The origin and loss of the ubiquitin activating enzyme gene on the mammalian Y chromosome

Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted and the Y chromosome gradually lost its non-essential genetic functions. This model was originally inferred from the occurrence of few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis and, more recently, the existence of X- Y homologous genes. The comparative analysis of such genes is a means by which the validity of this model can be evaluated. One well-studied example of an X-Y homologous gene is the ubiquitin activating enzyme gene ( UBE1 ), which is X-linked with a distinct Y-linked gene in many eutherian ('placental') and metatherian (marsupial) mammals. Nonetheless, no UBE1 homologue has yet been detected on the human Y chromosome. Here we describe a more extensive study of UBE1 homologues in primates and a prototherian mammal, the platypus. Our findings indicate that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage. Thus UBE1 illustrates the key steps of 'autosomal to X-specific' evolution of genes on the sex chromosomes.      

Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanding CAG repeat coding for polyglutamine in the huntingtin protein. Recent data have suggested the possibility that an N-terminal fragment of huntingtin may aggregate in neurons of patients with HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus, forming intranuclear neuronal inclusion bodies. An animal model of HD using the short N-terminal fragment of huntingtin has also been found to have intranuclear inclusions and this same fragment can aggregate in vitro . We have now developed a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus. Neuroblastoma cells transiently transfected with full-length huntingtin constructs with either a normal or expanded repeat had diffuse cytoplasmic localization of the protein. In contrast, cells transfected with truncated N-terminal fragments showed aggregation only if the glutamine repeat was expanded. The aggregates were often ubiquitinated. The shorter truncated product appeared to form more aggregates in the nucleus. Cells transfected with the expanded repeat construct but not the normal repeat construct showed enhanced toxicity to the apoptosis- inducing agent staurosporine. These data indicate that N-terminal truncated fragments of huntingtin with expanded glutamine repeats can aggregate in cells in culture and that this aggregation can be toxic to cells. This model will be useful for future experiments to test mechanisms of aggregation and toxicity and potentially for testing experimental therapeutic interventions.      

Rural teleradiology initiative: Accuracy of interpretation in the emergency setting

We report our 11/2-year experience with 24-hour consulting teleradiology coverage between a rural hospital and a tertiary care center. During this period, 215 studies were transmitted over a T-1 telephone line from Barnesville Hospital to Ohio State Hospital Medical Center. We interpreted 116 computed tomographic studies, of which 64 were head, 31 abdominal, 6 chest, 3 spinal, and 12 miscellaneous CT studies. We also interpreted 26 chest x-rays, 12 cervical spine series, 43 skeletal radiographs, 9 ultrasound studies, 7 scans, and 2 venograms. Comparison of digital to film interpretations demonstrated agreement in 211 of 215 cases, for a ratio of 98.1%.     

Omeprazole and visual disorders: seeing alternatives

In the WHO data base, visual disorders reported spontaneously with omeprazole, ranitidine and cimetidine, are very rare in the context of the widespread use of these drugs. There is a maximum reporting rate of severe visual impairment possibly ascribed to i.v. omeprazole of 0.94 reports per million treatment days in one year and in one country, Germany. This gives the worst quantitative case scenario for omeprazole by a single route of administration, to be compared with the worldwide reporting rate of all severe visual disorders by all routes of administration--0.008 reports per million treatment days. Moreover, the reported visual abnormalities have a varied pathophysiological aetiology and their number increased in Germany after the first signal was raised in that country. Thus, apart from a direct causal relationship, solicited reporting artifact is one alternate plausible explanation for the apparent excess of cases of visual disturbance to omeprazole compared with cimetidine and ranitidine. That reporting rates of clinical events on newly marketed drugs are generally higher than with older drugs is a second factor for higher reporting rates with omeprazole. Vasculitis has been suggested as an aetiological factor, but the even lower reporting rate of this reaction makes this an unlikely hypothesis without any other supporting evidence. The authors are unaware of any drug that has caused a vasculities solely affecting the eye. Information on the prevalence of relevant visual disorders in the community would have been of considerable help in interpreting this signal, and a case control study of visual events in relationship to severe illness would be of public health interest, since no data seems to exist concerning this.     

STUDY ON INTEROBSERVER AGREEMENT IN A GOITRE PREVALENCE SURVEY

Observers differ in their judgment while assessing physical signs in a patient. We had undertaken a goitre prevalence survey amongst school students in a Rural Health Training Centre, Pune district (Maharashtra) during October 1992. Four teams of trained observers were used for detection of goitre. This study was undertaken to estimate the extent and acceptability of interobserver agreement amongst the four teams. Observer variation/agreement was measured by two methods viz. kappa coefficient and proportion of agreement. The proportion of agreement appears to be a better measure of observer agreement as it could make a distinction between normality (absence of goitre) and abnormality (presence of goitre). In the present study, the proportion of agreement for abnormality ranged between 0.62 – 0.83. This measure was considered as indicating a good interobserver agreement in detecting goitre in the survey that was undertaken.KEY WORDS: Confidence intervals, Epidemiologic methods, Health surveys, Observer variation     

Co-ligation of alpha4beta1 integrin and TCR rescues human thymocytes from steroid-induced apoptosis

Maturation of thymocytes represents a sequence of events during which thymocytes expressing TCR with moderate avidity for self antigen/MHC are positively selected, whereas those with high or insufficient TCR avidity die. Glucocorticoids are produced intrathymically and can contribute to apoptosis of unselected thymocytes. Thymocytes differentiate in a close contact with epithelial cells, expressing vascular adhesion molecule-1 (VCAM-1) and secreting glucocorticoids, with bone marrow-derived macrophages, and with extracellular matrix containing fibronectin (FN) and collagen. Their contact with FN is mediated by alpha4beta1 and alpha5beta1 integrins. We examined the contribution of TCR and integrin signaling to the survival of thymocytes from dexamethasone (Dex)-induced apoptosis. We demonstrate that FN and VCAM-1 (both of which bind alpha4beta1 integrin), but not collagen, considerably augment TCR-mediated protection of thymocytes from Dex-induced apoptosis. This 'survival' signal is transduced through the alphabeta1, but not through the alpha5beta1 integrin. The observed protection from Dex-induced apoptosis correlated with an increase in bcl-2 protein levels. FN-alpha4beta1 and VCAM-1-alpha4beta1 engagement induced up-regulation bcl-2 protein, while alpha5beta1 binding to FN induced a negative signal that was blocked by anti- alpha5beta1 antibody. These data suggest that alpha4beta1 integrin may contribute to protection of thymocytes with moderate avidity TCR from glucocorticoid-induced death during intrathymic maturation.