Search PubMed⌕ Search

Biomedical subjects

D J Jenden

Publications and source records attributed to D J Jenden.

At least 19 recordsLinked to original sources
PubMed2001

Plasma choline in normal newborns, infants, toddlers, and in very-low-birth-weight neonates requiring total parenteral nutrition.

Choline deficiency is associated with hepatic abnormalities in adult volunteers and patients administered total parenteral nutrition (TPN). Preliminary investigation has suggested that plasma-free choline concentration (PFCh) is greater in neonatal animals, including humans, than in adults. The aims of this study were to determine the normal PFCh and phospholipid-bound choline concentration (PPLBCh) for newborns, infants, and toddlers and to determine the change during TPN. We also sought to determine the degree of fetal choline extraction, the relation between maternal and newborn plasma choline concentrations, and the relation between plasma choline status and normal newborn length, weight, and gestational age. Blood samples were obtained from 104 full-term newborns in two centers (Ben Taub and Maimonides), 25 mothers, 21 normal infants aged 20.3 +/- 11.8 wk, 12 normal infants aged 62.4 +/- 3.9 wk, and 14 preterm infants (gestational age = 28.9 +/- 2.2 wk) who required TPN. The vein PFChs were 28.1 +/- 13.0 nmol/mL (Ben Taub) and 68.1 +/- 16.9 nmol/mL (Maimonides). The artery PFChs were 27.1 +/- 13.0 nmol/mL (Ben Taub) and 57.9 +/- 11.6 nmol/mL (Maimonides). The vein PPLChs were 1004.7 +/- 246.6 nmol/mL (Ben Taub) and 1121.2 +/- 289.6 nmol/mL (Maimonides). The artery PPLChs were 1065.7 +/- 469.3 nmol/mL (Ben Taub) and 1106.9 +/- 285.8 nmol/mL (Maimonides). The vein-minus-artery differences for PFCh were 1.0 +/- 9.7 nmol/mL (Ben Taub) and 10.2 +/- 10.9 nmol/mL (Maimonides). The vein-minus-artery differences for PPLCh were -51.9 +/- 398.2 nmol/mL (Ben Taub General Hospital, Houston, Texas) and 14.4 +/- 254.3 nmol/mL (Maimonides, New York, New York). Maternal venous PFCh was 8.4 +/- 3.1 nmol/mL. Maternal venous PPLCh was 2592.1 +/- 584.0 nmol/mL (range = 1227.8-3729.0). Maternal venous PFCh correlated with newborn arterial PFCh (r = 0.53, P < 0.05) but not with newborn venous PFCh. No correlation was seen between maternal venous and newborn PPLCh. No significant differences were seen in PPLCh or choline extraction in Ben Taub versus Maimonides patients, although PFCh was significantly greater in the newborns from Maimonides (P < 0.05). The mean venous PFCh and PPLCh in the preterm infants before beginning TPN was 21.2 +/- 6.3 and 1366.8 +/- 339.1 nmol/mL, respectively. Just before initiation of tube feeding (4.0 +/- 2.7 d after TPN had been started), mean venous PFCh and PPLCh was 18.4 +/- 5.3 and 2251.8 +/- 686.9 nmol/mL, respectively. When TPN was discontinued and tube feeding increased to goal, after 10.8 +/- 10.4 d, venous PFCh and PPLCh was 22.6 +/- 8.7 and 2072.5 +/- 540.6 nmol/mL, respectively. Venous PFCh and PPLCh was 13.4 +/- 2.5 and 1827.5 +/- 327.0 nmol/mL, respectively in the older infant group. In conclusion, newborn PFCh is significantly greater than PFCh in adults but falls to adult levels within the first year of life. Low maternal PFCh may be associated with low newborn PFCh. Normal newborn plasma choline status has no bearing on intrauterine growth, although the role of maternal choline deficiency in underweight newborns is unknown. Newborn PPLCh is substantially below that of adults, which suggests its use in membrane synthesis during growth.

Adult↗
PubMed2000

Isolated hypermethioninemia: measurements of S-adenosylmethionine and choline.

The concentrations of methionine and S-adenosylmethionine (AdoMet) in plasma and free choline and phospholipid-bound choline in both plasma and red blood cells from individuals with isolated hypermethioninemia have been measured. The only genetic abnormalities identified in these individuals have been inactivating mutations in MAT1A, the gene that encodes the subunit of the isozymes of methionine adenosyltransferase (MAT), MAT I, and MAT III, expressed only in adult liver. These measurements were performed to learn more about AdoMet metabolism and to test the working hypotheses that inadequate delivery of AdoMet, or of choline or a choline derivative, from liver to brain might be a cause of the neurologic disease often found in humans with the most severe losses of MAT I/III activity. In striking contrast to the elevations of plasma AdoMet reported in control humans with hypermethioninemia resulting from methionine loading, plasma AdoMet levels were generally below the mean reference value in the MAT I/II-deficient hypermethioninemic patients. This is interpreted as a result of subnormal formation of AdoMet in liver due to the deficient activity of MAT I/III and resultant lower-than-normal delivery of AdoMet from liver to plasma. A low plasma AdoMet concentration in the presence of an elevated methionine provides a useful diagnostic tool that pinpoints the cause of a case of hypermethioninemia as defective MAT I/III activity. Plasma-free choline concentrations were also generally somewhat below normal in the hypermethioninemic patients. However, neither plasma AdoMet nor plasma choline concentrations were strikingly lower in MAT I/III-deficient individuals with neurologic abnormalities than in those without. These results thus fail to provide support for the working hypotheses in question.

Choline↗
PubMed1999

Folate nutriture alters choline status of women and men fed low choline diets.

Choline and folate share methylation pathways and, in studies of rats, were shown to be metabolically inter-related. To determine whether choline status is related to folate intake in humans, we measured the effect of controlled folate depletion and repletion on the plasma choline and phosphatidylcholine concentrations of 11 healthy men (33-46 y) and 10 healthy women (49-63 y) fed low-choline diets in two separate metabolic unit studies. Total folate intake was varied by supplementing low folate (25 and 56 microg/d for men and women, respectively) and low choline (238 and 147 mg/d for men and women, respectively) diets with pteroylglutamic acid for 2-6 wk following folate-depletion periods of 4-5 wk. The low folate/choline intakes resulted in subclinical folate deficiencies; mean plasma choline decreases of 28 and 25% in the men and women, respectively; and a plasma phosphatidylcholine decrease of 26% in the men (P < 0. 05). No functional choline deficiency occurred, as measured by serum transaminase and lipid concentrations. The decreases in choline status measures returned to baseline or higher upon moderate folate repletion and were more responsive to folate repletion than plasma folate and homocysteine. Feeding methionine supplements to the men did not prevent plasma choline depletion, indicating that folate is a more limiting nutrient for these methylation pathways. The results indicate that 1) choline is utilized as a methyl donor when folate intake is low, 2) the de novo synthesis of phosphatidylcholine is insufficient to maintain choline status when intakes of folate and choline are low, and 3) dietary choline is required by adults in an amount > 250 mg/d to maintain plasma choline and phosphatidylcholine when folate intake is low.

Adult↗
PubMed1998

Mapping of cerebral metabolic activation in three models of cholinergic convulsions.

Glucose utilization of four cerebral cortex and 35 subcortical regions (CGU) was analyzed in three models of cholinergic seizures induced by the following compounds: 1) soman (pinacolylmethylphosphonofluoridate) an organophosphorus cholinesterase inhibitor, 100 microg/kg SC after pretreatment with pyridostigmine 26 microg/kg IM (n = 6); 2) physostigmine, a carbamate cholinesterase inhibitor, 1.31 mg/kg infused IV over 75 min (n = 6); and 3) pilocarpine, a direct cholinergic agonist, 30 mg/kg SC (n = 6). Physostigmine and pilocarpine were preceded by 3 mmol/kg LiCl IP 20 hrs earlier. Animals injected with saline SC (n = 6) were used as controls. Step-wise discriminant analysis successfully classified 100% of the cases into the four experimental groups with data from only six regions. Pyridostigmine-soman induced the most widespread and greatest increases in CGU. More restricted and lower levels of activation were observed with Li-pilocarpine while Li-physostigmine induced significant increases in CGU only in globus pallidus, entopeduncular nucleus, and substantia nigra. These three regions, which are functionally related, were also activated in the other two models of cholinergic convulsions and may represent the initial step in cholinergic activation of the CNS. Li-pilocarpine failed to activate most of the brainstem and the superior colliculus. All cortical regions were activated by Li-pilocarpine and pyridostigmine-soman, while they were inhibited by Li-physostigmine. This phenomenon may be due in part to the lack of activation with physostigmine of the basal forebrain nuclei (lateral septum, medial septum, vertical and horizontal limbs of the diagonal band, and substantia innominata) resulting in a decreased drive of cortical metabolism.

Animals↗
PubMed1997

Cholinesterase inhibition improves blood flow in the ischemic cerebral cortex.

The ability of central cholinesterase inhibition to improve cerebral blood flow in the ischemic brain was tested in Sprague-Dawley rats with tandem occlusion of left middle cerebral and common carotid arteries. Cerebral blood flow was measured with lodo- 14C-antipyrine autoradiography in 170 regions of cerebral cortex. The regional distribution of blood flow was characterized in normal animals by cerebral blood flow maxima in the temporal regions. After 2 h ischemia, minimum cerebral blood flow values were found in the lateral frontal and parietal areas on the left hemisphere, and a new maximum was found in the right hemisphere in an area approximately symmetrical to the ischemic focus. Heptyl-physostigmine (eptastigmine), a carbamate cholinesterase inhibitor with prolonged time of action improved cerebral blood flow in most regions, with the exception of the ischemic core. The drug also enhanced the ischemia-induced rostral shift of cerebral blood flow maxima in the right hemisphere. The effects of eptastigmine were more marked 24 h after ischemia. Discriminant analysis showed that data from only 22 regions was sufficient to achieve 100% accuracy in classifying all cases into the various experimental conditions. The redistribution of cerebral blood flow to the sensorimotor area of the right hemisphere of animals with cerebral ischemia, a phenomenon possibly related to recovery of function, was also enhanced by eptastigmine.

Animals↗
PubMed1997

Cholinergic modulation of cerebral cortical blood flow changes induced by trauma.

These experiments tested the role of cholinergic mechanisms in the changes of cerebral cortical blood flow (CBF) induced by brain trauma. CBF was measured with Iodo-14C-antipyrine autoradiography, in 128 cerebral cortex regions of both hemispheres, distributed in eight coronal slices. The effects of a 6.3-mm diameter craniotomy over the left motor-sensory cortex with no weight drop, and of trauma (drop weight of 20 g from 30 cm height on left motor-sensory cortex through a 6.3 mm circular craniotomy) on CBF were studied at 2 and 24 h after the interventions. A group of control animals that received no intervention was also set up. Animals were treated with the cholinesterase inhibitor physostigmine salicylate (3.3 microg/kg/min i.v. infusion started 60 min before CBF measurements), the cholinergic blocker scopolamine hydrobromide (1 mg/kg i.v. pulse, 18 min before CBF measurements), or with the drugs vehicle (saline). A focus of decreased CBF at the site of impact was observed 2 h after trauma, extending caudally as far as the occipital cortex. CBF on the contralateral cerebral cortex was also decreased. Both phenomena reversed partially at 24 h. This spontaneous recovery of CBF was blocked by scopolamine. Physostigmine reversed the decrease in CBF of the traumatized cortex, partially around the contused area and completely in more distant regions. The cerebral cortex contralateral to the trauma showed significantly higher CBF 24 h after trauma when compared to intact controls or craniotomy that peaked at the area symmetrical to the center of trauma. This phenomenon was also enhanced by physostigmine and completely blocked by scopolamine. These results suggest a prominent role of cholinergic mechanisms in the vascular adjustments that accompany cerebral trauma.

Animals↗
PubMed1997

Sphingomyelin metabolism in rat liver after chronic dietary replacement of choline by N-aminodeanol.

Sphingomyelin (SM) is a structural element of cell membranes and lipoproteins, and participates in signal transduction. To determine whether a choline analog (N-amino-N,N-dimethylaminoethanol, N-aminodeanol, NADe) can be substituted for choline in the SM of liver, rats (male, Sprague-Dawley-derived) were fed a diet that was low in choline and methionine, and contained 35.5 mmol of NADe/kg. After 18 months, liver plasma membranes and microsomes contained 48.9 +/- 3.6 and 93.6 +/- 6.9 nmol/mg protein of phosphatidyl-NADe, respectively, and 3.2 +/- 0.2 and 3.5 +/- 0.1 nmol/mg protein of ceramide phospho-NADe. The SM content of microsomes from NADe-fed rats was about one-third lower than for the control, and phosphatidylcholine (PC) was reduced by < 10%; there was also a small decrease in PC, but not SM, in plasma membranes. In vitro assays of enzymes involved in SM metabolism found no change in PC:ceramide cholinephosphotransferase, but the NADe-fed animals had higher phosphatidylethanolamine:ceramide ethanolaminephosphotransferase activity, greater incorporation of methyl groups from [methyl-3H]-S-adenosyl methionine into SM, and a lower neutral sphingomyelinase activity. These results show that NADe-fed rats from considerable amounts of ceramide phospho- and phosphatidyl-NADe; however, liver plasma membranes retain relatively normal levels of PC and SM, perhaps due to increases in the de novo pathway for SM synthesis and decreases in SM turnover.

Animals↗
PubMed1996

In vivo 1H MRS choline: correlation with in vitro chemistry/histology.

We correlated the in vivo 1H Magnetic Resonance Spectroscopy (MRS) concentration of the choline peak (CHO) with in vitro chemical measures of choline-containing compounds and a histological grade of cellularity in 18 patients with neoplastic and infectious brain lesions. Gas-chromatography-mass-spectrometry (GCMS) was used to measure the concentrations of free choline (Cho), glycerophosphocholine (GPCho), phosphocholine (PCho) and phosphatidylcholine (PtdCho) from biopsies in the same area where MRS was performed. Cellular density, free Cho, PCho and GPCho were the strongest determinants of 1H MRS CHO while PtdCho was not. Just as the 1H MRS 2.0 peak reflects both the concentration of n-acetyl-l-aspartate and neuronal density, the 1H MRS 3.2 peak reflects the concentration of water-soluble choline-containing compounds and cellular density.

Brain↗
PubMed1996

Regulation of acetylcholine synthesis in the presence of hemicholinium mustard.

High affinity choline uptake (HACU) is a critical element in the synthetic pathway for acetylcholine (ACh), and is known to demonstrate activity-dependent regulation in vivo and in vitro. However, little is known about this important sodium-dependent transport protein at the biochemical level, and about the nature of its interaction with the ACh synthetic enzyme ChAT. Hemicholinium mustard (HCM), an irreversibly binding analog of hemicholinium-3 (HC3), was used to create a preparation with HACU that is completely inhibited in order to investigate the immediate source of Ch for ACh synthesis. Rat brain synaptosomes were pre-incubated with HCM and washed before transport incubations of increasing length (0-6 min) were carried out. The contribution of endogenous and extracellular (tracer) Ch to the ACh level was measured at each time point using a gas chromatography mass spectrometry (GCMS) system that allows quantitative measurement of endogenous (unlabelled; [2Ho]) Ch as well as tracer (deuterium-labelled; [2H4]) Ch. The hypothesis was that if an endogenous intraterminal Ch pool can be used for ACh synthesis, an increase in unlabelled ACh across time would be observed. In neither HCM-treated nor control synaptosomes was an increase observed in intraterminal (pellet) unlabelled ACh. To test the effects of high tissue demand, in other experiments synaptosomes were depolarized with addition of 40 mM KCl to the buffer after HCM treatment; again, no significant increase in intraterminal unlabelled ACh was observed across time. These experiments demonstrate that endogenous unlabelled Ch does not contribute to ACh synthesis, even when HACU is inactivated, and under conditions of high demand.

Acetylcholine↗
PubMed1996

Elevation of cerebrospinal fluid choline levels by nicotinamide involves the enzymatic formation of N1-methylnicotinamide in brain tissue.

Nicotinamide administration can elevate plasma and brain choline levels and produce a marginal increase in striatal acetylcholine levels in the rat. We now report that subcutaneous nicotinamide produces a substantial and long-lasting rise in cisternal cerebrospinal fluid (CSF) levels of choline in free-moving rats, possibly through the enzymatic formation of N1-methylnicotinamide (NMN) in brain. CSF choline levels peaked 2 hours after nicotinamide administration and were accompanied by increases in striatal, cortical, hippocampal and plasma choline levels. The enzymatic formation of [3H]NMN in rat brain was evaluated by incubating aliquots of rat brain cytosol with unlabelled nicotinamide and the methyl donor [3H]S-adenosylmethionine. High performance liquid chromatography and radiochemical detection demonstrated that [3H]NMN was specifically formed by a brain cytosolic enzyme. The production of [3H]NMN was dependent on exogenous nicotinamide and could be prevented by denaturing the cytosol. The metabolism of nicotinamide to NMN in rat brain may explain the rise in CSF choline levels since NMN, a quaternary amine, can inhibit choline transport at the choroid villus and reduce choline clearance.

Acetylcholine↗
PubMed1996

The influence of aging on whole body choline release and clearance.

We have confirmed that hypoxia elicits a substantial rise in blood choline levels in young adult rats. An intravenous infusion of tracer quantities of [2H4]-Ch, serial measurements of blood [2H0]-Ch and [2H4]-Ch, and a simple pharmacokinetic model were used to assess the bidirectional flux of choline between the central pool and peripheral pools before, during and after a period of imposed hypoxia, in rats ranging from 56 to 780 days of age. The results indicate that the age-dependence of the hypercholinemic response to hypoxia is predominantly due to an increase in the amount of choline released in response to hypoxia, and that changes in its clearance are relatively unimportant.

Aging↗
PubMed1996

Cholinergic control of cerebral blood flow in stroke, trauma and aging.

Enhancing the availability of endogenous acetylcholine by inhibition of cholinesterase with physostigmine, eptastigmine or soman at sub-toxic doses increases cerebral blood flow (CBF) and the response of this variable to changes in PaCO2. These effects are not correlated with metabolic activation, suggesting that the function of the cholinergic vasodilation is not merely to supply metabolic substrates. Since choline (Ch) can exchange between blood and the brain extracellular milieu the stage is set for possible feedback interactions between ACh synthesis and CBF. A negative feedback of CBF on ACh synthesis under conditions of a negative arteriovenous (A-V) difference for Ch across cerebral capillaries may contribute to stabilize GBF in ischemia. Eptastigmine and physostigmine significantly improve perfusion in experimental models of focal cerebral ischemia and traumatic brain injury respectively. During the short periods of time in which the A-V difference for Ch across the brain is positive, a positive feedback between cerebral free Ch and CBF may enhance the ability of the brain to recover Ch from the circulation for synthesis of membrane phospholipids. A loss of cholinergic cerebrovascular control may thus impair the survival of all cells within the CNS and contribute to the pathophysiology of dementia. Perhaps the view that the loss of cholinergic cells is the end point of Alzheimer's dementia could be modified to state that a cholinergic deficit may be the starting point of a decline in cerebral phospholipid turnover and cell membrane renewal that could lead to a generalized deterioration of cerebral function.

Acetylcholine↗
PubMed1996

In vivo proton magnetic resonance spectroscopy of the normal aging human brain.

The effect of age on brain metabolite concentrations was evaluated using localized proton magnetic resonance spectroscopy. This technique allows in vivo measurements of N-acetyl compounds (NA), total creatine (CR), choline-containing compounds (CHO), myo-inositol (MI), glutamate and glutamine (GLX), as well as the percentage of cerebrospinal fluid (CSF) and the brain water content within the brain region studied. Frontal gray matter and frontal white matter brain regions were examined in 36 normal healthy volunteers (19-78 years of age). Using a rigorous absolute quantitation method, with an external reference and atrophy correction, we found relatively stable concentrations of NA, a neuronal marker. In contrast, CR, CHO, MI, and the percentage of CSF increased in the gray matter with age. However, the brain water content decreased significantly with age (r = -0.72; p < 0.0001). No significant age-related changes in metabolite concentrations, CSF or brain water content were observed in the white matter regions. These findings demonstrate that biochemical alterations are associated with aging in the frontal gray matter. There might be an increase in the brain density as indicated by increased metabolite concentrations and decreased brain water content with aging.

Adult↗
PubMed1995

Effects of hypoxia and hypercapnia on whole body release and clearance of choline.

We have recently demonstrated an increase in arterial blood choline (Ch) concentration in normocapnic hypoxia and apnea. This could be due to enhanced release of free Ch from tissues, to decreased Ch clearance, or both. The present investigations was undertaken to determine the individual contributions of these processes to the whole body balance of Ch, using an intravenous infusion of tracer quantities of [2H4]Ch to assess the bidirectional flux between the central pool and peripheral pools. Rats were subjected to normocapnic hypoxia or hypercapnia; release and clearance of Ch were calculated using a simple model. Hypoxia caused an increase in Ch production and a decrease in Ch clearance. At severe levels of hypoxia, Ch clearance was essentially zero. Hypoxia was attended by progressive acidosis that was related to the magnitude of the hypoxic challenge. To determine the possible effects of acidosis per se on the variables measured, respiratory acidosis with normoxia was provoked by controlled administration of CO2. Under these conditions, parallel decreases in Ch production and Ch clearance were observed.

Acidosis↗
PubMed1995

Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation.

Patients receiving long-term total parenteral nutrition (TPN) develop hepatic steatosis as a complication. Our previous studies have shown this to be caused, at least in part, by choline deficiency. We studied four patients (1 man, 3 women) aged 50 +/- 13 years who had low plasma-free choline concentrations 4.8 +/- 1.7 (normal, 11.4 +/- 3.7 nmol/mL). The patients had received TPN for 9.7 +/- 4.7 years. They received parenteral nutrition solutions containing choline chloride (1 to 4 g/d) for 6 weeks. Abdominal computed tomography (CT) was performed at baseline, biweekly during the choline supplementation, and 4 weeks after discontinuation of choline. During choline administration, the plasma-free choline concentration increased into the normal range within 1 week in all four patients and remained at or above the normal range for all 6 weeks, but decreased back to baseline when choline supplementation was discontinued. Hepatic steatosis resolved completely, as estimated by CT. Liver density increased from -14.2 +/- 22.3 Hounsfield units (HU) to 8.4 +/- 10.3 HU at week 2 (P = .002); 9.6 +/- 10.7 HU at week 4 and 13.1 +/- 7.3 HU at week 6, as determined by the liver-spleen CT number difference obtained by the subtraction of the average spleen CT number (in HU) from the average liver CT number. This improvement continued up to 4 weeks after choline supplementation (13.8 +/- 2.8 HU). Hepatic steatosis was shown to have recurred in one patient after 10 weeks of return to choline-free parenteral nutrition. The hepatic steatosis associated with parenteral nutrition can be ameliorated, and possibly prevented, with choline supplementation. Therefore, choline may be an essential nutrient for patients who require long-term parenteral nutrition.

Adult↗