Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study.

High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study.

Background: Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods: BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results: Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7 months (95% CI 4.3-21.0), respectively. Conclusions: This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered: Clinicaltrials.gov, NCT01594229.

Unmet needs in the first-line treatment of follicular lymphoma.

For the majority of patients with newly diagnosed follicular lymphoma (FL), current treatments, while not curative, allow for long remission durations. However, several important needs remain unaddressed. Studies have consistently shown that ∼20% of patients with FL experience disease progression within 2 years of first-line treatment, and consequently have a 50% risk of death in 5 years. Better characterization of this group of patients at diagnosis may provide insight into those in need of alternate or intensive therapies, facilitate a precision approach to inform clinical trials, and allow for improved patient counseling. Prognostic methods to date have employed clinical parameters, genomic methods, and a wide assortment of biological and biochemical markers, but none so far has been able to adequately identify this high-risk population. Advances in the first-line treatment of FL with chemoimmunotherapy have led to a median progression-free survival (PFS) of approximately 7 years; creating a challenge in the development of clinical trials where PFS is a primary end point. A surrogate end point that accurately predicts PFS would allow for new treatments to reach patients with FL sooner, or lessen toxicity, time, and expense to those patients requiring little to no therapy. Quality of response to treatment may predict PFS and overall survival in FL; as such complete response rates, either alone or in conjunction with PET imaging or minimal residual disease negativity, are being studied as surrogates, with complete response at 30 months after induction providing the strongest surrogacy evidence to date. A better understanding of how to optimize quality of life in the context of this chronic illness is another important focus deserving of further study. Ongoing efforts to address these important unmet needs are herein discussed.

International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

Breakthrough therapies in B-cell non-Hodgkin lymphoma.

The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas. This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell's signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric antigen receptor T cells.

Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes.

BACKGROUND: Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described. PATIENTS AND METHODS: We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome. RESULTS: One hundred patients met inclusion criteria, with a median age of 32 years (range 18-84) at progression after BV. The median number of treatments before BV was 3 (range 0-9); 71 had prior autologous stem cell transplant. The overall response rate (ORR) to BV was 57%, and the median duration of BV therapy was 3 months (range 1-25). After disease progression post-BV, the most common treatment strategies were investigational agents (n = 30), gemcitabine (n = 15) and bendamustine (n = 12). The cumulative ORR to therapy was 33% (complete response 15%). After a median follow-up of 25 months (range 1-74), the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months, respectively. In multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40 g/l at disease progression were associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P = 0.11). CONCLUSIONS: Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era.

BACKGROUND: The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure. PATIENTS AND METHODS: We retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. RESULTS: After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. CONCLUSION: Induction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.

BACKGROUND: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma.

Lenalidomide is an oral non-chemotherapy immunomodulator with direct and indirect effects on non-Hodgkin lymphoma (NHL) cells and with single-agent activity in relapsed/refractory aggressive and indolent B-cell NHL, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, and follicular lymphoma. Based on the pivotal phase II MCL-001 trial of lenalidomide in heavily pretreated patients with relapsed/refractory MCL, lenalidomide was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL after failure of two prior therapies, one of which includes bortezomib, at a recommended starting dose of 25 mg on days 1-21 of each 28-day cycle. Lenalidomide enhanced the survival benefit in combination with rituximab in preclinical models, prompting clinical evaluation of the lenalidomide-rituximab (R2) combination. In phase II trials, lenalidomide 20 mg on days 1-21 in combination with different standard-dose rituximab schedules exhibited promising activity in both first-line and relapsed/refractory disease across multiple B-cell NHL subtypes. The feasibility of combining lenalidomide with immunochemotherapy, including R-CHOP and rituximab-bendamustine, has been demonstrated in phase I/II trials. These latter regimens are currently being evaluated in ongoing phase II and III trials. The role of lenalidomide monotherapy and R2 in maintenance therapy is also being examined. Based on available evidence, a comprehensive review of lenalidomide in all treatment phases of B-cell NHL-relapsed/refractory disease, first-line, and maintenance-is presented here.

Hand-rim forces and gross mechanical efficiency in asynchronous and synchronous wheelchair propulsion: a comparison.

To compare the force application characteristics at various push frequencies of asynchronous (ASY) and synchronous (SYN) hand-rim propulsion, 8 able-bodied participants performed a separate sub-maximal exercise test on a wheelchair roller ergometer for each propulsion mode. Each test consisted of a series of 5, 4-min exercise blocks at 1.8 m · s-1 - initially at their freely chosen frequency (FCF), followed by four counter-balanced trials at 60, 80, 120 and 140% FCF. Kinetic data was obtained using a SMARTWheel, measuring forces and moments. The gross efficiency (GE) was determined as the ratio of external work done and the total energy expended. The ASY propulsion produced higher force measures for FRES, FTAN, rate of force development & FEF (P<0.05), while there was no difference in GE values (P=0.518). In pair-matched push frequencies (ASY80:SYN60, ASY100:SYN80, ASY120:SYN100 and ASY140:SYN120), ASY propulsion forces remained significantly higher (FRES, FTAN, rate of force development & FEF P<0.05), and there was no significant effect on GE (P=0.456). Both ASY and SYN propulsion demonstrate similar trends: changes in push frequency are accompanied by changes in absolute force even without changes in the gross pattern/trend of force application, FEF or GE. Matched push frequencies continue to produce significant differences in force measures but not GE. This suggests ASY propulsion is the predominant factor in force application differences. The ASY would appear to offer a kinetic disadvantage to SYN propulsion and no physiological advantage under current testing conditions.

Hand-rim forces and gross mechanical efficiency at various frequencies of wheelchair propulsion.

To determine the effects of push frequency changes on force application, fraction of effective force (FEF) and gross efficiency (GE) during hand-rim propulsion. 8 male able-bodied participants performed five 4-min sub-maximal exercise bouts at 1.8 ms(-1); the freely chosen frequency (FCF), followed by 4 counter-balanced trials at 60, 80, 120 and 140% FCF. Kinetic data was obtained using a SMART(Wheel), measuring forces and moments. The GE was determined as the ratio of external work done and the total energy expended. Increased push frequency led to reductions in peak resultant force (P<0.05), ranging from 167 to 117 N and peak tangential force (P<0.05), ranging from 117 to 77 N. However, FEF only demonstrated a significant difference between 60% and 140% FCF (69 ± 9% and 63 ± 7, respectively; P<0.05). Work per cycle decreased significantly (P<0.05) and rate of force development increased significantly (P<0.05) with increased push frequency. GE values were significantly lower at 60%, 120% and 140% FCF than 80% and 100% FCF (P<0.05). No meaningful associations were present between FEF and GE. Under the current testing conditions, changes in push frequency are accompanied with changes in the absolute force values, albeit without changes in either the gross pattern/trend of force application or FEF. Changes in GE are not explained by different levels of force effectiveness.

A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

Variable intraspecific space use supports optimality in an apex predator.

Within optimality theory, an animal's home range can be considered a fitness-driven attempt to obtain resources for survival and reproduction while minimizing costs. We assessed whether brown bears (Ursus arctos) in two island populations maximized resource patches within home ranges (Resource Dispersion Hypothesis [RDH]) or occupied only areas necessary to meet their biological requirements (Temporal Resource Variability Hypothesis [TRVH]) at annual and seasonal scales. We further examined how intrinsic factors (age, reproductive status) affected optimal choices. We found dynamic patterns of space use between populations, with support for RDH and TRVH at both scales. The RDH was likely supported seasonally as a result of bears maximizing space use to obtain a mix of nutritional resources for weight gain. Annually, support for RDH likely reflected changing abundances and distributions of foods within different timber stand classes. TRVH was supported at both scales, with bears minimizing space use when food resources were temporally concentrated. Range sizes and optimal strategies varied among sex and reproductive classes, with males occupying larger ranges, supporting mate seeking behavior and increased metabolic demands of larger body sizes. This work emphasizes the importance of scale when examining animal movement ecology, as optimal behavioral decisions are scale dependent.

Temporal variation in the carrying capacity of a perennial grass population.

Density dependence and, therefore, K (carrying capacity, equilibrium population size) are central to understanding and predicting changes in population size (N). Although resource levels certainly fluctuate, K has almost always been treated as constant in both theoretical and empirical studies. We quantified temporal variation in K by fitting extensions of standard population dynamic models to 16 annual censuses of a population of the perennial bunchgrass Bouteloua rigidiseta. Variable-K models provided substantially better fits to the data than did models that varied the potential rate of population increase. The distribution of estimated values of K was skewed, with a long right tail (i.e., a few "jackpot" years). The population did not track K closely. Relatively slow responses to changes in K combined with large, rapid changes in K sometimes caused N to be far from K. In 13%-20% of annual intervals, K was so much larger than N that the population's dynamics were best described by geometric growth and the population was, in effect, unregulated. Explicitly incorporating temporal variation in K substantially improved the realism of models with little increase in model complexity and provided novel information about this population's dynamics. Similar methods would be applicable to many other data sets.

Mortality of a large wide-ranging mammal largely caused by anthropogenic activities.

With efforts to restore large mammal populations following extirpations, it is vital to quantify how they are impacted by human activities and gain insights into population dynamics in relation to conservation goals. Our objective was to characterize cause-specific mortality of black bears (Ursus americanus) throughout their range. We first quantified cause-specific mortality for 247 black bears in one harvested and two non-harvested populations. We then simulated a small recolonizing population with and without anthropogenic mortality. Lastly, we conducted a meta-analysis of all published black bear mortality studies throughout North America (31 studies of 2630 bears). We found anthropogenic mortality was greater than natural mortality, non-harvest anthropogenic mortality (e.g. poaching, defense of property, etc.) was greater in non-harvested populations, and harvesting was one of the major causes of mortality for bears throughout their range. Our simulation indicated that removing anthropogenic mortality increased population size by an average of 23% in 15 years. We demonstrated that bears are exposed to high levels of anthropogenic mortality, and the potential for human activities to slow population growth in expanding populations. Management and conservation of wide-ranging mammals will depend on holistic strategies that integrate ecological factors with socio-economic issues to achieve successful conservation and coexistence.

Effects of arm frequency during synchronous and asynchronous wheelchair propulsion on efficiency.

To further understand the possible underlying mechanisms of the low efficiencies in hand rim wheelchair propulsion, this study examined efficiency indices at different arm frequencies during two propulsion modes (synchronous and asynchronous). Fourteen male able-bodied participants performed VO2PEAK tests for both propulsion modes. Subsequently two sub-maximal exercise tests examining synchronous and asynchronous propulsion were completed at an individualised velocity (60% of VO2PEAK). The freely chosen arm frequency (FCF), followed by four counter-balanced trials at 60, 80, 120, and 140% of FCF were performed. Gross, net, and work efficiency were determined. Gross efficiency was significantly lower (p<0.05) at arm frequencies >100%, and participants were more efficient between 60 to 100% FCF. These arm frequencies corresponded to 76+/-22 to 126+/-36 and 70+/-18 to 116+/-30 pushes x min(-1) (synchronous and asynchronous respectively). Trends in VO2, gross and work efficiency suggest that 80% of FCF produced the best economy and efficiency during both propulsion modes (non-significant). Gross and work efficiency at 80% FCF were 6.8+/-0.7% and 13.0+/-4.6% for synchronous and 7.0+/-0.8% and 11.5+/-1.6% for asynchronous respectively. The results suggest that during both modes of propulsion the FCF is not necessarily the most efficient.

Evaluation of an innovative critical power model in intermittent vertical jump.

The aim of this study was to test if the critical power model can be used to determine the critical rest interval (CRI) between vertical jumps. Ten males performed intermittent countermovement jumps on a force platform with different resting periods (4.1+/-0.3 s, 5.0+/-0.4 s, 5.9+/-0.6 s). Jump trials were interrupted when participants could no longer maintain 95% of their maximal jump height. After interruption, number of jumps, total exercise duration and total external work were computed. Time to exhaustion (s) and total external work (J) were used to solve the equation Work=a+b x time. The CRI (corresponding to the shortest resting interval that allowed jump height to be maintained for a long time without fatigue) was determined dividing the average external work needed to jump at a fixed height (J) by b parameter (J/s). In the final session, participants jumped at their calculated CRI. A high coefficient of determination (0.995+/-0.007) and the CRI (7.5+/-1.6 s) were obtained. In addition, the longer the resting period, the greater the number of jumps (44+/-13, 71+/-28, 105+/-30, 169+/-53 jumps; p<0.0001), time to exhaustion (179+/-50, 351+/-120, 610+/-141, 1,282+/-417s; p<0.0001) and total external work (28.0+/-8.3, 45.0+/-16.6, 67.6+/-17.8, 111.9+/-34.6kJ; p<0.0001). Therefore, the critical power model may be an alternative approach to determine the CRI during intermittent vertical jumps.

Manipulation of rest period length induces different causes of fatigue in vertical jumping.

The aim of this study was to directly compare the causes of fatigue after a short- and a long-rest interval between consecutive stretch-shortening cycle exercises. Eleven healthy males jumped with different resting period lengths (short=6.1+/-1 s, long=8.6+/-0.9 s), performing countermovement jumps at 95% of their maximal jump height until they were unable to sustain the target height. After short- and long-rest, the maximal voluntary isometric contraction knee extension torque decreased (-7%; p=0.04), comparing to values obtained before exercise protocols. No change was seen from pre- to post-exercise, for either short- or long-rest, in biceps femoris coactivation (-1%; p=0.95), peak-to-peak amplitude (1%; p=0.95) and duration (-8%; p=0.92) of the compound muscle action potential of the vastus lateralis. Evoked peak twitch torque reduced after both exercise protocols (short=-26%, long=-32%; p=0.003) indicating peripheral fatigue. However, central fatigue occurred only after short-rest evidenced by a reduction in voluntary activation of the quadriceps muscle (-14%; p=0.013) measured using the interpolated twitch technique. In conclusion, after stretch-shortening cycle exercise using short rest period length, the cause of fatigue was central and peripheral, while after using long rest period length, the cause of fatigue was peripheral.

Stature loss and recovery following a period of loading: effect of time of day and presence or absence of low back pain.

BACKGROUND: Stature reductions in asymptomatic individuals, caused by a set load, are lower later in the day when stature is in the trough of diurnal variation; hence most stature reduction investigations are conducted in the morning. Recent evidence suggests that it is not the reductions in stature, but the recovery of stature, that is of greatest importance. The aim of this investigation was to establish whether stature recovery is also affected by time of day and to determine if any differences exist between a chronic low back pain and asymptomatic group. METHODS: Eleven chronic low back pain participants (age=32.8 SD 7.9 yrs, mass=74.4 SD 14.2 kg and height=1.73 SD 0.07 m) and 11 asymptomatic participants (age=31.0 SD 6.3 yrs, body mass=72.6 SD 11.5 kg and height=1.76 SD 0.09 m) underwent two 20 min loaded walking tasks (10% body mass), one in the morning (09:00) and one in the afternoon (14:00), followed by a 20 min unloaded recovery period. Measurements of stature were obtained throughout. FINDINGS: The asymptomatic group experienced significantly less stature reduction (P=0.05; ES=1.1) and greater stature recovery (P=0.02; ES=0.9) in the afternoon compared to the morning. The chronic low back pain group experienced a similar pattern to the asymptomatic group, however no significant difference between sessions for changes in stature was evident P=0.07. INTERPRETATION: Further investigations of stature recovery should be restricted to the morning when comparing individuals with and without chronic low back pain, as time of day appeared to have effect on stature recovery, particularly in the asymptomatic group. Time dependent differences in stature change between these two populations warrants further investigation.

Hemodynamic effects of isoproterenol and norepinephrine in acute cardiac tamponade.

The hemodynamic effects of isoproterenol infusion, 0.5 mug/kg per min were evaluated in eight intact anesthetized dogs during cardiac tamponade. During tamponade, the mean of pericardial pressures was increased from - 1.5 to 12.5 mm Hg, and the mean of right atrial pressures was increased from 1 to 12.4 mm Hg. Mean cardiac output fell from 144.8 to 44.8 ml/kg per min (P < 0.001), and rose to 105.6 ml/kg per min (P < 0.001) with isoproterenol. Mean cardiac stroke volume fell from 20.3 to 6.1 ml during tamponade (P < 0.001) and rose to 12.1 ml with isoproterenol (P < 0.001). The heart rate increased from 193.3 beats/min during tamponade to 217.5 beats/min with isoproterenol (P < 0.05). During isoproterenol infusion, the mean right atrial pressure and mean pericardial pressure decreased significantly. With cardiac tamponade, the mean blood pressure fell from 157.5 to 126.1 mm Hg (P < 0.01) and did not change significantly with isoproterenol, 11 additional animals were studied with norepinephrine infusion during tamponade. There were no consistent hemodynamic effects with infusions of 0.5 and 1 mug/kg per min. With norepinephrine 2, 5, and 10 mug/kg per min cardiac output rose in some experiments. Isoproterenol infusion increased the cardiac output during tamponade principally by increasing cardiac stroke volume and to a lesser degree by increasing the heart rate. It is postulated that the increased stroke volume resulted from an increased ejection fraction with greater decrease in end-systolic than end-diastolic ventricular volume. These effects are consistent with the known positive inotropic, peripheral vasodilator, and positive chronotropic effects of isoproterenol.