Sprinting with bilateral transtibial running-specific prostheses versus biological limbs - are they comparable? Comments on Beck et al. (2022).

Since publication of this paper (Royal Society open science, 2022. 9(1): p. 211799), the authors have published a correction clarifying that the paper presents a case study that '… did not meet the definition for research with regard to human subjects'. The data are incorrectly referred to as experimental because the study has no experimental control. Furthermore, the paper has been presented previously but the version presented here selectively omits several analyses, posing a significant risk of bias. Of the prosthetic-related disadvantages identified by the authors, the most substantive was a 40% increase in time to 20 m (59.5 s.d. below the mean for NA sprinters). However the analysis was incomplete: acceleration modelling for NA sprinters continued up to 98% of maximum velocity, while Fastest BA was truncated at approximately 80%. We extrapolated the model, revealing the duration of maximum acceleration for Fastest BA is approximately 100% longer than NA sprinters. Important differences in Fastest BA contact lengths (0.10-0.15 m) were also identified. We posit that together, these large and important differences in sprint biomechanics and their likely physiological consequences suggest that running with and without prosthetics are so different that, although running times may be similar, the precautionary principle should apply and, in the interests of athletic competition integrity, runners with and without prosthetics should continue to compete separately.

The impact of strength level on adaptations to combined weightlifting, plyometric, and ballistic training.

The purpose of this investigation was to determine whether the magnitude of adaptation to integrated ballistic training is influenced by initial strength level. Such information is needed to inform resistance training guidelines for both higher- and lower-level athlete populations. To this end, two groups of distinctly different strength levels (stronger: one-repetition-maximum (1RM) squat = 2.01 ± 0.15 kg·BM-1 ; weaker: 1.20 ± 0.20 kg·BM-1 ) completed 10 weeks of resistance training incorporating weightlifting derivatives, plyometric actions, and ballistic exercises. Testing occurred at pre-, mid-, and post-training. Measures included variables derived from the incremental-load jump squat and the 1RM squat, alongside muscle activity (electromyography), and jump mechanics (force-time comparisons throughout the entire movement). The primary outcome variable was peak velocity derived from the unloaded jump squat. It was revealed that the stronger group displayed a greater (P = .05) change in peak velocity at mid-test (baseline: 2.65 ± 0.10 m/s, mid-test: 2.80 ± 0.17 m/s) but not post-test (2.85 ± 0.18 m/s) when compared to the weaker participants (baseline 2.43 ± 0.09, mid-test. 2.47 ± 0.11, post-test: 2.61 ± 0.10 m/s). Different changes occurred between groups in the force-velocity relationship (P = .001-.04) and jump mechanics (P ≤ .05), while only the stronger group displayed increases in muscle activation (P = .05). In conclusion, the magnitude of improvement in peak velocity was significantly influenced by pre-existing strength level in the early stage of training. Changes in the mechanisms underpinning performance were less distinct.

Assessing muscle strength for the purpose of classification in Paralympic sport: A review and recommendations.

OBJECTIVES: Classification in Paralympic Sport aims to minimize the impact of 10 eligible types of impairment on the outcome of competition. Methods for assessing the extent to which a given body structure or function has been impaired are required, but are challenging because it is not possible to directly measure an absence or loss. Rather, impairment must be inferred by measurement of extant body structures or functions. METHODS: This manuscript reviews the literature concerning the assessment of strength with the aim of identifying and describing the most appropriate method for inferring strength impairment in para-athletes. RESULTS: It is posited that the most appropriate voluntary strength assessment method for inferring strength loss in para-athletes will be multi-joint, isometric tests performed at joint angles that facilitate maximum force production. CONCLUSIONS: Evidence suggests such methods will permit development of tests that are specific to a variety of para-sports and which are reliable, ratio-scaled, and resistant to training. Future research should: develop sport-specific tests which are suitable for assessment of athletes with strength impairments of variable severity and distribution; and scientifically evaluate the extent to which such tests permit strength impairment to be validly inferred, including specific evaluation of the extent to which such measures respond to athletic training.

How much does lower body strength impact Paralympic running performance?

OBJECTIVES: Development of evidence-based methods of Paralympic classification requires research quantifying the relative strength of association between ratio-scaled measures of impairment and athletic performance. The purpose of this study was to quantify the extent to which muscle strength affects running performance in runners with and without brain impairment. DESIGN: Cross-sectional study. METHODS: Participants were 41 male runners: 13 with brain impairments (RBI) and 28 non-disabled (NDR). All participants completed a maximal 60-m sprint and a novel battery of three lower limb isometric strength tests. RESULTS: RBI showed significantly lower strength scores compared with NDR on the more affected side in leg flexion (176 vs. 243 N), leg extension (993 vs. 1661 N) and plantarflexion (824  vs. 1457 N). Significant differences were also seen on the less affected side in plantarflexion (1072 vs. 1508 N). RBI were significantly slower in the acceleration phase (0-15 m) (3.2 s ± 0.3 vs. 2.8 s ± 0.2) and top speed phase (30-60 m) (4.3 s ± 0.6 vs. 3.8 s ± 0.3). Correlation analysis showed stronger relationships between strength and running performance in RBI than NDR; however, the correlations were not significant. CONCLUSIONS: This study evaluated measures to assess strength for the purposes of classification and found that the measures were significantly different in RBI compared with NDR indicating the tests were able to capture strength impairment in this population. This study indicates that strength may be an important impairment type to assess in this population, as impairments of muscle strength may influence the outcome of running performance in athletes with more severe impairments.

Effects of gold nanoparticles on erythrocyte hemolysis.

We studied hemolytic activity of gold nanoparticles added to the whole blood (ex vivo) and of nanoparticles coated and not coated with plasma components on erythrocytes in hypotonic medium (osmotic hemolysis) in vitro. Gold nanoparticles did not stimulate erythrocyte hemolysis after 4-h incubation with the whole blood ex vivo. Hemolysis tended to increase in the presence of small gold nanoparticles (5, 10, 20 nm) at the maximum concentration of 20 µM (by gold content) used in our study in comparison with the control. This tendency was detected during the 1st hour of the nanoparticles incubation with blood. Gold nanoparticles in the used concentrations (up to 20 µM of gold) coated with plasma components after preincubation with autologous plasma and nanoparticles without coating caused no osmotic hemolysis of erythrocytes in vitro.

Effect of gold nanoparticles coated with plasma components on ADP-induced platelet aggregation.

We studied the effect of gold nanospheres coated with components of autologous blood plasma on ADP-induced platelet aggregation. Gold nanoparticles in the chosen concentration range (5-40 µM) and particle size (5-30 nm) with or without coating produced no activating effect on platelet aggregation caused by aggregation inductor ADP in all applied doses (1.6, 2.0, and 5.0 µM). Nanoparticles with a diameter of >60 nm inhibited platelet aggregation. These findings and published data confirm the biological safety of gold nanoparticles for targeted delivery of drugs and phototherapy.

Studies of oxidant-induced changes in albumin transport function with a fluorescent probe K-35. Metal-catalyzed oxidation.

The dynamics of albumin transport function was studied during metal-catalyzed oxidation of albumin in diluted blood plasma from healthy donors and in the solution of purified albumin using fluorescent probe K-35. The changes were compared with the dynamics of free radical oxidation markers. For oxidation, different concentrations of Cu(2+), Fe(2+), Fe(3+) ions as well as EDTA and H(2)O(2) were used. Oxidative modification of proteins was assessed by carbonyl and bityrosine fluorescent products. Oxidation of plasma lipids was assessed by the levels of TBA-reactive products. It was found that oxidation markedly decreased effective concentration of albumin characterizing albumin binding capacity, and leads to accumulation of carbonyl products of protein oxidation, bityrosine fluorescent products in proteins, and TBA-active products of lipid oxidation. It was hypothesized that reduced effective concentration of albumin is related to impairment of its binding sites and/or accumulation of free-radical oxidation products filling the binding sites of albumin.

Studies of oxidant-induced changes in albumin transport function with a fluorescent probe k-35. Effect of hypochlorite.

The dynamics of changes in albumin transport function during hypochlorite-induced oxidation of isolated albumin in blood plasma and serum was studied with a fluorescent probe K-35. Binding of the probe K-35 to albumin was characterized by effective concentration of albumin. Oxidative modification of proteins was evaluated by the content of carbonyl products of protein oxidation and bityrosine fluorescent products. Oxidation with hypochlorite was accompanied by a decrease in the effective concentration of albumin in albumin, diluted plasma, and serum and accumulation of carbonyl products of protein oxidation and bityrosine fluorescent products. The decrease in the effective concentration of albumin during oxidation with hypochlorite can be explained by oxidative damage to albumin binding sites. Oxidative modification of probe K-35 binding sites with hypochlorite contributes to a decrease in effective concentration of albumin under pathological conditions.

Towards evidence-based classification in Paralympic athletics: evaluating the validity of activity limitation tests for use in classification of Paralympic running events.

OBJECTIVE: To classify Paralympic athletes, classifiers use test batteries to obtain an objective, pre-competition estimate of an athlete's training level. Five tests were evaluated to determine which combination explained the maximum variance in running performance in a non-disabled population. A non-disabled sample was required to permit psychometric evaluation of the tests without the confounding influence of impairment, and to provide an indication of normative performance. DESIGN: Sixty-seven non-disabled participants (male and female; mean (SD) age 24.78 (6.53) years) completed a six-test battery comprising a 30 m sprint (criterion activity limitation test) and five supplementary activity limitation tests: standing broad jump, four bounds, 10 m skip, running in place and split jumps. RESULTS: Test reliability was high for all tests (intraclass correlations = 0.80-0.99). Pearson correlations with the 30 m sprint were moderate to strong for standing broad jump (-0.82), four bounds (-0.80) and 10 m skip (0.67), but weaker for split jumps (0.35) and running in place (0.19). Multiple regression indicated that standing broad jump, four bounds and 10 m skip explained 75% of the variance in running performance. CONCLUSIONS: The test battery is reliable and valid in the non-disabled population and therefore has potential utility in Paralympic classification. Test results were normally distributed, a necessary prerequisite for meaningful interpretation of future studies in athletes with impairments. Further studies evaluating the battery in populations of athletes with impairments of coordination, strength and range of movement are now warranted.

CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ alpha beta T cell pool.

It is generally accepted that TCR alphabeta+ CD8+ T cells recognize immunogenic peptides bound to MHC-encoded class I molecules. This recognition is a major component of the cellular response mediating immune protection and recovery from viral infections and from certain intracellular bacterial infections. Here, we report two human CD8+ TCR alphabeta+ T cell lines specific for Mycobacterium tuberculosis Ags presented in the context of CD1a or CD1c Ag-presenting molecules. These T cells recognize lipid Ags and display cytotoxicity as well as strong Th cell type I cytokine responses. By extending presentation by the CD1 system to the major TCR alphabeta+ CD8+ T cell pool, this system gains wider applicability beyond the double negative subset of T cells previously shown to have this reactivity. This implies that previous assumptions about the role of CD8+ T cells in microbial immunity may require revision as the relative proportions of CD1-restricted and MHC class I-restricted CD8+ T cells are further defined.

Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells.

The human CD1b protein presents lipid antigens to T cells, but the molecular mechanism is unknown. Identification of mycobacterial glucose monomycolate (GMM) as a CD1b-presented glycolipid allowed determination of the structural requirements for its recognition by T cells. Presentation of GMM to CD1b-restricted T cells was not affected by substantial variations in its lipid tails, but was extremely sensitive to chemical alterations in its carbohydrate or other polar substituents. These findings support the view that the recently demonstrated hydrophobic CD1 groove binds the acyl chains of lipid antigens relatively nonspecifically, thereby positioning the hydrophilic components for highly specific interactions with T cell antigen receptors.

CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family.

Previous studies suggest that CD1 is a family of Ag-presenting molecules distantly related to those encoded by the MHC. However, of the four known human CD1 proteins, only CD1b has been shown to restrict Ag-specific T cell responses. In this study, we have shown that a second member of the human CD1 family, CD1c, could also mediate Ag presentation to T cells. Three T cell lines recognizing mycobacterial Ags in a CD1c-restricted manner were isolated from normal donor blood. These T cells were MHC unrestricted, and their recognition of Ag was independent of the products of the transporter associated with Ag presentation-1/2 and DMA/B genes that are generally required for Ag presentation by MHC-encoded Ag-presenting molecules. Furthermore, unlike MHC-restricted responses to peptides, the CD1c-restricted T cell lines recognized protease-resistant mycobacterial lipid Ags. These T cell lines also showed significant cytotoxicity toward CD1c-expressing target cells even in the absence of mycobacterial Ags, which was shown by clonal analysis to be mediated by a subpopulation of T cells directly reactive to CD1c molecules. Our findings establish the ability of a second member of the CD1 family to restrict responses of Ag-specific T cells, and thus support the general hypothesis that the CD1 family comprises a third lineage of Ag-presenting molecules that presents a novel class of foreign and self Ags to MHC-unrestricted T cells.

Antigen presentation by CD1 and MHC-encoded class I-like molecules.

Three known lineages of antigen-presenting molecules restrict T-cell responses to microbial antigens: MHC class I and MHC encoded class I like molecules present peptides derived from the proteolysis of intracellular pathogens, MHC class ii molecules present peptides derived from the proteolysis of extracellular pathogens and CD1 molecules present unique microbial lipids and glycolipids. Recent studies have indicated that CD1 molecules mediate a novel system of antigen presentation and that MHC-encoded class I-like molecules can present unique subsets of intracellularly derived peptides.

A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells.

A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (B7), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4-CD8- T cells lack CD28, and the costimulatory signals required for the activation of such cells are unknown. To understand the pathways of activation used by CD28- T cells, we have examined the costimulatory requirements of antigen-specific CD4-CD8- TCR(+)-alpha/beta circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or II, but by CD1b or CD1c, two members of a family of major histocompatibility complex-related molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B-LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1(+)-transfected B-LCL in the presence of antigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since both the CD1+ monocytes and CD1+ B-LCL transfectants expressed B7-1 and B7-2, and DN1 and DN6 lacked surface expression of CD28. We propose that these data define a previously unrecognized pathway of costimulation for T cells distinct from that involving CD28 and its counterreceptors. We suggest that this B7-independent pathway plays a crucial role in the activation and maintenance of tolerance of at least a subset of CD28- T cells.

Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells.

Human V gamma 2V delta 2+ T cells recognize mycobacterial nonpeptide antigens, such as isopentenyl pyrophosphate, and their synthetic analogs, such as monoethyl phosphate, through a TCR-dependent process. Here, we examine the presentation of these antigens. V gamma 2V delta 2+ T cells recognized secreted prenyl pyrophosphate antigens in the absence of other accessory cells but, under such conditions, required T cell-T cell contact. Recognition required neither the expression of classical MHC class I, MHC class II, or CD1a, CD1b, and CD1c molecules, nor MHC class I or class II peptide loading pathways. Fixed accessory cells also presented the prenyl pyrophosphate antigens to gamma delta T cells. Thus, in contrast with the presentation of conventional peptide antigens, protein antigens, and superantigens to alpha beta T cells, prenyl pyrophosphate antigens are presented to gamma delta T cells through a novel extracellular pathway that does not require antigen uptake, antigen processing, or MHC class I or class II expression. This pathway allows for the rapid recognition of bacteria by gamma delta T cells and suggests that gamma delta T cells play a role in the early response to bacterial infection.

MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity.

Genes encoding MHC class I-like, class II-like and CD1 molecules have evolved to assume specific immunological functions. Some class I-like molecules, including H-2M3 and Qa-2, present formylated bacterial peptides or have distinct peptide-binding motifs. The class II-like DMA and DMB gene products play a role in presentation of peptide antigen by class II molecules. By contrast, CD1 molecules appear to have evolved separately into presenters of nonprotein antigens and into TCR ligands with specialized roles in the immune response. Thus, class I-like, class II-like and CD1 molecules appear either to serve important independent functions or to complement MHC class I and class II. It is expected that future efforts will increasingly reveal the functional ramifications of these molecules.

Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells.

Major histocompatibility complex (MHC) class I and class II molecules bind immunogenic peptides and present them to lymphocytes bearing the alpha beta T-cell antigen receptor (TCR). An analogous antigen-presenting function also has been proposed for the non-MHC-encoded CD1 molecules, a family of non-polymorphic, beta 2-microglobulin-associated glycoproteins expressed on most professional antigen-presenting cells. In support of this hypothesis, CD1 molecules are recognized by selected CD4-CD8- alpha beta or gamma delta TCR+ T-cell clones, and we have recently shown that CD1 molecules restrict the recognition of foreign microbial antigens by alpha beta TCR+ T cells. But the substantial structural divergence of CD1 from MHC class I and class II molecules, raises the possibility that the antigens presented by the CD1 system may differ fundamentally from those presented by MHC-encoded molecules. Here we report that a purified CD1b-restricted antigen of Mycobacterium tuberculosis presented to alpha beta TCR+ T cells is mycolic acid, a family of alpha-branched, beta-hydroxy, long-chain fatty acids found in mycobacteria. This example of non-protein microbial antigen recognition suggests that alpha beta TCR+ T cells recognize a broader range of antigens than previously appreciated and that at least one member of the CD1 family has evolved the ability to present lipid antigens.

Consolidation with intraperitoneal cisplatin in first-line therapy of advanced ovarian cancer.

Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only "good-prognosis" patients.

Phase II study of esorubicin (4'deoxydoxorubicin) in anthracycline naive patients with ovarian cancer.

Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.

Phase IB study of low-dose intraperitoneal recombinant interleukin-2 in patients with refractory advanced ovarian cancer: rationale and preliminary report.

The biological activity of recombinant Interleukin-2 (rIL-2) administered intraperitoneally (ip) has not been determined and may differ significantly from the maximum tolerated dose (MTD). In this trial, the pharmacokinetics, toxicity, and biologic activity of a single ip dose were studied initially followed a week later by a 5-day ip rIL-2 given for 2 weeks every 28 days. Planned dose escalation was from 2 x 10(3) to 2 x 10(7) U given in 2 liters of D5W. Drug was obtained from the NCI and was administered through an ip port. Four patients received 1 U/ml and four patients received 10 U/ml. Preliminary data demonstrate an increase in the peritoneal fluid mononuclear cell count. Mononuclear cell phenotyping tested in the first eight patients showed a modest increase in Leu 2a+, Leu 15- cells, corresponding to CTL. A similar increase in Leu 19+ cells was also demonstrated (NK cells). Soluble IL-2 receptor was elevated in peritoneal fluid. Cytotoxicity against K562 and Daudi cell lines was not observed at the first two dose levels. Toxicity of treatment was minimal and related to abdominal distention. No objective responses were seen but in one patient we documented a reduction in serum CA-125 levels. The observed biologic response and lack of toxicity is promising and justifies further exploration of this immune-modulating approach.