Sustained Endurance Training Leads to Metabolomic Adaptation.

Endurance training induces several adaptations in substrate metabolism, especially in relation to glycogen conservation. The study aimed to investigate differences in the metabolism of lipids, lipid-like substances, and amino acids between highly trained and untrained subjects using targeted metabolomics. Depending on their maximum relative oxygen uptake (VO2max), subjects were categorized as either endurance-trained (ET) or untrained (UT). Resting blood was taken and plasma isolated. It was screened for changes of 345 metabolites, including amino acids and biogenic amines, acylcarnitines, glycerophosphocholines (GPCs), sphingolipids, hexoses, bile acids, and polyunsaturated fatty acids (PUFAs) by using liquid chromatography coupled to tandem mass spectrometry. Acylcarnitine (C14:1, down in ET) and five GPCs (lysoPC a C18:2, up in ET; PC aa C42:0, up in ET; PC ae C38:2, up in ET; PC aa C38:5, down in ET; lysoPC a C26:0, down in ET) were differently regulated in ET compared to UT. TCDCA was down-regulated in athletes, while for three ratios of bile acids CA/CDCA, CA/(GCA+TCA), and DCA/(GDCA+TDCA) an up-regulation was found. TXB2 and 5,6-EET were down-regulated in the ET group and 18S-HEPE, a PUFA, showed higher levels in 18S-HEPE in endurance-trained subjects. For PC ae C38:2, TCDCA, and the ratio of cholic acid to chenodeoxycholic acid, an association with VO2max was found. Numerous phospholipids, acylcarnitines, glycerophosphocholines, bile acids, and PUFAs are present in varying concentrations at rest in ET. These results might represent an adaptation of lipid metabolism and account for the lowered cardiovascular risk profile of endurance athletes.

An ergonomic welding torch reduces physical load response and improves welding quality in novices: a pilot study.

Objectives. This crossover pilot study aimed to compare the physical load response of an ergonomically improved welding torch versus a conventional torch. Methods. Ten inexperienced volunteers performed an experimental augmented virtual welding trial at chest height (ASME code 1G) and overhead (ASME code 4G) with both welding torches in random order. Skeletal muscle load and fatigue were assessed by surface electromyography and changes in isometric peak force. The sensation of pain, perceived exertion and welding execution quality were defined as further outcome parameters. Results. The muscle load response in three out of eight muscles was lower in favour of the ergonomic welding torch, which went along with a lower sensation of pain and a higher working accuracy. Conclusions. An ergonomically improved welding torch reduces the acute physical load response and sensation of pain, which ultimately allows performing better, and might contribute to prevention of musculoskeletal diseases in the long term.

Excessive Accumulation of Intracellular Ca2+ After Acute Exercise Potentiated Impairment of T-cell Function.

Ca2+ is an important intracellular second messenger known to regulate several cellular functions. This research aimed to investigate the mechanisms of exercise-induced immunosuppression by measuring intracellular calcium levels, Ca2+-regulating gene expression, and agonist-evoked proliferation of murine splenic T lymphocytes. Mice were randomly assigned to the control, sedentary group (C), and three experimental groups, which performed a single bout of intensive and exhaustive treadmill exercise. Murine splenic lymphocytes were separated by density-gradient centrifugation immediately (E0), 3h (E3), and 24h after exercise (E24). Fura-2/AM was used to monitor cytoplasmic free Ca2+ concentration in living cells. The combined method of carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling and flow cytometry was used for the detection of T cell proliferation. The transcriptional level of Ca2+-regulating genes was quantified by using qPCR. Both basal intracellular Ca2+ levels and agonist (ConA, OKT3, or thapsigargin)-induced Ca2+ transients were significantly elevated at E3 group (p<0.05 vs. control). However, mitogen-induced cell proliferation was significantly decreased at E3 group (p<0.05 vs. control). In parallel, the transcriptional level of plasma membrane Ca2+-ATPases (PMCA), sarco/endoplasmic reticulum Ca2+-ATPases (SERCA), TRPC1, and P2X7 was significantly downregulated, and the transcriptional level of IP3R2 and RyR2 was significantly upregulated in E3 (p<0.01 vs. control). In summary, this study demonstrated that acute exercise affected intracellular calcium homeostasis, most likely by enhancing transmembrane Ca2+ influx into cells and by reducing expression of Ca2+-ATPases such as PMCA and SERCA. However, altered Ca2+ signals were not transduced into an enhanced T cell proliferation suggesting other pathways to be responsible for the transient exercise-associated immunosuppression.

Exercise training reduces workload, improves physical performance, and promotes overall health in welders.

OBJECTIVES: Welders demonstrate a significant prevalence of work-related musculoskeletal disorders as indicated by high rates of illness-related absenteeism. The aim of the study was to investigate the effects of a 24-week exercise program on workload, physical performance, and overall health in welders. METHODS: Seventy-seven professional welders were assigned to either a control group (CG), an endurance training group (ETG), or a strength training group (STG). Both groups conducted a 24-week, standardized and progressive endurance or resistance exercise training program. Before (TP1) and after training (TP2) all participants performed an experimental welding task (EWT) in order to test the hypothesis that training would reduce the relative load (%MVC) of eight skeletal muscles measured by surface electromyography. Secondary outcome measures included further EWT-induced stress parameters and a series of health-related outcome measures. RESULTS: Results revealed a lower muscle load in participants of the ETG and STG for trapezius muscle at TP2 compared to T1 (P < .05 vs CG). Rate of perceived exertion and visual analogue scale were decreased, while increase of maximum EWT duration was found in participants of the ETG and STG after training (P < .05 vs CG). At T2, body fat (%) decreased and physical performance (bicycle exercise test, isometric strength of core muscles) increased in ETG and STG (P < .05). CONCLUSION: Both regular endurance and strength training represent effective strategies for reducing workload and improving physical performance of welders. The results emphasize the importance of physical fitness for welders and might motivate health professionals in steel-industry to offer access to exercise training programs.

Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status.

To date, the effects of endurance exercise training on lymphocyte physiology at the kinome level are largely unknown. Therefore, the present study used a highly sensitive peptide-based kinase activity profiling approach to investigate if the basal activity of tyrosine (Tyr) and serine/threonine (Ser/Thr) kinases of human lymphocytes is affected by the aerobic endurance training status. Results revealed that the activity of various tyrosine kinases of the FGFR family and ZAP70 was increased, whereas the activity of multiple Ser/Thr kinases such as IKKα, CaMK4, PKAα, PKCα+δ (among others) was decreased in lymphocytes of endurance trained athletes (ET). Moreover, functional associations between several differentially regulated kinases in ET-derived lymphocytes were demonstrated by phylogenetic mapping and network analysis. Especially, Ser/Thr kinases of the AGC-kinase (protein kinase A, G, and C) family represent exercise-sensitive key components within the lymphocytes kinase network that may mediate the long-term effects of endurance training. Furthermore, KEGG (Kyoto Encyclopedia of Genes and Genomes) and Reactome pathway analysis indicate that Ras as well as intracellular signaling by second messengers were found to be enriched in the ET individuals. Overall, our data suggest that endurance exercise training improves the adaptive immune competence by modulating the activity of multiple protein kinases in human lymphocytes.

Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk.

OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

Aerobic endurance training status affects lymphocyte apoptosis sensitivity by induction of molecular genetic adaptations.

Apoptosis is a genetically regulated form of programmed cell death which promotes the elimination of potentially detrimental immune cells. However, exercise-associated apoptosis is thought to induce a temporarily decline of the adaptive immune competence in the early post-exercise period. The purpose of the present study was to investigate if the aerobic endurance training status affects the sensitivity of human peripheral blood lymphocytes towards different types of apoptosis inducers and secondly, if this is mediated by the modulation of apoptosis-associated proteins and microRNAs. Collected at resting conditions, isolated lymphocytes of endurance trained athletes (ET) and healthy untrained subjects were either exposed to phytohemagglutinin-L (PHA-L), hydrogen peroxide (H2O2), or dexamethasone (DEX) as apoptosis inducer. Results revealed no significant differences between ET and UT in terms of lymphocyte apoptosis immediately following isolation as determined by flow cytometry using annexin V staining. After 24 h of ex vivo cultivation, lymphocytes of ET showed a reduced sensitivity to PHA-L-induced lymphocyte apoptosis which was accompanied by a noticeably up-regulation of the prominent apoptosis inhibitor genes X-linked inhibitor of apoptosis (XIAP) and Cyclin dependent kinase inhibitor 1B (CDKN1B) as analyzed by quantitative real-time PCR. Moreover, a trend was observed for the suppression of the corresponding pro-apoptotic miR-221. Lymphocyte apoptosis in control, H2O2 and DEX treated cells was not affected by aerobic endurance training status. However, distinct molecular signatures could be identified in un-treated control samples characterized by a counterbalanced modulation of pro- and anti-apoptotic mediators in ET. The results of the current study suggest that lymphocytes adapt to repetitive endurance exercise training by promoting lymphocyte homeostasis and increasing their resistance to apoptosis. This could be based on an up-regulation of anti-apoptotic proteins and a reduction in pro-apoptotic microRNAs which together tightly regulate the genetically defined apoptotic pathways governed by the type of apoptosis stimuli. Thus, the lymphocytes of endurance-trained athletes may be primed to counteract the transient immune suppression post-exercise.

Acute exercise-induced irisin release in healthy adults: Associations with training status and exercise mode.

There is a growing interest in exploring irisin response to acute exercise; however, the associations of acute exercise-induced irisin release with training status and exercise mode are not fully understood. This study was primarily designed to evaluate these associations. Sixteen healthy adults (8 trained versus 8 untrained) underwent a bout of cycling at 80% of maximal oxygen uptake (VO2max) for 50 min, with blood drawn pre-, 10-, and 180-min post-exercise. Another 17 healthy adults performed 2 bouts of graded exercise (cycling and running) until exhaustion on separate days using a randomized cross-over design, with blood taken pre-, 0-, 10-, and 60-min post-exercise. Circulating irisin, creatine kinase (CK), aspartate aminotransferase (AST), and myoglobin (Mb) were measured, and their respective areas under the curves (AUCs) were calculated. Irisin increased 10-min after 50 min of cycling at 80% of VO2max, while its changes from baseline to post-exercise and the amount of exercise-induced irisin release (presented as AUC) were comparable between trained and untrained adults (all P > .05). Irisin remained elevated 10-min post-exhausting running but decreased towards baseline 10-min post-exhausting cycling. Exhausting running induced an increase in irisin release for the whole course of exercise and recovery periods, but cycling did not. Acute exercise-induced irisin changes seemed not related to changes of CK, aspartate AST, and Mb in general. In conclusion, acute exercise-induced irisin release is not associated with training status but might be affected by training mode. Future studies are required to investigate which exercise mode might be most efficient in altering irisin.

Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer.

Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13-2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51-0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pair-wise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T-NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.

Other cancers in lung cancer families are overwhelmingly smoking-related cancers.

Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor.

Effects of Traumeel (Tr14) on recovery and inflammatory immune response after repeated bouts of exercise: a double-blind RCT.

PURPOSE: The purpose of this double-blind, randomized, placebo-controlled clinical trial was to investigate the effects of the natural combination medicine Traumeel (Tr14) consisting of 14 diluted biological and mineral components on the inflammatory immune response and recovery up to 72 h after repetitive bouts of bicycle tests. METHODS: Antigen-stimulated IL-1ra and IL-6 were defined as primary outcome measures. Moreover, various immunological and serum muscle damage markers were investigated. The evaluation was performed using the score of the area under the curve with respect to increase (AUCi) for 24 and 72 h after the second exercise test (EX2). RESULTS: The Tr14 group indicated a lower decrease of lymphocytes by tendency (p = 0.06) and a lower activation of lymphocyte activation markers (CD62L absolute: p = 0.04; CD69: p = 0.01 and CD69 absolute: p = 0.05) in the period 24 h after EX2. In addition, the Tr14 group indicated a higher expression of antigen-stimulated CCL3 (p = 0.01), CCL4 (p = 0.07) and serum CCL2 (p = 0.05) in the period 24 h after EX2. There was a tendentially lower decrease of monocytes (p = 0.09) and a lower expression of antigen-stimulated MMP-3 (p = 0.01) in the Tr14 group in the period 72 h after EX2. However, antigen-stimulated IL-1ra and IL-6 showed no group differences. CONCLUSION: In line with the previous results, it was shown that Tr14 attenuates the adaptive immune response partially. Furthermore, the results indicate that Tr14 is able to stimulate the innate immune system via an increased production of pro-inflammatory chemokines. It is speculated that the higher expression of chemokines might play a role in the regeneration and recovery after exercise.

Risk of other Cancers in Families with Melanoma: Novel Familial Links.

A family history of cutaneous melanoma ('melanoma') is a well-established risk factor for melanoma. However, less is known about the possible familial associations of melanoma with other discordant cancers. A risk for discordant cancer may provide useful information about shared genetic and environmental risk factors and it may be relevant background data in clinical genetic counseling. Using the Swedish Family-Cancer Database, we assessed the relative risk (RR) for any cancer in families with increasing numbers of first-degree relatives diagnosed with melanoma, including multiple melanoma, and in reverse order RR for melanoma in families of multiple discordant cancers. Close to 9% of melanoma was familial; among these 92% were in 2-case families and 8% in families with 3 cases or more. Cancers that were associated with melanoma, in at least two independent analyses, included breast, prostate, colorectal, skin and nervous system cancers. Other associations included cancer of unknown primary, acute myeloid leukemia/myelofibrosis and Waldenström macroglobulinemia/myeloma. Significant results, which appear biologically plausible, were also obtained for rare nasal melanoma and mesothelioma. Although small samples sizes and multiple comparisons were of concern, many of the above associations were internally consistent and provide new diverse leads for discordant familial association of melanoma.

Concordant and discordant familial cancer: Familial risks, proportions and population impact.

Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge.

Familial Associations Between Prostate Cancer and Other Cancers.

Prostate cancer (PCa) has a large familial component, but understanding of its genetic basis is fragmentary. Breast cancers may be associated with PCa, but whether this is true for other tumor types is poorly established. We used a novel approach to study familial associations of any type of cancer with PCa. We assessed the relative risk (RR) for all types of tumors as a function of the number of first-degree relatives diagnosed with PCa. We hypothesized that for a familial association to be real, the RR for a given type of cancer should increase with the number of PCa diagnoses. In families with multiple PCa patients, significantly increased risks were observed for female breast cancer (RR 1.37 for families with three men with PCa), kidney cancer (RR 2.32), nervous system tumors (RR 1.77; RR 2.40 when PCa was diagnosed before age 70 yr), and myeloma (RR 2.44; RR 6.29 when PCa was diagnosed before age 70 yr). Some evidence of association was also found for melanoma (RR 1.82) and endocrine tumors (RR 2.18). The consistency and magnitude of the effects suggest that familial PCa is genetically associated with breast, kidney, and nervous system tumors and myeloma. This suggestion has implications for clinical counseling and design of genetic studies. PATIENT SUMMARY: It is known that prostate cancer runs in families, but it is not known whether other cancers are common in such families. We showed that at least breast, kidney, and nervous system tumors and myeloma occur more often than by chance.

Common cancers share familial susceptibility: implications for cancer genetics and counselling.

BACKGROUND: It has been proposed that cancer is more common in some families than in others, but the hypothesis lacks population level support. We use a novel approach by studying any cancers in large three-generation families and thus are able to find risks even though penetrance is low. METHODS: Individuals in the nation-wide Swedish Family-Cancer Database were organised in three generations and the relative risk (RR) of cancer was calculated to the persons in the third generation by the numbers of patients with cancer in generations 1, 2 and 3. RESULTS: The RRs for any cancer in generation 3 increased by the numbers of affected relatives, reaching 1.61 when at least seven relatives were diagnosed. The median patient had two affected relatives, and 7.0% had five or more affected relatives with an RR of 1.46, which translated to an absolute risk of 21.5% compared with 14.7% in population by age 65 years. For prostate cancer, the RR was 2.85 with four or more affected family members with any cancer, and it increased to 14.42 with four or more concordant cancers in family members. RRs for prostate cancer were approximately equal (2.70 vs 2.85) if a man had one relative with prostate cancer or four or more relatives diagnosed with any cancer. CONCLUSIONS: A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks.

Exercise Affects T-Cell Function by Modifying Intracellular Calcium Homeostasis.

PURPOSE: The study aimed to investigate the effects of chronic moderate exercise on regulation of intracellular calcium signaling as an important link to proliferation capacity in murine splenic T lymphocytes. METHODS: Male CD1 Swiss mice were randomly assigned either to a control group (CG) or an exercise training group (EG). EG mice performed voluntary exercise for 3 months. Lymphocytes were isolated from murine spleens and intracellular calcium was determined by using Fura-2(AM) and fluorescence spectrometry. The combination of flow cytometry and carboxy-fluorescein succinimidyl ester labeling technique was used for determination of cell proliferation. The expression levels of Ca-regulating genes were determined by quantitative polymerase chain reaction (qPCR) analysis. RESULTS: Basal [Ca]i was significantly higher in mice from the EG compared with mice of the CG (P < 0.001, n = 6). Similarly, [Ca]i transients after stimulation with phytohemagglutinin, concanavalin A, and the anti-CD3 antibody induced were significantly increased in mice from the EG (P < 0.05, n = 5). However, no differences were found after stimulation with thapsigargin (P < 0.05, n = 5). CD3 T cells from EG showed higher mitogen-induced proliferation levels than from CG (P < 0.05/0.01, n = 5). The mRNA expression of cellular Ca-regulating genes, such as STIM1, Cav2.3, TRPV4, IP3R2, ORAI1, MCU, TRPM5, and TRPC1, were significantly downregulated (P < 0.05/0.01, n = 5). CONCLUSION: This study suggests that chronic moderate exercise improves intracellular Ca signaling in murine splenic lymphocytes. The enhanced availability of the second messenger Ca is followed by an improved cellular function such as cell proliferation. The downregulation of Ca homeostasis-related factor expression might be considered as a self-protective mechanism against elevated intracellular Ca signals.

Effects of Traumeel (Tr14) on Exercise-Induced Muscle Damage Response in Healthy Subjects: A Double-Blind RCT.

The present double-blind, randomized, placebo-controlled clinical trial intended to test whether ingestion of a natural combination medicine (Tr14 tablets) affects serum muscle damage and inflammatory immune response after downhill running. 96 male subjects received Tr14 tablets, which consist of 14 diluted biological and mineral components, or a placebo for 72 h after the exercise test, respectively. Changes in postexercise levels of various serum muscle damage and immunological markers were investigated. The area under the curve with respect to the increase (AUCi) of perceived pain score and creatine kinase (CK) were defined as primary outcome measures. While for CK the p value of the difference between the two groups is borderline, the pain score and muscle strength were not statistically significant. However, a trend towards lower levels of muscle damage (CK, p = 0.05; LDH, p = 0.06) in the Tr14 group was shown. Less pronounced lymphopenia (p = 0.02), a trend towards a lower expression of CD69 count (p = 0.07), and antigen-stimulated ICAM-1 (p = 0.01) were found in the verum group. The Tr14 group showed a tendentially lower increase of neutrophils (p = 0.10), BDNF (p = 0.03), stem cell factor (p = 0.09), and GM-CSF (p = 0.09) to higher levels. The results of the current study indicate that Tr14 seems to limit exercise-induced muscle damage most likely via attenuation of both innate and adaptive immune responses. This study was registered with ClinicalTrials.gov (NCT01912469).

Genetic variation in the major mitotic checkpoint genes associated with chromosomal aberrations in healthy humans.

Non-specific chromosomal aberrations (CAs) are microscopically detected in about 1% of lymphocytes drawn from healthy persons. Causes of CAs in general population are not known but they may be related to risk of cancer. In view of the importance of the mitotic checkpoint machinery on maintaining chromosomal integrity we selected 9 variants in main checkpoint related genes (BUB1B, BUB3, MAD2L1, CENPF, ESPL1/separase, NEK2, PTTG1/securin, ZWILCH and ZWINT) for a genotyping study on samples from healthy individuals (N = 330 to 729) whose lymphocytes had an increased number of CAs compared to persons with a low number of CAs. Genetic variation in individual genes played a minor importance, consistent with the high conservation and selection pressure of the checkpoint system. However, gene pairs were significantly associated with CAs: PTTG1-ZWILCH and PTTG1-ZWINT. MAD2L1 and PTTG1 were the most common partners in any of the two-way interactions. The results suggest that interactions at the level of cohesin (PTTG1) and kinetochore function (ZWINT, ZWILCH and MAD2L1) contribute to the frequency of CAs, suggesting that gene variants at different checkpoint functions appeared to be required for the formation of CAs.

Apoptosis of T-Cell Subsets after Acute High-Intensity Interval Exercise.

INTRODUCTION: High-intensity interval training (HIT) exercise has gained much interest in both performance and recreational sports. This study aims to compare the effect of HIT versus continuous (CONT) exercise with regard to changes of circulating T cells and progenitor cells. METHODS: Subjects (n = 23) completed an HIT test and an isocaloric CONT test. Blood samples were collected before, immediately after, and 3 and 24 h postexercise for the assessment of low differentiated (CD3CD28CD57), highly differentiated T cells (CD3CD28CD57), regulatory T cells (Tregs) (CD4CD25CD127), hematopoietic progenitor cells (CD45CD34), and endothelial progenitor cells (CD45CD34KDR) by flow cytometry. The detection of apoptosis was performed by using labeling with annexin V. To analyze potential mechanisms affecting T cells, several hormones and metabolites were analyzed. RESULTS: Both exercise tests induced an increase of catecholamines, cortisol, and thiobarbituric acid-reactive substances (P < 0.05). CONT induced a higher increase of apoptosis in low differentiated T cells compared with the HIT (CONT: 3.66% ± 0.21% to 6.48% ± 0.29%, P < 0.05; HIT: 3.43% ± 0.31% to 4.71% ± 0.33%), whereas HIT was followed by a higher rate of apoptotic highly differentiated T cells (CONT: 21.45% ± 1.23% to 25.32% ± 1.67%; HIT: 22.45% ± 1.37% to 27.12% ± 1.76%, P < 0.05). Regarding Tregs, HIT induced a mobilization, whereas CONT induced apoptosis in these cells (P < 0.05). The mobilization of progenitor cells did not differ between the exercise protocols. CONCLUSION: These results suggest that HIT deletes mainly highly differentiated T cells known to affect immunity to control latent infections. By contrast, CONT deletes mainly low differentiated T cells and Tregs, which might affect defense against new infectious agents.

The Immunomodulatory Effects of Physical Activity.

BACKGROUND: An individual's level of physical activity is one of a set of lifestyle and behavioral factors that can affect immune function and health. METHODS: The purpose of this review is to summarize the current knowledge in this research field and to review the recent developments in exercise immunology. RESULTS: Most studies show that regular exercise training increases immune competence and reduces the risk of infection compared to a sedentary lifestyle. In contrast, acute prolonged bouts of exercise and periods of intensified training are followed by a temporary increase in the risk of infection. These observations have been attributed to differential exercise-induced changes of a series of humoral and cellular immune system parameters. Furthermore, regular exercise training is a countermeasure against a persistent systemic inflammatory state which is a typical feature of cardiovascular and metabolic diseases is by lowering levels of pro-inflammatory cytokines. It is supposed that these effects are mediated by a modification of metabolic signals and innate immune regulation, the release of anti-inflammatory cytokines from muscle, the release of stress hormones, and a process known as browning of adipose tissue. CONCLUSION: The effects of physical activity on the immune system strongly depend on the mode and intensity of exercise or training. Thereby, considerable knowledge has accumulated concerning the significance of exercise as an important lifestyle factor for prevention and therapy of major chronic diseases.