Eating meals irregularly: a novel environmental risk factor for the metabolic syndrome

Background: Skipping meals is a common practice in our current society; however, it is not clear whether eating meals regularly is associated with the metabolic syndrome. Objective: Our aim was to assess the association of eating meals regularly with parameters of the metabolic syndrome and insulin resistance in a representative population‐based cohort of 60‐year‐old men and women. Methods and Procedures: A population‐based cross‐sectional study of 3,607 individuals (1,686 men and 1,921 women), aged 60 years, was conducted in Stockholm County, Sweden. Medical history, socioeconomic factors, and lifestyle data were collected by a questionnaire and a medical examination, which included laboratory tests. Results: Of the subjects who were regular eaters, 20% fulfilled the criteria for the metabolic syndrome vs. 27% of subjects who were irregular eaters (P < 0.0001). The adjusted odds ratio (OR) for having the greatest number of components of the metabolic syndrome in subjects who were regular eaters was 0.27 (95% confidence interval (CI), 0.13–0.54) using subjects who did not fulfill any criteria for the metabolic syndrome as a reference group. Eating meals regularly was also inversely related to insulin resistance (OR, 0.68 (95% CI, 0.48–0.97)) and to γ‐glutamyl transferase (OR, 0.52 (95% CI, 0.33–83)) after full adjustment. Discussion: Eating meals regularly is inversely associated to the metabolic syndrome, insulin resistance and (high) serum concentrations of γ‐glutamyl transferase. These findings suggest that eating meals irregularly may be part of several potential environmental risk factors that are associated with the metabolic syndrome and may have future implications in giving dietary advice to prevent and/or treat the syndrome.     

Accuracy of an image-free cup navigation system--an anatomical study]

The position of the acetabular cup is of decisive importance for the function of a total hip replacement (THR). Using the conventional surgical technique, correct placement of the cup often fails due to a lack of information about pelvic tilt. With CT-based and fluoroscopically-assisted navigation procedures the accuracy of implantation has been significantly improved. However, additional radiation exposure, high cost and the increased time requirement have hampered the acceptance of these techniques. The present anatomical study evaluates the accuracy of an alternative procedure--image-free navigation. This method requires little extra effort, does not substantially delay surgery, and needs no additional imaging. Press-fit cups were implanted in 10 human cadaveric hips with the help of the image-free navigation system, and the position of the cups was checked intraoperatively with a CT-based navigation system and postoperatively by computed tomography. All cups were implanted within the targeted safe zone with an average inclination of 44 degrees (range 40 degrees-48 degrees, SABW 2.7 degrees) and an average anteversion of 18 degrees (range 12-24 degrees, SABW 4.1 degrees). Analysis of accuracy of the image-free navigation software revealed only a small, clinically tolerable deviation in cup anteversion and cup inclination in comparison with the CT-based navigation system and the post operative CT scans. The evaluated image-free navigation system appears to be a practicable and reliable alternative to the computer-assisted implantation of acetabular cups in total hip arthroplasty.     

Induction of HIV-1-specific immunity after vaccination with apoptotic HIV-1/murine leukemia virus-infected cells

Ag-presenting dendritic cells present viral Ags to T cells after uptake of apoptotic bodies derived from virus-infected cells in vitro. However, it is unclear whether apoptotic virus-infected cells are capable of generating immunity in vivo. In this study, we show that inoculation of mice with apoptotic HIV-1/murine leukemia virus (MuLV)-infected cells induces HIV-1-specific immunity. Immunization with apoptotic HIV-1/MuLV-infected syngeneic splenocytes resulted in strong Nef-specific CD8(+) T cell proliferation and p24-induced CD4(+) and CD8(+) T cell proliferation as well as IFN-gamma production. In addition, systemic IgG and IgA as well as mucosa-associated IgA responses were generated. Moreover, mice vaccinated with apoptotic HIV-1/MuLV cells were protected against challenge with live HIV-1/MuLV-infected cells, whereas mice vaccinated with apoptotic noninfected or MuLV-infected splenocytes remained susceptible to HIV-1/MuLV. These data show that i.p. immunization with apoptotic HIV-1-infected cells induces high levels of HIV-1-specific systemic immunity, primes for mucosal immunity, and induces protection against challenge with live HIV-1-infected cells in mice. These findings may have implications for the development of therapeutic and prophylactic HIV-1 vaccines.     

Rheological and structural properties of aqueous alginate during gelation via the Ugi multicomponent condensation reaction

Turbidity, structure, and rheological features during gelation via the Ugi multicomponent condensation reaction of semidilute solutions of alginate have been investigated at different polymer and cross-linker concentrations and reaction temperatures. The gelation time of the system decreased with increasing polymer and cross-linker concentrations, and a temperature rise resulted in a faster gelation. At the gel point, a power law frequency dependence of the dynamic storage modulus (G' proportional, variant omega(n)(')) and loss modulus (G' ' proportional, variant omega(n)(' ')) was observed for all gelling systems with n' = n' ' = n. By varying the cross-linker density at a fixed polymer concentration (2.2 wt %), the power law exponent is consistent with that predicted (0.7) from the percolation model. The value of n decreases with increasing polymer concentration, whereas higher temperatures give rise to higher values of n. The elastic properties of the gels continue to grow over a long time in the postgel region, and at later stages in the gelation process, a solidlike response is observed. The turbidity of the gelling system increases as the gel evolves, and this effect is more pronounced at higher cross-linker concentration. The small-angle neutron scattering results reveal large-scale inhomogeneities of the gels, and this effect is enhanced as the cross-linker density increases. The structural, turbidity, and rheological features were found to change over an extended time after the formation of the incipient gel. It was demonstrated that temperature, polymer, and cross-linker concentrations could be utilized to tune the physical properties of the Ugi gels such as structure, transparency, and viscoelasticity.     

Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. More than 90 mutations in the copper-zinc superoxide dismutase (SOD1) gene cause a subset of familial ALS. Toxic properties have been proposed for the ALS-linked SOD1 mutants, but the nature of the toxicity has not been clearly specified. Cytoplasmic inclusion bodies containing mutant SOD1 and a number of other proteins are a pathological hallmark of mutant SOD1-mediated familial ALS, but whether such aggregates are toxic to motor neurons remains unclear. In this study, we identified a dynein subunit as a component of the mutant SOD1-containing high molecular weight complexes using proteomic techniques. We further demonstrated interaction and colocalization between dynein and mutant SOD1, but not normal SOD1, in cultured cells and also in G93A and G85R transgenic rodent tissues. Moreover, the interaction occurred early, prior to the onset of symptoms in the ALS animal models and increased over the disease progression. Motor neurons with long axons are particularly susceptible to defects in axonal transport. Our results demonstrate a direct "gain-of-interaction" between mutant SOD1 and dynein, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dynein functions. The aberrant interaction is potentially critical to the formation of mutant SOD1 aggregates as well as the toxic cascades leading to motor neuron degeneration in ALS.     

Isoforms of alanine aminotransferases in human tissues and serum--differential tissue expression using novel antibodies

Serum alanine aminotransferase (ALT) is used as a clinical marker of hepatotoxicity. Two forms of ALT have been identified, ALT1 and ALT2, encoded by separate genes. The cellular and tissue distribution of the different ALT proteins has not been characterized in humans, and their relative contribution to serum is unknown. Here, we describe the development of novel isoenzyme specific ALT1 and ALT2 antibodies and the expression of the enzymes in human cells and organs. In normal human tissue, high expression of ALT1 was found in liver, skeletal muscle and kidney and low levels in heart muscle and not detectable in pancreas. High ALT2 reactivity was detected in heart and skeletal muscle, while no ALT2 expression was found in liver or kidney. Using immunohistochemistry, strong ALT1 reactivity was found in hepatocytes, renaltubular epithelial cells and in salivary gland epithelial cells, while ALT2 was expressed in adrenal gland cortex, neuronal cell bodies, cardiac myocytes, skeletal muscle fibers and endocrine pancreas. Immunoprecipitation using ALT antibodies on normal human serums showed ALT1 to be mainly responsible for basal ALT activity. Together, the results points to a differential expression of ALT1 and ALT2 in human organs and substantiate a need for investigations regarding the possible impacts on ALT measurements.     

The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exercise-Induced Slow-Twitch Muscle Fibre Transformation in Humans

PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO_2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation.     

Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism

The p62/sequestosome 1 protein has been identified as a component of pathological protein inclusions in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). P62 has also been implicated in autophagy, a process of mass degradation of intracellular proteins and organelles. Autophagy is a critical pathway for degrading misfolded and/or damaged proteins, including the copper-zinc superoxide dismutase (SOD1) mutants linked to familial ALS. We previously reported that p62 interacted with ALS mutants of SOD1 and that the ubiquitin-association domain of p62 was dispensable for the interaction. In this study, we identified two distinct regions of p62 that were essential to its binding to mutant SOD1: the N-terminal Phox and Bem1 (PB1) domain (residues 1–104) and a separate internal region (residues 178–224) termed here as SOD1 mutant interaction region (SMIR). The PB1 domain is required for appropriate oligomeric status of p62 and the SMIR is the actual region interacting with mutant SOD1. Within the SMIR, the conserved W184, H190 and positively charged R183, R186, K187, and K189 residues are critical to the p62–mutant SOD1 interaction as substitution of these residues with alanine resulted in significantly abolished binding. In addition, SMIR and the p62 sequence responsible for the interaction with LC3, a protein essential for autophagy activation, are independent of each other. In cells lacking p62, the existence of mutant SOD1 in acidic autolysosomes decreased, suggesting that p62 can function as an adaptor between mutant SOD1 and the autophagy machinery. This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy–lysosome degradation pathway.     

Glutamatergic Dysbalance and Oxidative Stress in In Vivo and In Vitro Models of Psychosis Based on Chronic NMDA Receptor Antagonism

Background

The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.

Methods

The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.

Results

Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/− 10.4% S.E.M of control; p = 0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.

Conclusion

The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.