Vitamin D sufficiency associates with an increase in anti-inflammatory cytokines after intense exercise in humans.

The purpose of this study was to identify the influence of vitamin D status (insufficient vs. sufficient) on circulating cytokines and skeletal muscle strength after muscular injury. To induce muscular injury, one randomly selected leg (SSC) performed exercise consisting of repetitive eccentric-concentric contractions. The other leg served as the control. An averaged serum 25(OH)D concentration from two blood samples collected before exercise and on separate occasions was used to establish vitamin D insufficiency (<30ng/mL, n=6) and sufficiency (>30ng/mL, n=7) in young, adult males. Serum cytokine concentrations, single-leg peak isometric force, and single-leg peak power output were measured before and during the days following the exercise protocol. The serum IL-10 and IL-13 responses to muscular injury were significantly (both p<0.05) increased in the vitamin D sufficient group. The immediate and persistent (days) peak isometric force (p<0.05) and peak power output (p<0.05) deficits in the SSC leg after the exercise protocol were not ameliorated with vitamin D sufficiency. We conclude that vitamin D sufficiency increases the anti-inflammatory cytokine response to muscular injury.

Circulating pro-inflammatory cytokines are elevated and peak power output correlates with 25-hydroxyvitamin D in vitamin D insufficient adults.

The purpose of this study was to identify circulating cytokines, skeletal muscle strength, and peak power output in young adults with contrasting serum 25-hydroxyvitamin D (25(OH)D) concentrations. Serum 25(OH)D, inflammatory cytokines, muscle strength, and peak power output were, therefore, measured in young adults (25-42 years). Data were collected during the winter to avoid the seasonal influence on serum 25(OH)D. After serum 25(OH)D concentration measurements, subjects were separated into one of two groups: (1) vitamin D insufficient [serum 25(OH)D ≤32 ng/mL, n = 14], or (2) vitamin D sufficient [serum 25(OH)D >32 ng/mL, n = 14]. Following group allocation, serum 25(OH)D concentrations were significantly (p < 0.05) lower and pro-inflammatory cytokines [interleukin (IL)-2, IL-1ß, tumor necrosis factor-α, and interferon-γ] were significantly (all p < 0.05) greater in vitamin D insufficient adults. An anti-inflammatory cytokine (i.e., IL-10; p > 0.05), peak isometric forces (p > 0.05), and peak power outputs (p > 0.05) were not significantly different between vitamin D groups. However, peak power outputs correlated with serum 25(OH)D concentrations in vitamin D insufficient (r = 0.55, p < 0.05) but not in vitamin D sufficient adults (r = -0.27, p = 0.36). Based on these data, we conclude that vitamin D insufficiency, in part, could result in pro-inflammatory stress without altering muscular strength or function in young adults. Future research investigating the causality of the correlation between low-serum 25(OH)D and peak power output in young adults is required.

Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio.

The mechanism responsible for the decrease in vitamin D status (i.e., plasma or serum 25-hydroxyvitamin D (25(OH)D) concentration) during inflammatory stress is unknown in humans. Interferon (IFN)-γ is an inflammatory cytokine that regulates vitamin D metabolism in isolated immune cells, but data suggesting this regulation exists in vivo is lacking. The purpose of this study, therefore, was to associate circulating IFN-γ perturbations with 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)D) alterations during inflammatory stress in young adults recovering from anterior cruciate ligament (ACL) reconstruction. Plasma 25(OH)D, 1,25(OH)D and IFN-γ concentrations were measured in fasting blood draw samples obtained from twelve-male patients pre-surgery and 90-m, 3-d and 7-d post-surgery. 25(OH)D decreased significantly (p<0.05) after surgery, and strikingly, tended to inversely correlate (r=-0.32, p=0.058) with IFN-γ changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery. Additionally, 1,25(OH)D (r=0.37, p<0.05) and the 1,25(OH)D-to-25(OH)D ratio (r=0.52, p<0.05) changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery correlated with those of IFN-γ. These are the first reported in vivo findings suggesting that the 25(OH)D decrease and conversion to 1,25(OH)D increase with increasing IFN-γ in the circulation. We conclude that IFN-γ contributes to the decrease in vitamin D and the conversion of vitamin D to its active hormonal form in the circulation during inflammatory insult in humans.

Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08.

Among pediatric non-Hodgkin lymphomas, one of the most frequent types is lymphoblastic lymphoma (LBL). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but have not been evaluated for prognostic value in pediatric LBL. For the Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 13 patients were enrolled with cytogenetic analysis of LBL and on treatment protocol CCG-502. Pathology material and karyotypes at initial diagnosis were given central review. The patients were aged 6-13 years (median 9 years), with a male-to-female ratio of 12:1. All patients had advanced disease. Disease relapsed in six patients (event-free survival 54% +/- 14%, median 10.8 years). Chromosome abnormalities were identified in 11 (85%), and translocations at 14q11.2 likely involving the T-cell receptor alpha/delta locus (TCR A/D) occurred in 4 (31%). For patients with relapse, four had translocations t(1;14)(p32;q11.2), t(8;14)(q24.1;q11.2), t(11;14)(p13;q11.2), or t(9;17)(q34;q23), involving breakpoints in the regions of TAL1, MYC, LMO2, and NOTCH1, respectively. Pediatric advanced LBLs have a high frequency of chromosome abnormalities; in this limited study, these often involved translocations at 14q11.2, the site of TCR A/D. Translocations possibly involving TAL1, MYC, LMO2, or NOTCH1 may have contributed to poor outcome. Further studies are warranted in larger cohorts of children and adolescents with LBL to evaluate the prognostic significance.

Complex secondary chromosome abnormalities in advanced stage anaplastic large cell lymphoma of children and adolescents: a report from CCG-E08.

Among pediatric non-Hodgkin lymphomas, one of the most distinctive types is anaplastic large cell lymphoma (ALCL). Specific chromosomal abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but chromosome abnormalities have not been evaluated for prognostic value in pediatric ALCL. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, three patients were enrolled with cytogenetic analysis of ALCL and simultaneously enrolled on treatment protocol CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included ages of 9, 12, and 14 years, and a male/female ratio of 1:2. All patients had advanced disease (stage III). Disease progressed or relapsed in two patients, and one died. Chromosomal abnormalities, including t(2;5)(p23;q35), the ALK/NPM fusion gene, and complex karyotypes with multiple additional abnormalities, were identified in all three patients. In two patients with progressive disease or relapse, additional chromosomal abnormalities at 1q21 and 10q24, possibly involving MCL1 and HOX11/TCL3, respectively, may have contributed to worse outcome. Pediatric ALCL cases frequently have complex karyotypes and usually involve ALK/NPM translocations in this limited study. Additional chromosome abnormalities may be involved in the pathogenesis of ALCL. Further studies are warranted in larger cohorts of children and adolescents with ALCL.

Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report.

PURPOSE: Non-Hodgkin's lymphoma (NHL) arising in bone is a heterogeneous histologic type of NHL that includes large-cell lymphoma, lymphoblastic lymphoma, and small noncleaved-cell lymphoma. NHL arising in bone is well recognized in adults but is less well characterized and infrequent in children and adolescents. PATIENTS AND METHODS: We performed a retrospective review of Children's Cancer Group (CCG) studies treating children and adolescents with NHL over a 20-year period (CCG-551, CCG-501, CCG-502, CCG-503, CCG-552, CCG-5911, and CCG-5941) and determined the response and event-free survival (EFS) rates in 31 patients with NHL arising in bone. RESULTS: The patients ranged in age from 3 to 17 years (median, 11 years; mean, 11 years), and 64.5% were male. All 31 (100%) patients achieved complete response. For 31 patients with NHL arising in bone, the product-limit estimated 5-year EFS was 83.8% +/- 6.7%. EFS in 17 patients with localized disease (Murphy stages I and II) was 94.1% +/- 5.7%, and EFS in 14 patients with disseminated disease (Murphy stage III) was 70.7% +/- 12.4% (log-rank P =.10). EFS in 17 patients treated with chemotherapy and radiation was 70.1% +/- 11.2%, and EFS in 14 patients treated with chemotherapy without radiation was 100% (P =.03). EFS in 26 patients with histology-directed treatment (LSA2-L2 or ADCOMP for lymphoblastic, other therapy for nonlymphoblastic) was 92.2% +/- 5.3%, and in five patients with nonhistology-directed treatment it was 40.0% +/- 21.9% (P <.001). CONCLUSION: NHL arising in bone is a heterogeneous type of NHL that makes up approximately 2.0% of NHL in children and adolescents on CCG studies. Response and survival in this young age group seem superb, with histology-directed treatment protocols without radiation in both localized and disseminated disease.

Higher serum 25-hydroxyvitamin D concentrations associate with a faster recovery of skeletal muscle strength after muscular injury.

The primary purpose of this study was to identify if serum 25-hydroxyvitamin D (25(OH)D) concentrations predict muscular weakness after intense exercise. We hypothesized that pre-exercise serum 25(OH)D concentrations inversely predict exercise-induced muscular weakness. Fourteen recreationally active adults participated in this study. Each subject had one leg randomly assigned as a control. The other leg performed an intense exercise protocol. Single-leg peak isometric force and blood 25(OH)D, aspartate and alanine aminotransferases, albumin, interferon (IFN)-γ, and interleukin-4 were measured prior to and following intense exercise. Following exercise, serum 25(OH)D concentrations increased (p < 0.05) immediately, but within minutes, subsequently decreased (p < 0.05). Circulating albumin increases predicted (p < 0.005) serum 25(OH)D increases, while IFN-γ increases predicted (p < 0.001) serum 25(OH)D decreases. Muscular weakness persisted within the exercise leg (p < 0.05) and compared to the control leg (p < 0.05) after the exercise protocol. Serum 25(OH)D concentrations inversely predicted (p < 0.05) muscular weakness (i.e., control leg vs. exercise leg peak isometric force) immediately and days (i.e., 48-h and 72-h) after exercise, suggesting the attenuation of exercise-induced muscular weakness with increasing serum 25(OH)D prior to exercise. Based on these data, we conclude that pre-exercise serum 25(OH)D concentrations could influence the recovery of skeletal muscle strength after an acute bout of intense exercise.

Fluctuations in the skeletal muscle power-velocity relationship and interferon-γ after a muscle-damaging event in humans.

BACKGROUND: Skeletal muscle power is velocity-dependent under constant load conditions. Interferon (IFN)-γ is an inflammatory cytokine that regulates skeletal muscle recovery following insult in experimental animals. It is unknown if the power-velocity relationship and IFN-γ are modulated after a muscle-damaging event in humans. Therefore, the purpose of this study was to identify the power-velocity relationship and circulating IFN-γ concentration responses to a muscle-damaging event in humans. METHODS: Nine healthy males participated in this study. Each subject had one leg randomly assigned as the control leg. The other leg served as the treatment leg and performed an intense-stretch-shortening cycling (SSC) exercise protocol to induce muscle damage. To measure muscle damage and the power-velocity relationship, unilateral peak isometric force and power output (forces and velocities) measurements were performed prior to, immediately after, and during the days following the SSC protocol. The circulating IFN-γ concentrations were measured in serum samples obtained prior to, immediately after, and during the days following the SSC protocol. Statistical significance of single-leg isometric force and power output data were assessed using a two-way (time and leg treatment) analysis of variance (ANOVA) with repeated measures, followed by a Tukey's honestly significant difference (HSD) to test multiple pairwise comparisons. The statistical significance of the IFN-γ data were assessed using a one-way (time) ANOVA with repeated measures, followed by a Tukey's HSD to test multiple pairwise comparisons. RESULTS: In the treatment leg, significant (P < 0.05) peak isometric force deficits occurred immediately and persisted several days after the SSC protocol, thereby identifying muscle damage-induced weakness. During muscle weakness in the treatment leg, peak power was significantly (P < 0.05) depressed and the velocities at peak power were significantly (P < 0.05) slower. Interestingly, circulating IFN-γ concentrations decreased at 2 and 3 days after compared to those immediately following the SSC protocol. CONCLUSION: We conclude that the velocity to achieve a compromised peak power is reduced, and speculatively, the circulating IFN-γ excursion could be influential on the recovery of skeletal muscle after a muscle-damaging event in humans.

Different doses of supplemental vitamin D maintain interleukin-5 without altering skeletal muscle strength: a randomized, double-blind, placebo-controlled study in vitamin D sufficient adults.

BACKGROUND: Supplemental vitamin D modulates inflammatory cytokines and skeletal muscle function, but results are inconsistent. It is unknown if these inconsistencies are dependent on the supplemental dose of vitamin D. Therefore, the purpose of this study was to identify the influence of different doses of supplemental vitamin D on inflammatory cytokines and muscular strength in young adults. METHODS: Men (n = 15) and women (n = 15) received a daily placebo or vitamin D supplement (200 or 4000 IU) for 28-d during the winter. Serum 25-hydroxyvitamin D (25(OH)D), cytokine concentrations and muscular (leg) strength measurements were performed prior to and during supplementation. Statistical significance of data were assessed with a two-way (time, treatment) analysis of variance (ANOVA) with repeated measures, followed by a Tukey's Honestly Significant Difference to test multiple pairwise comparisons. RESULTS: Upon enrollment, 63% of the subjects were vitamin D sufficient (serum 25(OH)D ≥ 30 ng/ml). Serum 25(OH)D and interleukin (IL)-5 decreased (P < 0.05) across time in the placebo group. Supplemental vitamin D at 200 IU maintained serum 25(OH)D concentrations and increased IL-5 (P < 0.05). Supplemental vitamin D at 4000 IU increased (P < 0.05) serum 25(OH)D without altering IL-5 concentrations. Although serum 25(OH)D concentrations correlated (P < 0.05) with muscle strength, muscle strength was not changed by supplemental vitamin D. CONCLUSION: In young adults who were vitamin D sufficient prior to supplementation, we conclude that a low-daily dose of supplemental vitamin D prevents serum 25(OH)D and IL-5 concentration decreases, and that muscular strength does not parallel the 25(OH)D increase induced by a high-daily dose of supplemental vitamin D. Considering that IL-5 protects against viruses and bacterial infections, these findings could have a broad physiological importance regarding the ability of vitamin D sufficiency to mediate the immune systems protection against infection.

Vitamins E and C modulate the association between reciprocally regulated cytokines after an anterior cruciate ligament injury and surgery.

OBJECTIVE: : The purpose of this study was to identify the influence of vitamin E and C supplementation on inflammatory cytokines and the association between reciprocally regulated cytokines after anterior cruciate ligament surgery. DESIGN: : A double-blind, placebo-controlled study was conducted in men undergoing anterior cruciate ligament surgery who were randomly assigned to one of two groups (n = 10/group): (1) antioxidant (vitamins E and C) or (2) matching placebos starting ∼2 wks before (baseline) and concluding 3 mos after surgery. Plasma inflammatory cytokines were measured in fasting blood draw samples before and after anterior cruciate ligament surgery. RESULTS: : Plasma interleukin (IL) 1ß concentrations were double at 3 mos after surgery compared with baseline. Plasma IL-1ß increased to a greater (P < 0.05) extent relative to IL-4 in the placebo group (mean ± SE slope, 18.87 ± 0.68; r = 0.97) than in the antioxidant group (mean ± SE slope, 4.84 ± 0.42; r = 0.89). Similarly, the relative increase in IL-1ß to IL-2 was greater (P < 0.05) in the placebo (mean ± SE slope, 2.70 ± 0.21) than in the antioxidant (mean ± SE slope, 1.08 ± 0.23) group. CONCLUSIONS: : Vitamins E and C were ineffective in ameliorating the increases in IL-1ß but altered associations between reciprocally regulated cytokines after anterior cruciate ligament surgery.

Modulation of inflammation by vitamin E and C supplementation prior to anterior cruciate ligament surgery.

Muscle atrophy commonly follows anterior cruciate ligament (ACL) injury and surgery. Proinflammatory cytokines can induce and exacerbate oxidative stress, potentiating muscle atrophy. The purpose of this study was to evaluate the influence of prior antioxidant (AO) supplementation on circulating cytokines following ACL surgery. A randomized, double-blind, placebo-controlled trial was conducted in men undergoing ACL surgery, who were randomly assigned to either: (1) AO (200 IU of vitamin E (50% d-alpha-tocopheryl acetate and 50% d-alpha-tocopherol) and 500 mg ascorbic acid), or (2) matching placebos (PL). Subjects took supplements twice daily for 2 weeks prior to and up to 12 weeks after surgery. Each subject provided five blood samples: (1) baseline (Bsl, prior to supplementation and approximately 2 weeks prior to surgery), (2) presurgery (Pre), (3) 90 min, (4) 72 h, and (5) 7 days postsurgery. Following surgery, inflammation and muscle damage increased in both groups, as assessed by increased circulating IL-6, C-reactive protein, and creatine kinase. During AO supplementation, plasma alpha-T and AA increased while gamma-T concentrations decreased significantly (P< 0.05). At 90 min the AO group displayed a significant decrease in AA, an inverse correlation between AA and (interleukin) IL-8 (r(2)= 0.50, P< 0.05), and a significantly lower IL-10 response than that of the PL group. IL-10 was significantly elevated at 90 min and 72 h in the PL group. In summary, our findings show that circulating inflammatory cytokines increase and AO supplementation attenuated the increase in IL-10 in patients post-ACL surgery.

Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience.

Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) > or = 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients > or = 15-years-old compared with < 15-year-old was 34 +/- 7 versus 59 +/- 2% (P < 0.05), the 4-year EFS of M2/M3 compared with M1 BM was 38 +/- 5 versus 63 +/- 3% (P < 0.001), and the 4-year EFS with LDH > or = 500 IU/l compared with LDH < 500 IU/l was 49 +/- 3 versus 71 +/- 4% (P < 0.001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 +/- 6 versus 54 +/- 2%, P < 0.001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.

Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children's Cancer Group Study CCG-E08.

Among pediatric non-Hodgkin lymphomas, the most frequent type is small noncleaved-cell lymphoma (including Burkitt and Burkitt-like). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia (ALL); however, chromosome abnormalities have not been evaluated for prognostic value in pediatric Burkitt and Burkitt-like lymphomas. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 19 patients were enrolled with cytogenetic analysis of Burkitt or Burkitt-like lymphoma and simultaneously enrolled on treatment protocols CCG-503 or CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included an age range of 2 to 14 years (median 8 years) and a male:female ratio of 14:5. All patients had advanced disease (stages III and IV, or ALL). Disease relapsed in five patients (event-free survival 74%, median follow-up 10.4 years). Chromosome abnormalities were identified in 18 patients (95%) including t(8;14)(q24.1;q32) in 12 (63%); t(8;22)(q24.1;q11.2) in 1 (5%); partial duplication of 1q in 7 (37%); and 13q32 abnormalities in 2 (11%). In patients who had relapses, in addition to the t(8;14)(q24. ;q32), two had abnormalities of 13q32 and two had partial duplication of 1q. CMYC translocations were absent in Burkitt-like lymphomas from all three patients. Burkitt and Burkitt-like lymphomas in children have a high frequency of chromosome abnormalities. Burkitt lymphoma abnormalities often involve CMYC translocations, usually a t(8;14)(q24.1;q32). Additional chromosome abnormalities that involved 13q32 and partial duplication of 1q were associated with poor prognosis. Burkitt-like lymphomas were not associated with CMYC translocations. Further studies are warranted in larger cohorts of children and adolescents with Burkitt and Burkitt-like lymphomas.

Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience.

We reviewed the clinical characteristics, treatment, and outcome of 67 children with localized and 212 with disseminated large-cell lymphoma (LCL) treated during a 20-year period in 5 consecutive Children's Cancer Group (CCG) non-Hodgkin's lymphoma (NHL) trials. Clinical outcomes for patients treated on the four earlier studies with moderate-dose chemotherapy administered over 12-18 months were compared with patients treated most recently with short, intensive therapy. Median age at diagnosis was 12 years (range: 0-19 years). Male to female ratio was 1.8:1.0. Five-year event-free survival (EFS) was 92% +/- 3.3% and 50 +/- 3.5% for patients with localized LCL and disseminated LCL, respectively. After adjustment for lactate dehydrogenase (LDH), age at diagnosis, and BM involvement, short and intensive therapy as delivered on the most recent study, CCG-5911, was associated with an improved outcome (P< 0.05) compared to the four previous studies. Elevated LDH (> or = 500 IU/L) at diagnosis and young age (<5 years) were both significant independent predictors of poorer long-term EFS (P< 0.05). Long-term survival after relapse or other treatment failure was only 31% +/- 4.7%. In summary, more recent shorter and intense therapy appears to be associated with superior event-free survival for children and adolescents with disseminated LCL. Large numbers of patients treated with shorter and intense therapy are required to confirm these preliminary observations.