The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size.

Adipocyte size and number were determined in 288 subjects ranging in age from 4 mo to 19 yr. The study was performed in 110 obese and 178 non-obese subjects. 4-yr, longitudinal, follow-up studies were also performed in 132 subjects. The results demonstrate that the contribution of cell number and size to the growth of the fat depot in nonobese children varies with age. Deviations from this normal development were observed in obese children shortly after 1 yr of age. By 11 yr of age obese children exceeded the mean cell number found in nonobese adults. Indeed, obese subjects displayed more rapid and earlier elevations in both cell number and size, which were maintained throughout the study. Thus obese children display both quantitative and qualitative differences in fat tissue development when compared to nonobese children. The data indicate that the rate and type of adipose tissue cellular development one encounters in children may play a role in the development of the enlarged fat depots found in obese subjects.

Benzylpiperazine: "A messy drug".

Designer drugs are synthetic structural analogues/congeners of controlled substances with slightly modified chemical structures intended to mimic the pharmacological effects of known drugs of abuse so as to evade drug classification. Benzylpiperazine (BZP), a piperazine derivative, elevates synaptic dopamine and serotonin levels producing stimulatory and hallucinogenic effects, respectively, similar to the well-known drug of abuse, methylenedioxymethamphetamine (MDMA). Furthermore, BZP augments the release of norepinephrine by inhibiting presynaptic autoreceptors, therefore, BZP is a "messy drug" due to its multifaceted regulation of synaptic monoamine neurotransmitters. Initially, pharmaceutical companies used BZP as a therapeutic drug for the treatment of various disease states, but due to its contraindications and abuse potential it was withdrawn from the market. BZP imparts predominately sympathomimetic effects accompanied by serious cardiovascular implications. Addictive properties of BZP include behavioral sensitization, cross sensitization, conditioned place preference and repeated self-administration. Additional testing of piperazine derived drugs is needed due to a scarcity of toxicological data and widely abuse worldwide.

Impact of sepsis, lung injury, and the role of lipid infusion on circulating prostacyclin and thromboxane A(2).

OBJECTIVE: To investigate whether plasma levels of prostacyclin (PGI2) and thromboxane A(2) (TxA2) are a function of the infusion rate of soybean-based fat emulsions, severity of systemic inflammation, and pulmonary organ failure. DESIGN: Prospective, randomized, crossover study. SETTING: Intensive care unit of a university hospital. PATIENTS: Eighteen critically ill patients, ten presenting with severe sepsis, eight with SIRS or sepsis complicated with ARDS. INTERVENTIONS: Patients were randomly assigned to receive rapid fat infusion over 6 h (rFI) or slow fat infusion over 24 h (sFI) along with parenteral nutrition. MEASUREMENTS AND RESULTS: The stable prostanoids 6-keto-PGF1alpha and TxB2 were measured in arterial and mixed venous blood samples, and at 6-h periods trans-pulmonary balances (TPB) were calculated. Free linoleic acid fraction was determined in arterial blood. rFI induced greater increase of linoleic acid than sFI in both groups. Enhanced prostanoid levels and correlations with linoleic acid availabilities were found, however, in ARDS patients only, revealing the highest sepsis- and lung injury scores. Averaged TPB per 24 h was positive in the sepsis group and negative in the ARDS group as rFI induced lowest TPB values for TxB2 at 6 h. CONCLUSION: The quantity of prostanoids formed and their subsequent utilization are dependent on the availability of precursor linoleic acid and are probably affected by the severity of SIRS or sepsis and the existence of pulmonary organ failure, respectively. Because TxA2 might be extracted by the injured lung, rapid infusion of soybean-based fat emulsions should be avoided in patients suffering from severe pulmonary organ failure.

Branched-chain amino acid-induced hippocampal norepinephrine release is antagonized by picrotoxin: evidence for a central mode of action.

Previous studies indicated that administration of a 1:1:1 mixture of the branched-chain amino acids leucine, isoleucine, and valine (BCAA) decreased the response to pain. The present study investigates the effects of BCAA on release of norepinephrine (NE) from isolated hippocampal brain slices. BCAA evoked 3H-NE release in a concentration-dependent manner. This effect was antagonized by the gamma aminobutyric acid (GABA) receptor antagonist picrotoxin, again in a concentration-dependent manner, suggesting that the effect may be mediated via a GABA receptor. Given the role of NE and of GABA receptors in the central response to pain, it is possible that the BCAA may exert their antinociceptive properties through activation of GABA receptors.

Effect of substrate manipulation on reducing ischemia/reperfusion injury in isolated perfused rat hearts.

The objective of this investigation was to assess the effect of substrate manipulation on reducing ischemia/reperfusion injury (IRI). Isolated rat hearts were perfused with modified Krebs-Henseleit buffer containing either (in mM): glucose 11 (G1), glucose 22 (G2), or glucose 11 with either xylitol 11 (GX), mannitol 11 (GM), L-leucine 1 (GL), or L-glutamic acid 2 (GGA), respectively. Hearts were subjected to 10 min of global no-flow ischemia, followed by 20 min of reperfusion. Mean tissue perfusion, oxygen consumption, and peak left ventricular pressure (PLVP) were determined at baseline, in the first minute of regular heart rhythm following ischemia, and after 20 minutes of reperfusion. Reperfusion arrhythmia (in sec) was significantly (all p < 0.05) shorter in GGA (115 +/- 33) vs G1 (315 +/- 29) and G2 (273 +/- 33), and also in GL (161 +/- 26) vs G1. Dry/wet heart weight ratios were also greater in GGA (0.20), when compared with G2 (0.16), GX (0.17), GM (0.17), GM (0.17), and GL (0.17) (all p < 0.02), suggesting less cellular/interstitial edema. Percent recovery in PLVP was improved (p < 0.03) in GL (81 +/- 2) and GGA (81 +/- 2) vs. G2 (71 +/- 3), without significant alterations in oxygen consumption. Thus, cardiac IRI can be diminished by substrate manipulation, especially by augmentation of glutamate and leucine, most likely due to an improved anaerobic energy generation and utilization.

Effects of hypocaloric diet low in essential fatty acids on in vitro human adipose tissue prostaglandin production and essential fatty acid status.

Very-low-calorie, fat-free defined-formula diets have been routinely used to treat obese patients. However, the effect of feeding a defined-formula diet low or devoid of essential fatty acids (EFAs) on EFA metabolism has not been determined. The aim of this investigation was to determine the effect of 400 kcal/day of Optifast 70 on EFA metabolism as determined by serum and adipose tissue levels of omega-6 fatty acids and measurements of in vitro human adipose tissue prostaglandin production. Five obese subjects entered the study after 1 wk of weight maintenance and then were placed on 12 wk of weight reduction. Blood and tissue samples were obtained before and after 4, 8, and 12 wk of weight reduction. Subjects tolerated 12 wk of dieting without any adverse reactions and lost an average of 21.7 +/- 7.0 kg. There was no significant effect of weight reduction on the levels of linoleic or arachidonic acid found in adipose tissue. There was a significant decrease in adipose tissue prostaglandin production of prostacyclin I2, measured as 6-keto-PGF1 alpha, after 12 wk of weight reduction. There was no significant change in the levels of thromboxane A2, measured as TXB2. There was a significant increase in serum arachidonic acid levels with no change in linoleic acid levels. The results demonstrated that the use of a diet devoid of EFA had no significant effect on omega-6 EFA metabolism as measured by serum and tissue levels and the ability of adipose tissue to produce prostaglandins in vitro.

Long-term use of gamma-linolenic acid-enriched fat emulsion (PFE 4501): case report.

A new gamma-linolenic acid-enriched fat emulsion (PFE 4501) was given for 13 mo as part of a home parenteral nutrition regimen to a 28-yr-old patient with cystic fibrosis. Blood biochemistry, hematological data, and fatty acid profile were followed. No side effects were reported, and pulmonary function tests remained stable. gamma-Linolenic acid appears to be safe for clinical use and may benefit patients with derangements in essential fatty acid metabolism. The potential role of a gamma-linolenic acid-enriched intravenous fat emulsion is discussed.

Branched-chain amino acids and respiration.

A series of investigations suggest a specific role for BCAA in the regulation of respiration. In vitro incubation studies have shown that BCAAs improve the recovery of muscle force after fatigue. Further investigations revealed that leucine plays a key role in this action and acts in a manner not dependent on its use as an energy substrate. In humans, solutions enriched with BCAA have decreased PCO2 and stimulated the ventilatory response to hypercapnia, thereby corresponding to an enhanced ventilatory sensitivity with the administration of BCAA. The mechanisms for these actions are unknown. The most viable hypothesis is based on the ability of BCAA to decrease the synthesis of serotonin due to altered transport of AAs, including tryptophan, to the brain. Clinical studies have suggested a potency of BCAA in the treatment of respiratory dysfunction of preterm infants, as well as of patients with sleep apnea related to various disease states. The clinical applications of BCAA-enriched mixtures in respiratory diseases are still experimental, and many controversies exist concerning the validity of BCAA in clinical practice. Most TPN regimens contain BCAA approximating the average intake of BCAA in the Western diet. The question therefore remains whether additional BCAA supplementation is useful to achieve the suggested metabolic and pharmacological effects. Meticulous future studies are needed to establish the therapeutic value of BCAA in the treatment of various respiratory functions.

Parenteral use of medium-chain triglycerides: a reappraisal.

Over the last two decades, the clinical use of intravenous fat emulsions for the nutritional support of hospitalized patients has become routine. During this time long-chain triglycerides (LCT) derived from soybean and/or safflower oils were the exclusive lipid source for these emulsions, providing both a safe calorically dense alternative to dextrose and essential fatty acids needed for biologic membranes and the maintenance of immune function. During the past decade, the availability of novel experimental triglycerides for parenteral use has generated interest in the use of these substrates for nutritional and metabolic support. Medium-chain triglycerides (MCT), long advocated as a superior substrate for parenteral use, possess many unique physiochemical and metabolic properties that make them theoretically advantageous over their LCT counterparts. Although not yet approved in the United States, preparations containing MCT have been widely available in Europe. Intravenous MCT preparations, either as physical mixtures or structured lipids, have been used clinically in patients with immunosuppresion, critical illness, liver and pulmonary disease and in premature infants. Despite great promise, the clinical data comparing the efficacy of MCT-based lipid emulsions to their LCT counterparts has been equivocal. This may be due in part to the limited nature of the published clinical trials. Measures of efficacy for parenteral or enteral nutritional products has taken on new meaning, in light of the reported experience using immunomodulatory nutrients. Current concerns about cost of medical care and resource use warrant careful deliberation about the utility of any new and expensive therapy. Until clinical data can fulfill expectations derived from animal studies, it is difficult to advocate the general use of MCT-based lipid emulsions. Future clinical studies with MCT-based emulsions should have clear outcome objectives sufficient to prove their theorized metabolic superiority.

The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis.

The effects of parenteral nutrition supplemented with a lipid emulsion enriched with the omega-3 fatty acids (FA), eicosapentaenoate (20:5n-3) and docosahexaenoate (22:6n-3), derived from fish oil were compared to a standard lipid emulsion containing omega-6 FA in patients with cystic fibrosis (CF). Patients were randomized to receive either Omegavenous 10%, which contains fish oil (IFO), or Liposyn III 10% (control) daily for 1 mo at a dose of 150 mg/kg. There were no observed allergic or toxic reactions, no abnormalities in liver function tests or coagulation parameters. To assess the bioavailability of the lipid administered, measurement of plasma free fatty acid (FFA) levels were made of the essential FA. There were no adverse changes in plasma levels of the omega-6 FA (18:2n-6, 18:3n-6, 20:3n-6, and 20:4n-6), and plasma levels of the omega-3 FA (20:5n-3 and 22:6n-3) increased significantly during the 1-mo study. There were no significant changes in plasma FFA profiles of the essential FA for the patients receiving the control lipid. The effect of treatment on pulmonary function was also investigated. There were no significant changes in FVC, FEV1, PEFR, FEV1/ FVC, or FEF25-75 (absolute value or percentage) over the 4 weeks of study in the group receiving IFO or control. This preliminary investigation suggests that intravenous administration of fish oils enriched with long chain omega-3 FA to patients with CF is safe and bioavailable.

Impact of specific substrate supply on efficiency of cardiac function: an update.

Investigations of the mechanisms that modulate energy generation during states of altered cardiac metabolism have reached a point where there is both need and demand for novel approaches. The evidence discussed here strongly suggests that both energy generation and utilization in these states may be effectively strengthened by nutritional manipulation. Compared with standard treatments for ischemia/reperfusion injury or heart failure, nutritional therapy may present an important and less toxic approach by affecting the mechanisms of energy utilization during compromised cardiac states. We provide not only a conceptual framework for further experimental studies of myocardial metabolism during ischemia and reperfusion injury but also a basis for developing clinically applicable nutrients designed to improve deranged cardiac function. The use of traditional energy substrates, in conjunction with those that may be conditionally important during compromised cardiac states, potentially offers a useful therapeutic modality in the treatment of the cardiac patient.

Long-term parenteral nutrition in cystic fibrosis.

The effects of parenteral nutrition (PN) with high lipid content were studied in 18 cystic fibrosis patients in this pilot investigation. The patients were randomly assigned to one of two groups. During the first 4-mo period, group 1 received PN and group 2 received routine therapy. During the second 4-mo period, PN was discontinued in group 1 and instituted in group 2. When the effect of PN was considered for both treatment groups, its general effect was to increase body fat content with little or no impact on respiratory function, exercise tolerance, or recurrent infections. However, subsequent analysis and clinical observation suggested that patients receiving PN responded in two seemingly distinct patterns: some demonstrated apparent clinical improvement and benefit, and others did not. A positive response in pulmonary and exercise function was closely correlated to a rise in serum dihomo-gamma-linolenic acid (DHLA) concentrations during PN. Pulmonary function improved in patients who normalized their DHLA levels (vital capacity increased from 2.2 +/- 0.3 to 2.6 +/- 0.3 area %, p < 0.05), whereas those who continued to have undetectable levels of DHLA deteriorated (forced expiratory volume in 1 s decreased from 0.7 +/- to 0.6 +/- 0.1, p < 0.001). PN applied to malnourished patients with cystic fibrosis results in beneficial effects in a subgroup characterized by the presence of DHLA in serum; for the group as a whole, the positive effects are minimal.

Effect of emulsions of medium and long chain triglyceride on human adipose tissue prostaglandin production in vitro.

Preliminary in vitro studies have been performed to assess the effect of experimental lipid emulsions of varying fatty acid composition on human adipose tissue metabolism. Subcutaneous human adipose tissue was obtained during elective surgery and placed in tissue culture. Physical mixtures of long chain triglyceride (LCT) and/or medium chain triglyceride (MCT) were added to the tissue culture medium so that the final concentration was 400 mg/dl. After a 3-day incubation period the tissue was harvested, placed in buffer and used to determine in vitro production of the prostaglandins prostacyclin I2 (measured as its stable endproduct 6-keto PGF1 alpha), thromboxane A2 (measured as TXB2), and prostaglandin E2. Measurements of the fatty acid profile found in the neutral- and phospholipid fraction of the adipose tissue and fat cell size were also made. The results demonstrate that samples incubated in 100% MCT had the most significant increase in prostaglandin production whereas those incubated in 100% LCT had the most significant decrease in activity of the three prostaglandins assayed, when compared to controls. The addition of LCT to MCT caused a dose-related decrease in adipose tissue prostaglandin production. There were no significant changes in the profile of fatty acids found in the neutral- or phospholipid fraction of adipose tissue. The results indicate that the relative level of MCT/LCT incubated with human adipose tissue has a significant effect on prostaglandin production.

The antinociceptive effects of branched-chain amino acids: evidence for their ability to potentiate morphine analgesia.

The effect of branched-chain amino acids (BCAA) on pain threshold was studied in rats. Nociception was induced by the hot-plate analgesia meter, a method measuring supraspinally organized pain responses. After a single intravenous injection of BCAA (320 mg/kg), the percent change in latency time to the pain response significantly increased by 19% in 60 min, and by 22% in 75 min (p < 0.005), as compared to an injection of an equal volume of a standard concentration of an amino acid solution or physiological saline. Subsequently, we studied the interaction of BCAA with opioid-type analgesia. In combination with intravenously injected morphine (3 mg/kg), BCAA significantly potentiated and prolonged the action of morphine using the hot-plate test. From 5 min after morphine injection, the latencies to a pain response were markedly higher with the combination of BCAA and morphine (+80% and +89% at 5 min after morphine injection, if BCAA was administered 45 or 60 min prior to morphine injection, respectively) when compared with the effect of morphine alone (+13% at 5 min; p < 0.005). BCAA demonstrated analgesic effects, which, in combination with morphine, potentiated and prolonged the antinociceptive action of morphine. BCAA may represent a new adjunct treatment modality for acute and chronic pain, and give us further insight into the mechanisms of pain control.

Clinical and immunologic effects of lipid-based parenteral nutrition in AIDS.

The effect of lipid-based parenteral nutrition was assessed in eight patients with AIDS and weight loss of 10% or greater. All patients received home parenteral nutrition consisting of a lipid-based system with 50% of nonprotein calories given as fat. Measurements were made of body weight, serum albumin, and immune function as assessed by mitogen responses, P24 antigen levels and T-cell counts. Over a period of 2 months, weight gain and improved well-being were noted in all patients. An improved in vitro lymphocyte mitogenic response to phytohemagglutinin and to concanavalin A was also noted. No change in T-cell subsets was observed. Viral cultures and P24 serum levels also remained unchanged. Lipid-based parenteral nutrition is safe and probably efficacious in AIDS.

The effect of medium and long chain triglyceride on human adipose tissue metabolism.

Studies have been performed to assess the effects, in vivo and in vitro, of lipid emulsions on human adipose tissue prostaglandin production. Subcutaneous adipose tissue obtained either during elective surgery or by needle aspiration was studied in tissue culture or by using a perifusion apparatus. Physical mixtures of emulsions of long chain triglyceride (LCT) and/or medium chain triglyceride (MCT) were added to the tissue culture medium so that the final concentration was 400 mg/dl. After a 3-day incubation period the tissue was harvested, placed in buffer and used to determine in vitro production of prostaglandin E2, prostacyclin I2 (measured as its stable end product 6-keto PGF1 alpha) and thromboxane A2 (measured as TXB2) by radioimmunoassay. The results demonstrated that samples incubated in 100% MCT had the most significant increase in prostaglandin production, while those incubated in 100% LCT had the most significant decrease in activity of the three prostaglandins assayed. The addition of LCT to MCT caused a stepwise decrease in adipose tissue prostaglandin production. The data suggest a pharmacological rather than a physiological effect of lipid emulsions containing MCT and/or LCT on adipose tissue prostaglandin production. In vivo effects of a 20% safflower oil emulsion, containing high levels of the essential fatty acid linoleate, were assessed in five pediatric patients. Adipose tissue was obtained before and after two and four weeks of treatment. Fatty acid profiles and prostaglandin production were determined. The results demonstrated that intravenous fat infusion increased the concentrations of linoleic and arachidonic acids found in adipose tissue within a short interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Branched-chain amino acids and respiratory pattern and function in the neonate.

Branched-chain amino acids (BCAA) increase respiratory drive in adults and improve diaphragmatic function in vitro. This study was designed to examine the effects of increased amounts of BCAA in intravenous nutrition on respiratory function and episodes of apnea in premature infants. An open cross-over design was used, with each patient serving as his own control. Ten premature infants, 34 weeks' gestation or less, were observed. Mean gestational age was 30.6 weeks (range 27 to 33 weeks), mean birth weight was 1487 gm +/- 300 gm, and the age at study was 5 to 33 days. For three consecutive 24-hour periods, the infants received routine total parenteral nutrition (TPN) (30% BCAA), enriched TPN (53% BCAA), and routine TPN (30% BCAA). Pulmonary function, apnea frequency, blood chemistry, and amino acid pattern were measured. Enriched TPN resulted in significant increases in all infants in dynamic compliance, from 2.41 +/- 1.07 to 4.55 +/- 2.78 ml/cm H2O (p < 0.025), and in specific dynamic compliance from 1.67 +/- 0.64 to 3.1 +/- 1.51 ml/cm H2O/kg (p < 0.005). Total pulmonary resistance decreased from 40.3 +/- 23.3 to 24.0 +/- 20.9 cm H2O/L/sec (p < 0.05), and peak-to-peak pressure decreased from 5.96 +/- 0.93 to 4.09 +/- 2.34 cm H2O (p < 0.05). All values returned to baseline with resumption of the routine TPN. In four infants with significant apnea, the average number of episodes of apnea decreased from 58 during standard TPN to 11 with the enriched solution infusion during matched 12-hour periods (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[Fat-rich diets in patients with mild chronic obstructive lung disease (COPD)]. / Dietas ricas en grasa en pacientes con enfermedad pulmonar obstructiva crónica (EPOC) leve.

A study was made in stable patients suffering from mild COLD of the maximum capacity for ergometric cycle exercise and gas exchange at rest and during maximum exercise, measured by indirect calorimetry. During the period of study (3 months) one group of patients receive the usual diet while the other received an oral nutritional supplement rich in fats an minimum of 75% of their energy expenditure measured at rest. The patients studied, with mild COLD, were hypermetabolic, and although at rest they presented indirect calorimetry data such as would correspond to similar subjects, during exercise not just the limit on exercise became clear but also the alteration to ventilatory capacity and gas exchange. The fat-rich nutritional supplement administered for three months did not succeed in enhancing exercise capacity or in altering gas exchange during maximum exercise is stable patients with mild COLD.