Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger.

Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.

New-Onset Status Epilepticus in Pediatric Patients: Causes, Characteristics, and Outcomes.

BACKGROUND: Many pediatric patients presenting with status epilepticus have no history of seizures. METHODS: We retrospectively analyzed the clinical characteristics of patients aged one month to 21 years who presented during six consecutive years with convulsive status epilepticus and without a history of seizures. New-onset refractory status epilepticus was defined as status epilepticus refractory to two lines of treatment, without an identified cause in the first 48 hours. RESULTS: Of 460 patients with status epilepticus, 79 (17.2%) presented with new-onset status epilepticus, including four (0.9%) with new-onset refractory status epilepticus. Of those patients, 54.4% were female, and the median age was 3.5 years (IQR: 1.08 to 6.75). The median seizure duration was 20 minutes (IQR: 10 to 40 minutes). Etiology was unknown in 36.7%, symptomatic in 30.3%, provoked in 16.5%, and provoked with an existing symptomatic etiology in 16.5%. Patients were followed for a median duration of 63 months (IQR: 21 to 97). The mortality rate was 3.8%. Of 55 patients who were developmentally normal at baseline, 29.1% had a significant cognitive impairment at the last follow-up, and 20% had academic difficulties or behavioral problems. Patients with symptomatic etiology had greater odds of having cognitive and behavioral problems compared with patients with unknown etiology (odds ratio = 3.83, P = 0.012). CONCLUSIONS: Patients with new-onset status epilepticus are at risk for recurrent seizures, recurrent status epilepticus, death, and subsequent cognitive-behavioral impairment. Specific monitoring and care interventions might be required in this high-risk population.

Effectiveness of once-daily high-dose ACTH for infantile spasms.

There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.

Assessment of techniques used to evaluate the effect of posture and cardiac output on cerebral autoregulation.

In this study, the role of cardiac output in Cerebral Autoregulation was assessed. Mean arterial pressure, cerebral blood flow velocity (middle and anterior cerebral artery), stroke volume, cardiac output, total peripheral resistance and cerebral autoregulatory index were assessed in 3 healthy young males and 4 healthy young females during seated and upright thigh cuff testing. Two different methods (long axis left ventricular echocardiography and Modelflow) of evaluating stroke volume and cardiac output were compared. The results showed that cerebral autoregulation was less effective in the upright posture in all subjects. Females had better autoregulation in the anterior cerebral artery, whereas males had better autoregulation in the middle cerebral artery. Cardiac output does not appear to play an important role in cerebral autoregulation during thigh cuff testing. Estimations of cardiac output and stroke volume did not strongly correlate between Modeflow and long axis left ventricular echocardiography.