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J Hughes

Publications and source records attributed to J Hughes.

At least 289 records · Page 16Linked to original sources
PubMed1994

The CCK-B antagonist CI988 enhances the reflex-depressive effect of morphine in axotomized rats.

We have examined and compared the effect of systemic CI988, an antagonist of the cholecystokinin B receptor, and morphine on the flexor reflex in rats with intact sciatic nerves and after unilateral axotomy. Intravenous injection of 1 mg kg-1 morphine caused a moderate depression of the flexor reflex in normal and axotomized rats. The duration of morphine-induced depression was significantly shortened in axotomized animals. In contrast, the brief depressive effect of intravenous CI988 on the flexor reflex was significantly enhanced in axotomized rats. Combination of morphine and CI988 resulted in a significant potentiation of reflex depression in rats with intact or sectioned sciatic nerves. It is concluded that blockade of CCK-B receptor potentiated morphine-induced antinociception in rats after peripheral nerve injury.

Animals↗
PubMed1994

The mechanism of action of gastrin releasing peptide (GRP) in stimulating avian gastric acid secretion.

The mechanisms of action of gastrin and gastrin releasing peptide (GRP) in stimulating gastric acid secretion were examined in the anaesthetized turkey. Gastrin and GRP produced dose-dependent increases in acid secretion that were inhibited by the gastrin/CCK-B antagonist CI988. The antagonist did not affect the acid secretory responses to histamine or carbachol. A GRP antagonist (M216140) inhibited the acid response to GRP, but not gastrin. The results suggest that in birds, GRP stimulates acid secretion by release of gastrin, which acts in turn on classical gastrin/CCK-B receptors in the proventriculus.

Analysis of Variance↗
PubMed1994

Hepatitis B virus infection, the immune response and hepatocellular carcinoma.

More than 250 million people worldwide are chronically infected with the hepatitis B virus (HBV) and have a 200-fold increased risk of developing hepatocellular carcinoma (HCC). This is one of the most common cancers in the world with a geographical distribution highest in areas where HBV is endemic. A number of molecular mechanisms have been proposed to explain this correlation including an acutely transforming viral oncogene; chromosomal aberrations due to HBV integration (i.e. deletions, translocations, duplications); activation of cellular proto-oncogenes; inactivation of cellular anti-oncogenes; and transactivation of cellular genes by HBV gene products. HCC usually develops only after 20-30 years of persistent HBV infection accompanied by hepatocyte necrosis, inflammation and regenerative hyperplasia. Because HBV is not directly cytopathic, liver injury must be immune mediated. Factors that predispose HBV-infected individuals to develop HCC are chronicity, an immune response and liver injury rather than a direct genetic event. Hepatic injury and continuous hepatocyte regeneration may allow an accumulation of multiple mutational events sufficient for the emergence of HCC. Pathways which lead to chronicity, the immune response during HBV infection, mechanisms of pathogenesis and methods to prevent HBV infection are all relevant to the development of HCC. Recent studies characterizing the humoral and cellular immune responses in patients chronically infected with HBV and transgenic mouse models of HBV-specific immune tolerance and pathogenesis are providing new insights into the complex association between HBV infection and HCC.

Animals↗
PubMed1994

Purification, characterization, and cloning of alpha-hydroxynitrile lyase from cassava (Manihot esculenta Crantz).

alpha-Hydroxynitrile lyase (HNL, acetone cyanohydrin lyase, EC 4.1.2.37) was purified to homogeneity from young leaves of the cyanogenic tropical crop plant cassava (Manihot esculenta Crantz). The purified protein is a homo-trimer with a subunit relative molecular mass of 28,500 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The active protein is not glycosylated and does not contain a flavin group. HNL exhibits complex kinetics which vary according to substrate concentration and may be related to aggregation of the enzyme. HNL activity against two natural substrates, acetone cyanohydrin and 2-butanone cyanohydrin, and one nonphysiological substrate, 2-pentanone cyanohydrin, was demonstrated. N-terminal and internal peptide sequences, obtained from HNL digested with the endoproteinase Glu-C, were used to design degenerate oligonucleotide primers for polymerase chain reaction with single-strand cDNA, using purified mRNA from cotyledons as template. The resulting DNA fragment was used to probe a cassava cotyledon cDNA library. Four cDNA clones were isolated, sequenced, and shown to contain derived amino acid sequences identical to those obtained from the purified protein.

Aldehyde-Lyases↗
PubMed1994

Evidence that cholecystokinin induces immediate early gene expression in the brainstem, hypothalamus and amygdala of the rat by a CCKA receptor mechanism.

The effect of sulphated cholecystokinin octapeptide (CCK-8S) on immediate early gene expression in the rat CNS was investigated using the technique of in situ hybridization. A rapid and transient induction of c-fos, NGFI-A and NGFI-B (nerve growth factor-induced genes A and B) mRNA was demonstrated in the nucleus tractus solitarius (NTS), area postrema (AP), hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, and central nucleus of the amygdala, following peripheral administration of CCK-8S (1-100 micrograms/kg i.p.). In contrast, levels of c-jun, junB and junD mRNA were unaffected by the peptide. The closely related decapeptide, caerulein (50 micrograms/kg i.p.), induced the same pattern of IEG expression as CCK-8S, whereas the desulphated octapeptide, CCK-8DS (50 micrograms/kg i.p.), had no effect on levels of mRNA for any IEG studied. Expression of IEG mRNA in these areas was suppressed by bilateral subdiaphragmatic vagotomy, and by pretreatment with the selective CCKA receptor antagonist, devazepide (0.1 and 1 mg/kg i.p.). In contrast, CCK-8S induction of IEG mRNA was not blocked by pretreatment with the selective CCKB receptor antagonist, CI-988 (1 or 10 mg/kg i.p.). In addition, the selective CCKB receptor agonists, CCK-4 (50 micrograms/kg i.p.) or pentagastrin (2 mg/kg i.p.), failed to induce IEG expression in any of the areas studied. These results suggest that systemic CCK-8S primarily acts via CCKA receptors on vagal afferents to stimulate IEG mRNA expression in the rat CNS.

Amygdala↗
PubMed1994

Hallucinations following cardiac surgery in a paediatric intensive care unit.

Abnormal behaviour as a result of benzodiezapine withdrawal has been reported in children in intensive care. Other causes of abnormal behaviour may be as a result of intensive care unit (ICU) psychosis or delirium. ICU psychosis in adults is well documented but is rarely reported in children, hence this report on a child who suffered hallucinations after cardiac surgery, and discussion on possible causes and the need for greater awareness of this possible complication.

Cardiac Surgical Procedures↗
PubMed1994

Rational design of high affinity tachykinin NK2 receptor antagonists.

The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).

Amino Acid Sequence↗
PubMed1994

Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome.

Major genes which cause tuberous sclerosis (TSC) and autosomal dominant polycystic kidney disease (ADPKD), known as TSC2 and PKD1 respectively, lie immediately adjacent to each other on chromosome 16p. Renal cysts are often found in TSC, but a specific renal phenotype, distinguished by the severity and infantile presentation of the cystic changes, is seen in a small proportion of cases. We have identified large deletions disrupting TSC2 and PKD1 in each of six such cases studied. Analysis of the deletions indicates that they inactivate PKD1, in contrast to the mutations reported in ADPKD patients, where in each case abnormal transcripts have been detected.

Adolescent↗
PubMed1994

Ontogeny of granulosa cells in the ovary: lineage-specific expression of transforming growth factor beta 2 and transforming growth factor beta 1.

The differentiation of ovarian somatic cells into granulosa, interstitial, and thecal lineages, and the ovarian growth factor(s) potentially associated with the cytodifferentiation of granulosa cells during the perinatal period were investigated using cell type-specific protein markers. Ovaries collected from prenatal (Days 12-15 of pregnancy) and postnatal (Days 1-30) female hamsters were processed for immunohistochemical localization of transforming growth factor (TGF) beta (TGF beta 1, beta 2, and beta 3). Plasma levels of FSH, LH, progesterone, and estradiol-17 beta were detected by RIA. Prenatal hamster ovaries contained numerous mitotic oocytes and a few somatic cells. Only a fraction of somatic cells expressed barely detectable TGF beta 2 activity. Plasma FSH levels were quite detectable on postnatal Day 1 and increased gradually to reach a peak on Day 25, whereas LH did not increase until Day 12 and reached a plateau by postnatal Day 20. On postnatal Day 1, TGF beta 2 immunoreactivity was localized only in certain cells closely apposed to primordial oocytes. On postnatal Day 4, flattened, TGF beta 2-positive cells encircled individual oocytes, forming the very first cohort of primordial follicles. By Days 7 and 8, primary and early secondary follicles with intense TGF beta 2-positive cuboidal granulosa cells appeared. Subsequently, in large preantral follicles TGF beta 2 was expressed only in mural granulosa cells. On Day 13, TGF beta 1 and beta 2 immunoreactivities appeared for the first time in the interstitial cells. TGF beta 1 was localized in cells closely apposed to follicles, but TGF beta 2 activity was restricted to scattered cell clusters. Subsequently, the entire interstitium was positive for TGF beta 1 protein. These results suggest that differentiation of somatic cells into granulosa cells is the first event in ovarian morphogenesis; once the finite number of granulosa cells is selected, the residual cells differentiate into interstitium. Whether ovarian TGF beta 2 and TGF beta 1 are physiologically important in granulosa and interstitial cell differentiation needs further evaluation.

Animals↗
PubMed1994

Accuracy of reported family history of heart disease: the impact of 'don't know' responses.

BACKGROUND: Usual 'Yes/No' definitions of a family history of heart disease do not allow for 'Don't know' responses. In some families, misclassification of family history may result if these are not considered. AIMS: To study the accuracy of family history reporting and the impact of 'Don't know' responses. METHODS: We compared reported family history of coronary heart disease (CHD) and cancer among 360 deceased relatives of 59 probands with 'gold standard' diagnoses recorded on official death certificates. RESULTS: For first degree relatives, sensitivity of reporting was 81% for CHD, 86% for any heart disease and 60% for cancer, while for second degree relatives, sensitivity was 73%, 69% and 90%, respectively. When 'Don't know' responses were classified as 'No', sensitivity in first degree relatives was not affected, but in second degree relatives, it fell to 49%, 41% and 60%, respectively. Specificities were unchanged. These data show that in families where information beyond first degree relatives is considered, failing to account for 'Don't know' responses is likely to lead to misclassification of family history of CHD.

Adult↗
PubMed1994

A prospective study of the adverse effects of midazolam on withdrawal in critically ill children.

Fifty-three critically ill infants and children received midazolam as sedation in a regional intensive care unit. Assessment of the level of sedation was carried out at regular intervals on withdrawal of midazolam. Forty-nine patients were fully alert within 4 h of midazolam being stopped. Four patients took from 6 h to 1 week to become fully alert. Four patients had abnormal behaviour highly suggestive of midazolam withdrawal. The onset of abnormal behaviour was within 12 h of discontinuation of midazolam. The duration of the abnormal behaviour ranged from 3 h to 1 week. One child had a paradoxical reaction to midazolam. The overall incidence of adverse effects to midazolam in the patients studied was 17%. No adverse effects were observed in infants; all adverse effects were observed in children. We have shown that it is possible to prospectively study the toxicity of sedatives in critically ill infants and children.

Child↗
PubMed1994

Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.

Increases in mesangial cell number may herald glomerular scarring, but they are not irreversible. This study sought mechanisms by which surplus glomerular mesangial cells can be cleared. A small proportion of cultured mesangial cells exhibited typical morphological features of apoptosis (programmed cell death), which was increased by growth factor deprivation or exposure to cycloheximide, stimuli known to increase apoptosis in other cell types. Apoptosis was confirmed by typical internucleosomal chromatin cleavage. In vivo, clear morphological evidence of mesangial apoptosis leading to phagocytosis by neighboring mesangial cells was obtained in self-limited mesangial proliferation induced in rats by Thy1.1 antibody, apoptosis occurring approximately 10-fold more frequently than in the healthy rat glomerulus. Indeed, changes in glomerular cell number in Thy1.1 nephritis strongly suggested that apoptosis is the major cell clearance mechanism counterbalancing cell division, thereby mediating resolution of glomerular hypercellularity in experimental mesangial proliferation.

Animals↗
PubMed1994

Multiple secondary plant product UDP-glucose glucosyltransferase genes expressed in cassava (Manihot esculenta Crantz) cotyledons.

Six different putative UDP-glucose glucosyltransferase clones were isolated from a cassava cotyledon cDNA library probed with an Acc I-Bgl II restriction fragment from a UDP-glucose flavonoid 3-O-glucosyltransferase from Antirrhinum majus. The heterologous probe contained a glucosyltransferase consensus signature amino acid sequence which was also present in the cassava cDNA clones. Nucleotide and derived amino acid sequences are presented for two of the clones. Northern analysis showed different patterns of expression for the six genes in developing seedling tissues, indicating temporal and tissue-specific regulation. A comparative analysis was made of the six cassava clone derived amino acid sequences and other reported UDP-glucosyltransferase genes. Highly conserved residues in plant genes from three species allow redefinition of essential residues within the signature sequence for secondary plant product metabolism glucosyltransferase genes.

Amino Acid Sequence↗
PubMed1994

Assessment of proliferating cell nuclear antigen (PCNA) in breast cancer using anti-PCNA PC10 and 19A2: correlation with 5-bromo-2'-deoxyuridine or tritiated thymidine labeling and flow cytometric analysis.

We compared immunohistochemical staining by two monoclonal antibodies, PC10 and 19A2, to standard methods for cell proliferation, 3H-TdR or BrdU labeling index (S-LI) and S-phase fraction by flow cytometry (S-flow). One hundred thirty-two breast carcinomas were studied retrospectively using formalin fixed, paraffin embedded archival tissues on which S-LI and S-flow had been obtained originally. Percentages of tumor cells positive with PC10 and 19A2 correlated well (r = 0.736, p < 0.0001), although the mean marking index for 19A2 was lower and closer to reference measurements than the mean PC10 index. Correlations between PC10 or 19A2 vs. S-LI, S-flow or DNA ploidy (DNAI) were significant in a group of 64 tumors obtained between 1988 and June 1992, and poor in another group of 68 tumors obtained between 1985 and 1988, suggesting deterioration of stainability with prolonged storage. Discrimination of faint staining from negative nuclei was difficult on PCNA stained sections. Carnoy fixation did not improve results over those fixed with formalin. S-flow and S-LI predicted relapse-free survival, but PCNA indices did not. We conclude that PC10 and 19A2 immunostaining of formalin or Carnoy fixed archival breast cancer tissue correlated with reference measures of proliferation only in cases of short storage periods. Although statistically significant, levels of correlation were too low to use PCNA indices for prognosis.

Antibodies, Monoclonal↗
PubMed1994

Chronic conditions and risk of in-hospital death.

OBJECTIVE: This study examined the relationship of in-hospital death and 13 conditions likely to have been present prior to the patient's admission to the hospital, defined using secondary discharge diagnosis codes. DATA SOURCES AND STUDY SETTING: 1988 California computerized hospital discharge abstract data, including 24 secondary diagnosis coding slots, from all general, acute care hospitals. STUDY DESIGN: The odds ratio for in-hospital death associated with each of 13 chronic conditions was computed from a multivariable logistic regression using patient age and all chronic conditions to predict in-hospital death. DATA EXTRACTION: All 1,949,276 general medical and surgical admissions of persons over 17 years of age were included. Patients were assigned to four groups according to the mortality rate of their reason for admission; some analyses separated medical and surgical hospitalizations. PRINCIPAL FINDINGS: Overall mortality was 4.4 percent. For all cases, mortality varied by chronic condition, ranging from 5.3 percent for coronary artery disease to 18.6 percent for nutritional deficiencies. The odds ratios associated with the presence of a chronic condition were generally highest for patients in the rare mortality group. Although chronic conditions were more commonly listed for medical patients, the associated odds ratios were generally higher for surgical patients, particularly in lower mortality groups. CONCLUSIONS: Studies examining death rates need to consider the influence of chronic conditions. Chronic conditions had a particularly significant association with the likelihood of death for admission types generally associated with low mortality rates and for surgical hospitalizations. The accuracy and completeness of discharge diagnoses require further study, especially relating to chronic illnesses.

Adolescent↗