Differing Alterations of Odor Volatiles Among Pathogenic Stimuli.

Alterations of the volatile metabolome (the collection of volatiles present in secretions and other emanations) that occur in response to inflammation can be detected by conspecifics and chemometric analyses. Using a model system where mouse urinary metabolites are altered by treatment with lipopolysaccharide (found in the outer cell membrane of gram-negative bacteria), we hypothesized that alteration of body odor volatiles will vary according to the pathogen responsible for inducing the inflammation. We tested this hypothesis by treating mice with different immunogens that engage different immune signaling pathways. Results suggest that alterations of body odor volatiles resulting from inflammation do contain detailed information about the type of pathogen that instigated the inflammation and these differences are not merely dependent on the severity of the inflammatory event. These results are encouraging for the future of differential medical diagnosis of febrile diseases by analysis of the volatile metabolome. In particular, our data support the possibility that bacterial infections can be differentiated from viral infections such that antibiotic drug stewardship could be drastically improved by reducing unneeded treatments with antibiotics.

Cytokine contributions to alterations of the volatile metabolome induced by inflammation.

Several studies demonstrate that inflammation affects body odor. Volatile signals associated with inflammation induced by pyrogens like LPS are detectable both by conspecifics and chemical analyses. However, little is known about the mechanisms which translate detection of a foreign molecule or pathogen into a unique body odor, or even how unique that odor may be. Here, we utilized C57BL/6J trained mice to identify the odor of LPS-treated conspecifics to investigate potential pathways between LPS-induced inflammation and changes in body odor, as represented by changes in urine odor. We hypothesized that the change in volatile metabolites could be caused directly by the pro-inflammatory cytokine response mediated by TNF or IL-1ß, or by the compensatory anti-inflammatory response mediated by IL-10. We found that trained biosensors generalized learned LPS-associated odors to TNF-induced odors, but not to IL-1ß or IL-10-induced odors. Analyses of urine volatiles using headspace gas chromatography revealed distinct profiles of volatile compounds for each treatment. Instrumental discrimination relied on a mixture of compounds, including 2-sec-butyl-4,5-dihydrothiazole, cedrol, nonanal, benzaldehyde, acetic acid, 2-ethyl-1-hexanol, and dehydro-exo-brevicomin. Although interpretation of LDA modeling differed from behavioral testing, it does suggest that treatment with TNF, IL-1ß, and LPS can be distinguished by their resultant volatile profiles. These findings indicate there is information found in body odors on the presence of specific cytokines. This result is encouraging for the future of disease diagnosis via analysis of volatiles.

GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism.

Expression of the inflammatory cytokine TNF is tightly controlled. During endotoxin tolerance, transcription of TNF mRNA is repressed, although not entirely eliminated. Production of TNF cytokine, however, is further controlled by posttranscriptional regulation. In this study, we detail a mechanism of posttranscriptional repression of TNF mRNA by GAPDH binding to the TNF 3' untranslated region. Using RNA immunoprecipitation, we demonstrate that GAPDH-TNF mRNA binding increases when THP-1 monocytes are in a low glycolysis state, and that this binding can be reversed by knocking down GAPDH expression or by increasing glycolysis. We show that reducing glycolysis decreases TNF mRNA association with polysomes. We demonstrate that GAPDH-TNF mRNA binding results in posttranscriptional repression of TNF and that the TNF mRNA 3' untranslated region is sufficient for repression. Finally, after exploring this model in THP-1 cells, we demonstrate this mechanism affects TNF expression in primary human monocytes and macrophages. We conclude that GAPDH-TNF mRNA binding regulates expression of TNF based on cellular metabolic state. We think this mechanism has potentially significant implications for treatment of various immunometabolic conditions, including immune paralysis during septic shock.

Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis.

We reported that NAD(+)-dependent SIRT1, RELB, and SIRT6 nuclear proteins in monocytes regulate a switch from the glycolysis-dependent acute inflammatory response to fatty acid oxidation-dependent sepsis adaptation. We also found that disrupting SIRT1 activity during adaptation restores immunometabolic homeostasis and rescues septic mice from death. Here, we show that nuclear SIRT1 guides RELB to differentially induce SIRT3 expression and also increases mitochondrial biogenesis, which alters bioenergetics during sepsis adaptation. We constructed this concept using TLR4-stimulated THP1 human promonocytes, a model that mimics the initiation and adaptation stages of sepsis. Following increased expression, mitochondrial SIRT3 deacetylase activates the rate-limiting tricarboxylic acid cycle (TCA) isocitrate dehydrogenase 2 and superoxide dismutase 2, concomitant with increases in citrate synthase activity. Mitochondrial oxygen consumption rate increases early and decreases during adaptation, parallel with modifications to membrane depolarization, ATP generation, and production of mitochondrial superoxide and whole cell hydrogen peroxide. Evidence of SIRT1-RELB induction of mitochondrial biogenesis included increases in mitochondrial mass, mitochondrial-to-nuclear DNA ratios, and both nuclear and mitochondrial encoded proteins. We confirmed the SIRT-RELB-SIRT3 adaptation link to mitochondrial bioenergetics in both TLR4-stimulated normal and sepsis-adapted human blood monocytes and mouse splenocytes. We also found that SIRT1 inhibition ex vivo reversed the sepsis-induced changes in bioenergetics.

RelB: an outlier in leukocyte biology.

RelB is one of the more unusual members of the NF-κB family. This family, arguably the best known group of transcription regulators, regulates an astonishing array of cell types and biological processes. This includes regulation of cell growth, differentiation and death by apoptosis, and the development and function of the innate and adaptive-immune system. RelB is best known for its roles in lymphoid development, DC biology, and noncanonical signaling. Within the last few years, however, surprising functions of RelB have emerged. The N-terminal leucine zipper motif of RelB, a motif unique among the NF-κB family, may associate with more diverse DNA sequences than other NF-κB members. RelB is capable of direct binding to the AhR that supports the xenobiotic-detoxifying pathway. RelB can regulate the circadian rhythm by directly binding to the BMAL partner of CLOCK. Finally, RelB also couples with bioenergy NAD(+) sensor SIRT1 to integrate acute inflammation with changes in metabolism and mitochondrial bioenergetics. In this review, we will explore these unique aspects of RelB, specifically with regard to its role in immunity.

Fueling the flame: bioenergy couples metabolism and inflammation.

We review the emerging concept that changes in cellular bioenergetics concomitantly reprogram inflammatory and metabolic responses. The molecular pathways of this integrative process modify innate and adaptive immune reactions associated with inflammation, as well as influencing the physiology of adjacent tissue and organs. The initiating proinflammatory phase of inflammation is anabolic and requires glucose as the primary fuel, whereas the opposing adaptation phase is catabolic and requires fatty acid oxidation. The fuel switch to fatty acid oxidation depends on the sensing of AMP and NAD(+) by AMPK and the SirT family of deacetylases (e.g., SirT1, -6, and -3), respectively, which couple inflammation and metabolism by chromatin and protein reprogramming. The AMP-AMPK/NAD(+)-SirT axis proceeds sequentially during acute systemic inflammation associated with sepsis but ceases during chronic inflammation associated with diabetes, obesity, and atherosclerosis. Rebalancing bioenergetics resolves inflammation. Manipulating cellular bioenergetics is identifying new ways to treat inflammatory and immune diseases.

Job functions of Swedish public and private rehabilitation workers; their perceived level of importance and related knowledge.

OBJECTIVE: To investigate and gather knowledge of how important the various functions of Swedish rehabilitation workers are and whether this knowledge is equivalent to the demands of the vocational rehabilitation process. PARTICIPANTS: Swedish rehabilitation workers from both public and private sectors. METHODS: A questionnaire comprising 89 work task items was used to identify the major dimensions of the Swedish rehabilitation workers job in the rehabilitation process. A principle component factor analysis was performed on the 89 job-task items from the Swedish Task Inventory. RESULTS: The number of factors/dimensions that could be formed was only three, which is judged to be limited both in scope and depth. The level of perceived knowledge reported varied from limited to having the required competence. The results also reveal that the workers perceive their work tasks and the dimensions that make up their role function as being of moderate to low importance. Their perceived level of knowledge for the similar work task items and dimensions were rated moderate to low. Differences between the groups of rehabilitation workers were mixed. CONCLUSIONS: The vocational rehabilitation process offered in Sweden is limited. It appears that the level of knowledge within the area can and should be increased and that better education is needed in order to improve the quality of the vocational rehabilitation process and for further development to take place.

Job functions of Swedish public and private sector vocational rehabilitation workers.

PURPOSE: This study has had two main aims, the first to investigate and gather knowledge of the major job functions of Swedish rehabilitation workers, the second to study the frequency of use of these functions in the VR process. METHOD: Structured questionnaires were sent to Swedish rehabilitation workers from public and private sectors. To identify the major dimensions of Swedish rehabilitation workers' job in the vocational rehabilitation (VR) process, a principal component factor analysis was performed. RESULTS: Results revealed that there are four main factors (dimensions) that comprised the VR process in Sweden. The four factors (dimensions) are job development and career counselling; assessment and counselling interventions; workplace adjustment and employer consultation and client support, personnel development and public relations. CONCLUSIONS: The VR process in Sweden is limited in both its scope and depth. This when one compares with the results of studies carried out in the USA, who found seven and six dimensions, respectively. It is argued that it cannot be excluded that the negative trend of extensive sick leave and early pensions are attributable to the limitations in the VR process that have been found. Suggested is the urgent need to put resources in place that would support the further advancement of the knowledge and competencies of the VR services in Sweden.

Internal locus of control and vocational rehabilitation.

In previous studies, internal locus of control (ILC) has been pointed out as a key factor for return to work after vocational rehabilitation. The aim of the current study was to gain a deeper understanding of the concept of ILC in a Swedish vocational rehabilitation context. The study was based on data from 347 long-term sick-listed clients collected at the onset of vocational rehabilitation. A first bi-variate analysis showed that ILC was positively associated with physical functioning and general health, and negatively associated with bodily pain. The analysis also showed that women, more than men, reported high internal locus of control. After a second multivariate analysis, only bodily pain remained associated. It is concluded that there exist a strong and negative association between bodily pain and internal locus of control. Clients with severe pain often also suffer from low internal locus of control. This should be kept in mind when providing vocational rehabilitation.

Time for change: can empowerment be a solution to meet the perils of modern day working life?

Working life continues to undergo rapid change. This change creates greater demand and sophistication and causes employees to experience more pressure, professionally and personally. Thus, absences from work due to sickness and injuries increase. In Sweden, this problem has become serious. This article argues that psychological empowerment and individual control are two key factors that minimize the many perils faced by the modern worker and those seeking to return to the work force through the vocational rehabilitation process. The findings show that a shift in ideology is needed. Specifically, there must be a shift from scientific management and Weberian bureaucracy towards organizational structures, routines, and cultures that support and increase individual worker psychological empowerment and control.

Individual status at the start of rehabilitation: Implications for vocational rehabilitation programs.

UNLABELLED: This research investigated the situation of 143 unemployed sick leavers at the start of vocational rehabilitation in Sweden. It is argued in this paper that in order to gain a meaningful picture of the vocational rehabilitation process it is necessary to know and understand something of individual differences and status at the onset. In doing so, assessment was carried out of the possible influence of one contextual factor and five individual factors on health, duration of sick leave and unemployment. Findings suggest that individual differences exist in health status, length of sick leave and unemployment, at the upstart of vocational rehabilitating. Locus of control was found to exert important influence on the differences between the individuals in the study sample, with persons of external locus of control having a less favourable point of departure at the start of vocational rehabilitation compared to other groups. It is therefore assumed that these persons will be in greater need of support during the vocational rehabilitation process. The level of unemployment within a geographical area was also found to influence the length of sick leave. CONCLUSIONS: Our suggestion is for rehabilitation programs to be developed and selected to match the special needs and differences whether they are of individual or of social nature.