[Work-related Stress and the Allostatic Load Index - A Systematic Review]. / Arbeitsbedingter Stress und der Allostatic Load Index ­ eine systematische Übersichtsarbeit.

OBJECTIVES: Work-related stress is a growing social challenge and has been associated with reduced employee health, well-being, and productivity. One tool to measure the stress-related wear and tear of the body is the Allostatic Load Index (ALI). This review summarizes recent evidence on the association between work-related stress and ALI in working adults. METHODS: A systematic literature search following the PRISMA-Statement was conducted in 21 databases including Medline, PubPsych, MedPilot, and Cochrane Register. Publications addressing work related-stress and medical parameters using ALI were considered. Data on study population, analytic techniques, and results were tabulated. Methodological quality was evaluated using a standardized checklist. RESULTS: 9 articles were identified with a total of 3 532 employees from 5 countries reporting cross-sectional data from the years 2003-2013. Overall, 7 studies reported a positive and significant association between work-related stress and ALI, while 2 studies showed no or an insignificant association. Substantial heterogeneity was observed in methods applied and study quality. CONCLUSIONS: This systematic review provides evidence that work-related stress is associated with ALI in cross-sectional studies. This association needs to be demonstrated by future studies using longitudinal data on working populations.

Lower heart rate variability predicts increased level of C-reactive protein 4 years later in healthy, nonsmoking adults.

BACKGROUND: Inflammation and vagally mediated heart rate variability (vmHRV) have been implicated in a number of conditions including diabetes and cardiovascular disease. Consistent with the inflammatory reflex termed the 'cholinergic anti-inflammatory pathway', numerous cross-sectional studies have demonstrated negative associations between vmHRV and inflammatory markers such as C-reactive protein (CRP). The only prospective study, however, showed the opposite: higher CRP at baseline predicted higher high-frequency heart rate variability (HF-HRV) at follow-up. Thus, additional studies are needed to examine the prospective association between vmHRV and CRP. METHODS: Healthy employees participated in a voluntary on-site health assessment. Blood samples and ambulatory heart rate recordings were obtained, and night-time HF-HRV was calculated. Useable heart rate data were available in 2007 for 106 nonsmoking employees (9% women; age 44.4 ± 8 years), all of whom returned for an identical follow-up health assessment in 2011. Bootstrapped (500 replications) bivariate (r) and partial Pearson's correlations (ppc) adjusting for sex, age and body mass index at baseline (2007) were calculated. RESULTS: Zero-order correlations indicated that higher HF-HRV was associated with lower levels of CRP at both time-points (2007: r = -0.19, P < 0.05; 2011: r = -0.34, P < 0.001). After adjustment, HF-HRV remained a significant predictor of CRP (ppc = -0.20, P < 0.05). CONCLUSION: In this study, we have provided in vivo support for the cholinergic anti-inflammatory pathway in humans. Cardiac vagal modulation at baseline predicts level of CRP 4 years later. Our findings have important implications for the role of vmHRV as a risk factor for cardiovascular disease morbidity and mortality. Interventions targeted at vmHRV might be useful in the prevention of diseases associated with elevated systemic inflammation.

Modulation of neonatal myelopoiesis in newborn rats after 7 days' administration of either granulocyte-monocyte colony stimulating factor or interleukin-3.

Single-pulse administration of either recombinant human granulocyte-monocyte colony stimulating factor or recombinant human granulocyte colony stimulating factor to newborn rats has previously been demonstrated to increase the peripheral neutrophil count and modulate bone marrow (BM) neutrophil pools. In our present study, we investigated the effects of 7 d of either recombinant murine granulocyte-monocyte colony stimulating factor (rmGM-CSF) (75 micrograms/kg/d) or recombinant murine IL-3 (rm IL-3) (10 micrograms/kg/d) on newborn rat myelopoiesis. Sprague Dawley newborn rats (greater than or equal to 24 h) were injected (intraperitoneally) daily for 7 d with either rmGM-CSF, rmIL-3, or PBS/BSA. rmGM-CSF induced a significant increase in the peripheral neutrophil count on d 3 (p less than 0.03) and d 7 (p less than 0.001) (75% increase). Additionally, rmGM-CSF induced a 50% increase in the BM neutrophil storage pool (p less than 0.025). rmIL-3 increased the BM colony forming unit-granulocyte monocyte pool (p less than 0.001); however, it failed to increase the peripheral neutrophil count or BM neutrophil storage pool. Neither CSF increased the BM neutrophil proliferative pool or BM colony forming unit-granulocyte monocyte proliferative rate. Additionally, 7 d of rmGM-CSF with or without antibiotics did not synergistically alter the mortality rate after group B streptococcol inoculation. This study suggests that rmIL-3 appears to stimulate more neonatal myeloid committed progenitor cell activity compared with rmGM-CSF. Optimal modulation of neonatal myelopoiesis may require the use of a sequential combination of hematopoietic CSF, namely an early-acting CSF followed by a more lineage myeloid-specific CSF.

GM-CSF primes and modulates neonatal PMN motility: up-regulation of C3bi (Mo1) expression with alteration in PMN adherence and aggregation.

Neonatal polymorphonuclear leukocytes (PMNs) are deficient in the expression of the adherence protein C3bi (Mo1), and are associated with reduced physiological inflammatory responses. We evaluated the priming and direct stimulating effect of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on newborn PMN expression of C3bi (Mo1), PMN adherence and PMN aggregation. Cord PMNs were incubated with rhGM-CSF (Amgen 4 x 10(7) U/mg) for 0-15 min, and C3bi surface receptor expression measured by immunofluorescence with CD11b, adherence with nylon wool, and aggregation using a Payton aggregometer. RhGM-CSF (15 min) significantly induced Mo1 expression: 250 pM/L 129.4 +/- 5.3% of C (p less than 0.001) 500 pM/L 141.5 +/- 4.1% (p less than 0.001), 1,000 pM/L 150.2 +/- 1.3% (p less than 0.0001). RhGM-CSF (1,000 pM/L x 5 min) followed by A23187 also primed newborn PMNs for increased Mo1 expression 122 +/- 4.5% of C (p less than 0.001). Additionally, rhGM-CSF (10 min) induced significant PMN adherence 50 pM/L 117.9 +/- 8.3% and 100 pM/L 131.5 +/- 5.7% of C (p less than 0.04). RhGM-CSF additionally primed newborn PMNs (100 pM/L) for increased adherence following A23187 (107.9 +/- 0.6% of C), p less than 0.02. Lastly, rhGM-CSF primed newborn PMNs for increased aggregation following FMLP: 100 pM/L, 15 min, 138.1 +/- 14.1%, p less than 0.0001. Co-incubating murine-antihuman GM-CSF AB 100 micrograms/ml neutralized 86.8 +/- 7.0% of newborn PMN Mo1 up-regulation. These studies demonstrate that rhGM-CSF primes and directly stimulates newborn PMNs for increased in vitro expression of Mo1, adherence, and aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of neonatal rat myeloid kinetics resulting in peripheral neutrophilia by single pulse administration of Rh granulocyte-macrophage colony-stimulating factor and Rh granulocyte colony-stimulating factor.

Rh granulocyte-macrophage (GM) colony-stimulating factor (CSF) and rh granulocyte (G) CSF have been demonstrated to induce proliferation and maturation of myeloid stem cells and release of mature polymorphonucleocytes (PMNs) from human and animal adult bone marrows. Unfortunately, reduced bone marrow progenitor cells, neutrophil storage pool (NSP) depletion and peripheral neutropenia are characteristic of human and animal newborn bone marrows. We investigated the effect of administering intraperitoneal rhGM-CSF and rhG-CSF to Sprague-Dawley newborn rats (less than 36 h). Newborn rats treated with intraperitoneal CSF (3.0 micrograms/kg) demonstrated significant leukocytosis at 6 and 24 h: rhGM-CSF vs. control, WBC (10(3)/mm3), at 6 h, 8.0 +/- 0.5 vs 4.3 +/- 0.9 (p less than or equal to 0.003), and at 24 h, 7.7 +/- 1.7 vs. 3.8 +/- 0.2 (p less than or equal to 0.008); rhG-CSF vs. control WBC (10(3)/mm3) at 6 h, 6.6 +/- 1.2 vs 4.3 +/- 0.1 (p less than or equal to 0.03), and at 24 h, 8.1 +/- 0.2 vs. 3.75 +/- 0.2 (p less than or equal to 0.003). The absolute neutrophil count was also significantly elevated at 6 h following intraperitoneal CSF (3.0 micrograms/kg): RhGM-CSF vs. control 1,827 +/- 25 vs. 379 +/- 10 (p less than or equal to 0.001); rhG-CSF vs. control, 1,698 +/- 40 vs. 371 +/- 10.1 (p less than or equal to 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Seven-day administration of recombinant human granulocyte colony-stimulating factor to newborn rats: modulation of neonatal neutrophilia, myelopoiesis, and group B Streptococcus sepsis.

Single-pulse administration of rhG-colony-stimulating factor (CSF) to neonatal rats was previously demonstrated to induce peripheral neutrophilia and modulate bone marrow (BM) neutrophil storage and proliferative pools (NSP + NPP). In this study, we investigated the prolonged effects of 7 days of rhG-CSF therapy (5 micrograms/kg/per day). Sprague-Dawley newborn rats (less than or equal to 24 hours) were injected intraperitoneally (IP) (daily for 7 days) with rhG-CSF or phosphate-buffered saline/human serum albumin (PBS/HSA). RhG-CSF induced a significant early and late peripheral neutrophilia: 6,905 +/- 1,625 (day 1) and 9,223 +/- 515 microL (day 7) v 1,275 +/- 90/microL (P less than or equal to .0001). In addition, 7 days of rhG-CSF resulted in a significant increase in the BM NSP: 3,247 +/- 190/microL v 1,677 +/- 339/microL (P less than or equal to .001). There was, however, no depletion or significant change in the BM NPP. Seven days of rhG-CSF also induced a mild increase in BM CFU-GM colony formation (P less than or equal to .01). There was, however, no significant change in liver/spleen CFU-GM colonies or in the CFU-GM proliferative rate in either the BM or liver/spleen cultures. Finally, 7 days of prophylactic rhG-CSF therapy resulted in a synergistic response with antibiotic therapy and significantly modulated the mortality rate during experimental group B streptococcal sepsis (GBS) (100% v 50%) (GvsC) (P less than or equal to .001). Pulse rhG-CSF administered at 6 hours or 18 hours after GBS inoculation, however, failed to act synergistically with antibiotics to improve survival or prevent peripheral neutropenia. This study suggests that 7 days of prophylactic rhG-CSF therapy induces peripheral neutrophilia, myeloid maturation, increases neutrophil BM reserves and also may provide immunologic enhancement of neonatal host defense during experimental GBS in term neonatal rats.

Prophylactic or simultaneous administration of recombinant human granulocyte colony stimulating factor in the treatment of group B streptococcal sepsis in neonatal rats.

Despite the emergence of newer antibiotic treatments, group B streptococcal infection still carries a high mortality rate in the newborn and is characterized by reduced neutrophil proliferative pools, neutrophil storage pools, neutropenia, and polymorphonuclear cell dysfunction. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) has recently been demonstrated to induce neutrophilia and modulate neutrophil proliferative pools and neutrophil storage pools in the newborn rat. We therefore investigated the adjuvant effect of rhG-CSF given to group B streptococcus (GBS) septic Sprague-Dawley newborn (less than 36 h) rats treated with and without antibiotic therapy. After inoculation of GBS, a GBS survival curve established the LD50 at 50 h to be approximately 3 X 10(6) organisms/gm. Newborn rats were divided into four treatment groups after GBS inoculation. rhG-CSF was administered at the same time as GBS inoculation. At 24 h, there was approximately 100% survival in all groups. However, by 72 h after GBS inoculation, there was a significant difference in survival. Group 1, PBS/Alb, had a survival rate of 4%; group 2, rhG-CSF, 9%; group 3, antibiotics, 28%; and group 4, antibiotics plus rhG-CSF, 91% (p less than or equal to 0.001). Additionally, when rhG-CSF was administered prophylactically (6 h before GBS), a similar significant synergistic effect in survival was demonstrated with granulocyte colony stimulating factor plus antibiotics versus antibiotics alone (70 versus 10%) (p less than or equal to 0.01). These preliminary data suggest that either simultaneous or prophylactic pulse administration of rhG-CSF may have a synergistic and protective effect on survival in antibiotic-treated experimental GBS in the neonatal rat.

Lymphokines: enhancement by granulocyte-macrophage and granulocyte colony-stimulating factors of neonatal myeloid kinetics and functional activation of polymorphonuclear leukocytes.

Colony-stimulating factors, such as the granulocyte-macrophage and the granulocyte colony-stimulating factors (GM-CSF and G-CSF), are glycoproteins with biologic specificity defined by their ability to support proliferation and differentiation of hematopoietic cells of various lineages. Their physiologic activities include stimulation and proliferation of early stem cell precursors and functional activation of mature peripheral effector cells. Recently produced recombinant human (rh) GM-CSF and G-CSF have been demonstrated to regulate hematopoietic neutrophil progenitor colony growth; to stimulate the release of bone marrow neutrophil storage pools; and to prime mature effector functions, including chemotaxis, oxidative metabolism, phagocytosis, C3bi receptor expression, and antibody-dependent cytotoxicity in adults. We examined the effects of rh-GM-CSF on priming superoxide release and chemotaxis of neonatal (cord) polymorphonuclear leukocytes (PMNs) and of rh-G-CSF and rh-GM-CSF on bone marrow neutrophil egress in the neonatal rat. A time-response evaluation of the effect of rh-GM-CSF revealed enhanced release of superoxide by PMNs. PMN chemotaxis also was enhanced by rh-GM-CSF, with a maximal response occurring earlier than enhanced superoxide release. Intraperitoneal administration of rh-G-CSF or rh-GM-CSF to 1-day-old rats resulted in significant increases in white blood cell counts and significant early neutrophilia. Bone marrow examination revealed that the neutrophilia was secondary to egress and mild depletion of the neutrophil storage pool but that the neutrophil storage pool later returned to normal. These preliminary studies suggest that rh-GM-CSF and rh-G-CSF prime neonatal effector function and induces significant PMN egress and neutrophilia.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human granulocyte-macrophage colony-stimulating factor primes neonatal granulocytes for enhanced oxidative metabolism and chemotaxis.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) induces proliferation and differentiation of hematopoietic stem cells. Additionally, rhGM-CSF enhances the physiologic responses of adult polymorphonuclear leukocytes (PMN) especially with respect to oxidative metabolism and chemotaxis. Neonatal PMN are deficient in chemotaxis and have been demonstrated to have reduced oxidative responses in times of stress. We evaluated the priming effects of rhGM-CSF (1-100 pmol/L) on cord (neonatal) superoxide production and chemotaxis. Cord and adult PMN were incubated with 100 pmol/L rhGM-CSF (Amgen, 4 x 10(7) U/mg) for 0-120 min and stimulated with N-formyl-l-methionyl-l-leucyl-phenylalanine. RhGM-CSF enhanced O2- production at all time periods with maximal priming at 60 min (147.97 +/- 11.14% p less than or equal to 0.006) with less, but significant enhancement at 120 min (116.53 +/- 7.92% p less than or equal to 0.05). Maximal adult PMN O2- release occurred at 120 min (190.02 +/- 8.71% p less than or equal to 0.003) and was more pronounced than cord PMN.(ABSTRACT TRUNCATED AT 250 WORDS)