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Biomedical subjects

J Phillips

Publications and source records attributed to J Phillips.

At least 91 records · Page 5Linked to original sources
PubMed1998

Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription.

Several observations indicate that late-G1/S-phase-specific cellular functions may be required for herpes simplex virus (HSV) replication: (i) certain mutant HSV strains are replication impaired during infection of cells in the G0/G1 but not in the G1/S phase of the cell cycle, (ii) several late-G1/S-phase-specific cellular proteins and functions are induced during infection, and (iii) the activity of a cellular protein essential for expression of viral immediate-early (IE) genes, HCF, is normally required during the late G1/S phase of the cell cycle. To test the hypothesis that late-G1/S-phase-specific cellular functions are necessary for HSV replication, HEL or Vero cells were infected in the presence of the cell cycle inhibitors roscovitine (Rosco) and olomoucine (Olo). Both drugs inhibit cyclin-dependent kinase 1 (cdk-1) and cdk-2 (required for cell cycle progression into the late G1/S phase) and cdk-5 (inactive in cycling cells) but not cdk-4 or cdk-6 (active at early G1). We found that HSV replication was inhibited by Rosco and Olo but not by lovastatin (a cell cycle inhibitor that does not inhibit cdk activity), staurosporine (a broad-spectrum protein serine-threonine kinase inhibitor), PD98059 (an inhibitor specific for erk-1 and -2) or iso-Olo (a structural isomer of Olo that does not inhibit cdk activity). The concentrations of Rosco and Olo required to inhibit cell cycle progression and viral replication in both HEL and Vero cells were similar. Inhibition of viral replication was found not to be mediated by drug-induced cytotoxicity. Efforts to isolate Rosco- or Olo-resistant HSV mutants were unsuccessful, indicating that these drugs do not act by inhibiting a single viral target. Viral DNA replication and accumulation of IE and early viral RNAs were inhibited in the presence of cell cycle-inhibitory concentrations of Rosco or Olo. We therefore conclude that one or more cdks active from late G1 onward or inactive in nonneuronal cells are required for accumulation of HSV transcripts, viral DNA replication, and production of infectious virus.

Amino Acid Sequence↗
PubMed1998

Coexistent hairy cell leukaemia and chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) and hairy cell leukaemia (HCL) are chronic B-cell lymphoproliferative disorders (B-LPDs) with distinct clinical, morphological and immunocytochemical features. Transformation of CLL into other B-LPDs (prolymphocytic leukaemia (PLL) and large cell lymphoma) is a well recognised phenomenon. One previous report has suggested that HCL may also arise by clonal evolution from CLL. We report the case of a 75 year old man in whom a diagnosis of coexisting HCL was made seventeen years after an initial diagnosis of CLL. Immunoglobulin heavy chain rearrangement studies suggest that the two B-LPDs developed independently. A steady increase in the bone marrow HCL component at the expense of the CLL component was observed with time, suggesting that HCL may have a growth advantage over CLL.

Aged↗
PubMed1998

Net hepatic glucose output is normal on postoperative day 1 after liver transplantation.

The liver plays a central role in carbohydrate metabolism and glucose homeostasis; therefore, the rapid recovery of glucose homeostasis after liver transplantation (LT) is important. The purpose of this study was to evaluate hepatic and whole-body glucose production (WBGP) on postoperative day 1 after LT using a combination of arteriovenous differences and radioisotope techniques. Two groups of female commercially bred pigs with an average body weight of 31.9 +/- 1.4 kg were studied. A control group (n = 6) underwent laparotomy. A transplanted group (n = 6) was submitted to LT. All pigs were instrumented with catheters placed in the carotid artery and the hepatic, portal, and jugular vein, and flow probes were placed around the hepatic artery and portal vein. WBGP was measured by a primed constant infusion of 3-[3H]glucose 1 day postoperatively. Plasma glucose was 89 +/- 6 versus 98 +/- 7 mg/dL in the control and transplanted groups, respectively. WBGP was increased by 42 per cent in the transplanted group (2.54 +/- 0.17 vs 3.62 +/- 0.39 mg/kg.min), but the net hepatic glucose output was not different between the control and the transplanted groups (1.53 +/- 0.28 vs 1.68 +/- 0.31 mg/kg.min). These results demonstrate that net hepatic glucose output was not different between the control and transplanted pigs, suggesting that LT does not compromise the ability of the liver to produce glucose. However, the WBGP was increased by 42 per cent in the transplanted group, suggesting either a significant contribution from another organ or a significant intrahepatic utilization of glucose.

Animals↗
PubMed1997

Seed-specific immunomodulation of abscisic acid activity induces a developmental switch.

A single-chain Fv antibody (scFv) gene, which has previously been used to immunomodulate abscisic acid (ABA) activity in transgenic tobacco to create a 'wilty' phenotype, was put under control of the seed-specific USP promoter from Vicia faba and used to transform tobacco. Transformants were phenotypically similar to wild-type plants apart from their seeds. Anti-ABA scFv embryo development differed markedly from wild-type embryo development. Seeds which accumulated similar levels of a scFv that binds to oxazolone, a hapten absent from plants, developed like wild-type embryos. Anti-ABA scFv embryos developed green cotyledons containing chloroplasts and accumulated photosynthetic pigments but produced less seed storage protein and oil bodies. Anti-ABA scFv seeds germinated precociously if removed from seed capsules during development but were incapable of germination after drying. Total ABA levels were higher than in wild-type seeds but calculated free ABA levels were near-zero until 21 days after pollination. We show for the first time seed-specific immunomodulation and the resulting switch from the seed maturation programme to a germination programme. We conclude that the immunomodulation of hormones can alter the development programme of target organs, allowing the study of the directly blocked endogenous molecules and manipulation of the system concerned.

Abscisic Acid↗
PubMed1997

Ocular morbidity in very low birth-weight infants with intraventricular hemorrhage.

PURPOSE: To document ocular outcomes and prevalence of ocular disease in very low birth-weight infants with intraventricular hemorrhage. METHODS: We retrospectively reviewed the records of all surviving very low birth-weight infants (1,500 g or less) admitted to the neonatal intensive care unit of our institution during 1992 and 1993. Of 252 survivors, 74 had complete ophthalmologic examinations at a mean adjusted age of 11 months. Of these 74 infants, 38 had intraventricular hemorrhage. Chi-square and multivariate analysis were used for statistical testing, in controlling for race, sex, and birth weight, and for other disease processes associated with prematurity. RESULTS: Of 38 infants with intraventricular hemorrhage, strabismus occurred in 14 (37%), esotropia in 12 (32%), and exotropia in two (5%). Of the 20 infants with grades III and IV intraventricular hemorrhage, 11 (55%) had esotropia; none had exotropia. Infants with grades III and IV intraventricular hemorrhage were at significantly greater risk for the development of esotropia than were infants with less severe or no hemorrhage (odds ratio, 5.0; P = .04). Mean adjusted age at diagnosis of strabismus was 8.5 months. Infants with periventricular leukomalacia (odds ratio, 6.3; P = .036) and neonatal seizures (odds ratio, 7.3; P = .019) were at significantly greater risk of developing optic atrophy. CONCLUSIONS: Very low birth-weight infants with more severe neurologic morbidity are at significant risk for development of esotropia and optic atrophy. Ophthalmologic screening of all very low birth-weight survivors may allow earlier diagnosis and intervention for these at-risk infants.

Cerebral Hemorrhage↗
PubMed1997

Optimization of scFv antibody production in transgenic plants.

BACKGROUND: Plants offer various advantages for the production of pharmaceutical proteins over conventional production systems such as bacterial or mammalian cell culture. In order to explore transgenic plants for large-scale production and storage of recombinant antibodies we tried to optimize the accumulation and stability of functionally active single chain Fv (scFv) antibodies in transgenic tobacco plants. OBJECTIVES: Two different scFv antibodies which were expressed in different plant organs and plant cell compartments have been used for the study. Accumulation levels and antibody properties such as stability and antigen-binding activity were investigated. STUDY DESIGN: For ubiquitous expression in tobacco plants, transcription of the scFv genes was controlled by the strong cauliflower mosaic virus (CaMV) 35S promoter. We used seed specific legumin B4 (LeB4) and the unknown seed protein (USP) promoters from Vicia faba for storage organ specific expression. RESULTS: High accumulation of the two different scFv proteins in transgenic tobacco plants was only achieved by retention of the recombinant antibodies in the lumen of the endoplasmic reticulum (ER). Expression levels of scFv antibodies reached up to 4-6.8% of total soluble proteins (TSP) in leaves and up to 3-4% in ripe tobacco seeds. Transgenic tobacco seeds as well as tobacco leaves facilitated stable storage of ER-accumulated scFvs over an extended (seeds) or a short (leaves) period of time. Functionally active scFv proteins could be extracted after harvesting of the leaf material--drying and storage for 1 week at room temperature. Both the amount and the binding activity of the scFv proteins remained unchanged. CONCLUSION: A plant expression system where the scFv-proteins are targeted in the ER provides not only the highest accumulation level of active single chain Fv antibodies ever reported but also a short- or long-term storage of the foreign protein in the harvested plant material.

Chimera↗
PubMed1997

In utero lysis of amniotic bands.

Amniotic band syndrome is a sporadic condition that occurs in approximately 1:1200 to 1:15,000 live births and that may result in amputations, constrictions and other deformities of the fetus. Although some cases present with congenital anomalies that are beyond surgical repair, a selected group of fetuses may show isolated limb constriction. It has been speculated that, without treatment, amputation or severe dysfunction of the limb may occur. Despite these potential complications, surgical treatment for this selected group of fetuses has not been previously performed. We report two cases that were successfully treated using novel minimally invasive surgical techniques. The cases involved fetuses with amniotic band syndrome with associated limb constriction in which the amniotic band was surgically interrupted to avoid spontaneous amputation of the extremity. Adequate blood flow distal to the obstruction was preserved and significant functional improvement of the extremity occurred in both cases, preserving the limbs. These cases represent the first prenatal surgical intervention successfully used to treat constricting amniotic bands in humans. In addition, these cases represent the first time that a non-lethal fetal entity has been surgically treated in utero. The results of this innovative therapy will encourage the efforts to continue developing minimally invasive techniques for the correction of birth defects.

Adult↗
PubMed1997

Detection of infection with human immunodeficiency virus type 1 before seroconversion: correlation with clinical symptoms and outcome.

Early (pre-seroconversion) infection with human immunodeficiency virus type 1 (HIV-1) was identified in 50 of 267 participants in the Multicenter AIDS Cohort Study. These 50 men had a positive EIA result, which detected IgM antibody (n = 35), p24 antigen, or serum HIV RNA (n = 15) at their last "seronegative" visit. At that visit, the mean CD4 lymphocyte number (890/mm3 vs. 1038/mm3) was significantly lower than in men who subsequently seroconverted but had no evidence of early infection. The decline in CD4 cells was slower and the duration of AIDS-free time longer in the 19 men who were symptomatic in comparison to the 31 asymptomatic men with early infection, but differences were not significant.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Lipoprotein (a): a potential biological marker for unruptured intracranial aneurysms.

OBJECTIVE: The diagnosis and treatment of intracranial aneurysms (IAs) prior to rupture reduces the high morbidity and mortality associated with their occurrence. Elevated serum lipoprotein (a) [Lp(a)] level, an independent risk factor for atherogenesis, has been demonstrated in sporadic IA disease (1). The purpose of this study was to assess the degree of correlation between elevated Lp(a) levels and the occurrence of IAs in asymptomatic first degree relatives of index cases from three families exhibiting a familial tendency towards IA development. METHODS: 25 family members and 41 healthy controls were screened by random serum Lp(a) sampling. All family members received 4-vessel cerebral angiography. RESULTS: Eleven family members were found on angiography to harbour asymptomatic aneurysms and all were successfully treated by surgery. Of these 11, ten had significantly raised serum Lp(a) levels (> 30 mg%). Fourteen family members had negative angiograms. Eight of this latter group, mean age 43.6 +/- 3.8 years, had serum Lp(a) levels above the normal range. Mean Lp(a) levels were 53.7 +/- 1.2 mg% in subjects with aneurysms compared with 22.1 +/- 1.45 mg% in subjects without demonstrable aneurysms and 10.5 +/- 0.48 mg% in the control population. CONCLUSION: The prevalence of elevated Lp(a) levels in these families and the high degree of association of raised Lp(a) levels with the presence of IAs in several family members warrants follow up of angiographically negative young subjects. We require a case-control study to establish whether particular polymorphisms at the apoprotein (a) gene level are associated with the occurrence of IAs in these families.

Adult↗
PubMed1997

Initiation rate and duration of breast-feeding in the Melbourne aboriginal community.

Breast-feeding is important for child health and helps to protect the child against infections. The objective of this study was to determine baseline breast-feeding rates in the Melbourne Aboriginal community prior to a breast-feeding promotion project. A brief questionnaire was administered to 116 mothers of infants up to two years of age with a Melbourne metropolitan address. During their pregnancies, 99 (85.3 per cent) of the women had planned to breast-feed, and 98 (84.5 per cent, 95 per cent confidence interval (CI) 77.9 to 91.1 per cent) initiated breast-feeding. However, 10 (8.6 per cent) stopped within the first week, and seven (6 per cent) more stopped within the first four weeks. Only 50 per cent of the babies (CI 40.9 to 59.1 per cent) were still being breast-fed at three months of age and 32 per cent were still being breast-fed at six months of age (CI 23.5 to 40.5 per cent). Younger mothers were less likely to choose to breast-feed (73 per cent) than women 20 years and over (87 per cent) and were also more likely to stop breast-feeding within three months. A total of 45 (51.1 per cent) of the babies received food other than breast milk or formula earlier than the recommended minimum age of four months. These results are similar to those for the general Victorian population. They show that while most Aboriginal women choose to breast-feed, many cease breast-feeding before they had intended.

Adult↗
PubMed1997

Influences on infant-feeding beliefs and practices in an urban aboriginal community.

The Victorian Aboriginal Health Service initiated a project to increase breast-feeding rates in the Melbourne Aboriginal community. The results of focus-group discussions on infant-feeding experiences and beliefs provided a wealth of information for the design of appropriate interventions. Most women wanted and expected to breast-feed. Some chose artificial feeding because of embarrassment, a belief that it is as good as breast-feeding, or perceptions that breast-feeding is painful and inconvenient. The most common reasons that women stopped breast-feeding were sore nipples, worries about their supply of milk and tiredness. Lack of knowledge, hospital practices, lack of support and appropriate advice, and lack of confidence and self-esteem contributed to these problems. Disruption of the passing on of knowledge of healthy infant-feeding practices between generations is another cultural loss suffered by Aboriginal communities. Efforts to restore traditional rates of breast-feeding need to be under Aboriginal control and to take account of these influences.

Adolescent↗
PubMed1997

Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.

Testosterone-induced nitrogen retention in castrated male animals and sex-related differences in the size of the muscles in male and female animals have been cited as evidence that testosterone has anabolic effects. However, the effects of testosterone on body composition and muscle size have not been rigorously studied. The objective of this study was to determine the effects of replacement doses of testosterone on fat-free mass and muscle size in healthy hypogonadal men in the setting of controlled nutritional intake and exercise level. Seven hypogonadal men, 19-47 yr of age, after at least a 12-week washout from previous androgen therapy, were treated for 10 weeks with testosterone enanthate (100 mg/week) by im injections. Body weight, fat-free mass measured by underwater weighing and deuterated water dilution, and muscle size measured by magnetic resonance imaging were assessed before and after treatment. Energy and protein intake were standardized at 35 Cal/kg.day and 1.5 g/kg.day, respectively. Body weight increased significantly from 79.2 +/- 5.6 to 83.7 +/- 5.7 kg after 10 weeks of testosterone replacement therapy (weight gain, 4.5 +/- 0.6 kg; P = 0.0064). Fat-free mass, measured by underwater weighing, increased from 56.0 +/- 2.5 to 60.9 +/- 2.2 kg (change, +5.0 +/- 0.7 kg; P = 0.0004), but percent fat did not significantly change. Similar increases in fat-free mass were observed with the deuterated water method. The cross-sectional area of the triceps arm muscle increased from 2421 +/- 317 to 2721 +/- 239 mm2 (P = 0.045), and that of the quadriceps leg muscle increased from 7173 +/- 464 to 7720 +/- 454 mm2 (P = 0.0427), measured by magnetic resonance imaging. Muscle strength, assessed by one repetition maximum of weight-lifting exercises increased significantly after testosterone treatment. L-[1-13C]Leucine turnover, leucine oxidation, and nonoxidative disappearance of leucine did not significantly change after 10 weeks of treatment. There was no significant change in hemoglobin, hematocrit, creatinine, and transaminase levels. Replacement doses of testosterone increase fat-free mass and muscle size and strength in hypogonadal men. Whether androgen replacement in wasting states characterized by low testosterone levels will have similar anabolic effects remains to be studied.

Adult↗
PubMed1997

Lothian inter-agency child protection guidelines: impact on a children's NHS trust.

OBJECTIVE: To evaluate the process involved in cases of suspected child abuse within a children's NHS Trust, 6 months after implementation of new inter-agency Child Protection guidelines. DESIGN: Prospective evaluation of case records. SETTING: Four departments within a combined child health trust in Edinburgh. MAIN MEASURES: Review of practice within each department, according to the Inter-Agency guidelines. RESULTS: No standard procedure existed for the child protection process prior to the guidelines. In the first 6 months following implementation of the guidelines, a substantial increase in workload was experienced by community paediatricians. Medical examinations were better co-ordinated, with fewer children receiving repeated, intrusive examinations. However, note keeping was deficient, as 3% of referrals did not appear to be recorded in the case notes. Cross-referencing between departments was variable, with 81% of cases referred to Community Child Health not recorded in hospital case notes. CONCLUSIONS: The Inter-Agency guidelines have resulted in better coordination of the early referral stages. Deficiencies highlighted in this audit are due to record keeping and lack of liaison between departments within a combined children's trust.

Child Abuse↗
PubMed1997

Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression and increase survival in murine acquired immunodeficiency syndrome (MAIDS).

Ribonucleotide reductase inhibitors (RRIs) have been recently shown to inhibit retroviral replication. We examined a new series of RRIs, 3,4-dihydroxybenzohydroxamic acid (Didox) and 3,4,5-trihydroxybenzohydroxamidoxime (Trimidox) for their ability to alter disease progression in murine acquired immunodeficiency syndrome (MAIDS), both alone and in combination with 2',3'-dideoxyinosine (ddI). MAIDS disease was induced by inoculation of female C57BL/6 mice with the LP-BM5 murine leukemia virus (MuLV) and disease progression characterized by extensive peripheral lymphadenopathy and splenomegaly. Efficacy of treatment with these drugs was based upon their ability to influence survival and disease pathophysiology by monitoring the development of splenomegaly. Toxicity was determined by changes in body weight, total peripheral white blood cell count and hematocrit. Didox or trimidox monotherapy was associated with increased survival and decreased disease pathophysiology, with no apparent toxicity. Combined with ddI, their ability to reduce development of viral induced splenomegaly was enhanced compared to trimidox, didox or ddI alone. These results demonstrate RRIs have potent activity in reversing the disease manifestations characteristic of MAIDS. Further studies are warranted to determine human clinical efficacy.

Animals↗
PubMed1997

Snow mountain-like virus identified in young children with winter vomiting disease in South Africa.

Human caliciviruses have been reported to be associated with both epidemics of acute diarrhoeal illness and with sporadic cases of gastroenteritis in children. In this study, we report the identification of genogroup II small round-structured viruses or human caliciviruses associated with an outbreak of winter vomiting disease in South Africa. The virus was initially identified by electron microscopic examination of the stools and then further characterised by recombinant immunoassay with expressed capsid proteins to human caliciviruses from genogroups I and II. Both antigenically by the EIA and by sequence analysis of a region of the RNA-dependent RNA polymerase gene, the virus was shown to belong to genogroup II of the human Caliciviridae.

Amino Acid Sequence↗
PubMed1996

A discontinuous eight-amino acid epitope in human interleukin-3 binds the alpha-chain of its receptor.

We have previously reported that, within the first helix of human interleukin (IL)-3, residues Asp21 and Glu22 are important for interaction with the alpha- and beta-chains of the IL-3 receptor, respectively. In order to define more precisely the sites of interaction with the receptor, we have performed molecular modeling of the helical core of IL-3 and single amino acid substitution mutagenesis of residues predicted to lie on the surfaces of the A, C, and D helices. The resulting analogues were characterized for their abilities to stimulate proliferation of TF-l cells and for binding to the high affinity (alpha- and beta-chain; IL-3Ralpha/Rbeta) or low affinity (alpha-chain alone; IL-3Ralpha) IL-3 receptor. We found that in addition to Asp21, residues Ser17, Asn18, and Thr25 within the A helix and Arg108, Phe113, Lys116, and Glu119 within the D helix of IL-3 were important for biological activity. Analysis of their binding characteristics revealed that these analogues were deficient in binding to both the IL-3Ralpha/Rbeta and the IL-3Ralpha forms of the receptor, consistent with a selective impairment of interaction with IL-3Ralpha. Molecular modeling suggests that these eight amino acid residues are adjacent in the tertiary structure, consistent with a discontinuous epitope interacting selectively with IL-3Ralpha. On the other hand, Glu22 of IL-3 was found to interact preferentially with the beta-chain with bulky and positively charged substitutions causing greater than 10,000-fold reduction in biological activity. These results show fundamental differences between IL-3 and granulocyte-macrophage colony-stimulating factor in the structural basis for recognition of their receptors that has implications for the construction of novel analogues and our understanding of receptor activation.

Amino Acid Sequence↗