesvirus, Murid herpesvirus-4 (MuHV-4). The MuHV-4 M2 latency gene contains an H2-Kd -restricted T cell epitope, and wild-type but not M2(-) MuHV-4 was limited to very low level persistence in H2d mice. Mutating the epitope anchor residues increased viral loads and re-introducing the epitope reduced them again. Like the Kaposi's sarcoma-associated herpesvirus K1, M2 shows a high frequency of non-synonymous mutations, suggesting that it has been selected for epitope loss. In vivo competition experiments demonstrated directly that epitope presentation has a major impact on viral fitness. Thus, host MHC class I and viral epitope expression interact to set the long-term virus load.     

Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide

Mycobacterium tuberculosis is a facultative intracellular pathogen that inhibits phagosome maturation in macrophages thereby securing survival and growth. Mycobacteria reside in an early endocytic compartment of near-neutral pH where they upregulate production of complex glycolipids such as trehalose dimycolate. Here, we report that trehalose dimycolate coated onto beads increased the bead retention in early phagosomes, i.e. at a similar stage as viable mycobacteria. Thus, a single mycobacterial lipid sufficed to divert phagosome maturation and likely contributes to mycobacterial survival in macrophages. Previous studies showed that activated macrophages promote maturation of mycobacterial phagosomes and eliminate mycobacteria through bactericidal effectors including nitric oxide generated by inducible nitric-oxide synthase. We show that deceleration of bead phagosome maturation by trehalose dimycolate was abolished in immune-activated wild type, but not in activated nitric-oxide synthase-deficient macrophages, nor when hydroxyl groups of trehalose dimycolate were chemically modified by reactive nitrogen intermediates. Thus, specific host defence effectors of activated macrophages directly target a specific virulence function of mycobacteria.     

Propofol lipidic infusion promotes resistance to antifungals by reducing drug input into the fungal cell

Background  

The administration of non-antifungal drugs during patient hospitalization might be responsible for discrepancies between in vitro and in vivo susceptibility to antifungals. Propofol is often administered to intensive care units as a sedative.     

Access to health care among status Aboriginal people with chronic kidney disease

Background

Ethnic disparities in access to health care and health outcomes are well documented. It is unclear whether similar differences exist between Aboriginal and non-Aboriginal people with chronic kidney disease in Canada. We determined whether access to care differed between status Aboriginal people (Aboriginal people registered under the federal Indian Act) and non-Aboriginal people with chronic kidney disease.

Methods

We identified 106 511 non-Aboriginal and 1182 Aboriginal patients with chronic kidney disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m²). We compared outcomes, including hospital admissions, that may have been preventable with appropriate outpatient care (ambulatory-care–sensitive conditions) as well as use of specialist services, including visits to nephrologists and general internists.

Results

Aboriginal people were almost twice as likely as non-Aboriginal people to be admitted to hospital for an ambulatory-care–sensitive condition (rate ratio 1.77, 95% confidence interval [CI] 1.46–2.13). Aboriginal people with severe chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m²) were 43% less likely than non-Aboriginal people with severe chronic kidney disease to visit a nephrologist (hazard ratio 0.57, 95% CI 0.39–0.83). There was no difference in the likelihood of visiting a general internist (hazard ratio 1.00, 95% CI 0.83–1.21).

Interpretation

Increased rates of hospital admissions for ambulatory-care–sensitive conditions and a reduced likelihood of nephrology visits suggest potential inequities in care among status Aboriginal people with chronic kidney disease. The extent to which this may contribute to the higher rate of kidney failure in this population requires further exploration.Ethnic disparities in access to health care are well documented;^1,2 however, the majority of studies include black and Hispanic populations in the United States. The poorer health status and increased mortality among Aboriginal populations than among non-Aboriginal populations,^3,4 particularly among those with chronic medical conditions,^5,6 raise the question as to whether there is differential access to health care and management of chronic medical conditions in this population.The prevalence of end-stage renal disease, which commonly results from chronic kidney disease, is about twice as common among Aboriginal people as it is among non-Aboriginal people.^7,8 Given that the progression of chronic kidney disease can be delayed by appropriate therapeutic interventions^9,10 and that delayed referral to specialist care is associated with increased mortality,^11,12 issues such as access to health care may be particularly important in the Aboriginal population. Although previous studies have suggested that there is decreased access to primary and specialist care in the Aboriginal population,^13–15 these studies are limited by the inclusion of patients from a single geographically isolated region,¹³ the use of survey data,¹⁴ and the inability to differentiate between different types of specialists and reasons for the visit.¹⁵In addition to physician visits, admission to hospital for ambulatory-care–sensitive conditions (conditions that, if managed effectively in an outpatient setting, do not typically result in admission to hospital) has been used as a measure of access to appropriate outpatient care.^16,17 Thus, admission to hospital for an ambulatory-care–sensitive condition reflects a potentially preventable complication resulting from inadequate access to care. Our objective was to determine whether access to health care differs between status Aboriginal (Aboriginal people registered under the federal Indian Act) and non-Aboriginal people with chronic kidney disease. We assess differences in care by 2 measures: admission to hospital for an ambulatory-care–sensitive condition related to chronic kidney disease; and receipt of nephrology care for severe chronic kidney disease as recommended by clinical practice guidelines.¹⁸     

Dynamics of colour polymorphism in a changing environment: fire melanism and then what?

Studies of whether disturbance events are associated with the changing genetic compositions of natural populations may provide insights into the importance of local selection events in maintaining diversity, and might inform plans for the conservation and protection of that diversity. We examined the dynamics of a colour pattern polymorphism in a natural population of pygmy grasshoppers Tetrix subulata (Orthoptera: Tetrigidae) inhabiting a previously burnt clear-cut area. Data on morph frequencies for wild-caught and captive-reared individuals indicated that the initial dominance of black phenotypes following the fire event was followed by an increased diversity of the polymorphism. This was manifested as the appearance of a novel morph, a decreased incidence of the black morph, and a more even distribution of individuals across alternative morphs following the recurrence of vegetation. We also found that the colour patterns of captive-reared individuals resembled those of their parents and that the degree of within-clutch diversity increased between generations. Our comparisons of morph frequencies across generations and between environments within generations point to a genetic determination of colour pattern, and indicate that the polymorphism is influenced more strongly by selection than by plasticity or migration.     

Adaxial/abaxial specification in the regulation of photosynthesis and stomatal opening with respect to light orientation and growth with CO2 enrichment in the C4 species Paspalum dilatatum.

Whole-plant morphology, leaf structure and composition were studied together with the effects of light orientation on the dorso-ventral regulation of photosynthesis and stomatal conductance in Paspalum dilatatum cv. Raki plants grown for 6 wk at either 350 or 700 microl l(-1) CO(2). Plant biomass was doubled as a result of growth at high CO(2) and the shoot:root ratio was decreased. Stomatal density was increased in the leaves of the high CO(2)-grown plants, which had greater numbers of smaller stomata and more epidermal cells on the abaxial surface. An asymmetric surface-specific regulation of photosynthesis and stomatal conductance was observed with respect to light orientation. This was not caused by dorso-ventral variations in leaf structure, the distribution of phosphoenolpyruvate carboxylase (PEPC) and ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) proteins or light absorptance, transmittance or reflectance. Adaxial/abaxial specification in the regulation of photosynthesis results from differential sensitivity of stomatal opening to light orientation and fixed gradients of enzyme activation across the leaf.     

Detection and genetic characterization of porcine circovirus 2 isolates from the first cases of postweaning multisystemic and wasting syndrome in wild boars in Greece

In 2002, postweaning multisystemic wasting syndrome (PMWS) was diagnosed in a European female wild boar (Sus scrofa), based on the detection of porcine circovirus 2 (PCV2) DNA in various organs, including the uterus, and on histopathologic lesions. This is the first detection of PCV2 DNA in the uterus of a wild boar. Three years later (2005), a wild boar < 6-8 mo of age was found moribund. It presented wasting and dyspnea and finally died. PCV2 DNA was detected in tissue samples, and histopathologic lesions consistent with PMWS were observed. Both wild boars were from neighboring hunting areas in central Greece. Two PCV2 strains from the wild boars were genetically characterized and compared to other reported PCV2 sequences from wild boars and domestic pigs. The PCV-2 sequences from the wild boars in this study were closely related to each other and were grouped with two isolates from wild boars from Hungary. The phylogenetic analysis revealed that the virus might be transmitted between hunting areas. In addition, PCV2 may spread from domestic pigs to wild boars and vice versa.