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Obesity is a worldwide health concern associated with impaired physical function. It is not clear if contractile protein dysfunction contributes to the impairment of muscle function observed with obesity. The purpose of this study was to examine if diet-induced obesity affects contractile function of chemically permeabilized vastus intermedius fibres of male Sprague–Dawley rats expressing fast myosin heavy chain (MHC) IIa or slow MHC I. Rats consumed either a high-fat, high sucrose (HFHS) diet or a standard (CHOW) diet beginning as either weanlings (7-week duration: WEAN7 cohort, or 14-week duration: WEAN14 cohort) or young adults (12-week duration: ADULT12 cohort, 24-week duration: ADULT24 cohort). HFHS-fed rats had higher (P < 0.05) whole-body adiposity (derived from dual-energy X-ray absorptiometry) than CHOW-fed rats in all cohorts. Relative to CHOW diet groups, the HFHS diet was associated with impaired force production in (a) MHC I fibres in the ADULT24 cohort; and (b) MHC IIa fibres in the ADULT12 and ADULT24 cohorts combined. However, the HFHS diet did not significantly affect the Ca2+-sensitivity of force production, unloaded shortening velocity, or ratio of active force to active stiffness in any cohort. We conclude that diet-induced obesity can impair force output of permeabilized muscle fibres of adult rats. Novelty: We assessed contractile function of permeabilized skeletal muscle fibres in a rat model of diet-induced obesity. The high-fat, high-sucrose diet was associated with impaired force output of fibres expressing MHC I or MHC IIa in some cohorts of rats. Other measures of contractile function were not significantly affected by diet.

Childhood obesity is a major risk factor for heart disease during adulthood, independent of adulthood behaviours. Therefore, it seems that childhood obesity leads to partly irreversible decrements in cardiac function. Little is known about how obesity during maturation affects the mechanical properties of the heart. The purpose of this study was to evaluate contractile properties in developing hearts from animals with dietary-induced obesity (high-fat high-sucrose diet). We hypothesized that obesity induced during adolescence results in decrements in cardiac contractile function. Three-week-old rats (n = 16) were randomized into control (chow) or dietary-induced obesity (high-fat high-sucrose diet) groups. Following 14 weeks on the diet, skinned cardiac trabeculae fibre bundle testing was performed to evaluate active and passive force, maximum shortening velocity, and calcium sensitivity. Rats in the high-fat high-sucrose diet group had significantly larger body mass and total body fat percentage. There were no differences in maximal active or passive properties of hearts between groups. Hearts from the high-fat high-sucrose diet rats had significantly slower maximum shortening velocities and lower calcium sensitivity than controls. Decreased shortening velocity and calcium sensitivity in hearts of obese animals may constitute increased risk of cardiac disease in adulthood. Novelty Cardiac muscle from animals exposed to an obesogenic diet during development had lower shortening velocity and calcium sensitivity than those from animals fed a chow diet. These alterations in mechanical function may be a mechanism for the increased risk of cardiac disease observed in adulthood.

Highlights • Osteoarthritis (OA) is one of the leading causes of pain and disability worldwide, and a large percentage of patients with osteoarthritis are individuals with obesity. • Animals fed an obesity-inducing diet from adulthood had more knee joint damage when compared to both the control diet animals and animals fed a bad diet from a young age. • These findings indicate that dietary exposure time in young animals may induce less damage than exposure to bad diets during adulthood, indicating the importance of the onset of dietary challenge in studies that aim to assess the short-term influence of obesity-inducing diets on knee joint health., Background Osteoarthritis is one of the leading causes of pain and disability worldwide, and a large percentage of patients with osteoarthritis are individuals who are also obese. In recent years, a series of animal models have demonstrated that obesity-inducing diets can result in synovial joint damage (both with and without the superimposition of trauma), which may be related to changes in percentage of body fat and a series of low-level systemic inflammatory mediators. Of note, there is a disparity between whether the dietary challenges commence at weaning, representing a weanling onset, or at skeletal maturity, representing an adult onset of obesity. We wished to evaluate the effect of the dietary exposure time and the age at which animals are exposed to a high-fat and high-sucrose (HFS) diet to determine whether these factors may result in disparate outcomes, as there is evidence suggesting that these factors result in differential metabolic disturbances. Based on dietary exposure time, we hypothesized that rats fed an HFS diet for 14 weeks from weaning (HFS Weanling) would demonstrate an increase in knee joint damage scores, whereas rats exposed to the HFS diet for 4 weeks, starting at 12 weeks of age (HFS Adult) and rats exposed to a standard chow diet (Chow) would not display an increase in knee joint damage scores. Methods Male Sprague-Dawley rats were fed either an HFS diet for 14 weeks from weaning (HFS Weanling) or an HFS diet for 4 weeks, starting at 12 weeks of age (HFS Adult). At sacrifice, joints were scored using the modified Mankin Criteria, and serum was analyzed for a defined subset of inflammatory markers (Interleukin-6, leptin, monocyte chemoattractant protein-1, and tumor necrosis factor α). Results When the HFS Weanling and HFS Adult groups were compared, both groups had a similar percent of body fat, although the HFS Weanling group had a significantly greater body mass than the HFS Adult group. The HFS Weanling and HFS Adult animals had a significant increase in body mass and percentage of body fat when compared to the Chow group. Although knee joint damage scores were low in all 3 groups, we found, contrary to our hypothesis, that the HFS Adult group had statistically significant greater knee joint damage scores than the Chow and HFS Weanling groups. Furthermore, we observed that the HFS Weanling group did not have significant differences in knee joint damage scores relative to the Chow group. Conclusion These findings indicate that the HFS Weanling animals were better able to cope with the dietary challenge of an HFS diet than the HFS Adult group. Interestingly, when assessing various serum proinflammatory markers, no significant differences were detected between the HFS Adult and HFS Weanling groups. Although details regarding the mechanisms underlying an increase in knee joint damage scores in the HFS Adult group remain to be elucidated, these findings indicate that dietary exposure time maybe less important than the age at which an HFS diet is introduced. Moreover, increases in serum proinflammatory mediators do not appear to be directly linked to knee joint damage scores in the HFS Weanling group animals but may be partially responsible for the observed knee joint damage in the adults over the very short time of exposure to the HFS diet., Graphical abstract Image, graphical abstract

Advanced age has been shown to result in decreased compliance, shortening velocity, and calcium sensitivity of the heart muscle. Even though cardiac health has been studied extensively in elderly populations, relatively little is known about cardiac health and age for the first part of adulthood. The purpose of this study was to compare cardiac contractile properties across the first year of life in rats (between 17–53 weeks), corresponding to early to mid-adulthood. Hearts were harvested from rats aged 17-, 24-, 36-, and 53-weeks. Skinned cardiac trabecular fibre bundle testing was used to evaluate active and passive force properties, maximum shortening velocity, calcium sensitivity, and myosin heavy chain isoforms. Maximum active stress production was not different between age groups. Calcium sensitivity increased progressively, while shortening velocity remained unchanged after an increase from 17-and 24-weeks. Passive stiffness decreased between 17- and 24-weeks, but then increased progressively through to 53-weeks. Thus, many of the observed detrimental changes in systolic function (reduced shortening velocity and calcium sensitivity) associated with aging, do not seem to occur in early to mid-adulthood, while early signs of increased diastolic stiffness manifest within 53 weeks of age and may represent a first sign of decreasing heart function and health.

Background Converging evidence comparing barefoot (BF) and shod (SH) running highlights differences in foot-strike patterns and somatosensory feedback, among others. Anecdotal evidence from SH runners attempting BF running suggests a greater attentional demand may be experienced during BF running. However, little work to date has examined whether there is an attentional cost of BF versus SH running. Objective This exploratory study aimed to examine whether an acute bout of BF running would impact simple reaction time (SRT) compared to SH running, in a sample of runners naïve to BF running. Methods Eight male distance runners completed SRT testing during 10 min of BF or SH treadmill running at 70% maximal aerobic speed (17.9 ± 1.4 km h−1). To test SRT, participants were required to press a hand-held button in response to the flash of a light bulb placed in the center of their visual field. SRT was tested at 1-minute intervals during running. BF and SH conditions were completed in a pseudo-randomized and counterbalanced crossover fashion. SRT was defined as the time elapsed between the light bulb flash and the button press. SRT errors were also recorded and were defined as the number of trials in which a button press was not recorded in response to the light bulb flash. Results Overall, SRT later in the exercise bouts showed a statistically significant increase compared to earlier (p p p p > 0.05) or the number of SRT errors (17.6 ± 6.6 trials vs. 17.0 ± 13.0 trials, p > 0.05). Discussion In a sample of distance runners naïve to BF running, there was no statistically significant difference in SRT or SRT errors during acute bouts of BF and SH running. We interpret these results to mean that BF running does not have a greater attentional cost compared to SH running during a SRT task throughout treadmill running. Literature suggests that stride-to-stride gait modulation during running may occur predominately via mechanisms that preclude conscious perception, thus potentially attenuating effects of increased somatosensory feedback experienced during BF running. Future research should explore the present experimental paradigm in a larger sample using over-ground running trials, as well as employing different tests of attention.

The objective of this study is to understand the effectiveness of foam rolling (FR) as a recovery tool after exercise-induced muscle damage, analyzing thigh girth, muscle soreness, range of motion (ROM), evoked and voluntary contractile properties, vertical jump, perceived pain while FR, and force placed on the foam roller.Twenty male subjects (≥3 yr of strength training experience) were randomly assigned into the control (n = 10) or FR (n = 10) group. All the subjects followed the same testing protocol. The subjects participated in five testing sessions: 1) orientation and one-repetition maximum back squat, 2) pretest measurements, 10 × 10 squat protocol, and POST-0 (posttest 0) measurements, along with measurements at 3) POST-24, 4) POST-48, and 5) POST-72. The only between-group difference was that the FR group performed a 20-min FR exercise protocol at the end of each testing session (POST-0, POST-24, and POST-48).FR substantially reduced muscle soreness at all time points while substantially improving ROM. FR negatively affected evoked contractile properties with the exception of half relaxation time and electromechanical delay (EMD), with FR substantially improving EMD. Voluntary contractile properties showed no substantial between-group differences for all measurements besides voluntary muscle activation and vertical jump, with FR substantially improving muscle activation at all time points and vertical jump at POST-48. When performing the five FR exercises, measurements of the subjects' force placed on the foam roller and perceived pain while FR ranged between 26 and 46 kg (32%-55% body weight) and 2.5 and 7.5 points, respectively.The most important findings of the present study were that FR was beneficial in attenuating muscle soreness while improving vertical jump height, muscle activation, and passive and dynamic ROM in comparison with control. FR negatively affected several evoked contractile properties of the muscle, except for half relaxation time and EMD, indicating that FR benefits are primarily accrued through neural responses and connective tissue.

Foam rolling is thought to improve muscular function, performance, overuse, and joint range of motion (ROM); however, there is no empirical evidence demonstrating this. Thus, the objective of the study was to determine the effect of self-myofascial release (SMR) via foam roller application on knee extensor force and activation and knee joint ROM. Eleven healthy male (height 178.9 ± 3.5 cm, mass 86.3 ± 7.4 kg, age 22.3 ± 3.8 years) subjects who were physically active participated. Subjects' quadriceps maximum voluntary contraction force, evoked force and activation, and knee joint ROM were measured before, 2 minutes, and 10 minutes after 2 conditions: (a) 2, 1-minute trials of SMR of the quadriceps via a foam roller and (b) no SMR (Control). A 2-way analysis of variance (condition × time) with repeated measures was performed on all dependent variables recorded in the precondition and postcondition tests. There were no significant differences between conditions for any of the neuromuscular dependent variables. However, after foam rolling, subjects' ROM significantly (p < 0.001) increased by 10° and 8° at 2 and 10 minutes, respectively. There was a significant (p < 0.01) negative correlation between subjects' force and ROM before foam rolling, which no longer existed after foam rolling. In conclusion, an acute bout of SMR of the quadriceps was an effective treatment to acutely enhance knee joint ROM without a concomitant deficit in muscle performance.

Lymphoma is an AIDS defining illness and non-Hodgkin's lymphoma (NHL) is the second most common HIV related tumor after Kaposi's sarcoma. According to recent data NHL in known HIV/AIDS disease occu...

It is important that statistical tests should be reliable for small samples and rare events. Permutation tests (1) form an important class of tests that can provide “exact” results for small samples. Permutation tests themselves, however, have limitations which must be realized if they are to be used reliably. The paper shows, by illustrative examples, some uses and limitations of permutation tests.

Calling context--the set of active methods on the stack--is critical for understanding the dynamic behavior of large programs. Dynamic program analysis tools, however, are almost exclusively context insensitive because of the prohibitive cost of representing calling contexts at run time. Deployable dynamic analyses, in particular, have been limited to reporting only static program locations. This paper presents Breadcrumbs, an efficient technique for recording and reporting dynamic calling contexts. It builds on an existing technique for computing a compact (one word) encoding of each calling context that client analyses can use in place of a program location. The key feature of our system is a search algorithm that can reconstruct a calling context from its encoding using only a static call graph and a small amount of dynamic information collected at cold (infrequently executed) callsites. Breadcrumbs requires no offline training or program modifications, and handles all language features, including dynamic class loading. We use Breadcrumbs to add context sensitivity to two dynamic analyses: a data-race detector and an analysis for diagnosing null pointer exceptions. On average, it adds 10% to 20% runtime overhead, depending on a tunable parameter that controls how much dynamic information is collected. Collecting less information lowers the overhead, but can result in a search space explosion. In some cases this causes reconstruction to fail, but in most cases Breadcrumbs >produces non-trivial calling contexts that have the potential to significantly improve both the precision of the analyses and the quality of the bug reports.

OBJECTIVE To identify patients with late relapse of metastatic, nonseminomatous germ cell tumour (NSGCT) and to evaluate the patterns of relapse, treatment and outcome, as such relapse at >2 years after complete remission to treatment for metastatic disease (late relapse) is uncommon, but with prolonged follow-up is becoming increasingly recognized. PATIENTS AND METHODS Between 1980 and 2004, 1405 patients with testicular GCTs were identified who presented to Southampton University Hospital; 742 had NSGCTs or combined testicular GCTs, of whom 405 received primary chemotherapy for metastatic disease. In all, 329 (81%) patients achieved a complete response (CR) to initial treatment, with 101 of them (31%) requiring surgical resection of residual masses after chemotherapy. Any patient relapsing at >2 years after a CR to initial treatment (late relapse) was assessed in detail. RESULTS In all, 20 patients had a late relapse, 17 of whom received initial treatment locally and three of whom were initially treated elsewhere. Most (65%) late relapses were asymptomatic and detected by routine cross-sectional imaging or rising levels of tumour markers. Late relapse occurred at a median (range) of 108 (26–217) months (≈ 9 years) after CR. Fifteen (75%) patients underwent only surgery for late relapse, including five who had invasive malignant germ cell cancer within the resected specimens. Fourteen of 15 surgically treated patients remained alive at a median of 44 (9–184) months from initial treatment for late relapse; one had died with progressive recurrent germ cell/epithelial malignancy. Five (25%) patients were initially treated with chemotherapy for late relapse; three of them died from progressive germ cell cancer and the two survivors both had surgical excision of residual abnormalities after salvage chemotherapy. Overall, 15 of 20 (75%) men remain alive with no evidence of disease; one further patient is currently undergoing salvage treatment for his third relapse. CONCLUSIONS Late relapse is uncommon after modern therapy for metastatic GCTs. Surgical treatment for localized disease, where possible, is associated with prolonged disease-free and overall survival. By contrast, chemotherapy is associated with a low response rate and a poor outcome.

OBJECTIVE To review the clinical course and outcome of patients with germ cell cancer and liver metastases treated at one centre, as the presence of hepatic metastases, although rare, is a poor prognostic feature in germ cell cancer. PATIENTS AND METHODS The case records of all patients with germ cell cancer and liver metastases at presentation, and treated with chemotherapy at a medical oncology unit between 1984 and 2001, were reviewed. The treatment regimens, tumour responses and patient outcome were recorded. RESULTS Twenty-seven patients with germ cell cancer metastatic to the liver were identified. Complete biochemical and radiological responses were achieved in eight patients after initial chemotherapy and surgery for non-hepatic residual disease. Seven patients had only residual radiological hepatic abnormalities with normal tumour markers at the completion of initial treatment. There were no immediate hepatic resections and no further therapy was given. Serial computed tomography (CT) confirmed a progressive reduction in the size of hepatic lesions in six of seven patients. The persistence of residual hepatic abnormalities was not predictive of relapse, and overall survival of these patients (median survival 49 months, range 15-120) compared well with recent reports of such patients who have undergone hepatic resection. CONCLUSIONS Conservative management with regular assessment by CT is an acceptable alternative to immediate hepatic resection for patients with isolated residual radiological hepatic abnormalities on completing first-line therapy for metastatic germ cell cancer, and does not adversely affect their survival.

Introduction: The weekly alternating SV regimen was compared to standard ABVD. An initial randomised phase II pilot study was carried out to determine tolerability and response rate, following which the study was expanded into a phase III trial. Methods: Consenting patients (pts) with advanced HL (bulk disease, B symptoms and/or stage III/IV) were randomised between 6–8 cycles of ABVD or 12 weeks SV, to be followed in both arms by involved field irradiation (34–36Gy) to sites of initial bulk disease (>5cm) or splenic deposits, and to residual masses. In the phase III study radiotherapy was not required for ABVD pts who achieved complete remission. Drugs given were: ABVD (days 1 & 15): doxorubicin 25mg/m2, bleomycin 10000iu/m2, vinblastine 6mg/m2, dacarbazine 375mg/m2), q28. SV (mustine 6mg/m2, wks 1,5,9, doxorubicin 25mg/m2, wks 1,3,5,7,9,11, vinblastine 6mg/m2 wks 1,3,5,7,9,11, prednisone 40mg/m2 alternate days, vincristine 1.4mg/m2 wks 2,4,6,8,10,12, bleomycin 5000iu/m2 wks 2,4,6,8,10, 12, etoposide 60 mg/m2, 2 consecutive days wks 3,7,11). The primary outcome measure was progression-free survival (PFS). A total of 97 events were required to detect an improvement in 5-year PFS from 75% in ABVD to 85% in SV with a 5% significance level and 80% power. Results: 520 pts were randomized (261 ABVD, 259 SV) between 3/98 and 10/06. Median age was 35. 49% had stage I/II disease with bulk and/or B symptoms, 29% stage III, 22% stage IV. 74% of pts overall had B symptoms and 52% bulk disease. International Prognostic Score (IPS) showed 37% 0–1, 54% 2–3 and 9% 4–7. The treatment groups were well matched for baseline prognostic factors. 95% SV pts completed 12 weeks, and 94% ABVD had 6 (71%) or 7/8 (23%) cycles. Pulmonary toxicity grade III/IV was reported in 37 pts (27 ABVD, 10 SV). More non-pulmonary grade III/IV toxicities were reported in SV(19%) than in ABVD (8%). Radiotherapy was given in 62% overall: 72% SV and 53% ABVD. The overall response rate (CR, CRu, PR) at completion of all treatment was 90% for SV and 89% for ABVD. There was one death due to toxicity on the ABVD arm, and none in SV. With a median 4 years follow up, 113 pts (55 ABVD, 58 SV) had recurrent disease or died with a hazard ratio of 1.10 (95% CI =0.76, 1.59; p=0.61) and 5-year PFS of 76% in ABVD and 74% in SV, absolute difference 2% (95% CI= −5%, 11%). 40 pts died (22 ABVD, 18 SV) with a hazard ratio of 0.81 (95% CI=0.44, 1,52; p=0.51) and 5-year overall survival (OS) of 90% in ABVD and 92% in SV, absolute difference 2% (95% CI -5%, 5%). Pre-planned analysis of sub-groups did not show significant variation in these results according to stage or IPS. Conclusion: There is no evidence of a difference in PFS and OS between SV and ABVD in this trial, which made extensive use of consolidation radiotherapy and included a relatively favourable cohort. More pulmonary toxicity was reported for ABVD, while other toxicities were slightly higher with S V.