Biomedical subjects

R Duncan

Publications and source records attributed to R Duncan.

At least 73 records · Page 4Linked to original sources

PubMed1999

Rubella virus-induced apoptosis varies among cell lines and is modulated by Bcl-XL and caspase inhibitors.

Rubella virus (RV) causes multisystem birth defects in the fetuses of infected women. To investigate the cellular basis of this pathology, we examined the cytopathic effect of RV in three permissive cell lines: Vero 76, RK13, and BHK21. Electron microscopy and the TUNEL assay showed that the cytopathic effect resulted from RV-induced programmed cell death (apoptosis) in all three cell lines, but the extent of apoptosis varied among these cells. At 48 h postinfection, the RK13 cell line showed the greatest number of apoptotic cells, the Vero 76 cell line was approximately 3-fold less, and BHK21 had very few. An increased multiplicity of infection and longer time postinfection were required for the BHK21 cell line to reach the level of apoptotic cells in Vero 76 at 48 h. Purified RV induced apoptosis in a dose-dependent fashion, but not UV-inactivated RV or virus-depleted culture supernatant. Specific inhibitors of the apoptosis-specific proteases caspases reduced RV-induced apoptosis and led to higher levels of RV components in infected cells. To address the role of regulatory proteins in RV-induced apoptosis, the antiapoptotic gene Bcl-2 or Bcl-XL was transfected into RK13 cells. Although a high level of Bcl-2 family proteins was expressed, no protection was observed from apoptosis induced by RV, Sindbis virus, or staurosporine in RK13 cells. In BHK21 cells, however, increased expression of Bcl-XL protected cells from apoptosis. The observed variability in apoptotic response to RV of these cell lines demonstrates that programmed cell death is dependent on the unique properties of each cell and may be indicative of how selective organ damage occurs in a congenital rubella syndrome fetus.

Animals↗

PubMed1999

Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA.

Cationic polymers have the potential for DNA complexation and it is recognised that they may be useful as non-viral vectors for gene delivery. Highly purified chitosan fractions of < 5000 Da (N1), 5000-10,000 Da (N2) and > 10,000 Daltons (N3) were prepared and characterised in respect of their cytotoxicity, ability to cause haemolysis, ability to complex DNA as well as to protect DNA from nuclease degradation. Also the biodistribution of 125I-labelled chitosans was followed at 5 and 60 min after intravenous injection into male Wistar rats. All chitosan fractions displayed little cytotoxicity against CCRF-CEM and L132 cells (IC50 > 1 mg/ml), and they were not haemolytic (< 15% lysis after 1 and 5 h). Chitosan-DNA interaction at a charge ration of 1:1 was much greater than seen for poly(L-lysine) and complexation resulted in inhibition of DNA degradation by DNase II: 99.9 +/- 0.1, 99.1 +/- 1.5 and 98.5 +/- 2.0% for N1, N2 and N3, respectively. After intravenous injection, all the chitosans showed rapid blood clearance, the plasma levels at 1 h being 32.2 +/- 10.5% of recovered dose for N1 and 2.6 +/- 0.5% of recovered dose for N3. Liver accumulation was molecular mass dependent, being 26.5 +/- 4.9% of the recovered dose for N1 and 82.7 +/- 1.9% of the recovered dose for N3. The observations that the highly purified chitosan fractions used were neither toxic nor haemolytic, that they have the ability to complex DNA and protect against nuclease degradation and that low molecular weight chitosan can be administered intravenously without liver accumulation suggest there is potential to investigate further low molecular weight chitosans as components of a synthetic gene delivery system.

Animals↗

PubMed1999

Volume regulatory decrease in UMR-106.01 cells is mediated by specific alpha1 subunits of L-type calcium channels.

An early cellular response of osteoblasts to swelling is plasma membrane depolarization, accompanied by a transient increase in intracellular calcium ([Ca2+]i), which initiates regulatory volume decrease (RVD). The authors have previously demonstrated a hypotonically induced depolarization of the osteoblast plasma membrane, sufficient to open L-type Ca channels and mediate Ca2+ influx. Herein is described the initiation of RVD in UMR-106.01 cells, mediated by hypotonically induced [Ca2+]i transients resulting from the activation of specific isoforms of L-type Ca channels. The authors further demonstrate that substrate interaction determines which specific alpha1 Ca channel subunit isoform predominates and mediates Ca2+ entry and RVD. Swelling-induced [Ca2+]i transients, and RVD in cells grown on a type I collagen matrix, are inhibited by removal of Ca from extracellular solutions, dihydropyridines, and antisense oligodeoxynucleotides directed exclusively to the alpha1C isoform of the L-type Ca channel. Ca2+ transients and RVD in cells grown on untreated glass cover slips were inhibited by similar maneuvers, but only by antisense oligodeoxynucleotides directed to the alpha1S isoform of the L-type Ca channel. This represents the first molecular identification of the Ca channels that transduce the initiation signal for RVD by osteoblastic cells.

Animals↗

PubMed1999

Comparison of the beluga whale (Delphinapterus leucas) expressed genes for 5-aminolevulinate synthase with those in other vertebrates.

The cDNA and inferred amino acid sequences were determined for beluga whale (Delphinapterus leucas) erythroid (E) and housekeeping (H) forms of 5-aminolevulinate synthase (ALS), and they were compared with known sequences for five other vertebrates with particular attention to regulatory features. The cDNAs for whale ALS-E and -H encode, respectively, proteins of 582 and 640 amino acids. Sequence alignments suggest that the whale ALS-H, like those for rat and chicken, has an N-terminal mitochondrial targeting sequence of 56 amino acids. There is a high degree of amino acid conservation between the beluga whale proteins and those of other vertebrates, including regulatory elements and functional residues that have been defined in other ALSs. Both whale proteins contain three heme regulatory motifs suggesting that mitochondrial uptake may be regulated by heme. The ALS-E mRNA contains an iron responsive element in its 5'-untranslated region indicating that its expression may be post-transcriptionally regulated by cellular iron. This extensive structural similarity and the presence of the same regulatory elements found in other ALSs indicate that regulation of ALS in beluga whale is similar to that in other vertebrates.

5' Untranslated Regions↗

PubMed1999

HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo.

The aim of this study was to compare in vitro and in vivo HPMA copolymer platinates with cisplatin in terms of platinum release, toxicity and antitumour activity. N-(2-hydroxypropyl)methacrylamide (HPMA) conjugates containing peptidyl side-chains (Gly-Gly or Gly-Phe-Leu-Gly) terminating in either carboxylate or amino species were prepared. The carboxylate polymeric intermediate was reacted with cisplatin, and the polymeric diamine with potassium tetrachloroplatinate to produce HPMA copolymer platinates of Mw 25,000-31,000 Daltons with a platinum loading of 3-7 wt%. The diglycyl spacer was selected because it is non-biodegradable, whereas the tetrapeptide spacer is known to be cleaved by the lysosomal thiol-dependent proteases. In vitro the HPMA copolymer platinates displayed a range of platinum release rates at pH 7.4 and 5.5; from < 5%/24 h in the case of the diamino species which require enzymatic activation, to > 80%/24 h in the case of the carboxylate. Cisplatin and the fast releasing carboxylate species displayed IC50 values of 10 micrograms/ml Pt-equivalent against B16F10 cells in vitro, whereas the slow releasing conjugates were not cytotoxic over the dose range studied. Antitumour activity of HPMA copolymer platinates was first evaluated against L1210 and B16F10 tumours inoculated intraperitoneally (i.p.). When conjugates were administered i.p., the antitumour activity observed against L1210 tumours was within the range seen for free cisplatin (ratio of mean survival of treated animals to mean survival of controls, T/C, 1.20-1.70). Neither cisplatin nor HPMA copolymer platinates were active against intraperitoneal (i.p.) B16F10 tumours when administered i.p. However, when conjugates were administered intravenously (i.v.) to treat subcutaneous (s.c.) B16F10 tumours grown to palpable size, free cisplatin was still not active but the HPMA copolymer platinates bearing carboxylate and diamine platinates showed significant antitumour activity (T/C > 1.35). Throughout these studies, the polymer platinates were 5-15-fold less toxic than cisplatin in vivo. After i.v. administration, the blood clearance of HPMA copolymer platinate was considerably slower (t1/2 alpha approximately 10 h) than seen for free cisplatin (t1/2 alpha < 5 min). HPMA copolymer platinates (15 mg/kg Pt-equivalent) gave rise to an approximately 60-fold increase in Pt AUC in B16F10 tumour tissue than was achieved after administration of cisplatin at its maximum tolerated dose (MTD) (1 mg/kg).

Animals↗

PubMed1999

Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway?

Tumour capillaries are frequently hyperpermeable compared with normal vasculature, and thus they offer a much sought-after gateway for targeted delivery of cancer chemotherapy. Phase I clinical trials reported recently describe the first synthetic polymer-drug conjugate to be tested in man. N-(2-Hydroxypropyl)methacrylamide copolymer-doxorubicin (PK1, FCE 28068) displayed antitumour activity in chemotherapy-refractory patients, considerably reduced toxicity compared with doxorubicin, and evidence of tumour-selective targeting. With increasing understanding of the vector- and tumour-related factors that govern vascular permeability, non-viral vectors are being designed for tumour-selective targeting and subsequent intracytoplasmic delivery of macromolecular medicines such as genes, antisense oligonucleotides, proteins and peptides.

Journal Article↗

PubMed1999

Phylogenetic analysis of the 5-aminolevulinate synthase gene.

The evolution of 5-aminolevulinate synthase (ALS) was studied by acquiring sequence data and generating phylogenetic trees. Gene sequences were already available for a variety of vertebrates (which have both a housekeeping and an erythroid form of the gene), fungi, alpha-proteobacteria, and one protist and one protostome. In order to generate representative trees, ALS sequence data were acquired from various deuterostomes and protostomes. The species and tissues selected for study were beluga whale liver, hagfish blood, sea urchin gonadal tissue, cuttlefish hepatopancreas, horseshoe crab hepatopancreas, and bloodworm blood. The new sequences and those previously published were examined for the presence of heme-regulatory motifs (HRMs) and iron-responsive elements (IREs). The HRMs are present in almost all eukaryotic species, which suggests their fundamental role in the regulation of ALS. The IREs are present in all vertebrate erythroid forms of ALS, which indicates that in those animals, expression of the erythroid form of the enzyme and, hence, hemoglobin production can be influenced by the intracellular content of iron. The new sequences were aligned with previously reported ALS sequences, and phylogenetic analyses were performed. The resulting trees provided evidence regarding the timing of the gene duplication event that led to the two forms of the ALS gene in vertebrates. It appears that the housekeeping and erythroid forms of ALS probably arose before the divergence of hagfish from the deuterostome line leading to the vertebrates. The data also add to the evidence indicating that alpha-proteobacteria are the nearest contemporary relatives of mitochondria.

5-Aminolevulinate Synthetase↗

PubMed1999

Poly(amidoamine)s as potential endosomolytic polymers: evaluation in vitro and body distribution in normal and tumour-bearing animals.

Fusogenic peptides derived from viral coat proteins cause perturbation of the endosomal membrane and are often used to improve the transfection efficiency of non-viral vectors in vitro. However, fusogenic peptides have limited potential for use in vivo due to their inherent immunogenicity. Totally synthetic polymers that are endosomolytic should circumvent this problem and could be useful as components of non-viral delivery systems as long as they do not immediately localise in the liver after intravenous (i.v.) injection. Linear poly(amidoamine) polymers (PAAs) having amido- and tertiary amino-groups along the main polymer undergo pH-dependent conformational change and thus provide an ideal opportunity for design of polymers that display membrane activity at low pH. Here we describe four PAAs, ISA 1 (Mn = 6900 Da) and ISA 23 (Mn = 10,500 Da) and their analogues ISA 4 and ISA 22 (Mn approximately 8000 Da) containing approximately 1 mol% 2-p-hydroxyphenyl ethylamine to allow radioiodination and thus monitoring of their biodistribution. In vitro cytotoxicity was assessed by MTT assay after incubation of PAAs with B16F10 and Mewo cell lines. The IC50 values observed for all PAAs were > 2 mg/mL in comparison with poly(L-lysine) which displayed an IC50 in the range 0.01-0.1 mg/mL. At pH 7.4 none of the PAAs studied was haemolytic at 1 h at concentrations below 3 mg/mL. PAAs were subsequently incubated with rat red blood cells for 24 h (1 mg/mL) at different pHs. In contrast to poly(L-lysine) which was haemolytic at pH 7.4, 6.5 and 5.5, none of the PAAs was lytic at pH 7.4, but they became membrane active at lower pH (approximately 45% for ISA 4, 50% for ISA 22 and 90% for ISA 23). These observations were substantiated by SEM and confirm the pH-dependence of membrane activity. After i.v. injection to rats 125I-labelled ISA 4 was immediately taken up by the liver (> 80% recovered dose at 1 h) whereas 125I-labelled ISA 22 was not (liver uptake was < 10% recovered dose at 5 h). Furthermore, biodistribution studies in mice bearing subcutaneous B16F10 melanoma showed that 125I-labelled ISA 22 was still accumulating in tumour tissue after 5 h (2.5% dose/g). PAAs have potential as endosomolytic agents and quantitation of the endosome to cytoplasm transfer is warranted after i.v. administration.

Animals↗

PubMed1999

Regional cerebral perfusion and amytal distribution during the Wada test.

UNLABELLED: The distribution of sodium amytal and its effect on regional cerebral perfusion during the intracarotid amytal (Wada) test were investigated using high-resolution hexamethyl propyleneamine oxime (HMPAO) SPECT coregistered with the patient's MRI dataset. METHODS: Twenty patients underwent SPECT after intravenous HMPAO injection, and 5 patients had both intravenous and intracarotid injections in a double injection-acquisition protocol. RESULTS: All patients had hypoperfusion in the territories of the anterior and middle cerebral arteries. Basal ganglia perfusion was preserved in 20 of 25 patients. Hypoperfusion of the entire mesial temporal cortex was seen in 9 of 25 patients. Partial hypoperfusion of the whole mesial cortex or hypoperfusion of part of the mesial cortex was seen in 14 of 25 patients. In 2 of 25 patients, mesial temporal perfusion was unaffected. In 5 patients, the double acquisition showed a distribution of HMPAO delivery matching that of hypoperfusion, except for the following: (a) HMPAO was delivered to the basal ganglia and insula, where there was no hypoperfusion; (b) HMPAO was not delivered to the contralateral cerebellum, which did show hypoperfusion; and (c) in 1 patient, perfusion of the mesial temporal cortex was preserved despite intracarotid delivery of HMPAO. CONCLUSION: Some degree of hypoperfusion of medial temporal structures occurs in the great majority of patients during the Wada test. Partial inactivation of memory structures is therefore a credible mechanism of action of the test. The double acquisition protocol provided no evidence that mesial temporal structures are inactivated remotely by diaschisis. Perfusion in the basal ganglia and insular cortex is not affected by amytal.

Adult↗

PubMed1999

Dendrimer-platinate: a novel approach to cancer chemotherapy.

A polyamidoamine (PAMAM) dendrimer generation 3.5 with a sodium carboxylate surface was conjugated to cisplatin giving a dendrimer-platinate (dendrimer-Pt; 20-25 wt% platinum) which was highly water soluble and released platinum slowly in vitro. In vivo the dendrimer-Pt and cisplatin were equi-active i.p. against i.p. L1210, and at high dose dendrimer-Pt given i.p. showed activity against i.p. B16F10 whereas cisplatin did not. Additionally, when administered i.v. to treat a palpable s.c. B16F10 melanoma, the dendrimer-Pt displayed antitumor activity whereas cisplatin was inactive. Measurement of platinum levels in blood and tissues after i.v. injection of cisplatin (1 mg/kg) or dendrimer-Pt (15 mg/kg)-the maximum tolerated dose (MTD) of these compounds-showed selective accumulation of the dendrimer-Pt in solid tumor tissue by the EPR effect (a 50-fold increase in area under curve compared with cisplatin). The dendrimer-Pt was also less toxic (3- to 15-fold) than cisplatin and thus has potential for further investigation as a novel antitumor approach.

Animals↗

PubMed1999

Pharmacokinetics of PK1 and doxorubicin in experimental colon tumor models with differing responses to PK1.

PK1 is a synthetic N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (dox) conjugate currently undergoing Phase II evaluation in the United Kingdom. We have studied the activity of PK1 in three murine colon tumor models that differ in terms of morphology and vascularization in an attempt to determine which factors are most important in the tumor response to PK1. Vascular permeability was evaluated with Evans Blue, and pharmacokinetic studies in MAC15A and MAC26 used high-performance liquid chromatography to monitor both PK1 uptake and dox release in the tumors. Cathepsin B activity was assessed using a specific substrate. PK1 (40 mg x kg(-1) dox equivalent) was significantly more effective than dox alone (10 mg x kg(-1)) was against MAC15A tumors, which possess enhanced perfusion and retention, but not against MAC26 tumors, although MAC15A was also responsive to PK1 when grown as avascular micrometastatic deposits in the lung. Pharmacokinetic studies showed similar levels of PK1 in both tumors. Peak tumor levels of released dox were 7-fold greater in the responsive MAC15A tumor (53 microg x ml(-1)) compared with the less responsive MAC26 tumor (7.7 microg x ml(-1)) and more than 18-fold greater in MAC15A than when free dox was given. These differences in response correlated also with an increased lysosomal activity of cathepsin B. Calculated AUCs for intratumoral dox released were 431 microg x h x g(-1) and 775 microg x h x g(-1) for MAC15A and MAC26, respectively. These AUCs are 4-fold and 7-fold higher, respectively, than when dox is given alone. This study has shown that activity and the pharmacokinetics of PK1 and released dox are dependent on both the vascular properties and enzyme content of the tumors. These studies are likely to have clinical implications as aggressive tumors are known to have increased protease activity.

Animals↗

PubMed1999

Video-EEG and ictal SPECT in three patients with both epileptic and non-epileptic seizures.

We report scalp EEG and ictal SPECT findings in epileptic (complex partial) and non-epileptic seizures in three patients who experienced both types of event during presurgical investigation of medically intractable epilepsies. In all three patients, ictal SPECT showed localizing changes in cerebral blood flow during epileptic seizures, but showed no change during pseudoseizures. In two patients, the physical manifestations of the pseudoseizures were similar to those of the epileptic seizures, supporting the contention that physiological activation is unlikely to mimic ictal perfusion changes. In one patient, the EEG recording was rendered difficult to interpret by muscle artefact, while SPECT was clear and showed no change. SPECT is not a primary tool for diagnosis of pseudoseizures, but when patients undergoing presurgical investigation are injected during pseudoseizures, then SPECT is unlikely to show misleading perfusion changes due to activation effects, and may aid diagnosis where there is muscle artefact on EEG.

Adult↗

PubMed1999

Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.

The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.

Adult↗

PubMed1999

Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee.

PK1 comprises doxorubicin covalently bound to N-(2-hydroxypropyl)methacrylamide copolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release. Radically altered plasma and tumor pharmacokinetics, compared to free doxorubicin, and significant activity in animal tumors have been demonstrated preclinically. We aimed to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers. Altogether, 100 cycles were administered (range, 20-320 mg/m2 doxorubicin-equivalent) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34-72 years). The maximum tolerated dose was 320 mg/m2, and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m2. Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t(1/2) of 1.8 h and an elimination t(1/2) averaging 93 h. 131I-labeled PK1 imaging suggests PK1 is taken up by some tumors. Responses (two partial and two minor responses) were seen in four patients with NSCLC, colorectal cancer, and anthracycline-resistant breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-related toxicity, and proof of principle that polymer-drug conjugation decreases doxorubicin dose-limiting toxicities. The recommended Phase II dose is 280 mg/m2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.

Adult↗

PubMed1998

Characterization of two avian reoviruses that exhibit strain-specific quantitative differences in their syncytium-inducing and pathogenic capabilities.

We previously proposed that the conservation of the nonessential syncytium-inducing phenotype among all reported avian reovirus (ARV) isolates may reflect a mechanism for enhanced virus dissemination in vivo, which in turn could contribute to the natural pathogenicity of ARV. Direct testing of this hypothesis has been hampered by the lack of available virus strains with defined differences in their fusion-inducing capability. We now report on the characterization of two ARV strains, ARV-176 and ARV-138, that exhibited strain-specific differences in their fusogenic properties, which correlated with their pathogenic potential in embryonated eggs. Moreover, both virus strains possessed similar replicative abilities in cell culture, suggesting that the weakly fusogenic ARV-138 virus is specifically inhibited in its syncytium-inducing ability. To test the use of these viruses for reassortant studies aimed at assessing the role of cell fusion in viral pathogenesis, a preliminary genetic analysis was undertaken using a monoreassortant that contained nine genome segments from the parental ARV-138 virus and the S1 genome segment from the highly fusogenic and pathogenic ARV-176 parental virus. The monoreassortant possessed the full fusogenic potential of the ARV-176 parental virus and displayed enhanced embryo pathogenicity, providing the first genetic evidence implicating the ARV S1 genome segment in both syncytium formation and viral pathogenesis.

Animals↗

PubMed1998

Characterization of mRNA for hepatitis delta antigen: exclusion of the full-length antigenomic RNA as an mRNA.

Hepatitis delta virus (HDV) encodes a single protein, the hepatitis delta antigen (HDAg), which is thought to be translated from a 0. 8-kb RNA of antigenomic sense. This subgenomic RNA species is present in very small amounts in HDV-infected liver tissues and in cultured cells infected or transfected with HDV, and in some cases it cannot be detected at all. In contrast, HDAg protein is present in large amounts in all natural and experimental models of HDV infection. This study addresses whether other HDV RNA species, such as the antigenomic-sense, genome-size HDV RNA can also serve as the mRNA for HDAg synthesis. Taking advantage of the ability of herpes simplex virus (HSV) to degrade only polyadenylated mRNAs, we examined the effect of HSV coinfection on HDAg synthesis. It was shown that HSV infection did degrade the subgenomic 0.8-kb HDV mRNA but not HDV genome-length RNA. Under such conditions, HDAg synthesis was completely inhibited. Furthermore, the genome-length HDV RNA was found not to be associated with polysomes. Finally, in vitro translation studies demonstrated that HDAg could not be translated directly from the genome-length antigenomic-sense HDV RNA. These results suggest that only the subgenomic RNA species of HDV possesses properties characteristic of the mRNA for HDAg and that the genome-length RNA cannot be used for translating HDAg. In addition, we found that HDV RNA replication did not depend on de novo HDAg synthesis.

5' Untranslated Regions↗

PubMed1998

Comparison of bimanual examination with ultrasound examination before hysterectomy for uterine leiomyoma.

OBJECTIVE: To correlate the preoperative bimanual examination with ultrasound examination with regard to estimating the size of enlarged nongravid leiomyomatous uteri. METHODS: We performed a retrospective review of 161 patients who underwent hysterectomy for uterine leiomyoma between January 1994 and December 1994 and between July 1995 and April 1996. Uterine size was estimated clinically by bimanual examination. Ultrasound reports were reviewed. Uterine weights and dimensions in pathology reports were compared with findings on bimanual examination and ultrasonography. Body mass index (BMI) was calculated and patients were divided into two groups, one with BMIs of more than 30 and another with BMIs of less than or equal to 30. RESULTS: Ultrasound examination was ordered in 111 patients (68.9%) preoperatively. There was a strong correlation between the bimanual examination findings and the ultrasound dimensions. The equation for this relationship is ultrasound length (cm)=3.68 + 0.68 x number of weeks (r=.78, P < .001). Ultrasound length also was related strongly to size given in the pathologic reports; the equation for this relationship is ultrasound length (cm)=2.94 + 0.75 x pathology length (cm) (r=.73, P < .001). The correlation between bimanual examination and ultrasound findings was similar in obese and in nonobese patients, when uterine size could be estimated. CONCLUSION: There is a strong correlation between bimanual and ultrasound examinations with regard to determining the size of leiomyomatous uteri. Routine ultrasound is not indicated when an experienced examiner can assess uterine size. Ultrasonography may be appropriate when physical assessment is difficult, as in the case of obesity.

Body Mass Index↗

PubMed1998

Solid waste and pancreatic cancer: an ecologic study in Florida, USA.

BACKGROUND: Other than cigarette smoking, modifiable risk factors for pancreatic cancer have not been consistently identified. This study explored the ecologic relationship between pancreatic cancer incidence and measures of cigarette smoking, income, and solid waste collection for Florida's 67 counties. METHODS: We used Florida's population-based cancer registry to compare county-specific incidence rates of pancreatic cancer among Whites to median household income, the per county prevalence of cigarette smoking, and to measures of per capita municipal solid waste collected. RESULTS: County-specific incidence rates for pancreatic cancer ranged from 0 to 8.1 per 100,000 per year and were significantly correlated with income (r = 0.35), cigarette smoking (r = 0.39), and solid waste (r = 0.47). The correlation between pancreatic cancer and solid waste was largely attributable to one sub-component of solid waste, yard trash (grass clippings, and tree and shrub trimmings) (r = 0.42). Using a stepwise regression procedure, only cigarette smoking and yard trash remained significant in the model. CONCLUSIONS: These data suggest that some factor associated with grass and tree trimmings, e.g. insecticides and herbicides, may increase the risk for pancreatic cancer. This hypothesis is consistent with several reports of pancreatic cancer and insecticide exposure in individuals and may suggest new avenues for research in pancreatic cancer.

Florida↗