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Biomedical subjects

I Jeffrey

Publications and source records attributed to I Jeffrey.

16 recordsLinked to original sources
PubMed2003

Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen.

The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons.

Acidosis↗
PubMed2000

Differential requirements for caspase-8 activity in the mechanism of phosphorylation of eIF2alpha, cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells.

Previously we have reported that induction of apoptosis in Jurkat cells results in an inhibition of overall protein synthesis with the selective and rapid cleavage of eukaryotic initiation factor (eIF) 4GI. For the cleavage of eIF4GI, caspase-3 activity is both necessary and sufficient in vivo, in a process which does not require signaling through the p38 MAP kinase pathway. We now show that activation of the Fas/CD95 receptor promotes an early, transient increase in the level of eIF2alpha phosphorylation, which is temporally correlated with the onset of the inhibition of translation. This is associated with a modest increase in the autophosphorylation of the protein kinase activated by double-stranded RNA. Using a Jurkat cell line that is deficient in caspase-8 and resistant to anti-Fas-induced apoptosis, we show that whilst the cleavage of eIF4GI is caspase-8-dependent, the enhancement of eIF2alpha phosphorylation does not require caspase-8 activity and occurs prior to the cleavage of eIF4GI. In addition, activation of the Fas/CD95 receptor results in the caspase-8-dependent dephosphorylation and degradation of p70(S6K), the enhanced binding of 4E-BP1 to eIF4E, and, at later times, the cleavage of eIF2alpha. These data suggest that apoptosis impinges upon the activity of several polypeptides which are central to the regulation of protein synthesis and that multiple signaling pathways are involved in vivo.

Apoptosis↗
PubMed1997

Role of the interstitial cells of Cajal in the control of gut motility.

BACKGROUND: The interstitial cells of Cajal (ICCs) are a population of cells in the gastrointestinal tract which have a role in the control of gut motility. METHOD: A comprehensive review of the scientific literature was undertaken to assess current understanding of the morphology, structure, identification, distribution, development and function of these cells. RESULTS AND CONCLUSIONS: ICCs have an important role in the control of gut motility. Experimental evidence from animal studies suggests roles as pacemakers and coordinators of gut motor activity, and as intermediaries in the neural control of motility. With an increasing understanding of the distribution and behaviour of these cells in the healthy or diseased human gastrointestinal tract, there is the potential to develop novel therapeutic approaches to diseases that have gut dysmotility as a contributory factor.

Digestive System↗
PubMed1994

Effect of ethnic origin of mother on fetal outcome.

The outcome of 11046 infants, from 20 weeks' gestation, born to mothers of different ethnic origins within one London borough has been analysed. There was no difference in perinatal death rates between the Asian and white infants. Among those with mothers from Africa and the West Indies there were overall significantly more intrauterine deaths (26.8/1000 and 20.0/1000) and neonatal deaths (8.6/1000 and 9.6/1000) than for the white mothers (intrauterine deaths 8.3/1000; neonatal deaths 3.7/1000). At less than 28 weeks', gestation specific death rates were similar in all groups and the overall higher death rates were due to an increase in the proportion of preterm deliveries among the black mothers. From 28 to 36 weeks' gestation, black infants born alive had lower neonatal death rates (7.7/1000) than the white infants (19/1000). The cause of the increased incidence of preterm labour among the black mothers is uncertain, though differences in intrauterine infection rates may be an important factor.

Adult↗
PubMed1993

Comparative analysis of the regulation of the interferon-inducible protein kinase PKR by Epstein-Barr virus RNAs EBER-1 and EBER-2 and adenovirus VAI RNA.

The interferon-inducible protein kinase PKR interacts with a number of small viral RNA species, including adenovirus VAI RNA and the Epstein-Barr virus-encoded RNA EBER-1. These RNAs bind to PKR and protect protein synthesis from inhibition by double-stranded RNA in the reticulocyte lysate system. Using a peptide phosphorylation assay we show here that EBER-1, like VAI, directly inhibits the activation of purified PKR. A second Epstein-Barr virus RNA, EBER-2, also regulates PKR. EBER-1, EBER-2 and VAI RNA exhibit mutually competitive binding to the native or recombinant enzyme, as assessed by U.V. crosslinking experiments and filter binding assays. The affinities of all three RNAs for PKR in vitro are similar (Kd = ca. 0.3 nM). Since this protein kinase has been proposed to exert a tumour suppressor function in vivo, the ability of EBER-1 to inhibit its activation suggests a role for this small RNA in cell transformation by Epstein-Barr virus.

Adenoviridae↗
PubMed1993

Reversal of the double-stranded-RNA-induced inhibition of protein synthesis by a catalytically inactive mutant of the protein kinase PKR.

The interferon-inducible double-stranded-RNA(dsRNA)-dependent protein kinase PKR has been implicated in both the antiviral and cell growth-regulatory effects of the interferons. Over-expression of the wild-type form of this protein inhibits cell proliferation, whereas over-expression of inactive mutant forms transforms cells to a tumourigenic phenotype. It has been suggested that mutant PKR exerts a dominant negative effect on the activity of the wild-type protein kinase. We have investigated this possibility using the rabbit reticulocyte cell-free translation system in which protein synthesis is inhibited by dsRNA due to activation of PKR and phosphorylation of initiation factor eIF-2. Addition of a highly purified inactive PKR mutant, synthesised in a baculovirus-infected insect cell system, rescues protein synthesis from inhibition by low concentrations of dsRNA in a dose-dependent manner. The PKR mutant has no effect on protein synthesis in the absence of dsRNA or in the presence of another inhibitory protein kinase, the haem-controlled repressor. Inhibition of translation can be re-established in the presence of the mutant PKR by adding a higher concentration of dsRNA. These results suggest that inactive mutant PKR does exert a dominant negative effect on wild-type PKR and that this may be due to competition for dsRNA binding.

Animals↗
PubMed1984

Sites of recurrent tumour after 'curative' colorectal surgery: implications for adjuvant therapy.

The pattern of recurrent tumour following 'curative' colorectal surgery was examined in a necropsy series and a prospective clinical series. In the necropsy series the commonest pattern of recurrence was disseminated disease (73 per cent) and recurrence in a single site was much less common (27 per cent). In the clinical series recurrence in a single site was commoner (55 per cent). The difference between the two series is statistically significant (P = 0.02, chi 2), and is probably due to under-diagnosis of disseminated recurrence in the clinical series. In both series local recurrence and hepatic metastases occurred almost equally but usually as part of disseminated disease. We conclude that after 'curative' surgery for colorectal cancer, recurrence is usually disseminated (73 per cent) and therefore therapy adjuvant to surgery should be active systemically. Adjuvant therapy directed at a single site (e.g. radiotherapy or intrahepatic chemotherapy) should be combined with a systemic therapy.

Adult↗
PubMed1984

Cholelithiasis in a preterm infant.

A case of cholelithiasis in a preterm infant is described. The baby survived for 105 days, during which time she received multiple blood transfusions. Three pigment stones were found in the gallbladder at necropsy. It is suggested that they were a consequence of an excessive bilirubin load, the result of maintaining the hemoglobin above physiological levels.

Cholelithiasis↗
PubMed1983

Prognostic value of tumour thickness in cutaneous malignant melanoma.

The relation between survival and histological features in 91 patients with malignant melanoma was studied and the results were analysed by Clayton's method for interpretation of censored survival data. There was a significant correlation between tumour thickness and survival. The risk of dying from malignant melanoma after 10 years of follow up was less than 15% if the primary tumour was less than 1.5 mm thick but more than 80% if the lesion was thicker than 8 mm. The type of melanoma, level of invasion, mitotic rate, and presence of ulceration also correlated with survival, but these variables are related to tumour thickness.

Adult↗
PubMed1983

Osteoclast-type giant cell tumour of the pancreas.

A case of osteoclast-type giant cell tumour of the pancreas is described and the features of eight other previously reported patients are reviewed. Characteristically, these neoplasms are large at presentation and show focal haemorrhage and necrosis, but seem slow to give rise to metastases. Histological examination reveals numerous osteoclast-like giant cells set in a sarcomatous stroma, the appearances being similar to those seen in giant cell tumours of bone. They are distinct from pleomorphic giant cell carcinomas of the pancreas and may have a slightly better prognosis after resection than ordinary adenocarcinomas. The histogenesis of these rare tumours is unknown.

Giant Cell Tumors↗
PubMed1983

The pathology of meconium ileus equivalent.

A case of meconium ileus equivalent in a 25-year-old woman with cystic fibrosis is reported and the pathology of this condition is described. On gross examination the lumen of the terminal ileum was completely obstructed by a mass of inspissated faecal material with a putty-like consistency. The principal microscopic findings were plugging of the mucosal crypts with mucoid secretion, distention of goblet cells and the presence of a thick layer of mucus, admixed with faecal material, adherent to the mucosal surface. Mucin histochemistry demonstrated sulphomucin in the terminal ileum, although acidic mucins in the normal small intestine are almost exclusively non-sulphated.

Adult↗
PubMedDate not supplied

Polycystin expression during embryonic development of human kidney in adult tissues and ADPKD tissue.

Normal renal tissue, ranging from 8 weeks' gestation to full term to adult, was probed with polyclonal antibodies raised to peptide epitopes within the translated PKD1 gene sequence. Three antibodies were studied, all of which gave similar results. Renal tissue from patients with autosomal dominant polycystic kidney disease (ADPKD) and samples from normal adult liver, heart, brain, skeletal muscle and lymph node were also studied. Tissue staining demonstrated that the pattern of polycystin expression changed with gestational age in normal kidney. Whereas the precursors to the renal excretory unit were stained at 12 weeks, and the proximal and distal convoluted tubules stained to differing degrees throughout development, the glomeruli were poorly stained until full term and also in the adult. Extrarenal tissue stained in both adult and juvenile samples, with the exception of lymph node, which remained unstained. The intensity of polycystin staining increased in ADPKD renal tissue. The widespread distribution of polycystin was consistent with the systemic nature of ADPKD and the role of epithelial cells in the disease.

Adult↗
PubMedDate not supplied

Fragmentation of the ribosome to investigate RNA-ligand interactions.

RNA molecules perform a variety of important and diverse functions and, therefore, an understanding of their structure and interaction with proteins and ligands is essential. Large RNA molecules (for example, the ribosomal RNAs) are complex and hence reports describing their fragmentation into functional subdomains has provided a means for their detailed analysis. We present here an in vivo approach to study RNA-ligand interactions. This is based on the concept that an RNA fragment could mimic a drug-binding site present on the intact molecule. Overexpression of the fragment would sequester the drug thereby permitting the continued functioning of the ribosome and, thus, ensuring cell viability. Accordingly, a fragment of 16S rRNA encompassing the spectinomycin-binding domain in helix 34 (nucleotides 1046-1065 and 1191-1211) was cloned and in vivo expression resulted in drug resistance. Furthermore, an RNA fragment lacking flanking sequences to helix 34 was also selected from among a pool of random rRNA fragments and shown to confer spectinomycin resistance. A similar in vitro approach is also described for the analysis of rRNA molecules that interact with the yeast elongation factor 3 (EF-3).

Anti-Bacterial Agents↗