The effects of chest wall loading on perceptions of fatigue, exercise performance, pulmonary function, and muscle perfusion.

BACKGROUND: Load carriage (LC), which directly affects the chest wall and locomotor muscles, has been suggested to alter the ventilatory and circulatory responses to exercise, leading to increased respiratory muscle work and fatigue. However, studies exploring the impact of LC on locomotion increased internal work, complicating their interpretation. To overcome this issue, we sought to determine the effect of chest wall loading with restriction (CWL + R) on cycling performance, cardiopulmonary responses, microvascular responsiveness, and perceptions of fatigue. METHODS: In a randomized crossover design, 23 young healthy males (22 \ub1 4 years) completed a 5 km cycling time trial (TT) in loaded (CWL + R; tightened vest with 10% body weight) and unloaded conditions. After baseline pulmonary function testing (PFT; forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC), cardiopulmonary indices (HR, heart rate; O2 uptake, VO2; ventilation, VE; tidal volume, VT; and breathing frequency, Bf), rating of perceived exertion (RPE), lactate (BLa), and microvascular responses (oxy-, deoxy-, total hemoglobin; and tissue saturation; StO2) of the vastus lateralis using near infrared spectroscopy were collected during the TT; and PFT was repeated post-exercise. RESULTS: Pre-exercise, CWL + R reduced (p < 0.05) FVC (5.6 \ub1 0.8 versus 5.5 \ub1 0.7 L), FEV1 (4.8 \ub1 0.7 versus 4.7 \ub1 0.6 L), and FEV1/FVC (0.9 \ub1 0.1 versus 0.8 \ub1 0.1). CWL + R modified power output (PO) over time (interaction, p = 0.02), although the 5 km time (461 \ub1 24 versus 470 \ub1 27 seconds), VT (3.0 \ub1 0.3 versus 2.8 \ub1 0.8 L), Bf, VE, HR, VO2, microvascular and perceptual (visual analog scale, or VAS, and RPE) responses were unchanged (p > 0.05). CWL + R increased (p < 0.05) the average BLa (7.6 \ub1 2.6 versus 8.6 \ub1 3 mmol/L). CONCLUSIONS: Modest CWL + R negatively affects pre-exercise pulmonary function, modifies cycling power output over time, and increases lactate production during a 5 km cycling trial, although the cardiorespiratory, microvascular, and perceptual responses were unaffected

Chiropractic student diagnosis and management of headache disorders: A survey examining self-perceived preparedness and clinical proficiency.

ObjectiveTo explore the self-perceived preparedness and clinical proficiency in headache diagnosis and management of Australian chiropractic students in senior years of study.MethodsAustralian chiropractic students in the 4th (n = 134) and 5th year (n = 122) of 2 chiropractic university programs were invited to participate in an online cross-sectional survey. Descriptive analyses were conducted for all variables. Post hoc analyses were performed using simple linear regression to evaluate the relationship between self-perceived preparedness and correctness of headache diagnosis and management scores.ResultsAustralian chiropractic students in senior years demonstrated moderate overall levels of self-perceived preparedness and proficiency in their ability to diagnose and manage headache disorders. Final-year students had a slightly higher self-perceived preparedness and proficiency in headache diagnosis and management compared to those students in the 4th year of study. There was no relationship between self-perceived preparedness and correctness of headache diagnosis and management for either 4th- or 5th-year chiropractic students.ConclusionOur findings suggest that there may be gaps in graduate chiropractic student confidence and proficiency in headache diagnosis and management. These findings call for further research to explore graduate chiropractic student preparedness and proficiency in the diagnosis and management of headache disorders

Effects of Capsaicin on the Hemodynamic Responses to Handgrip Exercise: Potential Influence of Race

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Exercise training improves vascular function in patients with Alzheimer’s disease

Purpose: Vascular dysfunction has been demonstrated in patients with Alzheimer’s disease (AD). Exercise is known to positively affect vascular function. Thus, the aim of our study was to investigate exercise-induced effects on vascular function in AD. Methods: Thirty-nine patients with AD (79 ± 8 years) were recruited and randomly assigned to exercise training (EX, n = 20) or control group (CTRL, n = 19). All subjects performed 72 treatment sessions (90 min, 3 t/w). EX included moderate–high-intensity aerobic and strength training. CTRL included cognitive stimuli (visual, verbal, auditive). Before and after the 6-month treatment, the vascular function was measured by passive-leg movement test (PLM, calculating the variation in blood flow: ∆peak; and area under the curve: AUC) tests, and flow-mediated dilation (FMD, %). A blood sample was analyzed for vascular endothelial growth factor (VEGF). Arterial blood flow (BF) and shear rate (SR) were measured during EX and CTRL during a typical treatment session. Results: EX group has increased FMD% (+ 3.725%, p ' 0.001), PLM ∆peak (+ 99.056 ml/min, p = 0.004), AUC (+ 37.359AU, p = 0.037) and VEGF (+ 8.825 pg/ml, p = 0.004). In the CTRL group, no difference between pre- and post-treatment was found for any variable. Increase in BF and SR was demonstrated during EX (BF + 123%, p ' 0.05; SR + 134%, p ' 0.05), but not during CTRL treatment. Conclusion: Exercise training improves peripheral vascular function in AD. These ameliorations may be due to the repetitive increase in SR during exercise which triggers NO and VEGF upregulation. This approach might be included in standard AD clinical practice as an effective strategy to treat vascular dysfunction in this population

Inhibition of Rac controls NPM–ALK-dependent lymphoma development and dissemination

Nucleophosmin-anaplastic lymphoma kinase (NPM–ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM–ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM–ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM–ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas

Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas

Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D) to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D)- or MYC/K-ras(G12D)-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D)-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D) resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D) in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D) signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D) but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D). Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas

Loss of p19Arf Facilitates the Angiogenic Switch and Tumor Initiation in a Multi-Stage Cancer Model via p53-Dependent and Independent Mechanisms

The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms

Functional Interactions between Retinoblastoma and c-MYC in a Mouse Model of Hepatocellular Carcinoma

Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to control both overlapping and distinct cellular processes during cell cycle progression. However, how these two major cancer genes functionally interact during tumorigenesis is still unclear. Here, we sought to test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC), a deadly cancer type in which RB is frequently inactivated and c-MYC often activated. We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors. There was a trend for decreased survival in double mutant animals compared to mice developing c-MYC-induced tumors. Thus, loss of RB function does not provide a proliferative advantage to c-MYC-expressing HCC cells but the RB and c-MYC pathways may cooperate to control the polyploidy of mature hepatocytes