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Biomedical subjects

S Nagle

Publications and source records attributed to S Nagle.

15 recordsLinked to original sources
PubMed1997

Evidence for the involvement of the mammillary bodies and cingulum bundle in allocentric spatial processing by rats.

Comparisons were made between the behavioural effects of lesions in three inter-related limbic structures: the mammillary bodies, the fornix and the cingulum bundle/cingulate cortex. Cytotoxic lesions of the mammillary nuclei produced a marked deficit on reinforced T-maze alternation, but performance gradually improved with practice. Subsequent tests in a cross-maze and a radial-arm maze showed that the animals with mammillary body lesions failed to use allocentric cues, but were able to perform normally in an egocentric discrimination. Three groups of rats with different patterns of either crossed or unilateral radio frequency lesions of the cingulate region were given the same tasks. The profile of results indicated that disruption of those fibres in the cingulum bundle connecting the anterior thalamic nuclei with the hippocampal/retrohippocampal region was responsible for the observed impairments to T-maze alternation and radial-arm maze performance. There was also evidence that disconnection of frontal connections in the cingulum bundle might affect perseverative behaviour, but not allocentric processing. The results add support to the notion of a functional circuit that involves projections from the hippocampus to the mammillary bodies and anterior thalamic nuclei, and from there back to hippocampal/retrohippocampal regions via the cingulum bundle. This circuit appears to be vital for normal allocentric processing.

Animals↗
PubMed1996

The effects of discrete cingulum bundle lesions in the rat on the acquisition and performance of two tests of spatial working memory.

Rats received one of three different surgeries in which radiofrequency lesions were made in the cingulum bundle. These consisted of either: (i) two pairs of bilateral lesions at the mid and posterior levels of the tract (M + PCB, n = 9); (ii) a single pair of bilateral lesions at the posterior level of the tract (PCB, n = 5); or (iii) a single lesion in each hemisphere, one at a posterior level the other at a mid level (CCB, n = 6). Twelve other animals acted as surgical controls (SHAM). None of the groups of animals with cingulum bundle lesions was impaired on either the acquisition or performance of an automated delayed nonmatching-to-position task in an operant chamber. In fact, following combination of the three cingulum bundle groups it was found that the lesions resulted in a small, but significant improvement in performance of this task when compared with the SHAM animals. All three groups with tract lesions were, however, impaired on an alternation task in a T-maze. This double dissociation between the two tests of spatial working memory, coupled with the comparable scores of the three lesion groups, is seen as showing that the cingulum bundle is part of a neuroanatomical circuit subserving aspects of allocentric spatial memory. The relative mildness of the alternation deficit in the present study also suggests that the bundle must be completely destroyed bilaterally to produce a pronounced deficit.

Animals↗
PubMed1996

The effects of selective lesions within the anterior thalamic nuclei on spatial memory in the rat.

Groups of rats received cytotoxic lesions centred in either the anterior thalamic nucleus (AM), the anterior ventral and anterior dorsal thalamic nuclei (AV/AD), or all three nuclei combined (ANT.T). These lesions were made by injecting N-methyl-D-aspartate acid (NMDA). These rats, and a group of surgical controls (SHAM), were trained on a rewarded forced-alternation task in a T-maze. While the selective AM and AV/AD lesions produced an initial acquisition impairment, only the animals with combined lesions (ANT.T) showed a persistent deficit throughout the 16 acquisition sessions. Subsequent testing with a cross-maze confirmed that the SHAM, AV/AD, and AM groups were able to use allocentric cues, while the ANT.T group were impaired. In contrast none of the three anterior groups were impaired on a subsequent egocentric discrimination and reversal task run in the same apparatus. A final test using the eight arm radial-maze, revealed marked deficits in the ANT.T group as well as milder deficits in the AV/AD group. The results from these experiments help to confirm the importance of the anterior thalamic nuclei for allocentric tasks, but suggest that no region is pre-eminently important. The findings also help to account for other studies which have reported that anterior thalamic lesions have seemingly mild effects on tests of spatial memory.

Animals↗
PubMed1995

A comparison of the effects of anterior thalamic, mamillary body and fornix lesions on reinforced spatial alternation.

The effects of cytotoxic lesions in either the anterior thalamic nuclei or the mamillary bodies were compared with those of fornix lesions on a test of spatial working memory. All three lesions impaired acquisition of a forced alternation task in a T-maze, but the disruptive effects of the mamillary body lesions were significantly less than those following either fornix or anterior thalamic damage. When the alternation task was changed, so as to increase proactive interference, the impairment associated with mamillary body damage became more evident and was now equal in severity to that in the animals with anterior thalamic lesions. The fornix lesion group were the most impaired. In contrast, all three groups performed normally on a test of object recognition. The results add weight to the view that hippocampal--anterior thalamic connections are critical for normal spatial memory and that the relative contribution of the mamillary bodies is task dependent.

Animals↗
PubMed1995

A comparison of the effects of medial prefrontal, cingulate cortex, and cingulum bundle lesions on tests of spatial memory: evidence of a double dissociation between frontal and cingulum bundle contributions.

Rats were trained on an automated delayed nonmatching-to-position (DNMP) task. They then received cytotoxic lesions in either the medial prefrontal cortex (n = 13) or the cingulate and retrosplenial cortices (n = 8), or radiofrequency lesions in either the fornix (n = 6) or the cingulum bundle (n = 8). Twelve animals served as surgical controls. Only the fornical and medial prefrontal lesions disrupted DNMP performance, both groups showing a loss of accuracy and an increase in bias. The rats were then trained on a lever discrimination and reversal task, the medial prefrontal and fornical groups showing evidence of an increase in bias when compared with the cingulate cortex group. Finally, the rats were trained on a forced alternation task in a T-maze. Marked deficits were observed in the fornix and cingulum bundle groups, but the medial prefrontal and cingulate groups were unimpaired. The double dissociation between the effects of the prefrontal and cingulum bundle lesions highlights the very different nature of the two spatial tasks (DNMP and T-maze alternation), even though both involved a nonmatching rule. These findings may reflect the involvement of divergent outputs from the fornix-anterior thalamic pathway. One possibility is that anterior thalamic projections to the medial prefrontal cortex are concerned with processing egocentric information, while anterior thalamic projections to temporal regions via the cingulum bundle are concerned with allocentric information. The results also indicate that the effects of conventional lesions in the cingulate cortex and medial prefrontal cortex may be compromised by additional damage to the cingulum bundle.

Animals↗
PubMed1986

Genetic construction, expression, and melanoma-selective cytotoxicity of a diphtheria toxin-related alpha-melanocyte-stimulating hormone fusion protein.

The structural gene for diphtheria toxin, tox, has been modified at its Sph I site by the introduction of an oligonucleotide linker encoding a unique Pst I restriction endonuclease site and a synthetic oligonucleotide encoding alpha-melanocyte-stimulating hormone (alpha-MSH). The resulting fusion gene directs the expression of a diphtheria toxin-related alpha-MSH hybrid protein in which the diphtheria toxin receptor-binding domain has been replaced with alpha-MSH sequences. The chimeric toxin has been partially purified from periplasmic extracts of recombinant Escherichia coli K-12 and has been found to be selectively toxic for alpha-MSH receptor-positive human malignant melanoma NEL-M1 cells in vitro.

ADP Ribose Transferases↗
PubMed1984

Heterogeneity in the molecular basis of three types of hereditary persistence of fetal hemoglobin and the relative synthesis of the G gamma and A gamma types of gamma chain.

Restriction endonuclease analyses of DNA from one Black G gamma A gamma-HPFH homozygote and four Black and one Indian G gamma A gamma-HPFH heterozygotes have identified three different HPFH types which are the result of large deletions including the delta and beta genes. Two of the types are comparable to those characterized previously, but the third, which is present in the Indian heterozygote, shows a distinct difference in the size of the deletion. The 5' end point of the deletion in this type III G gamma A gamma-HPFH extends 0.5-1.0 kb beyond the 5' end point of one of the Black types of HPFH (type I). Each of the three types is associated with a distinct ratio between the G gamma and the A gamma chains, an observation supported by family data. The highest ratio is found in the heterozygote with the Indian type III G gamma A gamma-HPFH, with 69.3% G gamma chains, while the averages for the other types were 50.7% G gamma (type I) and 32.3% G gamma (type II).

Adult↗
PubMed1983

alpha Chain and gamma chain abnormal hemoglobins in newborn babies: structural and genetic aspects.

Structural studies and quantitative analyses were conducted on the hemoglobin of 55 newborn babies. Seven alpha chain variants (G-Philadelphia, Montgomery, Inkster, I-Philadelphia, Matsue-Oki, Winnipeg, and O-Indonesia) were present in 26 heterozygous newborns (17 black, eight Caucasian, and one Indonesian). The relative amount of the alpha X containing abnormal Hb F of the Hb G-Philadelphia and Hb Winnipeg babies was less than observed in heterozygous adults, which may indicate a decreased rate of assembly of the alpha X-gamma dimer over that of the alpha X-beta dimer. Of the 29 newborns with gamma chain variants, 16 were Caucasian babies; of these 15 had a Hb A gamma F-Hull heterozygosity and one a Hb G gamma F-Marietta heterozygosity. Six black babies were heterozygous for Hb A gamma F-Texas-I and six for Hb G gamma F-Port Royal. One Japanese baby had a heterozygosity for A gamma F-Iwata and a second was heterozygous for A gamma TF-Yamaguchi. Quantitative analyses of the isolated normal Hb Fo as well as an evaluation of the relative amounts of the Hb Fx in the red cell lysates gave data useful for a speculation of the genetic condition in each of these babies. It was concluded that the babies with the Hbs F-Texas-I, F-Iwata, F-Hull, and F-Marietta were simple heterozygotes with either the G gamma x A gamma/G gamma x A gamma X or the G gamma x A gamma/G gamma X x A gamma genic arrangement. The babies with Hb F-Port Royal had a G gamma x G gamma X/G gamma x A gamma arrangement, which may result from a (to be determined) gene conversion. The newborn baby with Hb F-Yamaguchi has the G gamma x A gamma x/A gamma T-X.-. genic arrangement, suggesting the presence of three distinctly different gamma chain genes of which one, the A gamma T-X gene, produces an A gamma chain (with threonyl at position gamma 75 and an Asn at position gamma 80) at a level usually seen for G gamma rather than A gamma chains. These studies were greatly facilitated by the use of high pressure liquid chromatographic methods.

Amino Acid Sequence↗
PubMed1983

The occurrence of different levels of G gamma chain and of the A gamma T variant of fetal hemoglobin in newborn babies from several countries.

The gamma chain compositions of the fetal hemoglobins of 2453 newborn babies from East Asian countries (1350 babies), from Italy, Yugoslavia, Bulgaria, and Georgia (417 Caucasian babies), and 686 black babies from Georgia were determined by high pressure liquid chromatography. Unusual results for a limited number of babies were confirmed by chemical analyses, and were evaluated further by family studies. Statistical analyses indicated high gene frequencies for the A gamma T chain in Italian (f = 0.237), Yugoslavian and Bulgarian (f = 0.238), and white Georgia babies (f = 0.224), a lower frequency in Japan (f = 0.178), and India (f = 0.173), and particularly in mainland China (f = 0.079). The A gamma T gene frequency in normal (AA) Black babies was 0.102. When a beta S or beta C mutation was also present this frequency was greatly decreased, particularly in babies with the AC condition (f = 0.036). These results suggest the near absence of the A gamma T mutation on the chromosome also carrying the beta C determinant. Most babies had the expected G gamma values which vary between 60 and 80%, but several (mainly black) babies had higher values (between 80 and 90%), while one normal black baby had a G gamma value of (nearly) 100%. This condition may be a form of A gamma +1-thalassemia and has been discussed in detail elsewhere (Blood 58:491-500, 1981). Thirty-five clinically normal (mainly Chinese, Indian, and Japanese) babies had G gamma values of about 40%. Twenty-six babies had A gamma I values of about 60%, while the remaining nine babies had A gamma T and A gamma I chains in a ratio of either 1 to 2 or 1 to 1. Two additional newborns did not produce any G gamma chains, but had only A gamma I chains or A gamma T chains. Family studies failed to indicate a specific hematological abnormality. These unusual ratios between the G gamma and A gamma (either A gamma I or A gamma T) chains have led to speculations regarding possible genetic abnormalities present in these infants.

China↗