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Biomedical subjects

D R Phillips

Publications and source records attributed to D R Phillips.

At least 91 records · Page 5Linked to original sources
PubMed1996

Evaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma.

A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.

Animals↗
PubMed1996

A comparison of manual diagnosis with a diagnosis established by a uni-level lumbar spinal block procedure.

The study was designed to test if a manipulative therapist (MT) using manual examination techniques alone or when accompanied by a verbal response from the subject as to the pain produced, could diagnose the lumbar segmental level responsible for a subjects low back pain and referred pain. The study consisted of prospective and retrospective parts where the MTs manual diagnosis of the symptomatic lumbar segmental level was compared to a segmental level diagnosis attained by subsequent or previous spinal anaesthetic blocks. In the prospective part of the study the MT's manual diagnosis was 94.12% and 52.9% sensitive in detecting the symptomatic lumbar segmental level with verbal and non-verbal subject responses, respectively. In the retrospective part of the study the MTs manual diagnosis was found to be 60.86% and 47.82% sensitive in detecting the symptomatic lumbar segmental level with verbal and non-verbal subject responses, respectively. In the prospective study the MT's manual diagnosis showed 100% and 80% specificity in detecting subjects with no history of low back pain with verbal and non-verbal subject responses, respectively, and 100% and 75% specificity in the retrospective study with verbal and non-verbal subject responses, respectively. Inter-therapist reliability analysis for the recording of passive physiological intervertebral movements (PPIVMs), passive accessory intervertebral movements (PAIVMs) and 'tissue response' showed percentage agreement rates ranging from 55% to 99%; 74% to 100% and 43% to 100%, respectively, with weighted kappa values ranging from -0.11 to 0.32; -0.15 to 0.24 and kappa values ranging from -0.16 to 0.28, respectively. This study demonstrates that a MT's manual examination when accompanied by a verbal subject response, is highly accurate in detecting the lumbar segmental level responsible for a subjects complaint.

Journal Article↗
PubMed1996

Effect of sulphur mustard on the initiation and elongation of transcription.

Sulphur mustard is a potent alkylating agent that causes severe vesication as well as systemic and genotoxic effects. Despite its long history as a chemical warfare agent, the mechanism of its toxicity remains unknown and no successful pharmacological intervention has yet been found. In this study we have examined the effects of mustard alkylation of DNA on transcriptional processes. Gel mobility shift analysis shows that mustard alkylation of the lac UV5 promoter increases the stability of the promoter-RNA polymerase binary complex. Following formation of the initiation complex and addition of elongation nucleotides, approximately 45% of the RNA polymerase in the initiated complex remained associated with the alkylated promoter, compared to only 7% remaining associated with the unalkylated promoter. For the RNA polymerase able to escape the initiation complex, mustard alkylation of the DNA template resulted in the production of truncated transcripts. Analysis of these truncated transcripts revealed that sulphur mustard alkylates DNA preferentially at 5'-AA, 5'-GG and 5'-GNC sequences on the DNA template strand and this is significantly different from the alkylation sites observed with nitrogen mustard. This study represents the first report at the molecular level of sulphur mustard-induced effects on transcriptional processes.

Alkylation↗
PubMed1996

Biophysical and biological evaluation of porphyrin-bisacridine conjugates.

Two novel porphyrin-bisacridine conjugates (1 and 2) were designed as bifunctional antitumour agents to combine the DNA-binding character of the acridines and the photosensitizing capacity of porphyrin, and have been subjected to biophysical and biological evaluation. The interactions of the conjugates with calf thymus DNA were evaluated using viscometric, spectrophotometric and stopped-flow sodium dodecyl sulphate (SDS) sequestration methods. Both conjugates acted as bis-intercalators via the two acridine chromophores and displayed a longer residence time on DNA relative to the parent acridine ligand. Their biological activity in vitro was studied against the C6 rat glioma, MCF-7, GBM and A431 cell lines. Both conjugates were cytotoxic to all four cell lines. The ID50 (C6 glioma) was essentially the same as that of the parent acridine for one conjugate, but was increased 20-fold for the other, while both conjugates were approximately 10-fold more cytotoxic than the parent porphyrin component. The tissue distribution of the two conjugates was assessed in nude mice xenografted with a human small cell lung carcinoma (POVD). There were large differences in the tissue distribution of the two conjugates, with conjugate 2 localizing 8-fold more in the tumour than conjugate 1.

Animals↗
PubMed1995

Procoagulant activity of reversibly acylated human factor Xa.

The plasma clotting factors used to treat hemophiliacs who have developed inhibitory antibodies have a shared history of limited clinical safety and utility. To improve on existing bypass factors, we have developed a reversibly acylated form of human plasma factor Xa capable of providing a time-dependent release of procoagulant activity. Factor Xa was treated with p-amidinophenyl p'-anisate to generate anisoyl Xa. The chemical modification of the protein involves acylation of the active site serine residue of factor Xa. Anisoyl Xa deacylated in a time, pH, and temperature-dependent manner. Active factor Xa generated on deacylation of anisoyl Xa exhibited amidolytic and prothrombinase complex activities in in vitro assays, the level being comparable to those of untreated factor Xa. When Anisoyl Xa was infused into rabbits, active factor Xa was generated on deacylation of the acylated enzyme, which shortened the activated partial thromboplastin time (APTT) in a dose-dependent manner. The duration of effect on rabbit APTT could be directly correlated to the level of human plasma factor Xa. Because anisoyl Xa bypasses the "tenase" complex that is compromised in hemophilia A and B and is unaffected by inhibitory antibodies, it has the potential to be used as an effective bypass therapy.

Acylation↗
PubMed1995

Nitrogen mustard inhibits transcription and translation in a cell free system.

Nitrogen mustard and its derivatives such as cyclophosphamide, chlorambucil and melphalan are widely used anti-cancer agents, despite their non-specific reaction mechanism. In this study, the effect of alkylation by nitrogen mustard of DNA and RNA (coding for a single protein) was investigated using both a translation system and a coupled transcription/translation system. When alkylated DNA was used as the template for coupled transcription and translation, a single translation product corresponding to the 62 kDa luciferase protein was synthesised. Production of the translated product encoded by this template was inhibited by mustard concentrations as low as 10 nM, and 50% inhibition occurred with 30 nM mustard. A primer extension assay employed to verify alkylation sites on the DNA revealed that all guanine residues on the DNA template are susceptible to alkylation by nitrogen mustard. Similarly, when alkylated RNA was used as the template for protein synthesis, the amount of the 62 kDa luciferase protein decreased with increasing mustard concentration and a range of truncated polypeptides was synthesised. Under these conditions 50% inhibition of translation occurred with approximately 300 nM mustard (i.e. approximately 10 times that required for similar inhibition using an alkylated DNA template). Furthermore, a gel mobility shift assay revealed that mustard alkylation of the RNA template results in the formation of a more stable retarded RNA complex. The functional activity of the luciferase protein decreased with alkylation of both the DNA and RNA templates, with a half-life of loss of activity of 1.1 h for DNA exposed to 50 nM mustard, and 0.5 h for RNA exposed to 50 microM mustard. The data presented support the notion that DNA is a critical molecule in the mode of action of mustards.

Alkylating Agents↗
PubMed1995

Use of oligonucleotides to define the site of interstrand cross-links induced by Adriamycin.

It has been known for several years that Adriamycin forms adducts and interstrand cross-links when reacted for long periods of time with bacterial and mammalian DNA in vitro, with the cross-link being restricted to 2 bp elements containing GpC sequences. The self-complementary 20mer deoxyoligonucleotide TA4T4GCA4T4A has been used in this study as a model of the apparent G-G cross-linking site at GpC sequences. The rate of formation of cross-links, as well as the dependence on both Adriamycin and Fe(III) concentration, were similar with this oligonucleotide as compared with calf thymus DNA. The cross-linking was demonstrated on both denaturing and non-denaturing sequencing gels. The half-life of the G-G cross-link was 40 h, consistent with that implied with high molecular weight, heterogeneous sequence DNA. Exonuclease III digests of adducts formed with 20mer deoxyoligonucleotides containing single, central G-G, G-I and I-I potential cross-links revealed that a guanine residue is required at both ends of the cross-link. No cross-linking was observed with a similar oligonucleotide containing only a single central (G.C) bp.

Animals↗
PubMed1995

Stability of adriamycin-induced DNA adducts and interstrand crosslinks.

The stability of adriamycin-induced DNA adducts and interstrand crosslinks was measured at 37 degrees C by three independent procedures. The loss of [14C]-labelled adducts was described by two first-order decays with half-lives of 7.4 h (60% amplitude) and 39 h (40%). The loss of the drug chromophore also exhibited a biphasic character, with half-lives of 6 h (65%) and approximately 150 h (35%). The decay of transcriptional blockages at an isolated, apparent interstrand GpC crosslinking site was described by two first-order processes, with half-lives of 3 h (65%) and 40 h (35%), whereas the decay of transcriptional blockages at an isolated guanine residue (apparent site of monoadduct) was completely described by a first-order decay with a half-life of 5.3 h. The loss of interstrand crosslinks was measured using a gel electrophoresis assay, and the decay was characterised by a single first-order process with a half-life of 4.7 h. Collectively, these values serve to define a model of the interstrand crosslink with unstable sites of attachment at both ends of the crosslink, with half-lives at either end being approximately 5 and 40 h. The adducts exhibited increasing lability with increasing pH, and were particularly unstable at pH 12, with a half-life of approximately 0.5 h. The adducts were also heat labile, with an overall melting temperature of 67 degrees C (10 min exposure) and this was also the thermal lability measured at three individual adduct sites probed by lambda exonuclease.

Animals↗
PubMed1995

Biodistribution of haematoporphyrin analogues in a lung carcinoma model.

In an attempt to identify novel compounds useful for the optimization of Photodynamic Therapy (PDT), the tissue localization of new synthetic porphyrins was compared with Photofrin II in nude mice xenografted with a human small cell lung cancer (POVD). Three haematoporphyrin analogues were selected for this study based on prior in vitro photosensitivity screening of a series of 15 such derivatives, as well as on the basis of improved localization in C6 gliomas in mice. Two of the porphyrins yielded better tumour:normal lung ratios than Photofrin II and, of these two, one (P13) is known to exhibit good photosensitization properties both in vitro and in vivo, and is therefore a good candidate as a lead compound for the development of porphyrins suitable for the photodynamic treatment of lung tumours.

Animals↗
PubMed1995

Aging trends--Hong Kong.

Aspects of demographic aging in Hong Kong are examined in this study. "By regional standards, many of Hong Kong's 1992 population of 5.9 million have a good standard of living and adequate housing. However, there are considerable discrepancies in wealth and well-being; elderly people are not always financially secure, and there are growing difficulties in maintaining the oft-cited mode of family care for elderly members. Hong Kong is a rapidly aging society and it is essential to see this process in the context of local and regional socioeconomic change and the future political linkages of the territory with China."

Adult↗
PubMed1995

Aging trends--Singapore.

"Three major inter-related issues have emerged concerning population aging in Singapore. The first two concerns are whether aging will increase dependency on the state for welfare and financial assistance and whether traditional family caring structures will survive and provide the care deemed necessary in the future. The third concern focuses on the potential impact of population aging on Singapore's future economic growth and development....A national policy on elderly persons has been formulated since 1989 and focuses on four main areas: employment of elderly people in the workforce; attitudes towards elderly people; community care; and residential care."

Adult↗
PubMed1995

Transcervical electrosurgical resection of submucous leiomyomas for chronic menorrhagia.

STUDY OBJECTIVE: To evaluate the effectiveness and safety of transcervical electrosurgical resection (TSR) of submucous leiomyomas with or without concomitant transcervical endomyometrial resection (TEMR) for chronic menorrhagia. DESIGN: Prospective observational study, with 6-month follow-up of all 208 women and up to 6-year follow-up of 185 (88.9%). SETTING: Gynecology departments of teaching, community, and proprietary hospitals. PATIENTS: Two hundred eight women with submucous leiomyoma requiring surgical treatment of menorrhagia between March 1988 and March 1994. INTERVENTIONS: All 208 women (age range 32-63 yrs) underwent TSR with a continuous-flow gynecologic resectoscope. In 88 of these women who had no desire to preserve fertility, concomitant TEMR was performed. MEASUREMENTS AND MAIN RESULTS: Six months postoperatively 113 (94.2%) of the 120 women who underwent only TSR reported normal menses and 85 (96.6%) had satisfactory results; 62 (70.5%) who had both TSR and TEMR were amenorrheic. Eleven (73%) of the 15 women who had TSR and wanted to conceive subsequently became pregnant. One hundred eighty-five (88.9%) of the 208 patients have been followed for as long as 6 years. Ninety (84.1%) of the 107 women who had only the initial TSR and 69 (88.5%) of the 78 who had initial TSR and TEMR had satisfactory results. Only five women (2.7%) required major abdominal surgery. Among those undergoing TSR and TEMR, 49 (62.8%) were amenorrheic for as long as 6 years after TSR and one or two TEMRs. Eight (3.8%) of the 208 women had perioperative complications: 6 (2.9%) had fluid overload, 1 (0.5%) had dilutional hyponatremia, and 1 (0.5%) had excessive postoperative bleeding requiring tamponade. CONCLUSIONS: We believe that TSR with or without concomitant TEMR is an effective and safe treatment for women with submucous leiomyomas suffering from chronic menorrhagia.

Abdomen↗
PubMed1995

Endometrial ablation for postmenopausal uterine bleeding induced by hormone replacement therapy.

STUDY OBJECTIVE: To determine the effectiveness of transcervical endometrial ablation or endomyometrial resection for treating refractory postmenopausal uterine bleeding induced by hormone replacement therapy (HRT). DESIGN: Prospective observational study. SETTING: Community, teaching, and proprietary hospitals. PATIENTS: Twenty-nine postmenopausal women experiencing troublesome uterine bleeding while taking hormones. INTERVENTIONS: Hormone manipulation, office hysteroscopy or sonohysterography, endometrial curettage, and transcervical endometrial ablation or endomyometrial resection were performed in all 29 patients. MEASUREMENTS AND MAIN RESULTS: Twenty-seven women (93.1%) who continued HRT became amenorrheic within 2 months of surgery. The two who did not have irregular, intermittent spotting, but neither one required or desired further surgical intervention. Five women discontinued HRT from 3 to 53 months postoperatively (mean 12.5 +/- 8.2 mo) because of apprehension about developing breast cancer and for personal reasons. The 24 (82.8%) who continued HRT were observed for as long as 99 months (mean 36.4 +/- 5.5 mo); 22 (91.6%) of them remained amenorrheic. Pathologic examination of tissue specimens revealed atrophic endometrium in 4 patients, adenomyosis in 7, simple hyperplasia in 4, submucous leiomyomas in 11, endometrial polyps in 4, and proliferative endometrium in 1. There were no perioperative complications. CONCLUSION: Endometrial ablation or endomyometrial resection was an effective alternative to discontinuing HRT for these postmenopausal women whose uterine bleeding was unrelieved by modification of their sex steroid regimens.

Aged↗
PubMed1995

100 laparoscopic hysterectomies in private practice and visiting professorship programs.

STUDY OBJECTIVE: To evaluate 100 laparoscopic hysterectomies and their variations in private practice and visiting professorship programs. DESIGN: A prospective observational study. SETTING: Gynecology departments of 17 teaching, community, and proprietary hospitals in the northeastern United States. PATIENTS: One hundred women who successfully underwent laparoscopic hysterectomy, 91 of whom were followed for 6 months. INTERVENTIONS: From July 1990 to August 1994, 108 women (mean age 41.6 yrs, range 38-68 yrs) for whom a vaginal hysterectomy was relatively contraindicated underwent a hysterectomy attempted by the laparoscopic route. The most common indications for hysterectomy were pelvic pain, chronic menorrhagia, and uterine leiomyomas. The women were classified according to hysterectomy, with groups comparable in age, weight, uterine size and weight, concomitant surgery performed, uterine and coexisting pathology, and history of pelvic surgery. Of the 108 women, 35 had laparoscopic hysterectomies (LH), 56 had laparoscopic-assisted vaginal hysterectomies (LAVH), and 9 had subtotal laparoscopic hysterectomies (SLH). Eight procedures were converted to laparotomy, two attempted LHs and six attempted LAVHs. In 22 cases, bipolar coagulation of vascular pedicles was done exclusively, in 58 the Endo GIA 30 stapler was used exclusively, and in 20 a combination of both modalities was used. Bilateral ureteral catheters were inserted 49 times. MEASUREMENTS AND MAIN RESULTS: There were eight complications (8.0%): two blood transfusions, two cases of transient, asymptomatic pyrexia, two abdominal wall hematomas, one Richter hernia, and one urinary tract infection. The hernia repair was the only delayed laparotomy. The mean (+/-SEM) surgical time was 123 +/- 8 minutes (range 45-235 min), and the mean hospital stay was 1.48 days +/- 0.4 (range 1-5 days). Ninety-five of the 100 women who successfully underwent a laparoscopic procedure returned to work within 2 weeks (range 4-14 days, range 15-53 days for the remaining 5). CONCLUSION: Hysterectomy performed or aided by the laparoscope, whether LH, LAVH, or SLH, is effective and safe as long as at least one member of the surgical team is an experienced and appropriately trained laparoscopic surgeon. Further studies are necessary to determine if the credentialing process for advanced laparoscopic surgery would be facilitated by a visiting professorship program.

Adult↗
PubMed1995

Aging in the United Kingdom: a review of demographic trends, recent policy developments and care provision.

"Although the U.K.'s population is not predicted to grow very much in the future, the population structure is changing and there is a shift towards a much older age distribution. The characteristics of demographic aging in the U.K. include a marked reduction in fertility rates, increasing rates of life expectation at birth..., increasing dependency ratios and variations in mortality and social class in old age. The U.K.'s demographic context has important implications for aged care policy and planning. This paper documents the demographic trends, reviews recent major policy changes and their impact on care provision, and discusses some of the emerging implementation issues that challenge the potential of such policies to meet the needs of an aging population."

Age Distribution↗
PubMed1995

Teenage pregnancy: a comparative study of teenagers choosing termination of pregnancy or antenatal care.

A comparative study of 167 pregnant teenagers in Devon attending either antenatal booking clinics or for National Health Service (NHS) termination of pregnancy was carried out to determine differences in their characteristics, use and experience of local family planning services. Teenagers presenting for termination of pregnancy were younger and more likely to say that they had wished to avoid getting pregnant. Whether the teenager was in a stable relationship was strongly associated with the outcome of the pregnancy, with single girls being more likely to choose a termination of pregnancy. The termination of pregnancy group were also more likely to be condom users, and to have learned about their method of contraception from school rather than from health care professionals. Teenagers' frequency of contact with family planning services suggested that teenagers choosing a termination were less likely than antenatal attenders to have attended regularly. This was mainly due to differences in behaviour among teenagers attending their general practitioner (GP) for contraceptive advice: teenagers having a termination were more likely to describe their visit to their GP as embarrassing. These findings have implications for local family planning services attempting to reduce the number of unwanted teenage pregnancies.

Abortion, Induced↗