ABSTRACT
BACKGROUND: As decontamination trends have evolved, gastric lavage (GL) has become a rare procedure. The current information regarding use, outcomes, and complications of GL could help refine indications for this invasive procedure. OBJECTIVES: We sought to determine case type, location, and complications of GL cases reported to a statewide poison control system. METHODS: This is a retrospective review of the California Poison Control System (CPCS) records from 2009 to 2012. Specific substances ingested, results and complications of GL, referring hospital ZIP codes, and outcomes were examined. RESULTS: Nine hundred twenty-three patients who underwent GL were included in the final analysis, ranging in age from 9 months to 88 years. There were 381 single and 540 multiple substance ingestions, with pill fragment return in 27%. Five hundred thirty-six GLs were performed with CPCS recommendation, while 387 were performed without. Complications were reported for 20 cases. There were 5 deaths, all after multiple ingestions. Among survivors, 37% were released from the emergency department, 13% were admitted to hospital wards, and 48% were admitted to intensive care units. The most commonly ingested substances were nontricyclic antidepressant psychotropics (n = 313), benzodiazepines (n = 233), acetaminophen (n = 191), nonsteroidal anti-inflammatory drugs (n = 107), diphenhydramine (n = 70), tricyclic antidepressants (n = 45), aspirin (n = 45), lithium (n = 36), and antifreeze (n = 10). The geographic distribution was clustered near regions of high population density, with a few exceptions. CONCLUSIONS: Toxic agents for which GL was performed reflected a broad spectrum of potential hazards, some of which are not life-threatening or have effective treatments. Continuing emergency physician and poison center staff education is required to assist in patient selection.
Subject(s)
Drug Overdose/therapy , Gastric Lavage/statistics & numerical data , Poison Control Centers/statistics & numerical data , Acetaminophen/poisoning , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/poisoning , Antidepressive Agents/poisoning , Benzodiazepines/poisoning , California , Child , Child, Preschool , Diphenhydramine/poisoning , Drug Overdose/etiology , Emergency Service, Hospital/statistics & numerical data , Female , Gastric Lavage/adverse effects , Gastric Lavage/trends , Humans , Infant , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Patient Admission/statistics & numerical data , Patient Discharge/statistics & numerical data , Poisoning/etiology , Poisoning/therapy , Referral and Consultation/statistics & numerical data , Treatment Outcome , Young AdultABSTRACT
The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin-2, the predominant lipin protein present in liver and the deficient gene product in the rare disorder Majeed syndrome. By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner. In liver, lipin-2 deficiency led to a compensatory increase in hepatic lipin-1 protein and elevated PAP activity, which maintained lipid homeostasis under basal conditions, but led to diet-induced hepatic triglyceride accumulation. As lipin-2-deficient mice aged, they developed ataxia and impaired balance. This was associated with the combination of lipin-2 deficiency and an age-dependent reduction in cerebellar lipin-1 levels, resulting in altered cerebellar phospholipid composition. Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients. Combined lipin-1 and lipin-2 deficiency caused embryonic lethality. Our results reveal functional interactions between members of the lipin family in vivo, and a unique role for lipin-2 in central nervous system biology that may be particularly important with advancing age. Additionally, as has been observed in mice and humans with lipin-1 deficiency, the pathophysiology in lipin-2 deficiency is associated with dysregulation of lipid intermediates.
Subject(s)
Aging/physiology , Cerebellum/physiology , Homeostasis/physiology , Liver/physiology , Nuclear Proteins/metabolism , Phosphatidate Phosphatase/metabolism , Analysis of Variance , Animals , Blood Cell Count , Blotting, Western , Bone and Bones/diagnostic imaging , Cerebellum/metabolism , DNA Primers/genetics , Galactosides , Gene Expression Profiling , Histological Techniques , Immunohistochemistry , Indoles , Liver/metabolism , Locomotion/physiology , Mice , Mice, Transgenic , Nuclear Proteins/deficiency , Phosphatidate Phosphatase/deficiency , Phospholipids/metabolism , Polymerase Chain Reaction , Psychomotor Performance , Radiography , Reflex, Startle/physiologyABSTRACT
Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.
Subject(s)
Nuclear Proteins/metabolism , Phosphatidate Phosphatase/metabolism , Serine/metabolism , Amino Acid Substitution , Anemia, Dyserythropoietic, Congenital/enzymology , Anemia, Dyserythropoietic, Congenital/genetics , Animals , Cell Line , Dermatitis/enzymology , Dermatitis/genetics , Fever/enzymology , Fever/genetics , Gene Expression Regulation, Enzymologic/genetics , Humans , Mice , Mutation, Missense , Nuclear Proteins/genetics , Organ Specificity/genetics , Osteomyelitis/enzymology , Osteomyelitis/genetics , Peroxisome Proliferator-Activated Receptors , Phosphatidate Phosphatase/genetics , Response Elements , Serine/genetics , SyndromeABSTRACT
CONTEXT: Lipin-1 functions in adipocyte triglyceride biosynthesis and in the regulation of gene expression, both of which may influence metabolic homeostasis. OBJECTIVE: Our objective was to determine whether variations in adipose tissue lipin-1 expression levels influence insulin sensitivity and gene expression in young healthy human subjects. DESIGN AND SUBJECTS: In 56 healthy young men (22.6 +/- 3.2 yr; 26.4 +/- 4.1 kg/m2) we determined insulin sensitivity by a euglycemic-hyperinsulinemic clamp, and whole body oxygen consumption and respiratory quotient by indirect calorimetry. We performed gene expression analysis in adipose tissue samples from human subjects and from lipin-1 transgenic mice using quantitative RT-PCR. RESULTS: In healthy young men, lipin-1 expression was positively correlated with insulin sensitivity (R2 = 0.22; P < 0.01), insulin-stimulated respiratory quotient (R2 = 0.16; P < 0.01), and maximal oxygen consumption during exercise (R2 = 0.16; P < 0.01). Lipin-1 mRNA levels were also correlated with expression of genes involved in lipid oxidation, uptake, and lipolysis, both in humans and in lipin-1 transgenic mice. The strongest correlation occurred between lipin-1 and peroxisome proliferator-activated receptor alpha (R2 = 0.74; P < 1 x 10(-7)), a nuclear receptor with a key role in fatty acid oxidation. CONCLUSION: Lipin-1 expression levels in adipose tissue of healthy young subjects and in mice are correlated with a favorable metabolic profile and expression of fatty acid oxidation genes.
Subject(s)
Adipose Tissue/metabolism , Insulin Resistance/physiology , Nuclear Proteins/biosynthesis , PPAR alpha/biosynthesis , Absorptiometry, Photon , Adolescent , Adult , Animals , Body Composition , Cohort Studies , Fasting/metabolism , Gene Expression , Humans , Lipid Metabolism/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nuclear Proteins/genetics , Oxygen Consumption/genetics , Oxygen Consumption/physiology , PPAR alpha/genetics , Phosphatidate Phosphatase , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for beta-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAP1 activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAP1 activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.
Subject(s)
Cyclic AMP/pharmacology , Glucocorticoids/pharmacology , Liver/metabolism , Nuclear Proteins/genetics , Phosphotransferases (Phosphate Group Acceptor)/metabolism , Animals , Cell Culture Techniques , Eating , Fasting , Gene Expression Regulation/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Liver/drug effects , Male , Pancreatitis-Associated Proteins , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic/drug effectsABSTRACT
We previously identified mutations in the Lpin1 gene, encoding lipin-1, as the underlying cause of lipodystrophy in the fatty liver dystrophy (fld) mutant mouse. Lipin-1 is normally expressed at high levels in adipose tissue and skeletal muscle, and deficiency in the fld mouse causes impaired adipose tissue development, insulin resistance, and altered energy expenditure. We also identified two additional lipin protein family members of unknown function, lipin-2 and lipin-3. Han et al. (Han, G. S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210-9218) recently demonstrated that the single lipin homolog in yeast, Smp2, exhibits phosphatidate phosphatase type-1 (PAP1) activity, which has a key role in glycerolipid synthesis. Here we demonstrate that lipin-1 accounts for all of the PAP1 activity in white and brown adipose tissue and skeletal muscle. However, livers of lipin-1-deficient mice exhibited normal PAP1 activity, indicating that other members of the lipin protein family could have PAP1 activity. Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity. Each of the three lipin family members showed Mg2+-dependent activity that was specific for phosphatidate under the conditions employed. The different lipins showed distinct tissue expression patterns. Our results establish the three mammalian lipin proteins as PAP1 enzymes and explain the biochemical basis for lipodystrophy in the lipin-1-deficient fld mouse.