New ways of initiating translation in eukaryotes.
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Animals↗
Biomedical subjects
R Duncan
Publications and source records attributed to R Duncan.
Preclinical evaluation of the cardiotoxicity of PK2: a novel HPMA copolymer-doxorubicin-galactosamine conjugate antitumour agent.
PK2 is a polymeric anticancer conjugate composed of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone and pendant doxorubicin (DOX) linked via a Gly-Phe-Leu-Gly peptide spacer. Additionally galactose residues are present to facilitate liver targeting. To justify clinical evaluation of PK2 it was necessary to determine its late cardiotoxicity compared to that of free DOX. A well standardised Sprague-Dawley rat model was used with either intravenous (i.v.) administration (4, 8 and 12 mg/kg DOX equivalent) or intraperitoneal (i.p.) administration (12, 18, 24 and 36 mg/kg DOX equivalent) of PK2. This variation in the route was due to the limited solubility of PK2 at higher doses. PK2 showed two to three times less acute toxicity (assessed by the maximum reduction in body weight in the first 2 weeks) than free DOX, and both compounds were less toxic when given i.p.. No animals given PK2 i.v. showed clinical signs of cardiotoxicity, the only toxicity seen was abnormal tooth growth (approximately 50% of the animals receiving 12 mg/kg, DOX equivalent). In contrast, several animals receiving free DOX (1-4 mg/kg) i.v. died due to cardiotoxicity in an approximately dose-related manner. All animals receiving free DOX (4 mg/kg) died by 12 weeks. Following i.p. administration of PKZ there were only two late deaths related to cardiotoxicity and these were in the 24 mg/kg DOX equivalent group. All animals receiving PK2 at the highest dose (36 mg/kg DOX equivalent) died within 4 weeks, cardiotoxicity was not the main contributing factor. In this study, PK2 displayed a approximately 5-fold reduction in cardiotoxicity relative to free DOX and this supported the progression of PK2 into early clinical investigation.
Animals↗
Impact of childhood rape and aggravated assault on adult mental health.
Associations among childhood assault (rape, aggravated assault, or both) and indices of adult mental health (posttraumatic stress disorder, major depressive episode) were examined in a national probability sample of 4,008 (weighted) women. Relationships among assault characteristics and these adult mental health indices were also investigated. Findings suggested particularly deleterious effects for childhood aggravated assault and rapes that caused additional physical injury.
Adolescent↗
Identification of a novel taxol-sensitive kinase activity associated with the cytoskeleton.
The microtubule-targeted drug, taxol, enhances assembly of alphabeta tubulin dimers into microtubules. Recent work has established that taxol also elicits diverse effects on intracellular signaling. In-gel kinase assays with myelin basic protein as substrate revealed that taxol treatment significantly (P </= 0.05) reduced the activity of a 55 kD kinase present in cytoskeletal extracts from CV-1 cells. In vitro phosphorylation of myelin basic protein by tubulin immunoprecipitates revealed a comparable activity, consistent with the association of this kinase activity with microtubules. This novel kinase activity was detected in the cytoskeletal fraction of several other cell types including 10T12 fibroblasts and PC-3 prostate carcinoma cells, but was not detected in cytoskeletal fractions from HeLa cells. This taxol-sensitive kinase activity may participate in conveying information about taxol-induced structural changes in microtubules to changes in intracellular signaling.
Animals↗
Rubella virus capsid protein induces apoptosis in transfected RK13 cells.
Rubella virus is an enveloped positive-strand RNA virus that can cause mild to severe birth defects or death in an infected fetus. RV induction of programmed cell death, demonstrated in cell culture, has been implicated in the pathogenesis. The timing of apoptosis, 48 h p.i., suggested that accumulation of RV structural proteins might induce cell death in infected cells. Expression of RV structural proteins, capsid, envelope glycoproteins E1 and E2, in transiently transfected RK13 cells was as potent an inducer of cell death as RV infection. Immunofluorescence microscopy revealed that RV structural protein transfected cells exhibited the condensed nuclei typical of apoptotic cell death. Transfection with the capsid protein construct, but not E2 and E1, resulted in as much cell death as joint expression of all three RV structural proteins. Capsid required a membrane-anchoring domain to induce cell death, but a heterologous polypeptide fused to the capsid membrane anchor did not cause apoptosis. Deletion mutants demonstrated that the apoptosis-inducing activity resides in the N-terminal 170 amino acids of capsid. Though apoptosis-inducing capsid constructs appear to have an ER sub-cellular localization, disruption of the ER calcium storage capacity does not correlate with cell death. Mechanisms consistent with these results are discussed.
Animals↗
Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo.
Dendrimers are highly branched macromolecules of low polydispersity that provide many exciting opportunities for design of novel drug-carriers, gene delivery systems and imaging agents. They hold promise in tissue targeting applications, controlled drug release and moreover, their interesting nanoscopic architecture might allow easier passage across biological barriers by transcytosis. However, from the vast array of structures currently emerging from synthetic chemistry it is essential to design molecules that have real potential for in vivo biological use. Here, polyamidoamine (PAMAM, Starburst), poly(propyleneimine) with either diaminobutane or diaminoethane as core, and poly(ethylene oxide) (PEO) grafted carbosilane (CSi-PEO) dendrimers were used to study systematically the effect of dendrimer generation and surface functionality on biological properties in vitro. Generally, dendrimers bearing -NH(2) termini displayed concentration- and in the case of PAMAM dendrimers generation-dependent haemolysis, and changes in red cell morphology were observed after 1 h even at low concentrations (10 microg/ml). At concentrations below 1 mg/ml CSi-PEO dendrimers and those dendrimers with carboxylate (COONa) terminal groups were neither haemolytic nor cytotoxic towards a panel of cell lines in vitro. In general, cationic dendrimers were cytotoxic (72 h incubation), displaying IC(50) values=50-300 microg/ml dependent on dendrimer-type, cell-type and generation. Preliminary studies with polyether dendrimers prepared by the convergent route showed that dendrimers with carboxylate and malonate surfaces were not haemolytic at 1 h, but after 24 h, unlike anionic PAMAM dendrimers they were lytic. Cationic 125I-labelled PAMAM dendrimers (gen 3 and 4) administered intravenously (i.v.) to Wistar rats ( approximately 10 microg/ml) were cleared rapidly from the circulation (<2% recovered dose in blood at 1 h). Anionic PAMAM dendrimers (gen 2.5, 3.5 and 5.5) showed longer circulation times ( approximately 20-40% recovered dose in blood at 1 h) with generation-dependent clearance rates; lower generations circulated longer. For both anionic and cationic species blood levels at 1 h correlated with the extent of liver capture observed (30-90% recovered dose at 1 h). 125I-Labelled PAMAM dendrimers injected intraperitoneally were transferred to the bloodstream within an hour and their subsequent biodistribution mirrored that seen following i.v. injection. Inherent toxicity would suggest it unlikely that higher generation cationic dendrimers will be suitable for parenteral administration, especially if they are to be used at a high dose. In addition it is clear that dendrimer structure must also be carefully tailored to avoid rapid hepatic uptake if targeting elsewhere (e.g. tumour targeting) is a primary objective.
Animals↗
A new class of fusion-associated small transmembrane (FAST) proteins encoded by the non-enveloped fusogenic reoviruses.
The non-enveloped fusogenic avian and Nelson Bay reoviruses encode homologous 10 kDa non-structural transmembrane proteins. The p10 proteins localize to the cell surface of transfected cells in a type I orientation and induce efficient cell-cell fusion. Mutagenic studies revealed the importance of conserved sequence-predicted structural motifs in the membrane association and fusogenic properties of p10. These motifs included a centrally located transmembrane domain, a conserved cytoplasmic basic region, a small hydrophobic motif in the N-terminal domain and four conserved cysteine residues. Functional analysis indicated that the extreme C-terminus of p10 functions in a sequence-independent manner to effect p10 membrane localization, while the N-terminal domain displays a sequence-dependent effect on the fusogenic property of p10. The small size, unusual arrangement of structural motifs and lack of any homologues in previously described membrane fusion proteins suggest that the fusion-associated small transmembrane (FAST) proteins of reovirus represent a new class of membrane fusion proteins.
Amino Acid Sequence↗
Serum levels of high-density lipoprotein phospholipids correlate inversely with severity of angiographically defined coronary artery disease.
In an attempt to assess the relationship between lipid abnormalities and severity of coronary artery disease, we measured serum levels of cholesterol (SC), triglycerides (TG), phospholipids (SP), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), high density lipoprotein cholesterol (HDL-C), and high density lipoprotein phospholipids (HDL-P), in 217 men undergoing diagnostic coronary arteriography. We found significantly higher mean values of HDL-P and HDL-C in men with normal coronaries, but no significant differences in the other measured lipids. While there was no significant difference in HDL-C among patients with one, two or three-vessel disease, there was a negative correlation between HDL-P levels and the severity of the disease. These observations suggest that prospective studies would be of merit to establish the relevance of HDL-P in the development of coronary artery disease.
Cholesterol↗
Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: a potential oral delivery system?
PURPOSE: To investigate systematically the effect of polyamidoamine (PAMAM) dendrimer size, charge, and concentration on uptake and transport across the adult rat intestine in vitro using the everted rat intestinal sac system. METHODS: Cationic PAMAM dendrimers (generations 3 and 4) and anionic PAMAM dendrimers (generations 2.5, 3.5, and 5.5) that were modified to include on average a single pendant amino group were radioiodinated using the Bolton and Hunter Reagent. 125I-Labelled dendrimers were incubated with everted sacs in vitro and the transfer of radioactivity into the tissue and serosal fluid was followed with time. RESULTS: The serosal transfer rates seen for all anionic generations were extremely high with Endocytic Indices (EI) in the range 3.4-4.4 microL/mg protein/h. The concentration-dependence of serosal transfer was linear over the dendrimer concentration range 10-100 microg/mL. For 125I-labelled generation 5.5 the rate of tissue uptake was higher (EI = 2.48+/-0.51 microL/mg protein/h) than seen for 125I-labelled generations 2.5 and 3.5 (0.6-0.7 microL/mg protein/h) (p < 0.05). The 125I-labelled cationic PAMAM dendrimers (generations 3 and 4) displayed a tissue uptake (EI = 3.3-4.8 microL/mg protein/h) which was higher (p < 0.05) than the rate of serosal transfer (EI = 2.3-2.7 microL/mg protein/h), probably due to nonspecific adsorption of cationic dendrimer to the mucosal surface. CONCLUSIONS: As the anionic PAMAM dendrimers displayed serosal transfer rates that were faster than observed for other synthetic and natural macromolecules (including tomato lectin) studied in the everted sac system, these interesting nanoscale structures may have potential for further development as oral drug delivery systems.
Animals↗
Neurobehavioural outcomes of penetrating and tangential gunshot wounds to the head.
OBJECTIVE: The objective of this study was to compare penetrating and tangential gunshot wounds to the head with regards to demographic, neurobehavioural and clinical outcome measures. METHODS: Twenty-nine patients with penetrating gunshot wounds (P-GSW) and 11 patients with tangential gunshot wound (T-GSW) to the head admitted to an acute neurotrauma service were compared using standardized neurobehavioural and clinical outcome measures. RESULTS: The mean GCS was 10.5 +/- 0.79 for the P-GSW group and 13.4 +/- 0.72 for the T-GSW group. The mean AIS-CNS for the P-GSW group was 5.00 +/- 0 and for the T-GSW group was 3.7 +/- 0.27. Significance was found on Digit Span (p < 0.05) and Block Design (p < 0.009) subtests. Outcomes between the two groups were similar, except for significant differences were found for acute length of stay (LOS) (P-GSW was 47.72 +/- 13.2 and T-GSW group was 13.0 +/- 1.3, p = 0.005) and for acute care charges (P-GSW group was $150,533 +/- 23,834 and T-GSW group was $70,712 +/- 16,587, p = 0.05). CONCLUSIONS: Initially, a penetrating gunshot wound is a more severe and costly injury than a tangential gunshot wound to the head, however T-GSW possess significant deficits and, if the patient survives past the acute phase of recovery, the two groups have similar functional outcomes. Future standard classification, neuropsychological, and clinical outcome measures.
Adult↗
A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures.
PURPOSE: This study compares the cognitive effects of topiramate (TPM) with those of valproate (VPA) using efficacious doses of each drug when used as adjunctive therapy to carbamazepine (CBZ). A key question of the study is to what extent a more gradual introduction of TPM improves tolerability and prevents cognitive impairment. METHODS: The study is a multicenter, randomized, observer-blinded, parallel-group clinical trial with VPA or TPM given as first-line add-on therapy to steady-state treatment with CBZ. TPM is introduced at 25 mg and increased with weekly 25mg/d increments to a minimum dosage of 200 mg/d. The target dosage ranges from 200 to 400 mg/d for TPM and is 1800 mg/d for VPA. The study evaluates cognitive function changes from baseline to end point (after 20 weeks of treatment) and during titration (after 8 weeks of treatment). The primary outcome measure is the difference between the treatments (TPM versus VPA) in change from baseline to end point and change from baseline to titration, using a 95% confidence interval approach. RESULTS: For the 10 baseline-to-end point comparisons, one test measuring short-term verbal memory (Rey Auditory Verbal Learning Test) yields a statistically significant difference between the treatments (p = 0.02), showing worsening for TPM and improvement of scores for VPA. The 10 baseline-to-titration comparisons also show one statistically significant difference, again for a test measuring short-term memory (Recognition of Words; p = 0.04), showing a larger change in the negative direction for TPM. None of the mood tests or the test for subjective complaints shows statistically significant differences between the treatments, although more scores are in the negative direction for TPM during titration. CONCLUSION: Although the pattern of changes in the negative direction seems consistent with clinical information, the differences found between the treatments are small. An important finding of our study is that, when the results are compared with those of other studies, it is clear that gradual introduction of TPM can reduce the extent of cognitive impairment (with a maximum of about 0.6 SD).
Adolescent↗
SPECT in focal epilepsies.
Brain perfusion changes during seizures were first observed in the 1930s. Single Photon Emission Computed Tomography (SPECT) was developed in the 1970s, and tracers suitable for the imaging of regional cerebral perfusion (rCP) became available in the 1980s. The method was first used to study rCP in the interictal phase, and this showed areas of low perfusion in a proportion of cases, mainly in patients with temporal lobe epilepsies. However, the trapping paradigm of tracers such as hexamethyl propyleneamine oxime (HMPAO) provided a practicable method of studying changes in rCP during seizures, and a literature was established in the late 1980s and early 1990s showing a typical sequence of changes during and after seizures of mesial temporal lobe origin; the ictal phase was associated with large increases in perfusion throughout the temporal lobe, with first the lateral, then the mesial temporal lobe becoming hypoperfused in the postictal phase. Activation and inhibition of other structures, such as the basal ganglia and frontal cortex, were also seen. Studies of seizures originating elsewhere in the brain have shown a variety of patterns of change, according to the structures involved. These changes have been used practically to aid the process of localisation of the epileptogenic zone so that epilepsy surgery can be planned. Some neuroreceptors (e.g. benzodiazepine receptors) can be studied using SPECT, and have shown localised abnormalities. SPECT has also been used to study brain function during the intracarotid amytal test. SPECT images of all kinds can be analysed using numerical techniques such as statistical parametric mapping, and such techniques promise to improve the yield of information from ictal studies.
Journal Article↗
Cerebello-olivary and lateral (accessory) cuneate degeneration in a juvenile American Miniature horse.
A 12-month-old American Miniature horse colt was presented to the Virginia Tech Veterinary Teaching Hospital with a 7-month history of progressive ataxia. Physical examination revealed a head intention tremor, base-wide stance, and ataxia. Necropsy findings were confined to the brain. There were bilateral areas of liquefactive necrosis and cavitation corresponding to the dorsal accessory olivary and lateral (accessory) cuneate nuclei. Cerebellar folia of the dorsal vermis were thin. Microscopically, the cerebellar cortex was characterized by patchy areas of Purkinje cell loss with associated variable thinning of the molecular and granule cell layers and astrogliosis. Dorsal accessory olivary and lateral cuneate nuclei were cavitated and had mild glial response around their periphery. Additionally, a focus of necrosis and neuropil vacuolization was found in the right putamen. These findings indicate the presence of a neurodegenerative disorder centered, but not confined to, the cerebellum and its connections in this American Miniature horse colt.
Animals↗
Technology architecture guidelines for a health care system.
Although the demand for use of information technology within the healthcare industry is intensifying, relatively little has been written about guidelines to optimize IT investments. A technology architecture is a set of guidelines for technology integration within an enterprise. The architecture is a critical tool in the effort to control information technology (IT) operating costs by constraining the number of technologies supported. A well-designed architecture is also an important aid to integrating disparate applications, data stores and networks. The authors led the development of a thorough, carefully designed technology architecture for a large and rapidly growing health care system. The purpose and design criteria are described, as well as the process for gaining consensus and disseminating the architecture. In addition, the processes for using, maintaining, and handling exceptions are described. The technology architecture is extremely valuable to health care organizations both in controlling costs and promoting integration.
Computer Systems↗
An enterprise web viewing system for clinical and administrative data
The authors will demonstrate the comprehensive web based viewing system for clinical and administrative data in widespread use in the Cedars-Sinai Health System. This system encompasses over a dozen disparate systems of varying ages, each of which originally had a unique user interface. The clinical viewing system is called Web/VS and is assessable from 400 clinical workstations in patient care areas as well as any network or remotely-connected workstation. The web viewing system includes a firewall and token based authentication system which allows secure access from the Internet. Encrypted wireless access to web-clipped clinical information is now in use by many physicians carrying Palm VII personal digital assistants.
Journal Article↗
Extensive sequence divergence and phylogenetic relationships between the fusogenic and nonfusogenic orthoreoviruses: a species proposal.
The orthoreoviruses can be divided into subgroups based on either their restricted host range or the unusual ability of certain members of this group of nonenveloped viruses to induce cell-cell fusion from within. Phylogenetic relationships cannot be inferred based on these biological properties because fusogenic reoviruses are present in both the avian and mammalian subgroups. To address this issue, the complete nucleotide sequences of the three S-class genome segments encoding the major sigma-class core, outer capsid, and nonstructural proteins of four fusogenic reoviruses were determined and used to establish the phylogeny of the orthoreoviruses. The viruses analysed included two strains of avian reovirus and the only known fusogenic mammalian reoviruses, Nelson Bay virus and baboon reovirus. Comparative sequence analysis of these fusogenic reoviruses and the prototypical nonfusogenic mammalian reoviruses indicated a highly diverged genus with both conserved and unique sequence-predicted structural motifs in the major sigma-class proteins. Phylogenetic analysis provided the basis for the first taxonomic subdivision of the orthoreoviruses into species classes based on inferred evolutionary relationships. It is proposed that the orthoreoviruses consist of at least four species that separate into three clades. The nonfusogenic mammalian reovirus species represent a single clade, and the fusogenic reoviruses separate into two distinct clades. The first clade of fusogenic reoviruses contains the avian reovirus- and Nelson Bay virus-type species, with the second clade being occupied by the single baboon reovirus isolate that represents a fourth orthoreovirus species.
Amino Acid Sequence↗
Management of drug budgets. Neurologists do not have confidence in Glasgow's method of managing drugs budget.
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Attitude of Health Personnel↗