Genetic score of power-speed and endurance track and field athletes.

Athletic excelling capability in a specific sport results from the combined influence of hundreds of genetic polymorphisms. The aim of the current study was to characterize athletes' polygenetic scores. We developed two polygenetic scores: (a) Power Genetic Distance Score based on two polymorphisms (PGDS2; ACE(I/D), ACTN3(C/T)) or five polymorphisms (PGDS5; ACTN3(C/T), ACE(I/D), IL6(-174G/C), NOS3(T/C), AGT(MET235THR)); and (b) Endurance Genetic Distance Score based on two polymorphisms (EGDS2; ACEI / D , ACTN3C / T ) or five polymorphisms (EGDS5; PPARGC1(AGly482Ser), PPAR(Aintron7G/C), PPARD(T294C), NRF2(A/C), HIF(C/T)). Eighty-two power-speed athletes, 87 endurance athletes, and 119 nonathletic controls participated in the study. Genomic DNA was extracted from peripheral blood. Power-speed athletes' mean PGDS2 (46.1) and PGDS5 (29.4) were significantly higher compared with their mean EGDS2 (36.4) and EGDS5 (23.1; P < 0.05, P < 0.01, respectively); and compared with controls' mean PGDS2 (36.6) and PGDS5 (24.2; P < 0.05, P < 0.05, respectively). Endurance athletes' mean EGDS2 (60.3) and EGDS5 (35.3) were significantly higher compared with their mean PGDS2 (26.9) and PGDS5 (21.8; P < 0.001, P < 0.001, respectively); and compared with controls' mean EGDS2 (51.2) and EGDS5 (26.1; P < 0.05, P < 0.001, respectively). We conclude that polygenetic scores can differentiate power-speed from endurance athletes. Whether these scores may be used to identify elite power-speed or endurance athletes' needs to be addressed in future studies.

Differences in MCT1 A1470T polymorphism prevalence between runners and swimmers.

Skeletal muscle is the major producer and user of lactate in the body. Therefore, transport of lactate across cells' membrane is of considerable importance. Lactate transport is mediated by proton-linked monocarboxylate transporter (MCT1). The A1470T polymorphism (rs1049434) in MCT1 gene influences lactate transport, with T allele associated with reduction of lactate transport rate and elevation in blood lactate levels. The aim of the current study was to compare allelic and genotype frequencies of MCT1 A1470T polymorphism among Israeli track-and-field athletes, swimmers, and non-athletes. Genomic DNA was extracted from 173 track-and-field athletes (age 17-50), 80 swimmers (age 16-49), and 128 non-athletes (age 19-29). Track-and-field athletes were assigned to three subgroups: long-distance runners, middle-distance runners, and power event athletes. Swimmers were assigned to two subgroups: long-distance swimmers and short-distance swimmers. Genotyping was performed using polymerase chain reaction. T-allele frequency was significantly higher among long-distance swimmers (45%) compared with long- and middle-distance runners (27% and 30%, respectively; P < 0.01). In addition, T-allele frequency was significantly higher among short-distance swimmers (40%) compared with power event athletes (25%, P < 0.01). Overall, T-allele frequency was significantly higher among swimmers (42%) compared with runners (27%, P < 0.001). More research is needed to clarify whether this polymorphism displays advantage for swimming performance.

Genetic aspects of exercise and rhabdomyolysis.

Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. Consequently, the circulatory levels of intracellular molecular components, such as creatine kinase, are commonly used to evaluate the severity of muscle damage. Nevertheless, there is a wide inter-individual variability in the phenotypic expression of muscle damage, which cannot be predicted by the age, race, body composition, and fitness level of each subject. This suggests that apart from environmental factors, genetic factors might also contribute to the development and progression of exercise-induced muscle damage. Recently, several gene-specific single nucleotide polymorphisms (SNPs) were found to be associated with severe exercise-induced muscle damage. The present manuscript reviews the pathophysiology of exertional muscle damage, emphasizing the influence of gene polymorphisms on its inter-individual severity. This knowledge may be useful for pediatricians for identifying individuals more susceptible to severe exertional muscle damage and related life-threatening comorbidities.

Bone strength in children with growing pains: long-term follow-up.

OBJECTIVES: To examine the changes in bone strength in a cohort of children with 'growing pains' (GP) after 5 years follow-up and the correlation with pain outcome. METHODS: Bone strength was measured by quantitative ultrasound. Subjects were 39 children with GP previously studied. Controls were normograms based on the measurement of bone speed of sound in 1085 healthy children. Current GP status was assessed by parental questionnaires. Bone strength was compared with pain outcome. RESULTS: We examined 30/39 (77%) patients after 5 years. Bone strength was significantly increased when compared to the first study (Z score 0.65±1.77 vs. -0.62±0.90, p<0.001). While overall there was no significant difference in the bone strength between the 16 (53%) patients whose GP resolved and the 14 (47%) who continued to have GP episodes (p=0.71), all 6 (20%) patients with a speed of sound Z-score <-1 continued to have GP (p=0.003). CONCLUSIONS: Our findings that pain improves in most patients parallel to the increase in bone strength may support the hypothesis of GP representing in some patients a local overuse syndrome.

Pedi-R-MAPP: The development of a nutritional awareness tool for use in remote paediatric consultations using a modified Delphi consensus.

BACKGROUND & AIMS: The Remote Malnutrition Application (R-MAPP) was developed during the COVID-19 pandemic to provide support for health care professionals (HCPs) working in the community to complete remote nutritional assessments, and provide practical guidance for nutritional care. The aim of this study was to modify the R-MAPP into a version suitable for children, Pediatric Remote Malnutrition Application (Pedi-R-MAPP), and provide a structured approach to completing a nutrition focused assessment as part of a technology enabled care service (TECS) consultation. METHODS: A ten-step process was completed: 1) permission to modify adult R-MAPP, 2) literature search to inform the Pedi-R-MAPP content, 3) Pedi-R-MAPP draft, 4) international survey of HCP practice using TECS, 5) nutrition experts invited to participate in a modified Delphi process, 6) first stakeholder meeting to agree purpose/draft of the tool, 7) round-one online survey, 8) statements with consensus removed from survey, 9) round-two online survey for statements with no consensus and 10) second stakeholder meeting with finalisation of the Pedi-R-MAPP nutrition awareness tool. RESULTS: The international survey completed by 463 HCPs, 55% paediatricians, 38% dietitians, 7% nurses/others. When HCPs were asked to look back over the last 12 months, dietitians (n = 110) reported that 5.7 ± 10.6 out of every 10 appointments were completed in person; compared to paediatricians (n = 182) who reported 7.5 ± 7.0 out of every 10 appointments to be in person (p < 0.0001), with the remainder completed as TECS consultations. Overall, 74 articles were identified and used to develop the Pedi-R-MAPP which included colour-coded advice using a traffic light system; green, amber, red and purple. Eighteen participants agreed to participate in the Delphi consensus and completed both rounds of the modified Delphi survey. Agreement was reached at the first meeting on the purpose and draft sections of the proposed tool. In round-one of the online survey, 86% (n = 89/104) of statements reached consensus, whereas in round-two 12.5% (n = 13/104) of statements reached no consensus. At the second expert meeting, contested statements were discussed until agreement was reached and the Pedi-R-MAPP could be finalised. CONCLUSION: The Pedi-R-MAPP nutrition awareness tool was developed using a modified Delphi consensus. This tool aims to support the technological transformation fast-tracked by the COVID-19 pandemic by providing a structured approach to completing a remote nutrition focused assessment, as well as identifying the frequency of follow up along with those children who may require in-person assessment.

Is there an interaction between BDKRB2 -9/+9 and GNB3 C825T polymorphisms and elite athletic performance?

The -9 deletion allele in the BDKRB2 -9/+9 polymorphism was associated previously with improved endurance performance. We compared the frequency distribution of the BDKRB2 -9/+9 (rs5810761) polymorphism between athletes (n=155) of sports with different demands (endurance runners; n=74 vs sprinters; n=81) as well as between athletes of different competitive levels (elite level; n=46 vs national level; n=109). These results were compared with those of 240 non-athletic healthy individuals. We also tested the influence of the interaction between the BDKRB2 -9/+9 and the GNB3 C825T (rs5443) genotypes in relation to endurance performance. Genotype distribution and allele frequencies were found to be similar in the endurance athlete, sprinter, and control groups (P=0.83 for genotype distribution and P=0.9 for allele frequencies). Similarly, no statistical differences were found between the subgroups of elite-level endurance athletes and national-level endurance athletes, or between elite-level and national-level sprinters (P>0.09 for all comparisons). There was no interaction between BDKRB2 -9/+9 and GNB3 C825T polymorphisms in relation to endurance performance (P=0.16 for interaction effect). In conclusion, the BDKRB2 +9/-9 polymorphism is not associated with endurance performance, at least among Israeli athletes, and the GNB3TT+BDKRB2 -9/-9 "optimal genotype" is not associated with endurance performance.

Hormonal response to Taekwondo fighting simulation in elite adolescent athletes.

Exercise training efficiency depends on the training load, as well as on the athlete's ability to tolerate it. The aim of the present study was to evaluate the effect of fighting simulation (3 fights, 6 min each, 30 min rest between fights) on anabolic (IGF-I, LH, FSH, estradiol, and testosterone) and catabolic hormones (cortisol) in elite, male (n = 10) and female (n = 10) adolescent (12-17 years) Taekwondo fighters. Blood samples were collected before the first and immediately after the third fight. The fighting simulation practice led to significant (p < 0.05) decreases in IGF-I (males -27.1 ± 25.6, females -22.4 ± 36.3 ng/ml), LH (males -0.7 ± 1.2, females -2.3 ± 3.3 U/L), and FSH (males -0.9 ± 0.5, females -1.5 ± 1.1 U/L), and to a significant increase (p < 0.05) in cortisol (males 141.9 ± 30.1, females 64.1 ± 30.6 mcg/dL) in both genders. Fighting simulation decreases in testosterone (males -1.9 ± 1.6, females -0.02 ± 0.06 ng/mL), and free androgen index (males -20.1 ± 21.5, females -0.3 ± 0.5) were significant (p < 0.05) only in male fighters. Exercise had no significant effect on estradiol, sex-hormone-binding globulins or thyroid function tests. Our data demonstrate that the physiologic and psychologic strain of a Taekwondo fighting simulation day led to a catabolic-type circulating hormonal response.

Allogeneic hematopoietic stem cell transplantation for patients with relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

Information regarding the curative role of allogeneic stem cell transplantation (allo-HCT) in systemic anaplastic large cell lymphoma (sALCL) is scarce. We analyzed the results of allo-HCT in patients with relapsed/refractory sALCL with special emphasis on the role of brentuximab vedotin (BV) as a bridge to allo-HCT. Forty-four patients (24 females, median age 38 years) with sALCL were included. Twenty-three patients (52%) received BV before allo-HCT; BV-treated patients were more heavily pretreated (≥3 lines of therapy in 74% vs. 38%, p = 0.04). Twenty-three patients (52%) were in complete remission (CR) at allo-HCT. Three-year nonrelapse mortality and incidence of relapse (IR) after allo-HCT were 7% and 40%, respectively. With a median follow-up of 39 (12-69) months for survivors, 3-year progression-free survival (PFS) and overall survival were 53% and 74%, respectively. Univariate analysis showed that heavily pretreated patients and those not in CR had a higher IR and a lower PFS. The use of BV before transplant did not impact on any of the outcomes. Allo-HCT is a curative therapeutic strategy in a significant proportion of patients with relapsed/refractory sALCL; BV does not seem to modify transplant-related outcomes but might be able to render more patients candidates for this curative treatment.

Short stature, celiac disease and growth hormone deficiency.

Celiac disease (CD) is a prevalent, genetically determined, autoimmune, chronic inflammatory state caused by intolerance to gluten that results mainly in gastrointestinal manifestations. One of the most common extra-intestinal manifestations of CD is short stature, and in some patients, short stature may be the presenting and only symptom of the disease, making the diagnosis of CD challenging. Impaired growth in children with CD results mainly from nutritional deficits, and withdrawal of gluten from the diet is frequently associated with a marked improvement of linear growth. In some patients, CD may be characterized by growth hormone (GH) resistance, as suggested by normal or elevated GH levels and low insulin-like growth factor-I (IGF-I) levels. Rarely, it has been shown that poor catch-up growth and/or IGF-I response to gluten-free diet may be due to the coexistence of celiac disease and GH deficiency. We present two children with coexisting CD and GH deficiency. One patient had MRI findings suggesting congenital isolated GH deficiency, and a possibility of developing multiple pituitary hormone deficiencies later in life.

Toxicity related to autologous peripheral blood haematopoietic progenitor cell infusion is associated with number of granulocytes in graft, gender and diagnosis of multiple myeloma.

BACKGROUND AND OBJECTIVES: We prospectively evaluated the infusion-related toxicity of autologous peripheral blood progenitor cells (PBPC) in 215 patients with haematologic malignancies or solid tumours. MATERIALS AND METHODS: PBPCs were collected by apheresis after mobilization with chemotherapy and/or granulocyte-colony-stimulating factor (G-CSF). The grafts were cryopreserved in 10% dimethyl sulfoxide (DMSO) and stored in liquid nitrogen. Patients were monitored for vital signs and symptoms of the toxicity during and after infusion. RESULTS: The adverse reactions were reported during 149 (56.9%) infusions. During 21.0% infusions occurred just one symptom classified as grade 1, while during 35.9% occurred multiple symptoms classified as grade 2. Logistic regression analysis showed that female gender, diagnosis of multiple myeloma and number of granulocytes infused per kg body weight were significant predictors of occurrence of adverse reactions during infusion. CONCLUSION: Our results indicate that beside the infused DMSO dose, the composition of graft as well as patient's diagnosis are also very important factors for infusion-related toxicity.

Correlation of morphological FAB classification and immunophenotyping: value in recognition of morphological, cytochemical and immunological characteristics of mixed leukaemias.

Correlation between the FAB classification and immunophenotype was studied in 169 consecutive adult patients with acute leukaemia (AL). The lineage of leukaemic cells could be determined in the majority of cases, whereas 3 patients (1.8%) remained unclassified. In 22 out of 71 patients (31%) with acute myeloid leukaemia (AML) FAB M1 and M2 types, and in 5 out of 16 patients (31%) with chronic myeloid leukaemia (CML) in myeloid blast crisis, leukaemic cells did not express myeloid lineage-related markers, indicating asynchronous expression of cell markers in a substantial proportion of patients. Flow cytometric two-colour immunofluorescence revealed mixed AL immunophenotype in 6 out of 169 patients (3.4%). This group included five CD2+AML (5% of AML tested) and one undifferentiated AL expressing CD10(CALLA), CDw65(VIM-2). The former group included FAB M1, M2, M3 and M4 forms of AML with a single cell population, and an AML M2 patient with both cytochemically and immunologically two separate populations of leukaemic cells. This further illustrates the heterogeneity of the target cell(s) for leukaemogenesis and the level of differentiation of AML cells. However, there was no difference in the treatment response and the remission duration between AML patients and patients with mixed phenotype AML.

Expression of haematopoietic progenitor cell-associated antigen BI-3C5/CD34 in leukemia.

The expression of progenitor cell-associated antigen CD34, defined with monoclonal antibody BI-3C5, was investigated in cells from 109 patients with leukaemia. No reactivity was found in chronic leukaemias, whereas 31% of acute myelogenous leukaemia (AML) and most non-T, non-B acute lymphoblastic leukaemia (ALL) expressed CD34. Examples of BI-3C5+ AML included M1 and M2 FAB types only; all but one were myeloperoxidase positive. In combination with pan-myeloid markers, BI-3C5 is useful for identification of immature myeloid cells.

Relationship between differing volumes of bone marrow aspirates and their cellular composition.

We compared the cellular composition of the first 1.0 ml volume bone marrow aspirate with that of an aliquot from the total bone marrow harvest at the end of the procedure in 17 healthy bone marrow donors. Each sample was assayed for its content of red blood cells, nucleated cells, CD2+, CD4+, CD8+, CD19+, HLA-DR+, CD56+, CD13+, CD33+, CD34+ and KiM8+ cells and CFU-GM. On the basis of data obtained, we estimated that the first 1.0 ml samples had 8.0 +/- 5.2% (SD) and the transplant samples 20.8 +/- 8.5% contamination with nucleated blood cells. The calculation revealed that both types of bone marrow samples had 100% volume contamination with peripheral blood, i.e. that bone marrow cells were aspirated within blood fluid volume. Nucleated cell concentration was 3-fold, and CFU-GM concentration 10-fold lower in the transplant than in the first-puncture 1.0 ml bone marrow samples. Various marker-positive cells appeared in transplant samples in concentrations that depended on their abundance in the first-puncture 1.0 ml and blood samples. Taken together, our data suggest that bone marrow harvesting would be substantially improved if individual aspirates were small in volume and taken from bone puncture sites as distant as possible.

Lymphocyte subsets in normal human bone marrow harvested for routine clinical transplantation.

Bone marrow and peripheral blood of 25 healthy bone marrow donors from our allogeneic bone marrow transplantation program were assessed for cell subsets bearing T11(CD2), T4(CD4), T8(CD8), B1(CD20) J5(CALLA, CD10), Mo1(CD11b), MY7(CD13). Mo2(CD14), MY9(CD33) and NKH-1 antigens. Bone marrow cell samples were taken for analysis at the start or at the end of the harvesting procedure of aspiration from the iliac crest. All samples were analysed on a flow cytometer at the lymphocyte window as obtained on the two-parameter (L90oLSxFALS) scatter diagram. There were no differences in the lymphocyte subset composition of bone marrow samples taken at the start or at the end of the harvesting procedure. In contrast to the majority of literature data, a high CD4/CD8 ratio was detected in bone marrow samples: it did not differ from that in the peripheral blood. The proportions of CD2 and CD4 T cell markers in the bone marrow correlated with those in the peripheral blood, thus further documenting a substantial bone marrow contamination with peripheral blood cells. A relatively large aspirate volume (4-5 ml) obtained from individual aspiration sites was identified as the only factor possibly accounting for the high-level contamination of bone marrow samples with peripheral blood. This conclusion was corroborated by low T cell proportions and low CD4/CD8 ratios found in the bone marrow washed from bone fragments and in bone marrow samples aspirated at first bone puncture in a volume of 1.0 ml. Taken together, these findings imply that less vigorous suction may decrease the number of T lymphocytes in bone marrow harvested for transplantation purposes.

Anxiety as a possible predictor of acute GVHD.

In order to determine the influence of anxiety on the development of BMT complications and survival, we analysed data on 35 consecutive patients undergoing BMT in our Centre between June 1992 and December 1994. All patients received bone marrow from HLA-identical MLC non-responsive siblings. For GVHD prophylaxis, all patients received cyclosporin (CsA) and short methotrexate (MTX). The diagnosis and severity of acute GVHD were defined according to the Seattle Transplant Team criteria. The patients were tested with the Spielberger STAI test as a measure of anxiety as a state (STAI-S) and as a trait (STAI-T). The STAI-S/1 and STAI-T/1 were performed during the first week of isolation (day -5 to day -3 prior BMT) and STAI-S/2 and STAI-T/2 at the end of the discharge from laminar air flow units (day +35 to day +40 post-transplant). During isolation all patients had daily psychiatric support. Out of 35 patients, 31 (89%) fulfilled the STAI-S and STAI-T during the first week and at discharge from laminar air flow isolation. The level of anxiety at the beginning of isolation as measured by STAI-S/1 and STAI-T/1 tests had been significantly higher in patients who subsequently developed acute grade II-IV GVHD as compared to patients with GVHD grade 0-I (P < 0.001), irrespective of age, sex or stage of the disease prior to BMT. In those patients who died, the STAI-S/1, STAI-T/1 and STAI-T/2 tests had been almost identical to those of surviving patients, while STAI-S/2 had been significantly higher (P = 0.034). These data clearly indicate an association between the level of anxiety and the risk for BMT complications, but this should be confirmed in further controlled clinical trials.

Allogeneic bone marrow transplantation for acute leukaemia--IGCI experience. International Group for Chemo-Immunotherapy.

From October 1984 to December 1994, 142 patients from six IGCI-BMT centers (78 acute myelogenous leukemia and 64 acute lymphoblastic leukemia) received allogeneic bone marrow from their HLA-identical sibling. The probability of LFS at 60 months is 41% for AML patients and 39% for ALL patients. A better LFS was documented in patients allografted in first CR compared to the patients treated in advanced stage of the disease. The overall relapse rate is 27% for AML patients and 45% for ALL patients. The relapse rate is higher for patients allografted in advanced stage of the disease (47 vs 26% at 60 months for AML and 55 vs 38% at 60 months for ALL). The incidence of moderate to severe acute GVHD is between 45-50% for both AML and ALL patients. Chronic GVHD was documented in 30% of AML patients and 38% of ALL patients. Transplant-related mortality for both AML and ALL is about 25%. Relapse and GVHD with or without infection are the main causes of death. These results confirmed that allogeneic BMT is very effective therapy for patients with acute leukemia, especially for patients transplanted in first CR.

Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia.

From May 1985 to July 1989, 76 patients with leukemia (30 acute myelogenous leukemia, 24 acute lymphoblastic leukemia and 22 chronic myeloid leukemia) were randomized to receive either cyclosporin (CSP) alone (n = 39) or CSP combined with methotrexate (CSP + MTX, n = 37) for graft-versus-host disease (GVHD) prophylaxis. Patients were conditioned with total body radiation and cyclophosphamide followed by bone marrow infusion from an HLA-identical sibling. Engraftment of the transplanted bone marrow was similar in both groups. The incidence of moderate to severe acute GVHD was significantly higher in the CSP group compared with the CSP + MTX group (20 (51%) versus 9 (25%), chi 2 = 4.76, p less than 0.02). There was no significant difference in the incidence of chronic GVHD. Survival was significantly better for the CSP + MTX group (63 +/- 16%) compared to CSP alone (42 +/- 18%). Leukemia-free survival tended to be better for the CSP + MTX group (55 +/- 17% versus 32 +/- 16%).

Total body irradiation with or without lung shielding for allogeneic bone marrow transplantation.

From June 1986 to June 1990, 64 patients with leukaemia (25 acute myelogenous leukaemia, 21 acute lymphoblastic leukaemia and 18 chronic myeloid leukaemia) undergoing marrow transplantation were randomized to receive cyclophosphamide (CY) and fractionated total body irradiation (TBI) without lung shielding (n = 33) or CY and fractionated TBI with lung shielding (n = 31, control group) as conditioning. Patients conditioned with TBI without lung shielding received a significantly higher total lung dose compared with the control group (p less than 0.0001). The 3-year leukaemia-free survival for patients receiving TBI without lung shielding is 54 +/- 18% versus 51 +/- 18% for patients receiving TBI with lung shielding (p = ns). There was no significant difference in the probability of leukaemia relapse (22 +/- 18% for TBI without lung shielding versus 24 +/- 18% for control group; p = ns). The probability of interstitial pneumonitis is 15 +/- 14% for TBI without lung shielding and 5 +/- 5% for TBI with lung shielding (p = ns). A higher incidence of lung fungal infection (15 versus 3%) and interstitial pneumonitis (12 versus 3%) has been documented in patients receiving TBI without lung shielding compared with the control group. The results indicate that higher radiation dose to the lung did not increase antileukaemic efficacy of TBI but seemed to be associated with the increased pulmonary toxicity.