Evaluation of encephalic ventricular volume from the magnetic resonance imaging scans of thirty-eight human subjects

Summary Accurate volume determination of the encephalic ventricles is of importance in several clinical conditions, including Alzheimer's presenile dementia, schizophrenia, and benign intracranial hypertension. Previous studies have investigated the accuracy with which magnetic resonance imaging (MRI) can be used in clinical practice to evaluate the encephalic ventricles. However, adequate evaluation of pathological conditions depends on a sufficient amount of morphometric data from normal subjects. To begin establishing this data base for normal subjects, we evaluated the MRI scans of 38 subjects found to have no apparent pathology and calculated the ventricular volume in each case by using methods previously developed in our laboratory. The results were then compared with published volumes determined from studies that used either ventricular casts or computerized tomographic scans. The average total ventricular volume for all 38 subjects was 17.4 cm³, while that for males was 16.3 cm³ and that for females was 18.0 cm³. A small but significant correlation was found between age of subject and ventricular volume, with ventricular size increasing with age.

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Evaluation du volume des ventricules cérébraux à partir des images obtenues en résonance magnétique nucléaire chez 38 sujets humains

Résumé La détermination exacte du volume des ventricules cérébraux est importante en clinique comme par exemple dans la démence présénile d'Alzheimer, la schizophrénie et l'hypertension intracrânienne bénigne. Des études antérieures ont étudié la fiabilité de la résonance magnétique nucléaire en pratique clinique pour évaluer le volume des ventricules cérébraux. Toutefois une évaluation correcte dans les conditions pathologiques implique une bonne connaissance des données morphométriques du sujet normal. Pour établir ces données sur « le sujet normal », nous avons étudié les coupes obtenues en IRM chez 38 sujets apparemment indemnes de toute pathologie; nous avons calculé le volume ventriculaire dans chaque cas en utilisant des méthodes mises au point auparavant dans notre laboratoire. Les résultats ont été ensuite comparés avec ceux obtenus par d'autres études utilisant soit des moules ventriculaires, soit des coupes tomographiques computérisées. Le volume ventriculaire total moyen chez 38 sujets est de 17,4 cm³, mais il est chez les sujets masculins de 16,3 cm³ et chez les sujets de sexe féminin de 18 cm³. Une corrélation faible mais significative a été trouvée entre l'âge du sujet et le volume ventriculaire, étant entendu que la taille du ventricule augmente avec l'âge.

     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities

An RNA-binding motif (RBM) gene family has been identified on the human Y chromosome that maps to the same deletion interval as the 'azoospermia factor' (AZF). We have identified the homologous gene family (Rbm) on the mouse Y with a view to investigating the proposal that this gene family plays a role in spermatogenesis. At least 25 and probably >50 copies of Rbm are present on the mouse Y chromosome short arm located between Sry and the centromere. As in the human, a role in spermatogenesis is indicated by a germ cell-specific pattern of expression in the testis, but there are distinct differences in the pattern of expression between the two species. Mice carrying the deletion Yd1, that maps to the proximal Y short arm, are female due to a position effect resulting in non-expression of Sry ; sex-reversing such mice with an Sry transgene produces males with a high incidence of abnormal sperm, making this the third deletion interval on the mouse Y that affects some aspect of spermatogenesis. Most of the copies of Rbm map to this deletion interval, and the Yd1males have markedly reduced Rbm expression, suggesting that RBM deficiency may be responsible for, or contribute to, the abnormal sperm development. In man, deletion of the functional copies of RBM is associated with meiotic arrest rather than sperm anomalies; however, the different effects of deletion are consistent with the differences in expression between the two species.      

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.      

Hepatic reinnervation following orthotopic liver transplantation in man.

We have studied changes in the pattern of intrinsic hepatic innervation in sequential liver biopsies from 16 patients who underwent orthotopic liver transplantation. Seventy-one needle biopsies were used, including specimens obtained at the time of transplantation (time zero) and up to 4 years post-transplantation; five transplant hepatectomy tissue blocks removed 3-32 months after transplantation were also assessed. Paraffin sections were immunostained with anti-PGP 9.5 and anti-S-100 to identify nerve fibres. All 'time zero' biopsies contained portal nerves and all but two showed staining of parenchymal fibres. After 1 week, no subsequent biopsies contained parenchymal fibres. The disappearance of portal fibres was less rapid and showed greater variability between patients, but they had all disappeared by 6 weeks and there was no positive staining between 6 and 60 weeks. Thereafter, a minority of biopsies showed innervation of a few small portal tracts. Samples from the porta hepatis, hepatectomy specimens, and needle biopsies containing large tracts showed persistence of major nerve trunks at all stages. Abnormally large nerve bundles were seen in some of these areas. The pattern of nerve staining showed no obvious relationship to the intensity of rejection changes. Our results suggest that there is a limited, delayed capacity for regeneration of portal, but not parenchymal, fibres in the transplanted human liver. The physiological significance of this long-term parenchymal denervation in transplanted livers remains to be determined.     

A monoclonal antibody raised against a synthetic peptide representative of part of the amino acid sequence of rat immunoglobulin E detects thermally induced changes in that region of the IgE molecule.

A mouse monoclonal antibody (mAb) has been produced by conventional cell fusion methods against a synthetic peptide, p123, representative of a portion of the CH4 domain of rat immunoglobulin E (IgE). This monoclonal antibody was reactive with both peptide and purified rat IgE (p.rat IgE) by indirect enzyme immunosorbent assay (ELISA), and its binding to p.rat IgE was found to be inhibitable by pre-incubation with rat ascitic fluid containing the immunocytoma 162 (IR162) IgE. Heating of the immunocytoma IgE in solution at 56 degrees for 1 hr resulted in its enhanced binding of the mAb. The effect of this treatment was investigated further using p.rat IgE heated at 56 degrees for various time intervals between 0 and 60 min. The mAb showed enhanced binding to IgE heated for as little as 10 min, a similar level of binding being shown by samples heated for 30 and 60 min. The degree of aggregation of the IgE molecules brought about by the heat treatments was measured by differential UV absorption. This revealed a decrease in the proportion of monomeric IgE with an accompanying increase in the percentage of dimer and larger aggregates with increased time of heating at 56 degrees. These absorption data, together with the ELISA inhibition data, suggest that, rather than inducing changes mediated by aggregation of the IgE molecules in solution, heating at 56 degrees causes subtle alterations in the conformation of individual IgE molecules at specific sites within their CH4 domains, one of which is detected by this mAb.     

Post-infantile giant cell hepatitis: histological and immunohistochemical study.

AIM--To determine the composition of the inflammatory infiltrate and to check for the presence of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in nine cases of post-infantile giant cell hepatitis. METHODS--The clinical, serological, and histological features of the nine cases were reviewed. Immunohistochemistry was used on liver biopsy specimens from six cases to: (i) characterise the lymphocytic infiltrate; (ii) assess the monocyte/macrophage response; (iii) detect "activated" perisinusoidal cells; and (iv) detect CMV and EBV antigens. Electron microscopic examination was carried out in two cases. RESULTS--Four patients had serological features suggestive of autoimmune chronic active hepatitis; in the other five cases the aetiology was obscure. Two patients presented with neurological symptoms. Hepatitis resolved completely in one patient; two patients showed clinical improvement; and one remained stable. Cirrhosis developed in three patients, one of whom proceeded to liver transplantation, and three patients died. Portal inflammation was present in all cases and lymphocytic piecemeal necrosis in eight cases, but intra-acinar inflammation associated with hepatocyte necrosis was observed in only five cases. The inflammatory infiltrate was composed predominantly of T lymphocytes; an increase in monocyte/macrophage cells was also observed. Mallory bodies, often with associated neutrophilic infiltrate, were present in four cases, and bilirubinostasis was a feature in four cases. "Activated" perisinusoidal cells were present, especially in relation to areas of inflammation, necrosis, and fibrosis. There was severe fibrosis or cirrhosis in five cases. Paramyxoviral nucleocapsids were not seen in the two cases examined ultrastructurally. CONCLUSIONS--Post-infantile giant cell hepatitis should be viewed as a heterogeneous clinical and aetiological entity encompassing cases of hepatitis with extensive giant cell hepatocyte transformation.