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Biomedical subjects

Jane M Bell

Publications and source records attributed to Jane M Bell.

17 recordsLinked to original sources
PubMed2006

Upregulated liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet.

We quantified incorporation rates of plasma-derived alpha-linolenic acid (alpha-LNA, 18:3n-3) into "stable" liver lipids and the conversion rate of alpha-LNA to docosahexaenoic acid (DHA, 22:6n-3) in male rats fed, after weaning, an n-3 PUFA-adequate diet (4.6% alpha-LNA, no DHA) or an n-3 PUFA-deficient diet (0.2% alpha-LNA, no DHA) for 15 weeks. Unanesthetized rats were infused intravenously with [1-14C]alpha-LNA, and arterial plasma was sampled until the liver was microwaved at 5 min. Unlabeled alpha-LNA and DHA concentrations in arterial plasma and liver were reduced >90% by deprivation, whereas unlabeled arachidonic acid (20:4n-6) and docosapentaenoic acid (22:5n-6) concentrations were increased. Deprivation did not change alpha-LNA incorporation coefficients into stable liver lipids but increased synthesis-incorporation coefficients of DHA from alpha-LNA by 6.6-, 8.4-, and 2.3-fold in triacylglycerol, phospholipid, and cholesteryl ester, respectively. Assuming that synthesized-incorporated DHA eventually would be secreted within lipoproteins, calculated liver DHA secretion rates equaled 2.19 and 0.82 micromol/day in the n-3 PUFA-adequate and -deprived rats, respectively. These rates exceed the published rates of brain DHA consumption by 6- and 10-fold, respectively, and should be sufficient to maintain normal and reduced brain DHA concentrations, respectively, in the two dietary conditions.

Animals↗
PubMed2006

Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats.

The extent to which the adult brain can derive some of its arachidonic acid (AA) through internalized synthesis from linoleic acid (LA) is uncertain. Thus, we determined for plasma-derived LA in vivo rates for brain incorporation, beta-oxidation, and conversion to AA. Adult male unanesthetized rats, reared on a diet enriched in LA but low in AA, were infused intravenously for 5 min with [1-(14)C]LA. Timed arterial samples were collected until the animals were killed at 5 min and the brain was removed after microwaving. Within plasma lipids, >96% of radioactivity was in the form of unchanged [1-(14)C]LA, but [(14)C]AA was insignificant (<0.2%). Eighty-six percent of brain radioactivity at 5 min was present as beta-oxidation products, whereas the remainder was mainly in 'stable' phospholipid or triglyceride as LA or AA (11 and <1%, respectively). Unesterified unlabeled LA rapidly enters brain from plasma, but its incorporation into brain total phospholipid and triglyceride, in the form of synthesized AA, is <1% of the amount that enters the brain. Thus, in rats fed even a diet containing low amounts of AA, the LA that enters brain is largely beta-oxidized, and is not a major source of AA in brain.

Animals↗
PubMed2006

Low liver conversion rate of alpha-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet.

We quantified the rates of incorporation of alpha-linolenic acid (alpha-LNA; 18:3n-3) into "stable" lipids (triacylglycerol, phospholipid, cholesteryl ester) and the rate of conversion of alpha-LNA to docosahexaenoic acid (DHA; 22: 6n-3) in the liver of awake male rats on a high-DHA-containing diet after a 5-min intravenous infusion of [1-(14)C]alpha-LNA. At 5 min, 72.7% of liver radioactivity (excluding unesterified fatty acid radioactivity) was in stable lipids, with the remainder in the aqueous compartment. Using our measured specific activity of liver alpha-LNA-CoA, in the form of the dilution coefficient lambda(alpha-LNA-CoA), we calculated incorporation rates of unesterified alpha-LNA into liver triacylglycerol, phospholipid, and cholesteryl ester as 2,401, 749, and 9.6 nmol/s/g x 10(-4), respectively, corresponding to turnover rates of 3.2, 8.7, and 2.9%/min and half-lives of 8-24 min. A lower limit for the DHA synthesis rate from alpha-LNA equaled 15.8 nmol/s/g x 10(-4) (0.5% of the net in corporation rate). Thus, in rats on a high-DHA-containing diet, rates of beta-oxidation and esterification of alpha-LNA into stable liver lipids are high, whereas its conversion to DHA is comparatively low and insufficient to supply significant DHA to the brain. High incorporation and turnover rates likely reflect a high secretion rate by liver of stable lipids within very low density lipoproteins.

Acyl Coenzyme A↗
PubMed2006

Resting and arecoline-stimulated brain metabolism and signaling involving arachidonic acid are altered in the cyclooxygenase-2 knockout mouse.

Abstract Studies were performed to determine if cyclooxygenase (COX)-2 regulates muscarinic receptor-initiated signaling involving brain phospholipase A2 (PLA2) activation and arachidonic acid (AA; 20 : 4n-6) release. AA incorporation coefficients, k* (brain [1-14C]AA radioactivity/integrated plasma radioactivity), representing this signaling, were measured following the intravenous injection of [1-14C]AA using quantitative autoradiography, in each of 81 brain regions in unanesthetized COX-2 knockout (COX-2(-/-)) and wild-type (COX-2(+/+)) mice. Mice were administered arecoline (30 mg/kg i.p.), a non-specific muscarinic receptor agonist, or saline i.p. (baseline control). At baseline, COX-2(-/-) compared with COX-2(+/+) mice had widespread and significant elevations of k*. Arecoline increased k* significantly in COX-2(+/+) mice compared with saline controls in 72 of 81 brain regions, but had no significant effect on k* in any region in COX-2(-/-) mice. These findings, when related to net incorporation rates of AA from brain into plasma, demonstrate enhanced baseline brain metabolic loss of AA in COX-2(-/-) compared with COX-2(+/+) mice, and an absence of a normal k* response to muscarinic receptor activation. This response likely reflects selective COX-2-mediated conversion of PLA2-released AA to prostanoids.

Animals↗
PubMed2006

Infection in renal transplantation: a case of acute Q fever.

Acute Q fever is a zoonotic infection that most often occurs as an asymptomatic or very mild febrile illness. A small percentage of patients go on to develop chronic Q fever months or even years after the acute infection. We present a case of acute Q fever occurring in a renal transplant recipient who developed severe systemic disease with renal involvement. Serological diagnosis was carried out, and the patient was treated successfully with antibiotic therapy. This case emphasizes Q fever as one of the atypical infectious agents that may have serious consequences in immunocompromised renal transplant recipients and reminds us of the importance of careful inquiry regarding personal or occupational activities that could lead to exposure to specific organisms.

Humans↗
PubMed2005

Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats.

It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDAR-mediated activation of phospholipase A2 (PLA2), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptor-mediated activation of PLA2. In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA2 activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.

Animals↗
PubMed2005

One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats.

Male rat pups at weaning (21 days of age) were subjected to a diet deficient or adequate in n-3 polyunsaturated fatty acids (n-3 PUFAs) for 15 weeks. Performance on tests of locomotor activity, depression, and aggression was measured in that order during the ensuing 3 weeks, after which brain lipid composition was determined. In the n-3 PUFA-deprived rats, compared with n-3 PUFA-adequate rats, docosahexaenoic acid (22:6n-3) in brain phospholipid was reduced by 36% and docosapentaenoic acid (22:5n-6) was elevated by 90%, whereas brain phospholipid concentrations were unchanged. N-3 PUFA-deprived rats had a significantly increased (P = 0.03) score on the Porsolt forced-swim test for depression, and increased blocking time (P = 0.03) and blocking number (P = 0.04) scores (uncorrected for multiple comparisons) on the isolation-induced resident-intruder test for aggression. Large effect sizes (d > 0.8) were found on the depression score and on the blocking time score of the aggression test. Scores on the open-field test for locomotor activity did not differ significantly between groups, and had only small to medium effect sizes. This single-generational n-3 PUFA-deprived rat model, which demonstrated significant changes in brain lipid composition and in test scores for depression and aggression, may be useful for elucidating the contribution of disturbed brain PUFA metabolism to human depression, aggression, and bipolar disorder.

Aggression↗
PubMed2005

Microarray analysis of rat brain gene expression after chronic administration of sodium valproate.

Valproic acid has been used to treat mania and bipolar disorder, but its mechanism of action is not agreed on. We used rat genome U34A Affymetrix oligonucleotide microarrays, containing 8799 known probesets, to determine the effect of 30-day daily intraperitoneal administration of valproate (200mg/kg) on rat brain gene expression. We found 87 down-regulated genes and 34 up-regulated genes of at least a 1.4-fold change in valproate-treated compared to control rats. The experiments were done on five independent samples for each group, each in duplicate. The genes affected are known to be involved in a variety of pathways, including synaptic transmission, ion channels and transport, G-protein signaling, lipid, glucose and amino-acid metabolism, transcriptional and translational regulation, phosphoinositol cycle, protein kinases and phosphatases, and apoptosis. Our results suggest that the therapeutic effect of valproate may involve the modulation of multiple signaling pathways.

Animals↗
PubMed2005

Chronic lithium administration to rats selectively modifies 5-HT2A/2C receptor-mediated brain signaling via arachidonic acid.

The effects of chronic lithium administration on regional brain incorporation coefficients k* of arachidonic acid (AA), a marker of phospholipase A2 (PLA2) activation, were determined in unanesthetized rats administered i.p. saline or 1 mg/kg i.p. (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A/2C receptor agonist. After injecting [1-(14)C]AA intravenously, k* (brain radioactivity/integrated plasma radioactivity) was measured in each of 94 brain regions by quantitative autoradiography. Studies were performed in rats fed a LiCl or a control diet for 6 weeks. In the control diet rats, DOI significantly increased k* in widespread brain areas containing 5-HT2A/2C receptors. In the LiCl-fed rats, the significant positive k* response to DOI did not differ from that in control diet rats in most brain regions, except in auditory and visual areas, where the response was absent. LiCl did not change the head turning response to DOI seen in control rats. In summary, LiCl feeding blocked PLA2-mediated signal involving AA in response to DOI in visual and auditory regions, but not generally elsewhere. These selective effects may be related to lithium's therapeutic efficacy in patients with bipolar disorder, particularly its ability to ameliorate hallucinations in that disease.

Amphetamines↗
PubMed2005

Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid.

We studied the effect of lithium chloride on dopaminergic neurotransmission via D2-like receptors coupled to phospholipase A2 (PLA2). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid (AA, 20:4 n-6), regional PLA2 activation was imaged by measuring regional incorporation coefficients k* of AA (brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D2-like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D2-like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate-putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate-putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D2-like receptor signaling involving PLA2 and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.

Animals↗
PubMed2005

alpha-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid.

Adult male unanesthetized rats, reared on a diet enriched in both alpha-linolenic acid (alpha-LNA) and docosahexaenoic acid (DHA), were infused intravenously for 5 min with [1-(14)C]alpha-LNA. Timed arterial samples were collected until the animals were killed at 5 min and the brain was removed after microwaving. Plasma and brain lipid concentrations and radioactivities were measured. Within plasma lipids, > 99% of radioactivity was in the form of unchanged [1-(14)C]alpha-LNA. Eighty-six per cent of brain radioactivity at 5 min was present as beta-oxidation products, whereas the remainder was mainly in 'stable' phospholipid or triglyceride as alpha-LNA or DHA. Equations derived from kinetic modeling demonstrated that unesterified unlabeled alpha-LNA rapidly enters brain from plasma, but that its incorporation into brain phospholipid and triglyceride, as in the form of synthesized DHA, is < or = 0.2% of the amount that enters the brain. Thus, in rats fed a diet containing large amounts of both alpha-LNA and DHA, the alpha-LNA that enters brain from plasma largely undergoes beta-oxidation, and is not an appreciable source of DHA within brain phospholipids.

Animals↗
PubMed2004

Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain.

BACKGROUND: Carbamazepine is a mood stabilizer used as monotherapy or as an adjunct to lithium in the treatment of acute mania or the prophylaxis of bipolar disorder. Based on evidence that lithium and valproate, other mood stabilizers, reduce brain arachidonic acid turnover and its conversion via cyclooxygenase to prostaglandin E(2) in rat brain, one possibility is that carbamazepine also targets the arachidonic acid cascade. METHODS: To test this hypothesis, carbamazepine was administered to rats by intraperitoneal injection at a daily dose of 25 mg/kg for 30 days. RESULTS: Carbamazepine decreased brain phospholipase A(2) activity and cytosolic phospholipase A(2) protein and messenger RNA levels without changing significantly protein and activity levels of calcium-independent phospholipase A(2) or secretory phospholipase A(2). Cyclooxygenase activity was decreased in carbamazepine-treated rats without any change in cyclooxygenase-1 or cyclooxygenase-2 protein levels. Brain prostaglandin E(2) concentration also was reduced. The protein levels of other arachidonic acid metabolizing enzymes, 5-lipoxygenase and cytochrome P450 epoxygenase, were not significantly changed nor was the brain concentration of the 5-lipoxygenase product leukotriene B(4). CONCLUSIONS: Carbamazepine downregulates cytosolic phospholipase A(2)-mediated release of arachidonic acid and its subsequent conversion to prostaglandin E(2) by cyclooxygenase. These effects may contribute to its therapeutic actions in bipolar disorder.

Analgesics, Non-Narcotic↗
PubMed2004

Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids.

Male rat pups (21 days old) were placed on a diet deficient in n-3 polyunsaturated fatty acids (PUFAs) or on an n-3 PUFA adequate diet containing alpha-linolenic acid (alpha-LNA; 18 : 3n-3). After 15 weeks on a diet, [4,5-3H]docosahexaenoic acid (DHA; 22 : 6n-3) was injected into the right lateral cerebral ventricle, and the rats were killed at fixed times over a period of 60 days. Compared with the adequate diet, 15 weeks of n-3 PUFA deprivation reduced plasma DHA by 89% and brain DHA by 37%; these DHA concentrations did not change thereafter. In the n-3 PUFA adequate rats, DHA loss half-lives, calculated by plotting log10 (DHA radioactivity) against time after tracer injection, equaled 33 days in total brain phospholipid, 23 days in phosphatidylcholine, 32 days in phosphatidylethanolamine, 24 days in phosphatidylinositol and 58 days in phosphatidylserine; all had a decay slope significantly greater than 0 (p < 0.05). In the n-3 PUFA deprived rats, these half-lives were prolonged twofold or greater, and calculated rates of DHA loss from brain, Jout, were reduced. Mechanisms must exist in the adult rat brain to minimize DHA metabolic loss, and to do so even more effectively in the face of reduced n-3 PUFA availability for only 15 weeks.

Analysis of Variance↗
PubMed2004

Renal biopsy in patients aged 80 years and older.

BACKGROUND: Renal abnormalities discovered in the elderly have often been considered the result of aging, hypertensive changes, and so on. Recently, we noted an increase in renal biopsies among patients 80 years and older. This is a demographic subset with little or no previously reported clinicopathologic correlation between renal biopsy findings and clinical syndromes. METHODS: We examined our files for all biopsies performed in patients 80 years and older and report 100 patients of a total of 3,227 biopsies (3.1%) from multiple referral centers. RESULTS: Significant differences in the disease spectrum were found in the very elderly, not only compared with studies of adults and children, but also compared with studies of renal biopsies in the elderly. Crescentic glomerulonephritis was the most common diagnosis in patients aged 80 years and older. Although membranous glomerulopathy is the most common cause of idiopathic nephrotic syndrome in studies of the elderly (23% to 38%) and adults (35% to 40%), only 15% of our patients aged 80 years and older with idiopathic nephrotic syndrome had membranous nephropathy. Overall, at least 40 of 100 biopsies performed on the very elderly showed a renal condition that would benefit from therapeutic intervention, and the remaining biopsies provided at least prognostic information and/or ruled out a more severe condition, preventing potentially harmful empiric therapy. CONCLUSION: As the population ages, more elderly patients are undergoing diagnostic renal biopsies. This study emphasizes the variance between clinical presentation and expected diagnosis compared with actual biopsy findings in patients aged 80 years and older.

Aged↗
PubMed2003

Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats.

Studies were performed to determine if the reported 'proconvulsant' action of lithium in rats given cholinergic drugs is related to receptor-initiated phospholipase A2 signaling via arachidonic acid. Regional brain incorporation coefficients k* of intravenously injected [1-14C]arachidonic acid, which represent this signaling, were measured by quantitative autoradiography in unanesthetized rats at baseline and following administration of subconvulsant doses of the cholinergic muscarinic agonist, arecoline. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, the mean baseline values of k* in brain auditory and visual areas were significantly greater than in rats fed control diet. Arecoline at doses of 2 and 5 mg/kg intraperitoneally increased k* in widespread brain areas in rats fed the control diet as well as the LiCl diet. However, the arecoline-induced increments often were significantly greater in the LiCl-fed than in the control diet-fed rats. Lithium's elevation of baseline k* in auditory and visual regions may correspond to its ability in humans to increase auditory and visual evoked responses. Additionally, its augmentation of the k* responses to arecoline may underlie its reported 'proconvulsant' action with cholinergic drugs, as arachidonic acid and its eicosanoid metabolites can increase neuronal excitability and seizure propagation.

Animals↗
PubMed2002

Analysis of gene expression with cDNA microarrays in rat brain after 7 and 42 days of oral lithium administration.

The gene expression profile in rat brain was examined using microarrays in rats fed lithium chloride for 7 days (subacute) or 42 days (chronic). Brain lithium concentrations were 0.39 mM and 0.79 mM (therapeutically relevant), at 7 and 42 days, respectively. Of the 4132 genes represented in the microarrays, 25 genes were downregulated by at least twofold and none was upregulated after 7 days of treatment. Expression of 50 genes was downregulated by at least two-fold at 42 days, without any being upregulated. Lithium treatment for 7 days did not affect at a measurable extent expression of 37 of the 50 genes that were downregulated at 42 days. Genes whose expression was changed at 42 days coded for a number of receptors, protein kinases, transcription and translation factors, markers of energy metabolism, and signal transduction. Thus, chronic lithium at a therapeutically relevant concentration reduced expression of a large number of genes involved in multiple signaling and other pathways, without increasing expression at a comparable extent.

Administration, Oral↗