Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort)

Exposure to polyunsaturated fatty acids (PUFA) influences immune function and may affect the risk of allergy development. Long chain PUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by FADS and ELOVL genes. In 211 subjects, we investigated whether polymorphisms in the FADS gene cluster and the ELOVL2 gene were associated with allergy or PUFA composition in serum phospholipids in a Swedish birth-cohort sampled at birth and at 13 years of age; allergy was diagnosed at 13 years of age. Minor allele carriers of rs102275 and rs174448 (FADS gene cluster) had decreased proportions of 20:4 n-6 in cord and adolescent serum and increased proportions of 20:3 n-6 in cord serum as well as a nominally reduced risk of developing atopic eczema, but not respiratory allergy, at 13 years of age. Minor allele carriers of rs17606561 in the ELOVL2 gene had nominally decreased proportions of 20:4 n-6 in cord serum but ELOVL polymorphisms (rs2236212 and rs17606561) were not associated with allergy development. Thus, reduced capacity to desaturase n-6 PUFAs due to FADS polymorphisms was nominally associated with reduced risk for eczema development, which could indicate a pathogenic role for long-chain PUFAs in allergy development.     

Socioeconomic inequalities in physical and mental functioning of British, Finnish, and Japanese civil servants: Role of job demand, control, and work hours

This study aims to evaluate whether the pattern of socioeconomic inequalities in physical and mental functioning as measured by the Short Form 36 (SF-36) differs among employees in Britain, Finland, and Japan and whether work characteristics contribute to some of the health inequalities. The participants were 7340 (5122 men and 2218 women) British employees, 2297 (1638 men and 659 women) Japanese employees, and 8164 (1649 men and 6515 women) Finnish employees. All the participants were civil servants aged 40–60 years. Both male and female low grade employees had poor physical functioning in all cohorts. British and Japanese male low grade employees tended to have poor mental functioning but the associations were significant only for Japanese men. No consistent employment-grade differences in mental functioning were observed among British and Japanese women. Among Finnish men and women, high grade employees had poor mental functioning. In all cohorts, high grade employees had high control, high demands and long work hours. The grade differences in poor physical functioning and disadvantaged work characteristics among non-manual workers were somewhat smaller in the Finnish cohort than in the British and Japanese cohorts. Low control, high demands, and both short and long work hours were associated with poor functioning. When work characteristics were adjusted for, the socioeconomic differences in poor functioning were mildly attenuated in men, but the differences increased slightly in women. This study reconfirms the generally observed pattern of socioeconomic inequalities in health for physical functioning but not for mental functioning. The role of work characteristics in the relationship between socioeconomic status and health differed between men and women but was modest overall. We suggest that these differences in the pattern and magnitude of grade differences in work characteristics and health among the 3 cohorts may be attributable to the different welfare regimes among the 3 countries.     

Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non-insulin-dependent diabetes mellitus albino rats

Objectives:

Punica granatum L., (Family: Punicaceae) is used in Indian Unani medicine for treatment of diabetes mellitus. Therefore, the present study was done to evaluate the antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of P. granatum in alloxan-induced diabetic rats.

Materials and Methods:

Healthy Wistar albino rats (100-150 g) were divided into four groups of six animals each. Groups A and B received normal saline [(10 ml/kg/day/per oral (p.o.)]; group C received ethanolic extract of leaves of P. granatum (500 mg/kg/p.o.); and group D received glibenclamide (0.5 mg/kg/day/p.o.). The extracts were given for 1 week in all groups. To induce diabetes, alloxan 150 mg/kg, intraperitoneal (i.p.) single dose was administered to groups B, C, and D. Blood glucose and serum lipids [Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoproteins (LDL), and High Density Lipoproteins (HDL)] and the atherogenic index were estimated after one week. For mechanism of antidiabetic action glycogen estimation on the liver, cardiac and skeletal muscle, and intestinal glucose absorption was done.

Results:

Group B showed a significant (P<0.01) increase in blood glucose as compared to group A. Groups C and D showed significant decrease (P<0.01) in blood glucose level in comparison to group B. The test drug showed a significant (P<0.01) increase in glycogen content in the liver, cardiac, and skeletal muscle; it significantly (P<0.01) reduced intestinal glucose absorption. Groups C and D showed significant (P<0.01) decrease in serum TC, TG, LDL, and AI as compared to Group B, which showed a significant (P<0.01) increase. Groups C and D showed significant (P<0.01) increase in serum HDL as compared to Group B, which showed a significant (P<0.01) decrease in all values.

Conclusion:

P. granatum leaves possess significant antidiabetic and antihyperlipidemic activity.KEY WORDS: Antioxidant, atherogenic index, blood glucose, flavonoids, glycogen     

A Multi-Method Approach to Assess the Self-Interaction Behavior of Infliximab

Attractive self-interaction processes in antibody formulations increase the risk of aggregation and extraordinarily elevated viscosity at high protein concentrations. These challenges affect manufacturing and application. This study aimed to understand the self-interaction process of Infliximab as a model system with pronounced attractive self-interaction. The association mechanism was studied by a multi-method approach comprising analytical ultracentrifugation, dynamic light scattering, small angle X-ray scattering, self-interaction bio-layer interferometry and hydrogen-deuterium exchange mass spectrometry. Based on our results, both Fab and Fc regions of Infliximab are involved in self-interaction. We hypothesize a mechanism based on electrostatic interactions of polar and charged residues within the identified areas of the heavy and the light chain of the mAb. The combination of fast and reliable screening methods and low throughput but high resolution methods can contribute to detailed characterization and deeper understanding of specific self-interaction processes.     

An open label Phase I trial of a live attenuated H6N1 influenza virus vaccine in healthy adults

Background

We describe the results of an open label Phase I trial of a live attenuated H6N1 influenza virus vaccine (ClinicalTrials.gov Identifier: NCT00734175).

Methods and findings

We evaluated the safety, infectivity, and immunogenicity of two doses of 10⁷ TCID₅₀ of the H6N1 Teal HK 97/AA ca vaccine, a cold-adapted and temperature sensitive live, attenuated influenza vaccine (LAIV) in healthy seronegative adults.Twenty-two participants received the first dose of the vaccine, and 18 received the second dose of vaccine 4 weeks later. The vaccine had a safety profile similar to that of other investigational LAIVs bearing avian hemagglutinin (HA) and neuraminidase (NA) genes. The vaccine was highly restricted in replication: two participants had virus detectable by rRT-PCR beyond day 1 after each dose. Antibody responses to the vaccine were also restricted: 43% of participants developed a serum antibody response as measured by any assay: 5% by hemagglutination-inhibition assay, 5% by microneutralization assay, 29% by ELISA for H6 HA-specific IgG and 24% by ELISA for H6 HA specific IgA after either 1 or 2 doses. Following the second dose, vaccine specific IgG and IgA secreting cells as measured by ELISPOT increased from a mean of 0.6 to 9.2/10⁶ PBMCs and from 0.2 to 2.2/10⁶ PBMCs, respectively.

Conclusion

The H6N1 LAIV had a safety profile similar to that of LAIV bearing other HA and NA genes, but was highly restricted in replication in healthy seronegative adults. The H6N1 LAIV was also not as immunogenic as the seasonal LAIV.     

DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice

Influenza vaccination practice, which is based on neutralizing antibodies, requires being able to predict which viral strains will be circulating. If an unexpected strain, as in the 1997 H5N1 Hong Kong outbreak, or even a pandemic emerges, appropriate vaccines may take too long to prepare. Therefore, strategies based on conserved influenza antigens should be explored. We studied DNA vaccination in mice with plasmids expressing conserved nucleoprotein (NP) and matrix (M) from an H1N1 virus. After vaccination, mice were challenged with A/H5N1 viruses of low, intermediate, and high lethality. A/NP+A/M DNA vaccination reduced replication of A/Hong Kong/486/97 (HK/486), a nonlethal H5N1 strain, and protected against lethal challenge with more virulent A/Hong Kong/156/97 (HK/156). After HK/156 exposure, mice survived rechallenge with A/Hong Kong/483/97 (HK/483), although the DNA vaccination alone protected poorly against this highly virulent strain. In the absence of antigenically matched hemagglutinin-based vaccines, DNA vaccination with conserved influenza genes may provide a useful first line of defense against a rapidly spreading pandemic virus.     

Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcgammaRII-dependent entry into B cells in vitro

Vaccine-induced antibodies can prevent or, in the case of feline infectious peritonitis virus, aggravate infections by coronaviruses. We investigated whether a recombinant native full-length S-protein trimer (triSpike) of severe acute respiratory syndrome coronavirus (SARS-CoV) was able to elicit a neutralizing and protective immune response in animals and analyzed the capacity of anti-S antibodies to mediate antibody-dependent enhancement (ADE) of virus entry in vitro and enhancement of replication in vivo. SARS-CoV-specific serum and mucosal immunoglobulins were readily detected in immunized animals. Serum IgG blocked binding of the S-protein to the ACE2 receptor and neutralized SARS-CoV infection in vitro. Entry into human B cell lines occurred in a FcgammaRII-dependent and ACE2-independent fashion indicating that ADE of virus entry is a novel cell entry mechanism of SARS-CoV. Vaccinated animals showed no signs of enhanced lung pathology or hepatitis and viral load was undetectable or greatly reduced in lungs following challenge with SARS-CoV. Altogether our results indicate that a recombinant trimeric S protein was able to elicit an efficacious protective immune response in vivo and warrant concern in the safety evaluation of a human vaccine against SARS-CoV.     

Unfairness and health: evidence from the Whitehall II Study

OBJECTIVE: To examine the effects of unfairness on incident coronary events and health functioning. DESIGN: Prospective cohort study. Unfairness, sociodemographics, established coronary risk factors (high serum cholesterol, hypertension, obesity, exercise, smoking and alcohol consumption) and other psychosocial work characteristics (job strain, effort-reward imbalance and organisational justice) were measured at baseline. Associations between unfairness and incident coronary events and health functioning were determined over an average follow-up of 10.9 years. PARTICIPANTS: 5726 men and 2572 women from 20 civil service departments in London (the Whitehall II Study). MAIN OUTCOME MEASURES: Incident fatal coronary heart disease, non-fatal myocardial infarction and angina (528 events) and health functioning. RESULTS: Low employment grade is strongly associated with unfairness. Participants reporting higher levels of unfairness are more likely to experience an incident coronary event (HR 1.55, 95% CI 1.11 to 2.17), after adjustment for age, gender, employment grade, established coronary risk factors and other work-related psychosocial characteristics. Unfairness is also associated with poor physical (OR 1.46, 95% CI 1.20 to 1.77) and mental (OR 1.54, 95% CI 1.19 to 1.99) functioning at follow-up, controlling for all other factors and health functioning at baseline. CONCLUSIONS: Unfairness is an independent predictor of increased coronary events and impaired health functioning. Further research is needed to disentangle the effects of unfairness from other psychosocial constructs and to investigate the societal, relational and biological mechanisms that may underlie its associations with health and heart disease.