Biomedical subjects

D L Arnold

Publications and source records attributed to D L Arnold.

At least 55 records · Page 3Linked to original sources

PubMed2000

Dosing via gavage or diet for reproduction studies: a pilot study using two fat-soluble compounds-hexachlorobenzene and aroclor 1254.

The choice of a dosing route for in vivo toxicological tests is often dictated by practical constraints. Reproduction studies are particularly challenging in this regard since the determination of no-effect levels and allowable daily intakes from reproduction data encompasses exposure of the dam to the test xenobiotic prior to pregnancy, during gestation and during lactation. The fetus/infant can be exposed to the xenobiotic as well as the dam's metabolic products of the test xenobiotic during gestation and lactation. We initiated a series of two-litter, pilot reproduction studies with Sprague-Dawley and Fischer 344 rats to specifically ascertain the amount of xenobiotic and its metabolites ingested by the nursing neonate on lactation days 4, 7, 12, 17 and 21, when its dam received the xenobiotic via its diet or by gavage. The xenobiotics studied in this initial series of experiments were hexachlorobenzene (HCB) and Aroclor(R) 1254 (polychlorinated biphenyls; PCBs). The dams were dosed for 28 days, mated to untreated males and then remated approximately 2 weeks after weaning their first litter to a second untreated male. Dietary levels of 10 ppm HCB or 10 ppm PCBs, and gavage doses of 0.9 mg HCB or 0.8 mg PCBs/kg body weight/day were chosen and resulted in similar doses of HCB and PCBs per unit of the body weight of the dam during the premating period. There were no apparent toxicological effects regarding the dam nor were any of the reproduction parameters (feed consumption, dam weight, litter size, pup weight, external anomalies and day 4 viability index) significantly different from control values. Following impregnation, the body weight of the dam increased appreciably during gestation, but its feed consumption increased only slightly. During lactation, the dam's feed consumption increased markedly while its body weight increased slightly. Consequently, when dams received the xenobiotic in their diet they consumed slightly less xenobiotic per unit of body weight during gestation when compared to the gavaged dams, whereas the situation was dramatically reversed during lactation. While the greater consumption of xenobiotic by the dietary-dosed dams during lactation did result in more HCB (P</=0.0001 for both litters) and PCBs/metabolites (litter one: P=0.05; litter two: P</=0.0001) in the suckling neonate's stomach contents in both generations, there was no evidence of any differences between the two litters when each sampling date was assessed separately, except for the day 4-HCB results when the litter one pups had more HCB in their stomachs (P=0.018). For the PCBs, the F344 neonates were found to have more PCBs in their stomachs (litter one P=0.0015; litter two P=0.002) than the Sprague-Dawley neonates. In addition, the amount of HCB, PCBs and fat in the neonates' stomachs decreased during lactation, as the pups age increased (P</=0.035). These preliminary results suggest that analogous amounts of HCB and PCBs given via diet or gavage may not result in similar lactational exposure by the suckling neonate.

Animals↗

PubMed2000

Consequences of Aroclor 1254 ingestion on the menstrual cycle of rhesus (Macaca mulatta) monkeys.

A group of 80 female rhesus (Macaca mulatta) monkeys were randomly distributed to four similar test rooms (20 monkeys/room) and then randomly allocated to one of five test groups (four females/test group/room). The objective of the study was to ascertain the toxicological and reproductive effects of Aroclor 1254 ingestion at dose levels of 0, 5, 20, 40 or 80 microg Aroclor 1254/kg body weight per day (Arnold et al., 1993a,b, 1995, 1996, 1997). It was deemed necessary to establish the menstrual patterns for all the monkeys both before and after the start of dosing so as to provide an appropriate baseline from which potential treatment effects could be ascertained. The data presented herein were obtained during the first 3 years after the start of dosing, or the study's pre-mating phase. At the end of the first 2 years of dosing, the monkeys attained a qualitative pharmacokinetic steady state regarding the levels of polychlorinated biphenyls in their adipose tissue. Upon termination of the study, a number of monkeys were found to have endometriosis, adenomyosis or uterine leiomyomas (Arnold et al., 1996, 1997). These monkeys were designated as having gynecological abnormalities which were considered to be a factor in the analysis of the menstrual data. The menstrual data (i.e. menses frequency, cycle length and menses duration) were subjected to a statistical assessment to see whether year, quarter, gynecological abnormalities or dose of Aroclor 1254 had any effect on menses frequency, menstrual cycle length (i.e. the first day of menses until the day prior to the start of the next menses) and/or menses duration (i.e. the number of days of haemorrhagic discharge). The only consistent statistically significant effect found was that gynecological abnormalities increased menses duration (P<0.05) in all 12 quarters of the premating observation period. This effect was significant during both the pre- (P=0.0004) and post- (P< or =0.0001) pharmacokinetic steady-state intervals. While there was some indication of seasonality regarding menstrual cycle length and menses duration when these data were compared on a quarterly basis during the first 2 years of the study (P=0.043; P< or =0.0001, respectively), this effect was not evident during the third year (P=0.21; P=0.31, respectively). In particular, the effect of quarter on menses cycle length was most evident during the first year, with the shortest cycles occurring during the first or spring quarter and the longest in the third or fall quarter. However, menses duration was shortest in the first quarter during the first 2 years and tended to peak in the second quarter of all 3 years, while generally diminishing in the third and fourth quarters. There was also an increase in menses duration with increasing time on test for all groups. In addition, Aroclor 1254 treatment appeared to have some effect on menses duration when menses duration was plotted against dose group, but the effect was not statistically significant (P>0. 05). It was concluded that the ingestion of Aroclor 1254 at dose levels up to 80 microg/kg body weight/day by rhesus monkeys did not have any appreciable biological effect on menstrual frequency, menstrual cycle length or menses duration. However, gynecological abnormalities significantly increased menses duration during the three-year observation period.

Animals↗

PubMed2000

MR spectroscopy and imaging in metabolic myopathies.

Magnetic resonance spectroscopy and imaging of muscle and brain offers new possibilities for noninvasive diagnosis of metabolic myopathies. These functional techniques allow assessment of the pathophysiology of these disorders and also can be used for monitoring disease evolution and response to therapy. In this article, the authors review the magnetic resonance spectroscopy and imaging features of mitochondrial encephalomyopathies, glycolytic disorders, and hypothyroidism.

Adenosine Triphosphate↗

PubMed2000

Neuronal dysfunction in children with newly diagnosed temporal lobe epilepsy.

We sought to determine whether neuronal dysfunction throughout the temporal lobes of children with temporal lobe epilepsy (TLE) is already as severe at the time of diagnosis as it is in patients with long-standing intractable TLE (INT-TLE). Proton magnetic resonance spectroscopic imaging was used to measure N-acetylaspartate/creatine (NAA/Cr) ratios in the temporal lobes of five consecutive children with newly diagnosed TLE (ND-TLE), five with INT-TLE, and 30 normal control subjects. The median age of those with ND-TLE and those with INT-TLE did not significantly differ (P = 0.92). All five patients with ND-TLE had bilateral reductions in the NAA/Cr ratio. Two of the five patients with INT-TLE had bilateral reductions in the NAA/Cr ratio; three had unilateral reductions in the NAA/Cr ratio. In the three patients with lesions the NAA/Cr ratio decrease extended outside these lesions. No significant differences were detected in any temporal lobe region between the ND-TLE and INT-TLE groups. The severity of the neuronal dysfunction in the children with ND-TLE was at least as severe as in those with INT-TLE and was not restricted to one temporal lobe, implying that the neuronal abnormalities observed in patients with TLE occur before the clinical manifestations.

Adolescent↗

PubMed2000

Excision from tRNA genes of a large chromosomal region, carrying avrPphB, associated with race change in the bean pathogen, Pseudomonas syringae pv. phaseolicola.

Pseudomonas syringae pv. phaseolicola (Pph) race 4 strain 1302A carries avirulence gene avrPphB. Strain RJ3, a sectoral variant from a 1302A culture, exhibited an extended host range in cultivars of bean and soybean resulting from the absence of avrPphB from the RJ3 chromosome. Complementation of RJ3 with avrPphB restored the race 4 phenotype. Both strains showed similar in planta growth in susceptible bean cultivars. Analysis of RJ3 indicated loss of > 40 kb of DNA surrounding avrPphB. Collinearity of the two genomes was determined for the left and right junctions of the deleted avrPphB region; the left junction is approximately 19 kb and the right junction > 20 kb from avrPphB in 1302A. Sequencing revealed that the region containing avrPphB was inserted into a tRNALYS gene, which was re-formed at the right junction in strain 1302A. A putative lysine tRNA pseudogene (PsitRNALYS) was found at the left junction of the insertion. All tRNA genes were in identical orientation in the chromosome. Genes near the left junction exhibited predicted protein homologies with gene products associated with a virulence locus of the periodontal pathogen Actinobacillus actinomycetemcomitans. Specific oligonucleotide primers that differentiate 1302A from RJ3 were designed and used to demonstrate that avrPphB was located in different regions of the chromosome in other strains of Pph. Deletion of a large region of the chromosome containing an avirulence gene represents a new route to race change in Pph.

Base Sequence↗

PubMed2000

Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis.

Axonal injury occurs even in the earliest stages of multiple sclerosis. Magnetic resonance spectroscopic imaging (MRSI) measurements of brain N:-acetylaspartate (NAA), a marker of axonal integrity, show that this axonal injury can occur even in the absence of clinically evident functional impairments. To test whether cortical adaptive responses contribute to the maintenance of normal motor function in patients with multiple sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine multiple sclerosis patients who had unimpaired hand function. We found that activation of the ipsilateral sensorimotor cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P = 0.001) with decreases in brain NAA. These results suggest that compensatory cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability, and that therapies directed towards promoting cortical reorganization in response to brain injury could enhance recovery from relapses of multiple sclerosis.

Aspartic Acid↗

PubMed2000

Using proton magnetic resonance spectroscopic imaging to predict in vivo the response of recurrent malignant gliomas to tamoxifen chemotherapy.

OBJECTIVE: Most patients with a malignant glioma spend considerable time on a treatment protocol before their response (or nonresponse) to the therapy can be determined. Because survival time in the absence of effective therapy is short, the ability to predict the potential chemosensitivity of individual brain tumors noninvasively would represent a significant advance in chemotherapy planning. METHODS: Using proton magnetic resonance spectroscopic imaging (1H MRSI), we studied 16 patients with a recurrent malignant glioma before and during treatment with high-dose orally administered tamoxifen. We evaluated whether 1H MRSI data could predict eventual therapeutic response to tamoxifen at the pretreatment and early treatment stages. RESULTS: Seven patients responded to tamoxifen therapy (three with glioblastomas multiforme; four with anaplastic astrocytomas), and nine did not (six with glioblastomas multiforme; three with anaplastic astrocytomas). Responders and nonresponders exhibited no differences in their age, sex, tumor type, mean tumor volume, mean Karnofsky scale score, mean number of weeks postradiotherapy, or mean amount of prior radiation exposure. Resonance profiles across the five metabolites measured on 1H MRSI spectra (choline-containing compounds, creatine and phosphocreatine, N-acetyl groups, lactate, and lipids) differed significantly between these two groups before and during treatment. Furthermore, linear discriminant analyses based on patients' in vivo biochemical information accurately predicted individual response to tamoxifen both before and at very early treatment stages (2 and 4 wk). Similar analyses based on patient sex, age, Karnofsky scale score, tumor type, and tumor volume could not reliably predict the response to tamoxifen treatment at the same time periods. CONCLUSION: It is possible to accurately predict the response of a tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. 1H MRSI has potential as a prognostic tool in the pharmacological treatment of recurrent malignant gliomas.

Administration, Oral↗

PubMed2000

Spatial extent of neuronal metabolic dysfunction measured by proton MR spectroscopic imaging in patients with localization-related epilepsy.

PURPOSE: To assess the spatial extent of the decrease in the neuronal marker N-acetyl-aspartate (NAA) relative to creatine (Cr) in patients with localization-related epilepsy, and to assess clinical differences between patients with and without widespread NAA/Cr reduction. METHODS: We studied 51 patients with localization-related epilepsy. Patients were divided into three groups according to the EEG investigation: (a) temporal lobe epilepsy (TLE, n = 21), (b) extratemporal lobe epilepsy (extra-TLE, n = 20), and (c) multilobar epilepsy (patients with a wider epileptogenic zone, n = 10). We acquired proton magnetic resonance (MR) spectrocopic imaging (1H-MRSI) of temporal and frontocentroparietal regions in separate examinations for both patients and controls. NAA/Cr values 2 standard deviations below the mean of normal controls were considered abnormal. RESULTS: Twenty-three (45%) patients including 12 with TLE had normal MR imaging including volumetric studies of the hippocampus. Forty-nine (96%) patients had low NAA/Cr, indicating neuronal dysfunction in either temporal and/or extratemporal 1H-MRSIs; 38% of patients with TLE and 50% of patients with extra-TLE also had NAA/Cr reduction outside the clinical and EEG-defined primary epileptogenic area. The NAA/Cr reduction was more often widespread in the multilobar group [six (60%) of 10] than in temporal or extratemporal groups [five (31%) of 16]. Nonparametric tests of (a) seizure duration, (b) seizure frequency, and (c) lifetime estimated seizures showed no statistically significant difference (p > 0.05) for TLE and extra-TLE patients with or without NAA/Cr reduction outside the seizure focus. CONCLUSIONS: Of patients with localization-related epilepsy, 40-50% have neuronal metabolic dysfunction that extends beyond the epileptogenic zone defined by clinical-EEG and/or the structural abnormality defined by MRI.

Adolescent↗

PubMed2000

Proton magnetic resonance spectroscopic imaging studies in patients with newly diagnosed partial epilepsy.

PURPOSE: To assess whether the N-acetyl aspartate (NAA) to creatine ratio (NAA/Cr) is abnormally low at the onset of epilepsy and whether successful treatment of seizures with antiepileptic drugs is sufficient for normalization of NAA/Cr. PATIENTS AND METHODS: Proton magnetic resonance spectroscopic imaging (1H-MRSI) was used to measure NAA/Cr in temporal lobes of eight patients with newly diagnosed epilepsy before or soon after starting medication. Six patients had follow-up 1H-MRSI examinations 7 months later. Clinical pattern of the seizures and the EEG findings suggested partial seizures in all and TLE in five patients. None of the patients had lesional epilepsy according to magnetic resonance imaging. RESULTS: Initial 1H-MRSI of the temporal lobes showed significantly low NAA/Cr values in five of eight patients. Five of six patients who had follow-up 1H-MRSI were seizure-free after using medication; the remaining patient did not take medication and continued to experience occasional auras. Wilcoxon rank sign comparison of NAA/Cr on initial 1H-MRSI examination and follow-up 1H-MRSIs showed no significant difference (Z = 135, p = 0.893, 2-tailed) for five seizure-free patients. CONCLUSIONS: Neuronal dysfunction is present at an early stage of the epileptic process. NAA/Cr recovery in seizure-free patients controlled with antiepileptic drugs is less evident, compared with successful surgical treatment. Thus, absence of seizures is not necessarily coupled with NAA/Cr improvement and observed variable response warrants further investigation.

Adult↗

PubMed2000

Lateralization of temporal lobe epilepsy (TLE) and discrimination of TLE from extra-TLE using pattern analysis of magnetic resonance spectroscopic and volumetric data.

PURPOSE: To examine whether or not pattern analysis of magnetic resonance volumetric (MRVol) and proton magnetic resonance spectroscopic imaging (1H-MRSI) data would enable (a) the accurate lateralization of temporal lobe epilepsy (TLE) and (b) the discrimination of TLE from extratemporal epilepsy (E-TLE). METHODS: For lateralization analysis, we used data from 150 nonforeign tissue lesional TLE patients [88 left-sided (L-TLE), 46 right-sided (R-TLE), and 16 bilateral (Bi-TLE)]. For the discrimination of TLE from E-TLE, we used data from 174 patients (145 with unilateral TLE, 14 with unilateral E-TLE, and 15 with widespread epileptogenic zones involving both the TL and extra-TL regions-multilobar epilepsy). A series of "leave-one-out" cross-validated linear discriminant analyses were performed using the MRVol and 1H-MRSI data sets to lateralize TLE and discriminate it from E-TLE. RESULTS: Lateralization: The leave-one-out linear discriminant analyses were able to correctly lateralize (with a posterior probability >0.50) 120 (90%) of the 134 L-TLE and R-TLE patients. Imposing higher posterior probability (>0.95) increased accuracy of lateralization to 98%, with only two discordant cases who underwent surgery on the side of electroencephalogram, and both had bad outcome. Discrimination: the leave-one-out linear discriminant analyses were able to correctly classify (with a posterior probability >0.50) 142 (89%) of the 159 TLE and E-TLE patients. Accuracy increased slightly as higher posterior probability cutoffs were imposed, with fewer patients being classified. CONCLUSIONS: Pattern analysis of 1H-MRSI and MRVol data can accurately lateralize TLE. Discriminating TLE from E-TLE was less accurate, probably due to the presence of temporal lobe damage in some patients with E-TLE reflecting dual pathology.

Amygdala↗

PubMed2000

Morphometric MRI analysis of the parahippocampal region in temporal lobe epilepsy.

Despite neuropathological and electrophysiological evidence for the involvement of parahippocampal structures in temporal lobe epilepsy (TLE), little attention has been paid to morphometric changes in these structures, and the relation of these changes to TLE. We performed high-resolution MRI volumetric analysis to examine in vivo the morphology of the parahippocampal region in 20 healthy subjects and 6 TLE patients with MRI evidence of unilateral hippocampal atrophy. In normal controls the standardized volume of the left entorhinal cortex (EC) was 1305 +/- 138 mm3 and that of the right EC was 1376 +/- 170 mm3; the left perirhinal cortex (PC) was 2900 +/- 554 mm3 and the right PC was 2771 +/- 486 mm3; the left posterior parahippocampal cortex (PPC) was 2499 +/- 583 mm3 and the right PPC was 2234 +/- 404 mm3. Using a 2 standard deviation cutoff from the mean of normal controls, we found ipsilateral to the seizure focus: (i) a reduction in the volume of the EC in all patients; (ii) a reduction of the PC in 2/6 (33%) patients; (iii) no reduction in the volume of the PPC in any patient. In 3/6 (50%) of patients, the EC was also abnormally small contralateral to the seizure focus. In patients with unilateral TLE, the EC is the most affected structure within the parahippocampal region. Whether this is due to a primary role of the EC in the genesis of TLE or is the consequence of its pivotal position in the reciprocal flow of information between the hippocampus and the neo- and limbic cortices remains to be explored.

Adult↗

PubMed2000

Multiple sclerosis: magnetization transfer MR imaging of white matter before lesion appearance on T2-weighted images.

PURPOSE: To determine the evolution of magnetization transfer (MT) in white matter regions before and after plaque development in patients with multiple sclerosis (MS). MATERIALS AND METHODS: In a 5-year longitudinal evaluation, 30 patients with MS underwent conventional magnetic resonance (MR) imaging, MT MR imaging, and clinical assessment. Cross-sectional data in 12 healthy subjects were also collected. Semiautomated lesion classification with use of T2-weighted MR images was used to measure the time course of the MT ratio (calculated with MR data acquired without and with MT saturation) in every voxel and to help analyze the relationship with the status of lesions depicted on T2-weighted images. RESULTS: There was a significant (P <.001) temporal decline in lesion MT ratio after lesion appearance on T2-weighted images. A significant (P <. 001) progressive decline in MT ratio was also present in voxels that later became lesions, prior to initial detection on T2-weighted images. Even 1(1/2) years prior to lesion appearance, the MT ratio (33.3%) in regions destined to become such lesions was significantly (P <.001) lower than that in both white matter in healthy subjects (41.3%) and other normal-appearing white matter in patients with MS (38.1%). CONCLUSION: The MT ratio reveals progressive focal abnormalities in MS that antedate by up to 2 years the appearance of lesions on T2-weighted MR images.

Adult↗

PubMed2000

Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree.

MELAS is a mitochondrial encephalomyopathy characterized clinically by recurrent stroke-like episodes, seizures, sensorineural deafness, dementia, hypertrophic cardiomyopathy, and short stature. The majority of patients are heteroplasmic for a mutation (A3243G) in the tRNAleu(UUR) gene in mitochondrial DNA (mtDNA). In cells cultured in vitro, the mutation produces a severe mitochondrial translation defect only when the proportion of mutant mtDNAs exceeds 95% of total mtDNAs. However, most patients are symptomatic well below this threshold, a paradox that remains unexplained. We studied the relationship between the level of heteroplasmy for the mutant mtDNA and the clinical and biochemical abnormalities in a large pedigree that included 8 individuals carrying the A3243G mutation, 4 of whom were asymptomatic. Unexpectedly, we found that brain lactate, a sensitive indicator of oxidative phosphorylation dysfunction, was linearly related to the proportion of mutant mtDNAs in all individuals carrying the mutation, whether they were symptomatic or not. There was no evidence for threshold expression of the metabolic defect. These results suggest that marked tissue-specific differences may exist in the pathogenic expression of the A3243G mutation and explain why a neurological phenotype can be observed at relatively low levels of heteroplasmy.

Adult↗

PubMed2000

Prognostic value of proton magnetic resonance spectroscopic imaging for surgical outcome in patients with intractable temporal lobe epilepsy and bilateral hippocampal atrophy.

The objective of this study was to assess which features of temporal lobe proton magnetic resonance spectroscopic imaging (1H-MRSI) are associated with satisfactory surgical outcome in patients with intractable temporal lobe epilepsy and bilateral hippocampal atrophy. We studied 21 patients with intractable temporal lobe epilepsy and bilateral hippocampal atrophy defined by magnetic resonance imaging volumetric measurements who underwent surgical treatment. 1H-MRSI was used to determine the relative resonance intensity ratio of the neuronal marker N-acetylaspartate to creatine + phosphocreatine (NAA/Cr) for mid and posterior temporal lobe regions of the left and right hemisphere, as well as an asymmetry index. Values lower than 2 SDs below the normal mean were considered abnormal. We used Engel's classification to assess surgical outcome with respect to seizure control. Eleven patients (52%) were in class I-II and 10 (48%) were in class III-IV. All 21 were operated on the side of maximal electroencephalographic (EEG) lateralization. Concordant lateralization of decreases in NAA/Cr to the side of surgery and normal NAA/Cr values in the contralateral posterior-temporal region were significantly associated with good surgical outcome: 11 (69%) of 16 patients with 1H-MRSI abnormalities concordant with EEG lateralization and none of the 5 patients with nonconcordant 1H-MRSI had a good outcome (class I-II); 10 (77%) of 13 patients with normal NAA/Cr contralateral to the EEG lateralization versus 1 (12.5%) of 8 of those with NAA/Cr reduction contralateral to EEG lateralization were in class I-II. Regression correlation analysis showed significant linear correlation between the midtemporal NAA/Cr relative asymmetry ratio and surgical outcome; the greater the asymmetry, the better the outcome. We conclude that discriminant 1H-MRSI features associated with favorable surgical outcome in patients with temporal lobe epilepsy and bilateral hippocampal atrophy were (1) concordant 1H-MRSI lateralization, (2) a greater side-to-side asymmetry of NAA/Cr, and (3) an absence of contralateral posterior NAA/Cr reduction.

Adolescent↗

PubMed2000

Heterogeneity of T-lymphocyte function in primary progressive multiple sclerosis: relation to magnetic resonance imaging lesion volume.

We found that in vitro migration and interferon-gamma production by lymphocytes derived from primary progressive multiple sclerosis patients preselected on the basis of a high T2-weighted lesion volume (>10 cm3) on magnetic resonance imaging, were increased compared with that in primary progressive multiple sclerosis patients with a low T2-weighted lesion volume (<3 cm3) and controls. Whether the heterogeneity of immune function within the primary progressive population will correlate with response to therapy remains to be established.

Adult↗

PubMed2000

Proton MR spectroscopy to assess axonal damage in multiple sclerosis and other white matter disorders.

Proton MR spectroscopy allows in vivo measurement of N-acetylaspartate in white matter, providing a biochemical index of axonal integrity. Several recent studies of patients with multiple sclerosis and other white matter disorders have shown both transient and sustained decreases in N-acetylaspartate in white matter lesions and in brain regions appearing normal on conventional MRI. These data have emphasised that a substantial amount of axonal damage or loss (presumably secondary to myelin pathology) is consistently present in most of these disorders. Recent post-mortem studies support these results. In contrast to changes seen with conventional MR imaging, decreases in N-acetylaspartate have shown a close correlation with changes in neurological status. This suggests that axonal damage may be more relevant than demyelination for determining chronic functional impairments in primary white matter diseases. Thus, serial measurement of brain N-acetylaspartate with proton MR spectroscopy can provide a reliable and clinically-relevant monitor of disease evolution. As pathological changes responsible for long-term morbidity are logically important targets for therapeutic agents, early treatment directed at axonal protection should be useful in these disorders.

Axons↗

PubMed2000

Proton MR spectroscopy in multiple sclerosis.

Axonal injury in multiple sclerosis (MS) is focal and diffuse, and is directly responsible for irreversible disability. Acute inflammatory events can be associated with reversible disability that may parallel reversible axonal injury. This in part accounts for the remission following relapses early in the disease. By the time there is clinical disability, substantial axonal injury already has occurred. This provides a strong rationale for the early limitation of inflammation and its consequences.

Aspartic Acid↗

PubMed1999

Identification of a pathogenicity island, which contains genes for virulence and avirulence, on a large native plasmid in the bean pathogen Pseudomonas syringae pathovar phaseolicola.

The 154-kb plasmid was cured from race 7 strain 1449B of the phytopathogen Pseudomonas syringae pv. phaseolicola (Pph). Cured strains lost virulence toward bean, causing the hypersensitive reaction in previously susceptible cultivars. Restoration of virulence was achieved by complementation with cosmid clones spanning a 30-kb region of the plasmid that contained previously identified avirulence (avr) genes avrD, avrPphC, and avrPphF. Single transposon insertions at multiple sites (including one located in avrPphF) abolished restoration of virulence by genomic clones. Sequencing 11 kb of the complementing region identified three potential virulence (vir) genes that were predicted to encode hydrophilic proteins and shared the hrp-box promoter motif indicating regulation by HrpL. One gene achieved partial restoration of virulence when cloned on its own and therefore was designated virPphA as the first (A) gene from Pph to be identified for virulence function. In soybean, virPphA acted as an avr gene controlling expression of a rapid cultivar-specific hypersensitive reaction. Sequencing also revealed the presence of homologs of the insertion sequence IS100 from Yersinia and transposase Tn501 from P. aeruginosa. The proximity of several avr and vir genes together with mobile elements, as well as G+C content significantly lower than that expected for P. syringae, indicates that we have located a plasmid-borne pathogenicity island equivalent to those found in mammalian pathogens.

Bacterial Proteins↗