MHC genes, body odours, and odour preferences.
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Choice Behavior↗
Biomedical subjects
D Penn
Publications and source records attributed to D Penn.
Characteristics of schizophrenia among persons with severe or profound mental retardation.
The symptoms of schizophrenia were examined in a residential sample of adults with severe or profound mental retardation. Three groups were compared: those with a significant elevation on the schizophrenia subscale of the Diagnostic Assessment for the Severely Handicapped (DASH-II) and a psychiatric diagnosis of schizophrenia; those with a significant elevation on the same subscale but no formal diagnosis of schizophrenia; and those with no elevation on any of the DASH-II subscales. A one-way analysis of variance showed statistically significant differences between the groups. Symptoms of schizophrenia among those in the first group were found to fall mainly into the categories of reality distortion and disorganization, with less evidence of negative symptoms.
Adult↗
Explaining the human demographic transition.
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Journal Article↗
Thought disorder and psychosocial functioning in schizophrenia: the concurrent and predictive relationships.
Recent findings have linked impairments in social performance among individuals with schizophrenia to deficits in cognition. However, one component of cognition, thought disorder (TD), has received little attention in its association with social functioning. The current investigation examined the cross-sectional and predictive relationships between bizarre-idiosyncratic thought and psychosocial functioning throughout the early course of schizophrenia and compared these relationships to those observed among individuals with affective disorders (i.e., bipolar disorder, manic type, and major depression without psychotic features). Participants were assessed on TD, work, and social functioning using standardized procedures across three follow-ups over an 8-year period. The cross-sectional relationships between TD and impairment in work performance were generally significant. TD also significantly predicted subsequent work functioning years later. Less support was found for the relationship between TD and social functioning. Finally, the relationship between TD and work performance appeared to be more consistent over time for the subjects with schizophrenia compared to those with affective disorders. The results suggest that techniques which minimize TD may have implications for occupational functioning among persons with chronic psychiatric disorders.
Adaptation, Psychological↗
Carnitine deprivation adversely affects cardiac performance in the lipopolysaccharide- and hypoxia/reoxygenation-stressed piglet heart.
Sepsis and hypoxia are important stressors for the neonate. Newborn infants receiving total parenteral nutrition are routinely deprived of carnitine and develop low carnitine plasma and tissue levels. Because of its high metabolic rate and dependence on fatty acids for energy, the newborn heart may be particularly vulnerable to stress in the face of an inadequate carnitine supply. To investigate whether carnitine deprivation affects cardiac performance under stress, 23 neonatal piglets received parenteral nutrition for 2-3 weeks that was either carnitine free (CARN -) or supplemented (CARN +) with L-carnitine (400 mg/L). Bacterial endotoxin (lipopolysaccharide (LPS), 250 microg/kg intravenous bolus) or saline vehicle was administered to anesthetized piglets 3 h prior to study of isolated perfused hearts. Left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure, and left ventricular developed pressure (LVDP) were measured in vitro under aerobic, hypoxic, and reoxygenation conditions in all animals. Plasma and tissue carnitine values were lower in CARN - than in CARN + piglets. In hearts from LPS-treated animals prior to hypoxia, there was no difference in ventricular compliance between CARN - and CARN + groups. LVSP and LVDP were lower in CARN - than CARN + hearts. During hypoxia, LVSP and LVDP fell, but left ventricular end diastolic pressure increased in hearts from both LPS- and saline- treated piglets. Reoxygenation led to poorer recovery in CARN - than CARN + hearts from LPS-treated animals, but not from saline controls. During hypoxia/reoxygenation, lactate efflux initially rose and then fell, while carnitine efflux increased continually. Acetyl- and medium-chain acylcarnitines were detected in the coronary effluent. Our findings suggest that carnitine deprivation diminishes heart carnitine concentrations and impairs cardiac recovery from combined endotoxic and hypoxic stress. Possible mechanisms include reduced acyl buffering and/or impaired transport of fatty acyl groups into mitochondria.
Animals↗
MHC-disassortative mating preferences reversed by cross-fostering.
House mice (Mus musculus domesticus) avoid mating with individuals that are genetically similar at the major histocompatibility complex (MHC). Mice are able recognize MHC-similar individuals through specific odour cues. However, to mate disassortatively for MHC genes, individuals must have a referent, either themselves (self-inspection) or close kin (familial imprinting), with which to compare the MHC identity of potential mates. Although studies on MHC-dependent mating preferences often assume that individuals use self-inspection, laboratory experiments with male mice indicate that they use familial imprinting, i.e. males learn the MHC identity of their family and then avoid mating with females carrying 'familial' MHC alleles. To determine if female mice use familial imprinting, we cross-fostered wild-derived female mouse pups into MHC-dissimilar families, and then tested if this procedure reversed their mating preferences compared with in-fostered controls. Our observations of the female's mating behaviour in seminatural social conditions and the genetic typing of their progeny both indicated that females avoided mating with males carrying MHC genes of their foster family, supporting the familial imprinting hypothesis. We show that MHC-dependent familial imprinting potentially provides a more effective mechanism for avoiding kin matings and reducing inbreeding than self-inspection.
Animals↗
Untrained mice discriminate MHC-determined odors.
Immune recognition occurs when foreign antigens are presented to T-lymphocytes by molecules encoded by the highly polymorphic genes of the major histocompatibility complex (MHC). House mice (Mus musculus) prefer to mate with individuals that have dissimilar MHC genes. Numerous studies indicate that mice recognize MHC identity through chemosensory cues; however, it is unclear whether odor is determined by classical, antigen-presenting MHC loci or closely linked genes. Previous studies have relied on training laboratory mice and rats to distinguish MHC-associated odors, but there are several reasons why training experiments may be inappropriate assays for testing if MHC genes affect odor. The aim of this study was to determine whether classical MHC genes affect individual odors and whether wild-derived mice can detect MHC-associated odors without training. In the first experiment, we found that wild-derived mice can be trained in a Y-maze to detect the odors of mice that differ genetically only in the MHC region. In the second and third experiments, we used a naturalistic habituation assay and found that wild-derived mice can, without training, distinguish the odors of mice that differ genetically only at one classical MHC locus (dm2 mutants).
Animals↗
How do major histocompatibility complex genes influence odor and mating preferences?
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Abortion, Habitual↗
Carnitine deprivation adversely affects cardiovascular response to bacterial endotoxin (LPS) in the anesthetized neonatal pig.
Sepsis and endotoxemia are important stressors for the neonate. Newborn infants receiving total parenteral nutrition are routinely deprived of carnitine. To investigate whether carnitine deprivation affects the neonate's ability to respond to endotoxin, 19 newborn piglets received parenteral nutrition for 2-3 weeks that was either carnitine free (CARN-) or supplemented (CARN+) with L-carnitine (400 mg/L). Cardiovascular performance, i.e., heart rate; blood pressure (BP); cardiac output (CO); systemic vascular resistance (SVR), and metabolic response, i.e., plasma glucose; lactate; tumor necrosis factor alpha; tissue nitric oxide; and urinary nitrites, were studied serially in anesthetized piglets for 3 h after endotoxin (lipopolysaccharide (LPS), 250 microg/kg intravenous bolus) or vehicle administration. Plasma and tissue carnitine values were lower in CARN- than in CARN+ piglets. Prior to LPS, no differences were found for most parameters (excepting lower diastolic BP and SVR in CARN- animals). Systolic, diastolic, and mean BP fell after LPS but recovered by the end of the experiment. Nadirs were lower in CARN- than in CARN+ piglets. CO tended to be higher in CARN- than in CARN+ animals and fell after LPS. SVR fell after LPS and was lower in CARN- than in CARN+ piglets. LPS-treated animals transiently increased urinary flow. By all measures (plasma tumor necrosis factor alpha, glucose and lactate, tissue nitric oxide, and urinary nitrite excretion), LPS provocation was similar for both groups. Chronologically, BP changes were more closely related to SVR than to CO. Our findings suggest that carnitine deprivation diminishes tissue carnitine concentrations and adversely affects cardiovascular response to LPS, in part mediated by the peripheral vasculature.
Anesthesia↗
Analysis of carnitine esters by radio-high performance liquid chromatography in cultured skin fibroblasts from patients with mitochondrial fatty acid oxidation disorders.
Acylcarnitines are important diagnostic markers for inborn errors of fatty acid oxidation, but their analysis in body fluids may not always be reliable. Recently, disease-specific acylcarnitine profiles generated by cultured skin fibroblasts were reported to facilitate the diagnosis by localizing a specific enzymatic defect in the mitochondrial beta-oxidation pathway. Using a novel methodologic approach, fibroblasts from 16 patients with inborn errors of fatty acid oxidation and 13 control subjects were preincubated with L-[3H]carnitine to label the intracellular carnitine pool. Cells were subsequently incubated with unlabeled palmitic acid and, after methanol extraction of cells and media, labeled free carnitine and acylcarnitines were analyzed by radio-HPLC. Quantitation was based on the integrated radioactivity of individual peaks relative to the total radioactivity recovered. In control cell lines, all saturated acylcarnitines were detected, and reference values were established. With the exception of one cell line deficient in electron transfer flavoprotein, all mutant cell lines showed abnormal and disease-specific relative concentrations of acylcarnitines. Advantages of the method include use of a small number of cells, no need for trypsinization and permeabilization of cells before incubation, simple extraction without purification of the specimen before HPLC, and relatively inexpensive equipment. The method allows a focused approach to the subsequent, more laborious confirmation of a particular disease by direct enzymatic and/or molecular analysis. It remains to be established whether the method can replace widely used global measurements of fatty acid oxidation rates in vitro that do not provide specific information about the enzyme deficiency involved.
Acyl-CoA Dehydrogenase↗
Access to emergency care under TennCare: do patients understand the system?
STUDY OBJECTIVE: To determine patient understanding of how to properly gain access to urgent and emergency medical care under TennCare, a government-mandated managed health care initiative designed to replace Medicaid in Tennessee. METHODS: We prospectively surveyed a convenience sample of ED patients at university hospital ED with an annual census of 50,000 during two periods (summer 1994 and summer 1995). In 1994, 250 TennCare patients were enrolled (part 1). In 1995, 199 were enrolled (part 2). RESULTS: Patients from seven different TennCare managed care organizations (MCOs) were interviewed. Thirty-eight percent of part 1 patients and 37% of part 2 patients did not have or did not know the names of their primary care physicians (PCPs). Fifty-eight percent of the part 1 patients who knew their PCPs' names had never visited them. This figure had decreased to 25% by the time part 2 patients were surveyed. Seventy-three percent of part 1 patients interviewed did not call their PCPs before coming to the ED. This figure had decreased to 48% by the time part 2 patients were interviewed. Thirty-two percent of part 1 patients were aware that they were supposed to contact the PCP before visiting the ED, whereas 94% of part 2 patients were aware of this requirement. Thirty-one percent of part 1 patients and 40% of part 2 patients who tried to contact their PCPs were unsuccessful, most often because of a delay on the part of PCPs in returning calls. Fifty-six percent of part 1 patients and 69% of part 2 patients did not know that they might be held responsible for the bill if an ED visit was not considered a true emergency and was not approved by the MCO. CONCLUSION: Improvements in communication of pertinent information must be implemented in managed care systems such as TennCare to better inform participants of the proper use of the system. MCOs will not reduce inappropriate use of the ED if patients are not aware of their responsibilities and do not know their PCPs or how to gain access to them. PCP responsiveness to patients must also be improved.
Adult↗
Neonatal nutritional carnitine deficiency: a piglet model.
The clinical significance of nutritional carnitine deficiency remains controversial. To investigate this condition under controlled conditions, an animal model was developed using the parenterally alimented, carnitine-deprived newborn piglet. Forty-five piglets received total parenteral nutrition for 2-3 wk that was either carnitine-free or supplemented with 100-400 mg/L L-carnitine. Blood and a muscle biopsy were taken at the initial surgery. Carnitine balance studies were performed at 11-14 d of age. Blood, liver, heart, and skeletal muscle were taken at sacrifice for analysis of carnitine, electron microscopy, and oxidation studies. Carnitine-deprived piglets were in negative carnitine balance and had lower blood, urine, and tissue levels of carnitine than carnitine-supplemented animals. There was a positive correlation between excretion and plasma concentrations of free carnitine with an apparent renal threshold between 15 and 35 micromol/L. Plasma levels were correlated with liver and heart, but not muscle, concentrations of total acid-soluble carnitine. Carnitine-deprived piglets had evidence of lipid deposition in liver and skeletal muscle and tended to have a higher incidence of muscle weakness and cardiac failure. Basal rates of oxidation of [14C]palmitate to 14CO2 and 14C-acid-soluble products were lower in liver homogenates from carnitine-deprived piglets than in those from carnitine-supplemented animals and increased in a dose-dependent fashion with the addition of L-carnitine (0, 50, and 500 micromol/L) in vitro. In summary, carnitine deprivation in the neonatal piglet resulted in low carnitine status and morphologic/functional disturbances compatible with carnitine deficiency. The described animal model appears to be suitable for the investigation of neonatal nutritional carnitine deficiency.
Animals↗
The nature of selection on the major histocompatibility complex.
Only natural selection can account for the extreme genetic diversity of genes of the major histocompatibility complex (MHC). Although the structure and function of classic MHC genes is well understood at the molecular and cellular levels, there is controversy about how MHC diversity is selectively maintained. The diversifying selection can be driven by pathogen interactions and inbreeding avoidance mechanisms. Pathogen-driven selection can maintain MHC polymorphism based on heterozygote advantage or frequency-dependent selection due to pathogen evasion of MHC-dependent immune recognition. Empirical evidence demonstrates that specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both heterozygote advantage and frequency-dependent models. Additional research is needed to discriminate between these mechanisms. Infectious agents can precipitate autoimmunity and can potentially contribute to MHC diversity through molecular mimicry and by favoring immunodominance. MHC-dependent abortion and mate choice, based on olfaction, can also maintain MHC diversity and probably functions both to avoid genome-wide inbreeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often treated as competing alternatives, we believe that they all fit into a coherent, internally consistent thesis. It is likely that at least in some species, all of these mechanisms operate, leading to the extreme diversification found in MHC genes.
Animals↗
Quantitation of short- and medium-chain acylcarnitines in plasma by radioisotopic exchange/high-performance liquid chromatography.
A method for the quantitation of short- and medium-chain acylcarnitines in plasma and its clinical application are described. The method is based on enzymatic exchange of L-[3H]carnitine into the acylcarnitine pool, subsequent separation of labeled acylcarnitines by high-performance liquid chromatography, and quantitation of the radioactivity by a beta flowthrough detector. Since only acylcarnitines are detected, no sample cleanup procedure is required. Isotopic equilibrium, a prerequisite for accurate quantitation, was reached in plasma after 1 h of incubation for all acylcarnitines except isovalerylcarnitine which required a longer incubation time. No significant hydrolysis of acylcarnitines occurred during the incubation. Linearity was demonstrated after adding increasing amounts of individual acylcarnitines to plasma. The method is highly sensitive requiring no L-carnitine administration to the patient and differentiates short-chain acylcarnitine isomers. It is suitable for the detection of a number of inborn errors of organic acid and fatty acid metabolism.
Carboxylic Ester Hydrolases↗
Comments on quantitation of carnitine esters by high-performance liquid chromatography.
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Carboxylic Ester Hydrolases↗
Detection of inborn errors of fatty acid oxidation from acylcarnitine analysis of plasma and blood spots with the radioisotopic exchange-high-performance liquid chromatographic method.
Sixty-one plasma samples from patients with inborn errors of fatty acid oxidation and from control subjects were analyzed in a blinded fashion for acylcarnitines by the radioisotopic exchange-high-performance liquid chromatographic method. All samples from patients with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency (n = 30), some of which had been stored in a frozen state for several years, showed a prominent octanoylcarnitine peak. In all blood spots from 11 patients with MCAD deficiency, octanoylcarnitine was also detected. Control plasma specimens and blood spots contained small amounts of octanoylcarnitine; however, the octanoylcarnitine/acetylcarnitine ratio differentiated patients with MCAD deficiency. Longer-chain acylcarnitines were found in plasma of all three patients with defects in long-chain fatty acid oxidation. Plasma and blood spots from a patient with multiple acyl-coenzyme A dehydrogenase deficiency contained C4-acylcarnitine, hexanoylcarnitine, octanoylcarnitine, and decanoylcarnitine. The results suggest that the method may be highly sensitive in detecting MCAD deficiency and other defects in fatty acid oxidation from plasma or blood spots.
Acyl-CoA Dehydrogenase↗
Errors in estimating peritoneal fluid by bioelectrical impedance analysis and total body electrical conductivity.
Whole-body bioelectrical impedance analysis (BIA) and total body electrical conductivity (TOBEC) have been used to estimate body composition and generalized changes in total body water (TBW). The sensitivity of these methods to measure small, rapid, localized changes in body water has not been fully evaluated. We compared the prediction of TBW by whole-body and segmental BIA and TOBEC with deuterium oxide dilution (D2O) in 10 control subjects and 7 renal failure patients receiving continuous ambulatory peritoneal dialysis (CAPD) prior to and after dialysate infusion. Using D2O as the reference method, there was no significant mean residual error between TBW predicted by BIA and TOBEC in controls (-1.2 +/- 1.5 and -0.9 +/- 1.0 kg) and CAPD patients pre-infusion (-1.0 +/- 2.0 and 0.29 +/- 2.01 kg). After infusing 1.9 +/- 0.18 kg dialysate, the mean residual error between change in body weight and the three methods was -0.44 +/- 0.53 kg for D2O (p < 0.1), -1.7 +/- 0.25 kg for BIA (p < 0.0001), and 1.2 +/- 0.4 kg for TOBEC (p < 0.001). Segmental BIA detected a 7.6% reduction in trunkal resistance with no significant change across the limbs, consistent with abdominal fluid accumulation. It is concluded that whole-body BIA underpredicts and TOBEC overpredicts small changes in peritoneal fluids.
Adolescent↗
Impaired fatty acid oxidation in children on valproic acid and the effect of L-carnitine.
Fatty acid oxidation was studied in 12 patients (aged 3 to 19 years) receiving valproic acid (VPA), predominantly as monotherapy, before and after 1 month of L-carnitine supplementation (50 mg/kg/day po) in order to determine whether L-carnitine plays a role in preventing the hepatotoxic effects of this drug. Five of these patients were also studied prior to VPA treatment. Only one patient taking VPA had an abnormally low plasma free carnitine. Acyl-/free carnitine ratios were elevated in five patients on VPA and normalized after L-carnitine supplementation. Mean plasma concentrations of free fatty acids, beta-OH-butyrate, and cumulative excretion of 13CO2 after administration of 1-13C-octanoic acid were not changed by VPA or L-carnitine treatment. Urinary dicarboxylic acids, acylglycines, and octanoylcarnitine were elevated during VPA therapy and unaltered by L-carnitine. These results suggest that, in patients at low risk for VPA-induced hepatotoxicity (patients aged > 2 years and taking VPA as monotherapy), VPA causes metabolic abnormalities resembling those found in inborn errors of mitochondrial beta-oxidation which are not corrected by L-carnitine.
Adolescent↗