Possible mitochondrial dysfunction and its association with antiretroviral therapy use in children perinatally infected with HIV.

BACKGROUND: Mitochondrial dysfunction has been associated with both human immunodeficiency virus (HIV) infection and exposure to antiretroviral therapy. Mitochondrial dysfunction has not been widely studied in HIV-infected children. We estimated the incidence of clinically defined mitochondrial dysfunction among children with perinatal HIV infection. METHODS: Children with perinatal HIV infection enrolled in a prospective cohort study (Pediatric AIDS Clinical Trials Group protocols 219 and 219C) from 1993 through 2004 were included. Two clinical case definitions of mitochondrial dysfunction, the Enquête Périnatale Française criteria and the Mitochondrial Disease Classification criteria, were used to classify signs and symptoms that were consistent with possible mitochondrial dysfunction. Adjusted odds ratios of the associations between single and dual nucleoside reverse-transcriptase inhibitor use and possible mitochondrial dysfunction were estimated using logistic regression. RESULTS: Overall, 982 (33.5%) of 2931 children met 1 or both case definitions of possible mitochondrial dysfunction. Mortality was highest among the 96 children who met both case definitions (20%). After adjusting for confounders, there was a higher risk of possible mitochondrial dysfunction among children who received stavudine regardless of exposure to other medications (odds ratio, 3.44 [95% confidence interval, 1.91-6.20]) or who received stavudine-didanosine combination therapy (odds ratio, 2.23 [95% confidence interval, 1.19-4.21]). Exposure to lamivudine and to lamivudine-stavudine were also associated with an increased risk of mitochondrial dysfunction. CONCLUSIONS: Receipt of nucleoside reverse-transcriptase inhibitors, especially stavudine and lamivudine, was associated with possible mitochondrial dysfunction in children with perinatal HIV infection. Further studies are warranted to elucidate potential mechanisms of nucleoside reverse-transcriptase inhibitor toxicities.

Vitamins are Indeed Vital Amines: A Discussion of 3 Deficiencies With Neurologic Manifestations.

Optimal functioning of the human nervous system depends on a constant supply of nutrients, vitamins, and minerals. In the developed world, nutritional deficiencies are relatively rare and infrequently present with neurologic manifestations. These neurologic disorders can be mistaken for inflammatory and/or autoimmune phenomena. This manuscript describes 2 pediatric cases with neurologic signs/symptoms arising from vitamin deficiencies-(1) optic neuropathy and (2) Wernicke encephalopathy associated with a Guillain-Barre-like pattern of weakness. The 2 cases and the subsequent discussion of vitamin A, B1, and B12 deficiencies underscore the value of taking a thorough dietary history and emphasize risk factors for these 3 nutritional deficiencies.

Carnitine in parenteral nutrition.

Several new functions or metabolic uses of carnitine and improvements in assessment of carnitine status impact carnitine dosing recommendations. Carnitine dosing will likely be customized for patients at different stages of the life cycle and for patients with dysfunction of different organs. Nutrition supplementation of carnitine should be 2-5 mg x kg(-1) x day(-1) and be administrated via the route used for administration of macronutrients. Pharmacologic supplementation of carnitine should be 50-100 mg x kg(-1) x day(-1) and be reserved for the removal of toxic compounds from the body.

Safety and Efficacy of Atorvastatin in Human Immunodeficiency Virus-infected Children, Adolescents and Young Adults With Hyperlipidemia.

BACKGROUND: Human immunodeficiency virus (HIV)-infected children receiving antiretroviral therapy (ART) have increased prevalence of hyperlipidemia and risk factors for cardiovascular disease. No studies have investigated the efficacy and safety of statins in this population. METHODS: HIV-infected youth 10 to <24 years of age on stable ART with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL for ≥6 months initiated atorvastatin 10 mg once daily. Atorvastatin was increased to 20 mg if LDL-C efficacy criteria (LDL-C < 110 mg/dL or decreased ≥30% from baseline) were not met at week 4. Primary outcomes were safety and efficacy. RESULTS: Twenty-eight youth initiated atorvastatin; 7 were 10-15 years and 21 were 15-24 years. Mean baseline LDL-C was 161 mg/dL (standard deviation 19 mg/dL). Efficacy criteria were met at week 4 by 17 of 27 (63%) participants. Atorvastatin was increased to 20 mg in 10 participants. Mean LDL-C decreased from baseline by 30% (90% confidence interval: 26%, 35%) at week 4, 28% (90% confidence interval: 23%, 33%) at week 24 and 26% (90% confidence interval: 20%, 33%) at week 48. LDL-C was less than 110 mg/dL in 44% at week 4, 42% at week 12 and 46% at weeks 24 and 48. Total cholesterol, non high-density lipoprotein (non-HDL)-C and apolipoprotein B decreased significantly, but IL-6 and high-sensitivity C-reactive protein did not. Two participants in the younger age group discontinued study for toxicities possibly related to atorvastatin. CONCLUSIONS: Atorvastatin lowered total cholesterol, LDL-C, non HDL-C and apolipoprotein B in HIV-infected youth with ART-associated hyperlipidemia. Atorvastatin could be considered for HIV-infected children with hyperlipidemia, but safety monitoring is important particularly in younger children.

Presence of arachidonoyl-carnitine is associated with adverse cardiometabolic responses in hypertensive patients treated with atenolol.

INTRODUCTION: Atenolol, a commonly prescribed ß blocker for hypertension, is also associated with adverse cardiometabolic effects such as hyperglycemia and dyslipidemia. Knowledge of the mechanistic underpinnings of these adverse effects of atenolol is incomplete. OBJECTIVE: We sought to identify biomarkers associated with risk for these untoward effects of atenolol. We measured baseline blood serum levels of acylcarnitines (ACs) that are involved in a host of different metabolic pathways, to establish associations with adverse cardiometabolic responses after atenolol treatment. METHODS: Serum samples from Caucasian hypertensive patients (n = 224) who were treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study were interrogated using a quantitative LC/MS assay for a large number of unique ACs in serum. For the 23 ACs that were detected in serum from ≥80 % of all patients, we conducted linear regression for changes in cardiometabolic factors with baseline AC levels, baseline cardiometabolic factors, age, sex, and BMI as covariates. For the 5 ACs that were detected in serum from 20 to 79 % of the patients, we similarly modeled changes in cardiometabolic factors, but with specifying the AC as present/absent in the regression. RESULTS: Among the 28 ACs, the presence (vs. absence) of arachidonoyl-carnitine (C20:4) was significantly associated with increased glucose (p = 0.0002), and was nominally associated with decreased plasma HDL-C (p = 0.017) and with less blood pressure (BP) lowering (p = 0.006 for systolic BP, p = 0.002 for diastolic BP), after adjustment. CONCLUSION: Serum level of C20:4 is a promising biomarker to predict adverse cardiometabolic responses including glucose and poor antihypertensive response to atenolol.

Practical approach to metabolic assessments in the pediatric human immunodeficiency virus outpatient clinic.

BACKGROUND: Metabolic assessment is not a routine part of the care of pediatric HIV-positive patients in the outpatient setting, although research studies are demonstrating an increasing prevalence of metabolic abnormalities in this population. Addition of metabolic assessments to routine clinic care can be hindered by the perception that collection of the data needed for the assessments will need too much clinic time and too many clinic resources to be practical. METHODS: A method to provide metabolic assessments using minimal clinic resources while offering educational opportunities for university students was developed and implemented at the University of Florida Pediatric Immunology and Infectious Diseases weekly clinic. The success rate of metabolic assessment data collection from all clinic patients and the impact of data collection on the flow of clinic activity were monitored for a 12-month period. RESULTS: The metabolic assessment team interviewed 87% of all patients who came to the 454 clinic during the 12-month period and performed a complete metabolic assessment for 75% of the HIV-positive patients interviewed. Addition of metabolic assessments to the routine care of each patient did not result in any noticeable adverse effect on the functionality of the clinic. CONCLUSIONS: Addition of metabolic assessments to the routine clinic care of pediatric HIV positive patients can be an educational opportunity for university students and provide the clinic staff with changes in parameters indicative of metabolic abnormalities and without noticeable changes in maintaining the patient schedule at each clinic.

Development of the piglet neonatal intensive care unit for translational research.

The piglet is an important animal model in biomedical research; many aspects of its anatomy, physiology and metabolism are similar to those of the human neonate. The authors describe a neonatal intensive care unit (NICU) for piglets. This unit allows researchers to model neonatal care in the NICU and can be used for a range of research studies. The authors hope that the model they describe can serve as a template for other investigators who would like to design their own piglet NICUs.

Acylcarnitines: role in brain.

l-carnitine is present in mammalian cells as free carnitine and acylcarnitines. The acylcarnitine profile has been shown to be useful in identifying inborn errors of metabolism and to be altered under different metabolic conditions. While carnitine's most widely known function is its involvement in beta-oxidation of fatty acids, it may also have other roles in metabolism. The importance of acylcarnitines in tissues with high rates of beta-oxidation such as heart and muscle is intuitive. However, acylcarnitine and carnitine supplementation have resulted in beneficial effects in the treatment of various neurological diseases, even though fat is not the major fuel for brain. Recent data indicate new, multifactorial roles for acylcarnitines in neuroprotection. Brain acylcarnitines can function in synthesizing lipids, altering and stabilizing membrane composition, modulating genes and proteins, improving mitochondrial function, increasing antioxidant activity, and enhancing cholinergic neurotransmission. Currently a relatively small subset of acylcarnitines is usually investigated. More research is needed on the use of acylcarnitines in the treatment of neurological diseases using a list of acylcarnitines encompassing a wide range of these molecules. In summary, carnitine is not merely a cofactor in beta-oxidation, but rather it has many known and yet to be discovered functions in physiology.

Carnitine and lipid metabolism

Carnitine, a short-chain nitrogen containing carboxylic acid, is found in meat and dairy foods. Carnitine aids in a shuttle process that makes long-chain, fatty-acid coenzyme A derivatives available for B-oxidation. Normal healthy adults have adequate carmitine stores and do not require dietary carnitine. However, neonates, chronically and critically ill patients with decreased muscle and liver carnitine store seen to benefit from carnitine supplementation to enhance their tolerance of metabolic stress