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Biomedical subjects

G J Moore

Publications and source records attributed to G J Moore.

At least 37 records · Page 2Linked to original sources
PubMed1999

Lithium at 50: have the neuroprotective effects of this unique cation been overlooked?

Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted.

Animals↗
PubMed1999

Design and synthesis of a potent cyclic analogue of the myelin basic protein epitope MBP72-85: importance of the Ala81 carboxyl group and of a cyclic conformation for induction of experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP), such as guinea pig sequence MBP72-85. Two linear and one cyclic analogues based on MBP72-85 have been synthesized and evaluated for EAE induction in Lewis rats. The linear peptide Gln1-Lys2-Ser3-Gln4-Arg5-Ser6-Gln7-+ ++Asp8-Glu9-Asn10-Pro11-Val12 (1) was found to induce EAE, while substitution of the Asp residue at position 8 with Ala resulted in an analogue (2) which suppressed the induction of EAE by its parent peptide. Nuclear magnetic resonance studies of analogue 1 in dimethyl sulfoxide (DMSO) using TOCSY/ROESY techniques revealed a head-to-tail intramolecular interaction (ROE connectivity between betaVal12-gammaGln1), indicating a pseudocyclic conformation for the immunogenic peptide 1. A conformational model was developed using NMR constraints and molecular dynamics. Based on this model, a novel amide-linked cyclic analogue has been designed and synthesized by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9, respectively, of linear analogue 1. The cyclic analogue (3) had similar activity to the linear peptide 1, and the EAE effects induced by cyclic analogue 3 were completely suppressed by co-injection with the Ala81-substituted analogue 2 in Lewis rats. The similar potencies of analogues 1 and 3 support the proposed cyclic comformation suggested for analogue 1 from NMR studies and computer modeling and provides the basis for designing more potent molecules with improved properties such as increased resistance to degradation.15 The present findings suggest that a cyclic conformation for the MBP72-85 epitope positions the carboxyl group of Asp81 correctly and presumably other side groups of the peptide such as Arg78 in a manner which enables functional binding of the trimolecular complex MHC-peptide-T cell receptor resulting in EAE.

Alanine↗
PubMed1999

Evidence of altered energy metabolism in autistic children.

1. In this pilot study, the authors investigated the hypotheses there are increased concentrations of lactate in brain and plasma and reduced brain concentrations of N-acetyl-aspartate (NAA) in autistic children. 2. NAA and lactate levels in the frontal lobe, temporal lobe and the cerebellum of 9 autistic children were compared to 5 sibling controls using MRS. Plasma lactate levels were measured in 15 autistic children compared to 15 children with epilepsy. 3. Preliminary results show lower levels of NAA cerebellum in autistic children (p = 0.043). Lactate was detected in the frontal lobe in one autistic boy, but was not detected any of the other autistic subjects or siblings. 4. Plasma lactate levels were higher in the 15 autistic children compared to 15 children with epilepsy (p = 0.0003). 5. Higher plasma lactate in the autistic group is consistent with metabolic changes in some autistic children. The findings of altered brain NAA and lactate in autistic children suggest that MRS may be useful characterizing regional neurochemical and metabolic abnormalities in autistic children.

Adolescent↗
PubMed1999

Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness.

OBJECTIVE: The most widely accepted hypothesis regarding the mechanism underlying lithium's therapeutic efficacy in manic-depressive illness (bipolar affective disorder) is the inositol depletion hypothesis, which posits that lithium produces a lowering of myo-inositol in critical areas of the brain and the effect is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were investigated longitudinally in 12 adult depressed patients with manic-depressive illness. METHOD: Medication washout (minimum 2 weeks) and lithium administration were conducted in a blinded manner. Regional brain myo-inositol levels were measured by means of quantitative proton magnetic resonance spectroscopy at three time points: at baseline and after acute (5-7 days) and chronic (3-4 weeks) lithium administration. RESULTS: Significant decreases (approximately 30%) in myoinositol levels were observed in the right frontal lobe after short-term administration, and these decreases persisted with chronic treatment. The severity of depression measured by the Hamilton Depression Rating Scale also decreased significantly over the study. CONCLUSIONS: This study demonstrates that lithium administration does reduce myo-inositol levels in the right frontal lobe of patients with manic-depressive illness. However, the acute myo-inositol reduction occurs at a time when the patient's clinical state is clearly unchanged. Thus, the short-term reduction of myo-inositol per se is not associated with therapeutic response and does not support the inositol depletion hypothesis as originally posited. The hypothesis that a short-term lowering of myo inositol results in a cascade of secondary signaling and gene expression changes in the CNS that are ultimately associated with lithium's therapeutic efficacy is under investigation.

Adult↗
PubMed1999

Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications.

In an attempt to find the key to reducing the excessive morbidity and mortality seen with mood disorders, our laboratory has been extensively investigating lithium's mechanisms of action in an integrated series of clinical and preclinical studies. We have found that the chronic administration of the 2 structurally highly dissimilar agents, lithium and valproate, brings about a strikingly similar reduction in protein kinase C (PKC) alpha and epsilon isozymes in rat frontal cortex and hippocampus. In view of PKC's critical role in regulating neuronal excitability and neurotransmitter release, we have postulated that PKC inhibition may have antimanic efficacy. In a small study, we have found that tamoxifen (which, in addition to its estrogen receptor blockade, is also a PKC inhibitor) has marked antimanic efficacy. These exciting preliminary results suggest that PKC inhibitors may represent a novel class of improved therapeutic agents for bipolar disorder, and this is under further investigation. The beneficial effects of mood stabilizers require a lag period for onset of action and are generally not immediately reversed upon drug discontinuation; such patterns of effects suggest alterations at the genomic level. We have therefore undertaken a series of studies to investigate the effects of these agents on the AP-1 family of transcription factors and have found that both drugs increase AP-1 DNA binding activity in areas of rodent brain ex vivo and in human neuronal cells in culture. Both treatments also increase the expression of a reporter gene driven by an AP-1-containing promoter, and mutations in the AP-1 sites of the reporter gene promoter markedly attenuate these effects. Both treatments also increase the expression of several endogenous proteins, whose genes are known to be regulated by AP-1. Although the precise mechanisms have not been fully elucidated, preliminary results suggest that these effects may be mediated, in part, by mitogen-activating protein kinases and glycogen synthase kinase 3beta. We have also utilized mRNA reverse transcription-polymerase chain reaction (RT-PCR) differential display to identify concordant changes in gene expression induced by the chronic administration of both lithium and valproate. We have identified concordant changes in a number of cDNA bands by both lithium and valproate. Cloning and characterizing of these genes is currently underway. The identification of the functions of these genes offers the potential not only for improved therapeutics for reducing the morbidity and mortality associated with mood disorders, but may also provide important clues about the underlying pathophysiology.

Bipolar Disorder↗
PubMed1999

An extended three-stage treatment to correct a severe skeletal and dental discrepancy.

A report of a case of extended treatment of a patient with severe mandibular retrognathism and an Angle Class II division 1 malocclusion. Initial fixed appliance treatment reduced incisor protrusion. A second phase utilising a Teuscher appliance achieved improved facial and dental relations through excellent mandibular growth. A third phase of fixed Edgewise treatment finalised dental relations.

Cephalometry↗
PubMed1998

Design and synthesis of small semi-mimetic peptides with immunomodulatory activity based on myelin basic protein (MBP).

Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). Analogs of these disease-associated peptides have been identified with disease progression upon coimmunization. Usage of peptides, with disease-specific immunomodulatory capacity in vivo is limited, however, due to their sensitivity to proteolytic enzymes. Alternative approaches include the development of mimetic molecules which maintain the biological function of an original peptide, yet are stable and able to elicit their response in pharmacological quantities. A novel technique was employed to design a series of semi-mimetic peptides, based on the guinea pig MBP72-85 peptide used to induce EAE in Lewis rats. We used isonipecotic (iNip) and aminocaproic (Acp) acids as templates. Acp-MBP72-85 peptide derived analogues were effective in inducing EAE compared to iNip-peptide analogues which were ineffective at 350 micrograms. These findings suggest that the design and synthesis of semi-mimetic peptide molecules with immunomodulatory potential is possible and that eventually these molecules may form the basis for the development of novel and more effective disease-specific therapeutic agents.

Amino Acid Sequence↗
PubMed1998

Proton magnetic resonance spectroscopy in pediatric neuroradiology.

This review reports on recent developments in proton magnetic resonance spectroscopy (MRS) and its potential clinical application in pediatric neuroradiology. An overview of the essential principles of the methodology including pulse sequences and their practical application is provided. Each of the major neurochemical compounds found in the pediatric brain and its potential clinical significance is reviewed. Special consideration is given to issues of quantitation and maturational changes in neurochemistry which are unique to the developing brain. Examples of potential clinical applications of proton MRS are given in a brief case report format. Finally, the direction of likely future developments and the need for further investigation of proton MRS in pediatric populations is discussed. This review will provide the reader with a basic foundation for deciding when a proton MRS exam may be helpful for diagnosis and for the interpretation of proton MRS findings in the pediatric neuroradiology setting.

Brain Chemistry↗
PubMed1998

Case study: caudate glutamatergic changes with paroxetine therapy for pediatric obsessive-compulsive disorder.

Neurobiological models for obsessive-compulsive disorder (OCD) have consistently implicated the caudate nucleus in the pathophysiology of this disorder. OCD symptoms improved markedly in a 9-year-old boy treated with paroxetine, a selective serotonin reuptake inhibitor, for whom pre/posttreatment proton magnetic resonance spectroscopic examinations were acquired to assess the relationship between neurochemical profile in the caudate nucleus, symptom severity, and treatment with paroxetine. Striking changes of the glutamate resonance in the caudate were observed after 12 weeks of paroxetine treatment. These data provide further support for glutamatergic-serotonin pathway involvement in the caudate nucleus of OCD patients.

Caudate Nucleus↗
PubMed1998

Proton magnetic resonance spectroscopy in children with Sturge-Weber syndrome.

Quantitative proton magnetic resonance spectroscopy was performed on six children with Sturge-Weber syndrome following gadolinium enhanced magnetic resonance imaging (MRI). MRI revealed only unilateral involvement in all cases. The mean concentration (mmol/kg wet weight) of the neuronal marker N-acetyl-aspartate was significantly reduced by 37% in the ipsilateral gadolinium enhanced volume of interest compared to a similarly placed contralateral volume of interest (5.39 +/- 1.70 [SD] vs 8.50 +/- 1.14, P < .005, two-tailed paired Student's t-test). Decreased N-acetyl-aspartate in the ipsilateral volume of interest was observed in all patients studied. No significant differences were found in the concentrations of creatine/phosphocreatine or choline compounds between the ipsilateral and contralateral volumes of interest. These findings give possible new insight into the pathophysiology of this disease and suggest that quantitative proton magnetic resonance spectroscopy may be useful for the early characterization and monitoring of neuronal dysfunction or loss in infants and children with Sturge-Weber syndrome.

Adolescent↗
PubMed1997

Two-dimensional proton chemical-shift imaging of human muscle metabolites.

Large lipid signals and strong susceptibility gradients introduced by muscle-bone interfaces represent major technical challenges for in vivo proton MRS of human muscle. Here, the demonstration of two-dimensional proton chemical-shift imaging of human muscle metabolites is presented. This technique utilizes a chemical-shift-selective method for water and lipid suppression and automatic shimming for optimal homogeneity of the magnetic field. The 2D1H CSI technique described facilitates the acquisition of high-spatial-resolution spectra, and allows one to acquire data from multiple muscle groups in a single experiment. A preliminary investigation utilizing this technique in healthy adult males (n = 4) revealed a highly significant difference in the ratio of the creatine to trimethylamine resonance between the fast and slow twitch muscle groups examined. The technique is robust, can be implemented on a commercial scanner with relative ease, and should prove to be a useful tool for both clinical and basic investigators.

Adult↗
PubMed1997

Conformational analysis of the thrombin receptor agonist peptides SFLLR and SFLLR-NH2 by NMR: evidence for a cyclic bioactive conformation.

The conformational properties of the pentapeptide Ser-Phe-Leu-Leu-Arg (P5), a human thrombin receptor-derived sequence forming part of a tethered ligand which activates the thrombin receptor, and its more active amide derivative Ser-Phe-Leu-Leu-Arg-NH2 (P5-NH2), have been studied by proton NMR spectroscopy in dimethylsulfoxide. Measurements of nuclear Overhauser effects, performed using two-dimensional rotating frame nuclear Overhauser (ROESY) and one-dimensional nuclear Overhauser enhancement (NOE) spectroscopy, revealed that P5 exists mainly in an extended conformation. However, proton-proton 1D-NOEs between Phe C alpha H and Ser C alpha H Leu3 C alpha H and Leu3 NH, and Leu4 C alpha H and Leu4 NH, as well as between the Ser and Arg sidechains, also implicated a minor conformer for P5 having a curved backbone and a near-cyclic structure. In contrast to P5, measurements of NOEs and ROEs for P5-NH2 revealed a more stabilized cyclic structure which may account for its higher biological potency. Thus strong interresidue sequential NH (i)-NH (i + 1) interactions, as well as C-terminal carboxamide to N-terminal side-chain interactions, i.e., Arg CONH2 to Phe ring and Arg CONH2 to Ser C alpha/C beta beta', observed at lower levels of the ROESY spectrum, supported a curved backbone structure for SFLLR-NH2. Since the higher potency P5-NH2 analogue adopts predominantly a cyclic structure, a cyclic bioactive conformation for thrombin receptor agonist peptides is suggested.

Amino Acid Sequence↗
PubMed1996

Quality of life outcomes after primary radiotherapy for squamous cell carcinoma of the base of tongue.

PURPOSE: To determine quality of life functional outcome after primary radiotherapy for carcinoma of the base of tongue. METHODS AND MATERIALS: At the University of Florida, essentially all patients with squamous cell carcinoma of the base of tongue are treated with primary continuous-course, external-beam radiotherapy alone or followed by a neck dissection. Fifty-three patients who remained continuously free of disease at 2 to 23 years were eligible to participate in an assessment of the posttreatment quality of their lives. Three patients could not be located for quality of life assessment, and one patient refused to participate, leaving 49 evaluable patients. Radiotherapy doses were 60 to 75 Gy in once daily fractions, or 74 to 79 Gy in twice daily fractions. The subjective Performance Status Scale for Head and Neck Cancer, which assigns a functional score ranging from 0 to 100, was completed by each of the patients during routine follow-up appointments. The scale measures ability to eat in public, understandability of speech, and normalcy of diet. RESULTS: Patients treated with external-beam radiotherapy alone had excellent results with regard to eating in public though scores showed a decline as T stage increased (average scores were T1: 90.6%; T2: 88.1%; T3: 82.8%; T4: 75.0%). Results for understandability of speech were T1: 93.75%; T2: 100%; T3: 82.8%; and T4: 87.5%. Fixation of the tongue at diagnosis was not a predictor of poor function. Normalcy of diet scores likewise decreased with increasing T stage: T1: 93.8%; T2: 89.5%; T3: 71.3%; T4: 60.0%. The addition of a neck dissection had no impact on the functional outcomes that were evaluated. Functional results did not deteriorate with prolonged follow-up of more than 5 years. Results were compared with those from the literature for patients treated by surgery plus postoperative radiotherapy or external-beam irradiation plus interstitial 192Ir implant. The functional results of high-dose external-beam irradiation alone in the present series were similar to those reported after external plus interstitial irradiation. The functional results after both types of radiation treatment were superior to results for patients who underwent surgery. CONCLUSIONS: Functional outcomes after external-beam radiotherapy were similar to those after external-beam plus 192Ir implant, and were superior to the results of surgical resection. Planned postradiotherapy neck dissection did not affect the analyzed functional endpoints. Function appeared to be stable by 5 years without subsequent change.

Adult↗
PubMed1996

Synthesis and contractile activities of cyclic thrombin receptor-derived peptide analogues with a Phe-Leu-Leu-Arg motif: importance of the Phe/Arg relative conformation and the primary amino group for activity.

Based on the minimal peptide sequence (Phe-Leu-Leu-Arg) that has been found to exhibit biological activity in a gastric smooth muscle contractile assay for thrombin receptor-activating peptides, the cyclic peptide analogues cyclo(Phe-Leu-Leu-Arg-Acp) (1), cyclo(Phe-Leu-Leu-Arg-epsilon Lys) (2), and cyclo(Phe-Leu-Leu-Arg-Gly) (3) have been synthesized by the solid-phase method using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoroborate or 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate as cyclization reagents. The contractile activities of compounds 1-3 have been compared with that of the linear thrombin receptor-activating peptide (TRAP) Ser-Phe-Leu-Leu-Arg-NH2 (compound 4) using a gastric smooth muscle strip assay. Compound 2, wherein the epsilon-amino group of lysine was coupled to the alpha-carboxyl of arginine, exhibited a contractile activity comparable to that of the linear TRAP, compound 4. However compound 1, wherein the aminocaproic linker group yielded a ring size the same as for compound 2 but without a primary amino group, exhibited a contractile activity 600-1000-fold lower than compounds 2 and 4. Compound 3, which exhibited partial agonist activity, was about 100-fold less potent than either compound 2 or 4. NMR spectroscopy of compound 2 revealed a proximity of the Phe and Arg side chains, leading to a molecular model generated by distance geometry and molecular dynamics, wherein the Phe and Arg residues are shown in proximity on the same side of the peptide ring. We conclude that the Phe and Arg side chains along with the primary amino group form an active recognition motif that is augmented by the presence of a primary amino group in the cyclic peptide. We suggest that a comparable cyclic conformation may be responsible for the interaction of linear TRAPs with the thrombin receptor.

Amino Acid Sequence↗