Oxidation of [U-13 C]glucose in the human brain at 7T under steady state conditions.

PURPOSE: Disorders of brain energy metabolism and neurotransmitter recycling have been implicated in multiple neurological conditions. 13 C magnetic resonance spectroscopy (13 C MRS) during intravenous administration of 13 C-labeled compounds has been used to measure turnover rates of brain metabolites. This approach, however, requires prolonged infusion inside the magnet. Proton decoupling is typically required but may be difficult to implement with standard equipment. We examined an alternative approach to monitor glucose metabolism in the human brain. METHODS: 13 C-enriched glucose was infused in healthy subjects outside the magnet to a steady-state level of 13 C enrichment. Subsequently, the subjects were scanned at 7T for 60 min without 1 H decoupling. Metabolic modeling was used to calculate anaplerosis. RESULTS: Biomarkers of energy metabolism and anaplerosis were detected. The glutamate C5 doublet provided information about glucose-derived acetyl-coenzyme A flux into the tricarboxylic acid (TCA) cycle via pyruvate dehydrogenase, and the bicarbonate signal reflected overall TCA cycle activity. The glutamate C1/C5 ratio is sensitive to anaplerosis. CONCLUSION: Brain 13 C MRS at 7T provides information about glucose oxidation and anaplerosis without the need of prolonged 13 C infusions inside the scanner and without technical challenges of 1 H decoupling, making it a feasible approach for clinical research. Magn Reson Med 78:2065-2071, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

A single blind comparison of lithium and lamotrigine for the treatment of bipolar II depression.

BACKGROUND: Treatment studies are lacking for patients with bipolar II disorder (BDII). The objective of this study was to compare lamotrigine (LTG) and lithium (Li) monotherapy for the treatment of BDII depression. METHODS: Patients with BDII acute depression were randomized to open-label monotherapy with LTG or Li, and evaluated by trained raters blinded to treatment. Patients were titrated to 200 mg/day of LTG over 8 weeks or at least 900 mg/day of Li over 2 weeks (serum level 0.6-1.2 mEq/L), and seen biweekly for 16 weeks. The primary outcome variable was change in the Hamilton Depression Rating Scale 17-item (Ham-D(17)), evaluated using mixed effects random regression. RESULTS: Both groups showed significant improvement from baseline to endpoint on the Ham-D(17) (p<0.0001), with no between group differences (p=0.95). Seventy-two percent of the population was rapid cycling by DSM-IV criteria. No differences in response were noted between rapid cyclers and non-rapid cyclers. Early termination for any cause was 42%. The Li group reported significantly more side effects, although drop-out due to side effects did not differ between groups. LIMITATIONS: This study was limited by an open treatment design, a lack of placebo arm, and uneven treatment groups. CONCLUSIONS: Lamotrigine and lithium were effective monotherapy for BDII depression, with comparable response and remission rates. Naturalistic design and lack of placebo limit conclusions, though patient history indicated long standing depression unlikely to be alleviated by time. Patients who received Li reported more side effects, but this did not appear to impact drop-out rates.

Quetiapine for the continuation treatment of bipolar depression: naturalistic prospective case series from the Stanley Bipolar Treatment Network.

Continuation treatment for bipolar disorder often consists of a mood stabilizer and a second-generation antipsychotic. Quetiapine has been shown to be an effective treatment for acute mania and acute bipolar depression, but there are limited data for its use in continuation treatment. This study examined the effectiveness of open-label adjunctive quetiapine therapy for continuation treatment in patients with bipolar disorder. Prospectively collected life chart data from 63 outpatients with bipolar disorders, most recent episodes depressed, manic, or cycling, who received adjunctive quetiapine therapy as part of standard acute treatment were analyzed. Patients had 4 or more weeks of prequetiapine baseline data and at least 2 weeks of quetiapine treatment with no other medication changes. Patients were grouped by baseline symptoms; depression only, mania only, or both mania and depression (cycling group). Owing to small mania and well groups (n=4), differences between depression and cycling groups were examined and mania and well groups excluded. Fifty-five patients were included in the analyses. The primary outcome measure was change in mood severity from baseline to change in treatment regimen, as measured by the NIMH Life Charting Method. Patients received adjunctive quetiapine for a mean of 122 (SD=149) days. Both groups showed significant improvement in depression ratings and time spent depressed by week 10. Both groups showed significant improvement in overall mood. No between-group differences in improvement were found. Adjunctive quetiapine may be useful as continuation treatment in bipolar populations with both pure depressive and cycling symptoms. Further controlled studies are warranted.

Clinical Aspects of Glucose Transporter Type 1 Deficiency: Information From a Global Registry.

Importance: Case reports regularly document unique or unusual aspects of glucose transporter type 1 deficiency (G1D). In contrast, population studies from which to draw global inferences are lacking. Twenty-five years after the earliest case reports, this deficiency still particularly affects treatment and prognostic counseling. Objective: To examine the most common features of G1D. Design, Setting, and Participants: In this study, data were collected electronically from 181 patients with G1D through a web-based, worldwide patient registry from December 1, 2013, through December 1, 2016. The study used several statistical methods tailored to address the age at onset of various forms of G1D, associated manifestations, natural history, treatment efficacy, and diagnostic procedures. These factors were correlated in a predictive mathematical model designed to guide prognosis on the basis of clinical features present at diagnosis. Results: A total of 181 patients with G1D were included in the study (92 [50.8%] male and 89 female [49.2%]; median age, 9 years; age range, 0-65 years). As previously known, a relatively large variety of common phenotypes are characteristic of the G1D syndrome, including movement disorders, absence epilepsy (typical and atypical), and myoclonic and generalized epilepsies. The 3 main novel results are (1) the feasibility of effective dietary therapies (such as the modified Atkins diet) other than the ketogenic diet, (2) the relatively frequent occurrence (one-fourth of cases) of white matter magnetic resonance imaging abnormalities, and (3) the favorable effect of early diagnosis and treatment regardless of treatment modality and mutation type. In fact, the most important factor that determines outcome is age at diagnosis, as reflected in a predictive mathematical model. Conclusions and Relevance: The results reveal several changing notions in the approach to G1D syndrome diagnosis and treatment, such as the perceived absolute requirement for a ketogenic diet, the assumed lack of structural brain defects, and the potential existence of genotype-phenotype correlations, all of which are contested by the registry data.

Challenges in the management of bipolar depression.

Bipolar depression has started to receive more attention in clinical trials only relatively recently, despite the fact that patients spend more time in the depressed phase than in the manic phase of bipolar disorder. The diagnosis and management of bipolar depression are challenging, and many patients are undiagnosed or misdiagnosed due to symptom similarities with unipolar depression or other illnesses and/or comorbidities. Untreated or inappropriately treated bipolar depression adds to the burden of illness and is associated with a greater risk of suicide. Treatment options include lithium, lamotrigine, atypical antipsychotics, and traditional antidepressants, such as the selective serotonin reuptake inhibitors. However, traditional antidepressants are recommended with caution due to their potential risk of switching patients into mania. Some atypical antipsychotics have shown efficacy in bipolar depression, although longer-term studies are warranted. The choice of treatment for different subgroups of patients with bipolar depression, including those with comorbid anxiety, may vary and also needs further study. Other important issues that require further investigation include the recognition of the core features of bipolar depression and the threshold symptoms for treatment, as well as the optimal treatment choices for monotherapy or combination therapy, and acute versus long-term management of bipolar depression.

Characterization of successful and failed autoresuscitation in human infants, including those dying of SIDS.

Our purpose was to identify and further characterize physiologic mechanisms relevant to autoresuscitation from hypoxic apnea in infants dying suddenly and unexpectedly. We studied cardiorespiratory recordings of 24 infants (age range, 0.8-21 months) who died suddenly while being monitored at home. These recordings were analyzed for features indicated by studies in animal models to be characteristic of hypoxic gasping, and of recovery from bradycardia and apnea associated with gasping (e.g., autoresuscitation). Findings in 5 infants diagnosed as having sudden infant death syndrome were compared with 6 non-SIDS infants whose deaths resulted from other conditions. Additionally, we studied 15 healthy infants during sleep, using home monitor and other respiratory recording techniques, in order to obtain comparison data. We found in recordings from 23 of 24 subjects that hypoxic gasps with characteristic features occurred immediately preceding death. A unique pattern of complex, closely spaced gasps ("double" or "triple" gasps) was present in many subjects. Evidence of partially successful autoresuscitation closely following one or more gasps occurred in 11 subjects, while another 4 had evidence of complete autoresuscitation with return of normal heart rate and resolution of apnea on one or more occasions. Significant differences between SIDS infants and those dying from other causes included increased occurrence of complex gasps and decreased occurrence of partial or complete autoresuscitation in the SIDS infants. The non-SIDS cases were different from the SIDS cases in that only one had "double" gasps (n = 7), while none had "triple" gasps, as compared with 4 out of 5 SIDS cases with these patterns (P < 0.05, chi-square). Also, in contrast with the SIDS cases, more of the cases with specific postmortem diagnoses had evidence of partial (5 out of 6 cases) or complete (1 out of 6 cases) autoresuscitation (P < 0.05, chi-square). We conclude that partial or complete autoresuscitation by gasping is not uncommon in moribund infants during the first year of life. Failure of autoresuscitation mechanisms other than failure to initiate gasping may be characteristic of infants dying of SIDS. Some SIDS infants appear to be different from infants dying with other diagnoses with respect to efficacy and characteristics of hypoxic gasping.

Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement.

IMPORTANCE: Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients. OBJECTIVE: To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin. DESIGN, SETTING, AND PARTICIPANTS: Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis. INTERVENTION: Supplementation of the regular diet with food-grade triheptanoin. MAIN OUTCOMES AND MEASURES: First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements. RESULTS: One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin. CONCLUSIONS AND RELEVANCE: Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.

The safety, acceptability, and effectiveness of acupuncture as an adjunctive treatment for acute symptoms in bipolar disorder.

OBJECTIVE: There is growing interest in the utility of nonpharmacologic treatments for mood symptoms, including mood elevation and depression associated with bipolar disorders. The purpose of this research was to provide preliminary data on the safety, effectiveness, and acceptability of adjunctive acupuncture in the acute treatment of hypomania and depression associated with bipolar disorder. METHOD: Two randomized trials were conducted to assess the benefits of adjunctive acupuncture for symptoms of depression and hypomania in patients with bipolar disorder (DSM-IV criteria). For 20 patients experiencing symptoms of hypomania, targeted acupuncture (points specific to symptoms) was compared to acupuncture points off the acupuncture meridian over 12 weeks (from May 2000 through May 2003). For patients experiencing symptoms of depression (n = 26), targeted acupuncture was compared to acupuncture for nonpsychiatric health concerns over 8 weeks (from November 2001 through May 2003). Preexisting psychotropic medications were maintained at stable doses throughout study participation. RESULTS: Regardless of acupuncture assignment or symptom pattern at entry, all patients experienced improvement over the course of study participation. There was evidence that acupuncture treatment did target the symptom dimension of interest (mood elevation in Study I, depression in Study II). There were few negative side effects and no attrition directly associated with adjunctive acupuncture. CONCLUSIONS: Novel methodologies are needed to assess the utility of acupuncture as adjunctive treatment of mood episodes associated with bipolar disorder. We observed similar benefits associated with "placebo" acupuncture experiences and active treatment. Further studies are warranted. TRIAL REGISTRATION (STUDY II): (ClinicalTrials.gov) Identifier: NCT00071669.

Absence of an increase in cardiorespiratory events after diphtheria-tetanus-acellular pertussis immunization in preterm infants: a randomized, multicenter study.

OBJECTIVE: The American Academy of Pediatrics recommends immunization of preterm infants at 2 months' chronological age with diphtheria-tetanus-acellular pertussis vaccine, regardless of birth weight and gestational age. Several investigators have reported an increased incidence of cardiorespiratory events in preterm infants after immunization. Consequently, many primary care providers do not adhere to American Academy of Pediatrics guidelines. The purpose of this study was to reexamine the relationship between diphtheria-tetanus-acellular pertussis and cardiorespiratory events in preterm infants by using a random control study design and an objective assessment of cardiorespiratory events. METHODS: Ten hospitals enrolled 191 infants who were born at <37 weeks' gestational age at 56 to 60 days' chronological age. Infants were randomly assigned to a group that received diphtheria-tetanus-acellular pertussis immunization (n = 93) or a control group that did not (n = 98). Recording monitors were used continuously during the next 48 hours to document prolonged apnea and prolonged bradycardia. The presence and number of episodes during the 48-hour period were compared between groups by using chi(2) and t tests. RESULTS: In the diphtheria-tetanus-acellular pertussis group, 16.1% experienced at least 1 episode of prolonged apnea compared with 20.4% of control infants. One or more prolonged bradycardia events occurred in 58.1% of immunized infants and 56.1% of the control infants. The frequency of episodes was not significantly different between groups. The immunization group and the control group each had an average of 0.5 episodes of prolonged apnea. The mean number of prolonged bradycardia episodes was 2.6 in the immunization group and 2.7 in the control group. CONCLUSIONS: Preterm infants who received diphtheria-tetanus-acellular pertussis at 2 months after birth were no more likely to experience prolonged apnea and bradycardia than were control infants. This study supports the American Academy of Pediatrics recommendation regarding diphtheria-tetanus-acellular pertussis immunization at 2 months of age for preterm infants.

Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder.

OBJECTIVE: Oxcarbazepine was compared to divalproex to assess clinical effectiveness of a proven agent, divalproex, against a newer, less studied agent, oxcarbazepine, in the treatment of hypomania. METHOD: Thirty patients with bipolar disorder, currently hypomanic, were randomized to receive oxcarbazepine or divalproex as add-on or monotherapy for 8 weeks. A rater blind to treatment assignment performed all symptom ratings. Hypomania and depression were rated using the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms-Clinician Version (IDS-C). Random regression models were used to assess clinical symptom scores. RESULTS: There were no significant differences of YMRS or IDS-C scores between groups. Mean YMRS scores at baseline were 22.07+/-5.86 and 20.53+/-6.02 for the oxcarbazepine and the divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the YMRS was 63.8% and 79.0% for oxcarbazepine and divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the IDS-C was 48.7% versus 19.7% for oxcarbazepine and divalproex groups, respectively. Significant antimanic efficacy was noted for each medication. Both medications were generally well tolerated. CONCLUSION: In this pilot study, oxcarbazepine was as effective as divalproex in the treatment of hypomania. Further controlled trials are warranted.

Implementing a personalized resource management program for a small medical library by using LinkOut.

End users want easy access to electronic full-text articles from their desktops. This small medical library has implemented an easy and cost-effective resource management program to meet this user need. This column will describe the implementation, use, and maintenance of the National Library of Medicine's LinkOut, a personalized resource management program that provides immediate access to the library's online journal full-text holdings via hyperlinks.