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.

Different as night and day: Patterns of isolated seizures, clusters, and status epilepticus.

Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient-reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed-effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions. In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36-1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34-1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79-0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26-1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44-1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05-1.39). With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults.

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.

Phenotype of GABA-transaminase deficiency.

OBJECTIVE: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. METHODS: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. RESULTS: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. CONCLUSIONS: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.

Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency.

The incidence of succinic semialdehyde dehydrogenase (SSADH) deficiency, an autosomal recessive inherited disorder of GABA degradation, is unknown. Upon a recent diagnosis of a new family of affected fraternal twins from the Punjabi ethnic group of India, case ascertainment from the literature and our database was done to determine the number of confirmed cases along with their geographic distribution. The probands presented with global developmental delay, infantile onset epilepsy, and a persistent neurodevelopmental disorder upon diagnosis at 10 years of age with intellectual disability, expressive aphasia, and behavioral problems most prominent for hyperactivity. Gamma-hydroxybutyric aciduria and homozygous ALDH5A1 c.608C>T; p.Pro203Leu mutations were confirmed. Identification of all available individual cases with clinical details available including geographic or ethnic origin revealed 182 patients from 40 countries, with the largest number of patients reported from the USA (24%), Turkey (10%), China (7%), Saudi Arabia (6%), and Germany (5%). This study provides an accounting of all published cases of confirmed SSADH deficiency and provides data useful in planning further studies of this rare inborn error of metabolism.

Predictors of Timely Access of Oncology Services and Advanced-Stage Cancer in an HIV-Endemic Setting.

BACKGROUND: Three-quarters of cancer deaths occur in resource-limited countries, and delayed presentation contributes to poor outcome. In Botswana, where more than half of cancers arise in HIV-infected individuals, we sought to explore predictors of timely oncology care and evaluate the hypothesis that engagement in longitudinal HIV care improves access. METHODS: Consenting patients presenting for oncology care from October 2010 to September 2014 were interviewed and their records were reviewed. Cox and logistic models were used to examine the effect of HIV and other predictors on time to oncology care and presentation with advanced cancer (stage III or IV). RESULTS: Of the 1,146 patients analyzed, 584 (51%) had HIV and 615 (54%) had advanced cancer. The initial clinic visit occurred a mean of 144 days (median 29, interquartile range 0-185) after symptom onset, but subsequent mean time to oncology care was 406 days (median 160, interquartile range 59-653). HIV status was not significantly associated with time to oncology care (adjusted hazard ratio [aHR] 0.91, 95% confidence interval [CI] 0.79-1.06). However, patients who reported using traditional medicine/healers engaged in oncology care significantly faster (aHR 1.23, 95% CI 1.09-1.40) and those with advanced cancer entered care earlier (aHR 1.48, 95% CI 1.30-1.70). Factors significantly associated with advanced cancer included income <$50 per month (adjusted odds ratio [aOR] 1.35, 95% CI 1.05-1.75), male sex (aOR 1.45, 95% CI 1.12-1.87), and pain as the presenting symptom (aOR 1.39, 95% CI 1.03-1.88). CONCLUSION: Longitudinal HIV care did not reduce the substantial delay to cancer treatment. Research focused on reducing health system delay through coordination and navigation is needed. IMPLICATIONS FOR PRACTICE: The majority (54%) of patients in this large cohort from Botswana presented with advanced-stage cancer despite universal access to free health care. Median time from first symptom to specialized oncology care was 13 months. For HIV-infected patients (51% of total), regular longitudinal contact with the health system, through quarterly doctor visits for HIV management, was not successful in providing faster linkages into oncology care. However, patients who used traditional medicine/healers engaged in cancer care faster, indicating potential for leveraging traditional healers as partners in early cancer detection. New strategies are urgently needed to facilitate diagnosis and timely treatment of cancer in low- and middle-income countries.

A pediatric epilepsy diagnostic tool for use in resource-limited settings: A pilot study.

OBJECTIVE: It is estimated that nearly 80% of the 50 million people affected with epilepsy globally live in regions where specialist care and diagnostic tests are scarce and care is often delivered through a primary health provider with limited training. To improve diagnostic accuracy of the history and physical examination, we developed and piloted a questionnaire to discriminate between focal versus generalized epilepsy, with the future goal to guide medication choices. METHODS: Through literature review and retrospective chart review of 75 children with epilepsy at Boston Children's Hospital, a 15-item questionnaire was developed. Simple motor seizures were excluded for the purposes of this questionnaire. The questionnaire was then translated in local dialects and prospectively validated at Muhimbili National Hospital in Dar Es Salaam, Tanzania, and University Teaching Hospital in Lusaka, Zambia. Children 6months-18years of age with suspected or active epilepsy were identified, and a nonphysician administered the questionnaire to the patient's caregiver. Next, each patient was evaluated by a pediatric neurologist blinded to the questionnaire results, and together with locally obtained but remotely interpreted EEG, an electroclinical diagnosis was made. The questionnaire data were compared with this clinical gold standard. RESULTS: A total of 59 children participated: 28 from Tanzania and 31 from Zambia. Sixteen patients were excluded: 5 were excluded because of incomplete data, and 11 did not meet criteria for epilepsy based on initial screening questions. Of the remaining 43 patients, 28 had focal or multifocal epilepsy (65%), and 15 (35%) had generalized epilepsy. The questionnaire had a sensitivity of 78% and positive predictive value of 81.5%. Data were analyzed using a Rasch model, testing the questionnaire's internal consistency, reliability, and its discriminative validity in classifying focal versus generalized epilepsy against an electroclinical diagnosis. The mean epilepsy score for focal epilepsy was 0.084 logits compared with -1.147 logits for generalized epilepsy, demonstrating a large effect size [F (1, 41)=13.490, p<0.001]. CONCLUSIONS: Our questionnaire provides a straightforward method to improve diagnostic accuracy, and could assist in bridging the diagnostic gap in pediatric epilepsy in resource-limited settings. This tool was specifically designed to be easily implemented by any healthcare provider. This pilot study prompts broader prospective validation in additional settings for further refinement, and for performance assessment of impact on provider's practice, ability to guide medication choices, and ultimately improve treatment outcomes in resource-limited regions.

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.

Addressing the growing cancer burden in the wake of the AIDS epidemic in Botswana: The BOTSOGO collaborative partnership.

Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources.

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.