Predictors of changes in cerebral perfusion and oxygenation during obstructive sleep apnea

Obstructive sleep apnea syndrome (OSAS) is a common sleep disorder. Severe OSAS defined as apnea–hypopnea index (AHI) ≥ 30/h is a risk factor for developing cerebro-cardiovascular diseases. The mechanisms of how repetitive sleep apneas/hypopneas damage cerebral hemodynamics are still not well understood. In this study, changes in blood volume (BV) and oxygen saturation (StO2) in the left forehead of 29 newly diagnosed severe OSAS patients were measured by frequency-domain near-infrared spectroscopy during an incremental continuous positive airway pressure (CPAP) titration protocol together with polysomnography. The coefficients of variation of BV (CV-BV) and the decreases of StO2 (de-StO2) of more than 2000 respiratory events were predicted using linear mixed-effect models, respectively. We found that longer events and apneas rather than hypopneas induce larger changes in CV-BV and stronger cerebral desaturation. Respiratory events occurring during higher baseline StO2 before their onsets, during rapid-eye-movement sleep and those associated with higher heart rate induce smaller changes in CV-BV and de-StO2. The stepwise increased CPAP pressures can attenuate these changes. These results suggest that in severe OSAS the length and the type of respiratory event rather than widely used AHI may be better parameters to indicate the severity of cerebral hemodynamic changes.

Dramatic changes in mitochondrial substrate use at critically high temperatures: a comparative study using Drosophila

ABSTRACTEctotherm thermal tolerance is critical to species distribution, but at present the physiological underpinnings of heat tolerance remain poorly understood. Mitochondrial function is perturbed at critically high temperatures in some ectotherms, including insects, suggesting that heat tolerance of these animals is linked to failure of oxidative phosphorylation (OXPHOS) and/or ATP production. To test this hypothesis, we measured mitochondrial oxygen consumption rate in six Drosophila species with different heat tolerance using high-resolution respirometry. Using a substrate–uncoupler–inhibitor titration protocol, we examined specific steps of the electron transport system to study how temperatures below, bracketing and above organismal heat limits affect mitochondrial function and substrate oxidation. At benign temperatures (19 and 30°C), complex I-supported respiration (CI-OXPHOS) was the most significant contributor to maximal OXPHOS. At higher temperatures (34, 38, 42 and 46°C), CI-OXPHOS decreased considerably, ultimately to very low levels at 42 and 46°C. The enzymatic catalytic capacity of complex I was intact across all temperatures and accordingly the decreased CI-OXPHOS is unlikely to be caused directly by hyperthermic denaturation/inactivation of complex I. Despite the reduction in CI-OXPHOS, maximal OXPHOS capacity was maintained in all species, through oxidation of alternative substrates – proline, succinate and, particularly, glycerol-3-phosphate – suggesting important mitochondrial flexibility at temperatures exceeding the organismal heat limit. Interestingly, this failure of CI-OXPHOS and compensatory oxidation of alternative substrates occurred at temperatures that correlated with species heat tolerance, such that heat-tolerant species could defend ‘normal’ mitochondrial function at higher temperatures than sensitive species. Future studies should investigate why CI-OXPHOS is perturbed and how this potentially affects ATP production rates.

Effect of changing NAVA levels in preterm infants with RDS

Objective: to examine the effect of changing levels of support (NAVA-level) during neurally adjusted ventilatory assist (NAVA) in preterm infant with respiratory distress syndrome (RDS) on electrical diaphragm activity. Methods: we included preterm infants admitted to the NICU, who were clinically stable and supported with NAVA, either via an endotracheal tube or via a nasal interface. Patients were recruited in the first 24 hours after the start of NAVA. Following a predefined titration protocol, NAVA levels were progressively increased starting from a level of 0,5 cmH2O/µV and with increments of 0,5 cmH2O/µV every 3 minutes, up to a maximum level of 4,0 cmH2O/µV. Respiratory and ventilation parameters were continuously recorded. Results: Ten patients were studied on NIV-NAVA and three on invasive NAVA. The NIV-NAVA patients had an average gestational age at birth of 31,4 + 3,2 weeks and an average birth weight of 1615 + 609 g. For all patients a breakpoint could be identified during the titration study. The breakpoint was on average at a level of 2,35 + 0,63 cmH2O/µV in the NIV-NAVA group. With increasing NAVA levels, the respiratory rate decreased significantly. For the other parameters no clear trend was observed. No severe complications occurred. Conclusion: Preterm neonates with RDS supported with NAVA display a typical biphasic response to changing NAVA-levels with an identifiable breakpoint. This breakpoint was at a higher NAVA-level than commonly used in this clinical situation, suggesting that higher levels might be needed to optimally support preterm neonates with RDS.

Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer

In the absence of curative therapies, treatment of metastatic castrate-resistant prostate cancer (mCRPC) using currently available drugs can be improved by integrating evolutionary principles that govern proliferation of resistant subpopulations into current treatment protocols. Here we develop what is coined as an ‘evolutionary stable therapy’, within the context of the mathematical model that has been used to inform the first adaptive therapy clinical trial of mCRPC. The objective of this therapy is to maintain a stable polymorphic tumor heterogeneity of sensitive and resistant cells to therapy in order to prolong treatment efficacy and progression free survival. Optimal control analysis shows that an increasing dose titration protocol, a very common clinical dosing process, can achieve tumor stabilization for a wide range of potential initial tumor compositions and volumes. Furthermore, larger tumor volumes may counter intuitively be more likely to be stabilized if sensitive cells dominate the tumor composition at time of initial treatment, suggesting a delay of initial treatment could prove beneficial. While it remains uncertain if metastatic disease in humans has the properties that allow it to be truly stabilized, the benefits of a dose titration protocol warrant additional pre-clinical and clinical investigations.

Dramatic changes in mitochondrial substrate use at critically high temperatures: a comparative study using Drosophila

Ectotherm thermal tolerance is critical to species distribution, but at present the physiological underpinnings of heat tolerance remain poorly understood. Mitochondrial function is perturbed at critically high temperatures in some ectotherms, including insects, suggesting that heat tolerance of these animals is linked to failure of oxidative phosphorylation (OXPHOS) and/or ATP production. To test this hypothesis we measured mitochondrial oxygen consumption rates in six Drosophila species with different heat tolerance using high-resolution respirometry. Using a substrate-uncoupler-inhibitor titration protocol we examined specific steps of the electron transport system to study how temperatures below, bracketing and above organismal heat limits affected mitochondrial function and substrate oxidation. At benign temperatures (19 and 30°C), complex I-supported respiration (CI-OXPHOS) was the most significant contributor to maximal OXPHOS. At higher temperatures (34, 38, 42 and 46°C), CI-OXPHOS decreased considerably, ultimately to very low levels at 42 and 46°C. The enzymatic catalytic capacity of complex I was intact across all temperatures and accordingly the decreased CI-OXPHOS is unlikely to be caused directly by hyperthermic denaturation/inactivation of complex I. Despite the reduction in CI-OXPHOS, maximal OXPHOS capacities were maintained in all species, through oxidation of alternative substrates; proline, succinate and, particularly, glycerol-3-phosphate, suggesting important mitochondrial flexibility at temperatures exceeding the organismal heat limit. Interestingly, this compensatory oxidation of alternative substrates occurred at temperatures that tended to correlate with species heat tolerance, such that heat-tolerant species could defend “normal” mitochondrial function at higher temperatures than sensitive species. Future studies should investigate why CI-OXPHOS is perturbed and how this potentially affects ATP production rates.

Abstract 16468: Low Dose Amiodarone is Safe and Effective in Control of Atrial Fibrillation

Introduction: Amiodarone is the most effective drug for the treatment of atrial fibrillation (AF), but long-term administration of standard doses can have prohibitive side effects. Little data is available for use of lower doses. We sought to determine the lowest effective dose for rhythm control in a single physician practice. Methods: Consecutive AF patients treated with Amiodarone using a down-titration schema were prospectively followed. The goal was the lowest dose providing effective rhythm control defined as less than 1% AF burden in patients with devices (42% of patients) or no symptoms or no AF on ECG at last office visit in non-device patients. Results: 170 patents (89M, 81F) were followed for a mean period of 63 months (range 12-177). 79 of 170 (46%) had devices (6 ILR, 29 PM, 27 ICD, 17 CRT). 5 patients had drug-related transient side effects, including 1 transient hyperthyroidism. No patient had pulmonary fibrosis or death. 130 of 170 patients (76%) had successful control of AF. Table 1 shows the number of patents effectively controlled at each weekly dose level. 51% had success at less than or equal to 400mg per week. Renal disease, systolic heart failure with reduced ejection fraction, and advanced age were common comorbidities. Conclusions: Low-dose Amiodarone is safe and effective for control of AF in most patients if carefully used in a down-titration protocol. Device diagnostics aid in patient management.