The effects of mitoquinone pretreatment on doxorubicin-induced acute cardiac dysfunction

Introduction: Doxorubicin (DOX) is a widely used anti-cancer drug notorious for its irreversible cardiac toxicity. Currently, Dexrazoxane is the only FDA-approved treatment for this toxicity. However, Dexrazoxane still bears some serious adverse events, and developing new strategies to mitigate DOX-induced heart damage is critical. Our lab has shown that pretreatment of the H9c2 myoblast cells with mitoquinone (MitoQ), a mitochondrial-targeted antioxidant, and significantly improved cells’ resiliency to DOX. This study aimed to determine if MitoQ pretreatment can preserve cardiac function against DOX-induced damage in isolated rat hearts. Objectives: The effects of DOX and MitoQ on cardiac function were evaluated in isolated rat hearts. Moreover, the benefits of MitoQ pretreatment on DOX-induced cardiac dysfunction were also assessed. Methods: Langendorff heart preparation was performed after anesthesia of male SD rats (275-325 g). Hearts were isolated and retrograde perfused with Krebs’ buffer at a constant pressure of 80 mmHg with 37 ⁰C and pH of 7.35-7.45. Cardiac parameters, including left ventricle end-systolic pressure (LVESP), left ventricle end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP=LVESP-LVEDP), maximal rate of rise of LVP (dP/dt(max)), and heart rate (HR), were measured by a pressure transducer placed in the left ventricle of the rat heart. After obtaining a stable initial cardiac function, DOX (20 µM or 25 µM) or MitoQ (0.1-0.5 or 1-2.5 µM) were infused into the heart for 60 min. to determine the individual drug\u27s effects on the cardiac function. Moreover, another set of hearts was pretreated with MitoQ (0.25-0.5 or 1-2.5 µM) for 10-15 min before giving DOX (25 µM) to evaluate if MitoQ pretreatment would mitigate DOX-induced cardiac dysfunction. Cardiac functions were recorded every 5 min. throughout the experiments. The ratio between the final and initial recordings was calculated and compared among experimental groups. Results: Acute infusion of DOX into the isolated hearts dose-dependently reduced some cardiac parameters. Higher dose DOX (25 μM, n=5) induced a higher reduction in the ratios of LVESP, LVDP, and dP/dt(max) to 0.39±0.05, 0.35±0.06, and 0.26±0.05 than those of lower dose DOX infusion (20 μM, n=2; 0.77±0.01, 0.75±0.01, and 0.57±0.01), respectively. DOX had no effects on LVEDP and HR. Moreover, lower doses of MitoQ (0.1-0.5 μM, n=6) only slightly reduced HR to 0.77±0.01 without affecting other parameters. By contrast, higher doses of MitoQ (1-5 μM, n=4) reduced the ratios of LVESP, LVDP, dP/dt(max), and HR to 0.72±0.12, 0.51±0.18, and 0.45±0.17 0.65±0.07, respectively. Interestingly, MitoQ pretreatment before DOX (25 µM) exhibited better cardiac function accompanied by reduced HR than DOX alone. Higher MitoQ (1-2.5 µM) pretreatment improved the ratios of cardiac LVESP, LVDP, and dP/dt(max) to 0.67±0.14, 0.65±0.16, and 0.40±0.09, which were higher than those of lower dose MitoQ (0.25-0.5 μM, n=3; 0.49±0.11, 0.44±0.11, and 0.36±0.08), respectively. Conclusion: The preliminary data suggest that infusion of DOX into the heart acutely attenuated cardiac systolic function. Higher doses of MitoQ, not lower doses, also suppressed cardiac function. MitoQ pretreatment mitigated DOX-induced heart dysfunction. Acknowledgement: The project is funded by CCDA at PCOM

Functional Activation and Effective Connectivity Differences in Adolescent Marijuana Users Performing a Simulated Gambling Task

Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (\u3e5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, ?Wins? and ?Losses? were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during ?Wins? and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during ?Losses.? Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both ?Wins? and ?Losses.? However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the ?Losses? condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity

Upper extremity impairments in women with or without lymphedema following breast cancer treatment

Breast-cancer-related lymphedema affects ∼25% of breast cancer (BC) survivors and may impact use of the upper limb during activity. The purpose of this study is to compare upper extremity (UE) impairment and activity between women with and without lymphedema after BC treatment. 144 women post BC treatment completed demographic, symptom, and Disability of Arm-Shoulder-Hand (DASH) questionnaires. Objective measures included Purdue pegboard, finger-tapper, Semmes-Weinstein monofilaments, vibration perception threshold, strength, range of motion (ROM), and volume. Women with lymphedema had more lymph nodes removed (p < .001), more UE symptoms (p < .001), higher BMI (p = .041), and higher DASH scores (greater limitation) (p < .001). For all participants there was less strength (elbow flexion, wrist flexion, grip), less shoulder ROM, and decreased sensation at the medial upper arm (p < .05) in the affected UE. These differences were greater in women with lymphedema, particularly in shoulder abduction ROM (p < .05). Women with lymphedema had bilaterally less elbow flexion strength and shoulder ROM (p < .05). Past diagnosis of lymphedema, grip strength, shoulder abduction ROM, and number of comorbidities contributed to the variance in DASH scores (R 2 of 0.463, p < .001). UE impairments are found in women following treatment for BC. Women with lymphedema have greater UE impairment and limitation in activities than women without. Many of these impairments are amenable to prevention measures or treatment, so early detection by health care providers is essential

The effects of ascorbic acid and sodium ascorbate on doxorubicin-induced H9c2 cell damage

INTRODUCTION: Doxorubicin causes high superoxide levels in the mitochondria contributing to cardiotoxicity. Ascorbic acid (AA) and sodium ascorbate (SA) are antioxidants and may mitigate doxorubicin-induced heart cell damage. OBJECTIVE: This study determined the effects of AA and SA on doxorubicin-induced cell damage. METHODS: AA or SA (10-4000 uM) were tested alone or cotreated with doxorubicin (40 uM) on H9c2 cells. Some cells were pretreated with AA and SA for 24 hours before doxorubicin. Cell viability and superoxides were evaluated using a cell counting kit and Mitosox assay, respectively. RESULTS: AA and SA (10-2000 uM) alone increased cell viability by 17-31% (n=3), accompanied by decreased mitochondrial superoxides by 6-29% (n=2) when compared to the non-treated control. However, higher doses of AA and SA (4000 uM, n=2) decreased cell viability and tripled mitochondrial superoxide levels relative to the non-treated control. Furthermore, when compared to doxorubicin-treated cells, cotreatment of SA or AA (100 uM, n=3) showed a maximum increase of cell viability by 21± 6% and 29± 18%, respectively; and pretreatment of SA or AA (100 uM, n=5) showed a maximum increase of cell viability by 46± 2% and 57± 3%, respectively. Pretreatment of AA also reduced mitochondrial superoxide by 47± 4% (n=2) compared to doxorubicin-treated cells. CONCLUSION: Preliminary data suggest that pretreatment of AA and SA exerted better cardiac protection against doxorubicin than cotreatment in H9c2 cells. The effects of pretreatment may be related to the reduction of mitochondrial superoxide. However, high levels of AA and SA showed pro-oxidant properties

Functional Activation and Effective Connectivity Differences in Adolescent Marijuana Users Performing a Simulated Gambling Task

Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (>5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, “Wins” and “Losses” were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during “Wins” and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during “Losses.” Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both “Wins” and “Losses.” However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the “Losses” condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity

Informed consent for innovative surgery: A survey of patients and surgeons

BACKGROUND: Unlike new drugs and medical devices, most surgical procedures are developed outside clinical trials, without regulatory oversight. Surgical professional organizations have discussed how new procedures should be introduced into practice, without agreement on what topics informed consent discussions must include. To provide surgeons with more specific guidance, we wanted to determine what information patients and surgeons consider essential to disclose before an innovative surgical procedure. METHODS: 85 attending surgeons and 383 adult postoperative patients completed surveys. Using a 6-point Likert scale, participants rated the importance of discussing 16 types of information preoperatively for 3 techniques (standard open, laparoscopic, robotic) offered for a hypothetical partial hepatectomy. RESULTS: Compared with surgeons, patients placed more importance on nearly all types of information, particularly volumes and outcomes. For all 3 techniques, around 80% of patients indicated that they could not decide on surgery without being told whether it would be the surgeon’s first time doing the procedure. When considering an innovative robotic surgery, a clear majority of both patients and surgeons agreed that it was essential to disclose the procedure’s novel nature, potentially unknown risks and benefits, and whether it would be the surgeon’s first time performing the procedure. CONCLUSIONS: To promote informed decision making and autonomy among patients considering innovative surgery, surgeons should disclose the procedure’s novel nature, potentially unknown risks and benefits, and whether the surgeon would be performing the procedure for the first time. When accurate volumes and outcomes data are available, surgeons should also discuss these with patients