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Biomedical subjects

D Gerrelli

Publications and source records attributed to D Gerrelli.

At least 19 recordsLinked to original sources
PubMed2001

Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant.

Loop-tail (Lp) is a naturally occurring mouse mutant that develops severe neural tube defects. In this study, we describe complex cardiovascular defects in Lp homozygotes, which include double-outlet right ventricle, with obligatory perimembranous ventricular septal defects, and double-sided aortic arch, with associated abnormalities in the aortic arch arteries. Outflow tract and aortic arch defects are often related to abnormalities in the cardiac neural crest, but using molecular and anatomic markers, we show that neural crest migration is normal in Lp/Lp embryos. On the other hand, the heart fails to loop normally in Lp/Lp embryos, in association with incomplete axial rotation and reduced cervical flexion. As a consequence, the ventricular loop is shifted posteromedially relative to its position in wild-type embryos. This suggests that the observed cardiac alignment defects in the Lp mutant may be secondary to failure of neural tube closure and incomplete axial rotation. Double-sided aortic arch is a rare finding among mouse models. In humans, it is usually an isolated malformation, only rarely occurring in combination with other cardiac defects. We suggest that the double-sided arch arises as a primary defect in the Lp mutant, unrelated to the alignment defects, perhaps reflecting a role for the (as-yet-unknown) Lp gene in maintenance/regression of the aortic arch system.

Animals↗
PubMed1998

Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (Lp) mouse: a model of severe neural tube defects.

Mouse embryos homozygous for the loop-tail (Lp) mutation fail to initiate neural tube closure at E8.5, leading to a severe malformation in which the neural tube remains open from midbrain to tail. During initiation of closure, the normal mouse neural plate bends sharply in the midline, at the site of the future floor plate. In contrast, Lp/Lp embryos exhibit a broad region of flat neural plate in the midline, displacing the sites of neuroepithelial bending to more lateral positions. Sonic hedgehog (Shh) and Netrin1 are expressed in abnormally broad domains in the ventral midline of the E9.5 Lp/Lp neural tube, suggesting over-abundant differentiation of the floor plate. The notochord is also abnormally broad in Lp/Lp embryos with enlarged domains of Shh and Brachyury expression. The paraxial mesoderm shows evidence of ventralisation, with increased expression of the sclerotomal marker Pax1, and diminished expression of the dermomyotomal marker Pax3. While the expression domain of Pax3 does not differ markedly from wild-type, there is a dorsal shift in the domain of Pax6 expression in the neural tube at caudal levels of Lp/Lp embryos. We suggest that the Lp mutation causes excessive differentiation of floor-plate and notochord, with over-production of Shh from these midline structures causing ventralisation of the paraxial mesoderm and, to a lesser extent, the neural tube. Comparison with other mouse mutants suggests that the enlarged floor plate may be responsible for the failure of neural tube closure in Lp/Lp embryos.

Animals↗
PubMed1997

Failure of neural tube closure in the loop-tail (Lp) mutant mouse: analysis of the embryonic mechanism.

Loop-tail (Lp) is unique among mouse mutants in failing to initiate neural tube closure at the cervical/hindbrain boundary (so-called 'Closure 1'), at the 5-7 somite stage. Lp/Lp embryos go on to develop a malformation that closely resembles cranio-rachischisis, the most severe neural tube defect found in humans. We investigated several possible embryological mechanisms that may underlie this failure of neural tube closure in Lp. The genotypes of Lp/Lp, Lp/+ and +/+ embryos from mixed litters were identified using the polymerase chain reaction to amplify a polymorphic microsatellite sequence that is very closely linked to Lp. At post-neurulation stages of development, Lp/Lp embryos have a shortened body axis, which could suggest a defect of axial elongation as the primary anomaly in Lp. However, we found that axial elongation is normal in Lp homozygotes prior to the stage of defective Closure 1, indicating that the shortened body axis of later embryos is a secondary effect of the neurulation anomaly, or an independent effect of the Lp mutation. Some workers have reported cell proliferation rates to be abnormal in later stage Lp/Lp embryos. We observed variations in [3H]thymidine labelling index, and mitotic index, between embryonic tissues, and between embryos at different somite stages. However, Lp/Lp, Lp/+ and +/+ embryos had closely similar cell proliferation parameters, arguing against a mechanism based on faulty embryonic growth. Thirdly, we tested the hypothesis that the defect in loop-tail results from an inability of the neural folds to become apposed, specifically at the site of Closure 1. By tying a silk suture around the embryonic axis, at the future site of Closure 1, we were able to effect convergence of the neural folds at this site. Neural fold closure failed to progress along the body axis in sutured Lp/Lp embryos, however, in contrast to operated Lp/+ and +/+ embryos which exhibited normal progression of neural tube closure. The embryonic defect in loop-tail appears, therefore, to involve either a general inability of the spinal neural folds to become apposed along the spinal region, or a defect in the process of neural fold fusion.

Animals↗
PubMed1997

Mechanisms of normal and abnormal neurulation: evidence from embryo culture studies.

The method of whole embryo culture has been used extensively in analyzing the mechanisms underlying formation of the mammalian neural tube. These studies have provided insight into the cell lineage of the various tissues that comprise the neurulation stage embryo, the role of microfilaments, extracellular matrix and cell proliferation in the morphogenetic events of neural tube closure and the action of specific genes and gene products in establishment of the nervous system. This information is of considerable importance not only as a means of elucidating the processes of normal embryogenesis but also to shed light on the pathogenesis of important human birth defects.

Animals↗
PubMed1994

Antagonistic effects of retinoic acid and thyroid hormone on the expression of the tissue-specific splicing protein SmN in a clonal cell line derived from rat heart.

The SmN protein is a tissue-specific splicing factor which is expressed only in adult heart and brain but not in other tissues. Although a role for SmN in modulating tissue specific alternative splicing decisions in the heart and brain has been suggested, its precise function and the processes regulating its expression remain unclear. We show here that SmN is expressed in the H9c2 clonal cell line derived from rat heart and that its expression in these cells is affected by a variety of members of the steroid/thyroid hormone family. In particular thyroid hormone and retinoic acid exhibit antagonistic effects on SmN expression with thyroid hormone treatment producing large increases in expression whilst retinoic acid treatment virtually abolishes expression. These findings are discussed in terms of the regulation of SmN expression and the potential role of this factor in the response of cardiac cells to members of the steroid/thyroid hormone family.

Animals↗
PubMed1993

The cardiac form of the tissue-specific SmN protein is identical to the brain and embryonic forms of the protein.

The SmN protein is a component of small nuclear ribonucleoprotein particles and closely related to the ubiquitously expressed SmB and B' splicing proteins. However, SmN is only expressed in a limited range of tissues and cell types such as brain, heart and early embryonic cells. The isolation of cDNA clones derived from the mRNA encoding SmN in different cell types has indicated that the brain and embryonic forms of the protein are identical and are encoded by a distinct gene to that encoding SmB and B'. It has been suggested however, that the cardiac form of SmN is encoded by a distinct mRNA which is derived from a different gene from that encoding the brain and embryonic forms of SmN. By using the polymerase chain reaction as well as cDNA cloning we have shown that this is not the case and that the cardiac, brain and embryonic forms of the protein are identical and are translated from the same mRNA encoded by a single gene. The significance of this finding is discussed in terms of the complex expression pattern of this gene and the possible functional role of SmN.

Amino Acid Sequence↗
PubMed1992

The intronless mouse gene for the tissue specific splicing protein SmN is a processed pseudogene containing a stop codon after thirty-one amino acids.

The SmN protein is a component of small ribonucleoprotein particles which is closely related to the ubiquitously expressed splicing proteins SmB and B' but is expressed in only a small number of cells and tissues. We have isolated a mouse SmN-related sequence which lacks introns and contains multiple changes from the SmN cDNA sequence including a stop codon after thirty-one amino acids which would prevent it encoding functional SmN protein. This indicates that this intronless gene is a processed pseudogene and that the functional gene has yet to be isolated. In agreement with this southern blotting of mouse DNA with SmN probes reveals bands, additional to those derived from the pseudogene, which are characteristic of an intron-containing SmN gene. The relationship of the pseudogene to the functional SmN gene and to an intronless SmN-related sequence in the rat genome is discussed.

Amino Acid Sequence↗
PubMed1991

The relationship between appetite and plasma non-esterified fatty acid levels in housed calves.

Non-esterified fatty acid (NEFA) levels in housed, 3-month-old calves were monitored in two experiments designed to establish (i) the effect of diet and time of sampling in relation to feeding on blood levels; and (ii) the relationship between appetite and plasma NEFA in animals on chopped hay. In the first experiment, a significant drop in NEFA levels was recorded after feeding. Furthermore, the NEFA levels of calves maintained on concentrate were significantly lower than those on hay throughout the post-feeding period. In the second study, a significant negative correlation was established between NEFA levels and intake of chopped hay in (i) ad-lib-fed calves infected with the abomasal nematode Ostertagia ostertagi; (ii) worm-free animals pair-fed with those in group (i); and (iii) ad-lib-fed worm-free calves. Regression analysis of raw and transformed data from all three groups combined also yielded significant correlations. It is suggested that the measurement of blood NEFA may be a useful indirect indicator of feed intake in conditioned housed calves offered hay diets.

Animal Feed↗
PubMed1989

Ostertagia ostertagi infection in the calf: effects of a trickle challenge on appetite, digestibility, rate of passage of digesta and liveweight gain.

The effects of a trickle challenge with the equivalent of 10,000 infective Ostertagia ostertagi larvae per day on appetite, digestibility, rate of passage of digesta and liveweight gain were investigated in 12 calves assigned to infected, pair-fed control and ad libitum-fed control groups. Digestibility of cellulose, nitrogen, organic matter and dry matter was determined using insoluble acid detergent fibre as a marker on two occasions during the study: (i) Between days 31 and 38, when abomasal dysfunction was greatest; and (ii) between days 52 and 58, beginning approximately one week after anthelmintic treatment (day 46). Rate of passage of digesta was measured using chromium mordanted hay, fed to each calf after each digestibility study period. Voluntary feed intake of the infected group was significantly reduced from day 37 with the greatest depression (77 per cent) occurring just before anthelmintic treatment. The drop in appetite was responsible for nearly 73 per cent of the difference in liveweight gain between the infected and ad libitum fed control groups. The apparent digestibility coefficient of nitrogen was significantly depressed (22 per cent) in the infected group though was restored to control levels by anthelmintic treatment. The rate of passage of digesta was significantly reduced in both pair-fed control (50 per cent) and infected (74 per cent) groups. Anthelmintic treatment increased the latter though only to pair-fed control group levels. It is suggested that the marked hypergastrinaemia seen in the infected calves may have been in part responsible for the decreased rate of passage of digesta and in turn for the drop in appetite.

Animals↗
PubMed1989

Ostertagia ostertagi infection in the calf: effects of a trickle challenge on the hormonal control of digestive and metabolic function.

Metabolic effects of a trickle challenge with the equivalent of 10,000 infective Ostertagia ostertagi larvae per day were investigated in 12 calves allocated to infected, pair-fed control or ad libitum-fed control groups. Changes in hormone levels reflecting abomasal, pituitary and pancreatic function were monitored using radioimmunoassay techniques previously validated for use in cattle. A range of metabolic profile parameters and blood metabolites was also measured. Feed intake of the infected calves began to decline as blood gastrin and pepsinogen levels reached a peak. The depression in appetite recorded in this group was responsible for significant increases in plasma urea and non-esterified fatty acid levels and associated with an increase in growth hormone/insulin ratio. No significant difference in glucagon levels was recorded between groups. A decline in blood albumin values was also shown in the infected group and associated with a drop in nitrogen digestibility. A significant depression in circulating calcium levels was related to either the hypoalbuminaemia or impaired mineral absorption in the intestine. A decrease in plasma cholesterol values in the infected group was associated with changes in digestive function.

Animals↗
PubMed1989

Effect of omeprazole treatment on feed intake and blood gastrin and pepsinogen levels in the calf.

Previous work has shown blood gastrin levels to be elevated and appetite depressed in ostertagia-infected calves. A possible relationship between raised blood gastrin values and feed intake was investigated in worm-free animals using the human gastric acid secretion inhibitor, omeprazole. An initial dose-titration experiment established that administration of the drug by intravenous injection at 1.95 mg kg-1 (four times the recommended human dose rate) resulted in a marked (5.2-fold) increase in blood gastrin levels in the calf. Daily administration of omeprazole by intravenous injection at 2 mg kg-1 for four days in a subsequent experiment resulted in a significant depression in feed intake (up to 40.4 per cent) which was accompanied by a significant rise in blood gastrin levels (peak 940 pg ml-1; 6.5-fold increase over control values). It is suggested that such a rise in hormone levels would reduce reticuloruminal and abomasal motility, slow down the passage of ingesta and, in turn, lead to a reduction in appetite.

Administration, Oral↗
PubMed1988

Blood gastrin and pepsinogen responses to subclinical infection with Ostertagia ostertagi in adult dairy cattle.

Blood gastrin and pepsinogen responses to a single infection with 100,000 Ostertagia ostertagi infective larvae in lactating dairy cows were investigated. None of the infected cows showed signs of clinical ostertagiasis, nor was there any difference in live weight gain, milk yield or faecal egg count between groups. Pepsinogen levels of the infected group were significantly elevated between days 3 and 24 after infection (peak 1041 mU tyrosine; day 14). In contrast, there was no significant difference in blood gastrin levels between infected and control animals suggesting that few adult worms had become established in the former group. These data are compared with the increases in both gastrin and pepsinogen levels recorded in susceptible calves exposed to the same level, pattern and strain of ostertagia infection in a previous experiment. It is suggested that gastrin assay may be of value in adult cattle for indicating when elevated pepsinogen levels are merely associated with a rise in larval intake and not with the establishment of large adult worm burdens.

Animals↗