Biomedical subjects
Publications and source records attributed to R Parker.
Medications are often dispensed in hospital on a drug round, regardless of whether this is the best time for the individual patient. Drug rounds do not enable patients to learn about their medications while in hospital. Self-administration of medication allows patients to receive education about their medications and increases the chances of compliance.
The present study was designed to explore the activity of platinum compounds in cisplatin-resistant cell lines, the unselected cell lines of the National Cancer Institute's Anticancer Drug Screen, and the potential for use in combination. The activities of four platinum compounds in cisplatin-resistant KB and A2780 cells were investigated. The cells were highly resistant to cisplatin and cross-resistant to carboplatin, but less than one-tenth as resistant to oxaliplatin and tetraplatin. Cellular accumulation of all platinum compounds was decreased in both resistant cell lines. When the activities of cisplatin and oxaliplatin were evaluated in the National Cancer Institute's Anticancer Drug Screen, marked differences were observed. Evaluation of the activity profile using the COMPARE program revealed a different pattern for both agents: the cisplatin activity profile was similar to those of other diamine-platinum compounds, alkylating agents including melphalan, and camptothecin analogs, whereas the activity profile of oxaliplatin resembled those of other "dach" (diaminocyclohexane) platinum compounds and of acridine derivatives. The sensitivity profiles are influenced by the target(s)/mechanism(s) of action and the mechanism(s) of resistance of a drug. The dissimilarity in profiles suggests that these two platinum compounds have a different target(s)/mechanism(s) of action, a different mechanism(s) of resistance, or most likely both. Studies evaluating combinations of cisplatin/oxaliplatin suggest that the activities of these two agents are at least additive and possibly synergistic. Oxaliplatin has a different spectrum of activity and low cross-resistance to cisplatin and should be valuable in cisplatin refractory patients or in combination with cisplatin.
The decay rates of eukaryotic transcripts can be determined by sequence elements within an mRNA. One example of this phenomenon is the rapid degradation of the yeast MATalpha1 mRNA, which is promoted by a 65 nt segment of its coding region termed the MATalpha1 instability element (MIE). The MIE is also capable of destabilizing the stable PGK1 transcript. To determine how the MIE accelerates mRNA turnover we examined the mechanism of degradation of the MATalpha1 transcript. These experiments indicated that the MATalpha1 mRNA was degraded by a deadenylation-dependent decapping reaction which exposed the transcript to 5'-->3' exonucleolytic digestion. Deletion of the MIE from the MATalpha1 mRNA decreased the rate at which this mRNA was decapped. In contrast, insertion of the MIE into the PGK1 transcript caused an increase in the rate of deadenylation of the resulting chimeric mRNA. These observations suggest that the MIE promotes rapid mRNA decay by increasing the rates of deadenylation and decapping, with its primary effect on mRNA turnover depending on additional features of a given transcript. These results also strengthen the hypothesis that deadenylation-dependent decapping is a common pathway of mRNA decay in yeast and indicate that an instability element within the coding region of an mRNA can effect nucleolytic events that occur at both the 5'- and 3'-ends of an mRNA.
A major pathway of messenger RNA degradation in eukaryotic cells is initiated by shortening of the poly(A) tail, which, at least in yeast, triggers a decapping reaction, thereby exposing the mRNA to 5' --> 3' degradation. Decapping is the key step in this decay pathway because the transcript body is rapidly degraded following decapping. Accordingly, decapping is the site of numerous controls, including inhibition of decapping by the poly(A) tail and modulation of mRNA decapping rate by specific sequences. Moreover, a specialized decay pathway that degrades aberrant transcripts triggers rapid mRNA decapping independently of poly(A)-tail shortening. We have identified a yeast gene, termed DCP1, that encodes the decapping enzyme, or an essential component of a decapping complex. The protein Dcp1 is required for the normal decay of many unstable and stable yeast mRNAs, as well as mRNAs that are decapped independently of deadenylation. These results indicate that mRNA-specific rates of decapping, and thus decay, will result from differences in the interaction of the DCP1 decapping enzyme with individual transcripts.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
OBJECTIVE: To describe platinum-based chemotherapy combined with local treatment modalities as an alternative to external beam radiotherapy for intraocular retinoblastoma. DESIGN: Platinum levels were measured by atomic absorption analysis in the tumors of 2 patients with retinoblastoma given carboplatin 5 or 2.5 hours before enucleation. Platinum levels in heated vs nonheated Greene melanoma tumors in rabbits were compared. A retrospective review of 172 affected eyes in 136 consecutive patients treated for retinoblastoma between January 1990 and December 1995 was performed. From 1990 to 1992, all treatable eyes initially received systemic carboplatin, 560 mg/m2, followed by 15 to 30 minutes of continuous diode laser hyperthermia (thermochemotherapy). Since 1992, larger tumors were treated initially with 3 monthly cycles of carboplatin, etoposide, and vincristine sulfate to reduce tumor volume (chemoreduction) followed by sequential aggressive local therapy (SALT) during examinations under anesthesia every 2 to 3 weeks. OUTCOME MEASURE: Treatment success was defined as eradication of tumor without enucleation or external beam radiotherapy. RESULTS: Significant therapeutic platinum levels were measured in the human tumors 2.5 and 5 hours after carboplatin administration. Increasing the temperature by 9 degrees C for 15 minutes doubled platinum levels in the rabbit model. Of the 38 eyes with Reese-Ellsworth group 1 through 5b tumors that were treated primarily with thermochemotherapy, all 24 eyes with group 1 and 2 tumors were treated successfully and two of the 4 eyes with group 3 tumors and all 10 eyes with group 5b tumors were treated unsuccessfully. Chemoreduction plus SALT was the primary treatment in 35 eyes and was successful in all 10 eyes with group 1 through 4 tumors and unsuccessful in all 7 eyes with extensive subretinal seeding and all 18 eyes with group 5b tumors with vitreous seeding. Seventy patients received carboplatin or carboplatin, vincristine, and etoposide, with myelosuppression, occasionally associated with bacteremia, being the main side effect. Transfusions were required in 15% of patients. Radiation retinopathy occurred in all 6 eyes treated with iodine 125 plaques. CONCLUSIONS: Thermochemotherapy is successful primary treatment for Reese-Ellsworth group 1 and 2 retinoblastomas. For larger tumors in the absence of vitreous or extensive subretinal seeding, 3 cycles of chemoreduction followed by SALT eradicates residual viable tumor. Chemoreduction plus SALT was not successful in eyes with diffuse vitreous or extensive subretinal seeding. Prior chemotherapy increases the risk for radiation retinopathy following 125I plaque therapy. External beam radiotherapy can safely be avoided in the primary treatment of Reese-Ellsworth groups 1 through 4 nondispersed retinoblastoma.
Gustatory sweating has been only rarely reported in diabetes mellitus and is thought to be due to axonal regeneration within the autonomic nervous system. We investigated the relationship of gustatory sweating to other diabetic complications. 196 patients in four groups (diabetic nephropathy, diabetic neuropathy, diabetic controls, and non-diabetic renal failure) were questioned about gustatory sweating. Somatic and autonomic neuropathy were assessed by clinical signs, vibration perception threshold, and heart rate variability. Sixty-nine percent of patients with nephropathy and 36% of those with neuropathy reported gustatory sweating, whereas less than 5% reported it in the other two groups. Five subjects reported that gustatory sweating either disappeared or significantly improved immediately after renal transplantation. Analysis of the nephropathy and neuropathy groups separately showed a strong correlation between gustatory sweating and degree of neuropathy (p < 0.01). This study shows that gustatory sweating is much more common than previously believed and demonstrates that it is often very closely linked with diabetic nephropathy.
The 5' cap structure of eukaryotic mRNAs is significant for a variety of cellular events and also serves to protect mRNAs from premature degradation. Analysis of mRNA decay in Saccharomyces cerevisiae has shown that removal of the 5' cap structure is a key step in the turnover of many yeast mRNAs, and that this decapping is carried out by Dcp1p. In addition to the yeast decapping enzyme, other activities that can cleave the 5' cap structure have been described. These include two mammalian enzymes and two viral activities that cleave cellular mRNA cap structures as part of their life cycle. Here we review these various decapping activities and discuss their biological roles.
Clinical and health services research will play a more important role in group practice organizations because it provides a vehicle to identify and answer critical questions. Study initiatives can identify, describe, quantify, and help predict trends in clinical practice. Systematic investigation is a means to link structure and processes of care to clinical parameters, patient outcomes, and cost variables. Findings can be used to support sound clinical, quality of care, and educational decision making. The ultimate goal of research is to promote the appropriate access and delivery of quality care in a cost-effective manner.
The decay of several yeast mRNAs occurs by a mechanism in which deadenylation precedes decapping and subsequent 5'-to-3' exonucleolytic decay. In order to identify gene products required for this process of mRNA turnover, we screened a library of temperature-sensitive strains for mutants with altered mRNA degradation. We identified seven mutations in four genes that inhibited mRNA turnover. Two mutations were alleles of the XRN1 5'-to-3' exoribonuclease known to degrade mRNAs following decapping. One mutation defined a new gene, termed DCP1, which in subsequent work was demonstrated to encode a decapping enzyme or a necessary component of a decapping complex. The other mutations defined two additional genes, termed MRT1 and MRT3 (for mRNA turnover). Mutations in the MRT1 and MRT3 genes slow the rate of deadenylation-dependent decapping, show transcript-specific effects on mRNA decay rates, and do not affect the rapid turnover of an mRNA containing an early nonsense codon, which is degraded by a deadenylation-independent decapping mechanism. Importantly, cell extracts from mrt1 and mrt3 strains contain normal levels of the decapping activity required for mRNA decay. These observations suggest that the products of the MRT1 and MRT3 genes function to modulate the rates of decapping that occur following deadenylation.
Explore the source record for details and available documents.
SCOPE: This review summarizes the main issues discussed during Track D, which examined the societal impact of HIV/AIDS, and responses to the epidemic by individuals, families, communities and societies worldwide. Micro- and macrolevel issues addressed included the development, implementation and evaluation of programmes for prevention and care; policy development and implementation; structural issues such as the impact of gender relations, development and migration on the development of the epidemic; and the social and economic impact of HIV/AIDS on affected societies and communities. RECURRENT THEMES: Presentations provided strong evidence that peer-led, community-based programmes offer particularly effective ways of working, and that participatory research involving affected communities provides useful results for the design and evaluation of programmes and policies. This is the case across settings, issues, populations and countries. FUTURE DIRECTIONS: Emerging needs include how best to ensure sustainability of national and international responses, how best to scale up successful interventions for wider reach, and how best to work with systematically marginalized, neglected groups and populations. Research priorities include the characterization of the multiple determinants of HIV-related vulnerability, and the evaluation of interventions that take these complex determinants as their starting point. A more coherent and strategic response requires less separation between the different constituencies involved in AIDS work, and the more sustained involvement of people living with HIV/AIDS themselves.
The first step in the decay of many eukaryotic mRNAs is shortening of the poly(A) tail. In yeast, deadenylation leads to mRNA decapping and subsequent 5' --> 3' exonucleolytic degradation of the transcript body. We have determined that the major poly(A)-binding protein Pab1p plays at least two critical roles in this pathway. First, mRNAs in pab1 delta strains were decapped prior to deadenylation. This observation defines a new function for Pab1p as an inhibitor of mRNA decapping. Moreover, mutations that inhibit mRNA turnover suppress the inviability of a pab1 delta mutation, suggesting that premature mRNA decapping in pab1 delta strains contributes to cell death. Second, we find that Pab1p is not required for deadenylation, although in its absence poly(A) tail shortening rates are significantly reduced. In addition, in the absence of Pab1p, newly synthesized mRNAs had poly(A) tails longer than those in wild-type strains and showed an unexpected temporal delay prior to the initiation of deadenylation and degradation. These results define new and critical functions for Pab1p in the regulation of mRNA decapping and deadenylation, two important control points in the specification of mRNA half-lives. Moreover, these results suggest that Pab1p functions in additional phases of mRNA metabolism such as mRNP maturation.
Based on the above mechanisms of mRNA degradation, an integrated model of mRNA turnover can be proposed (Figure 1). In this model, all polyadenylated mRNAs would be degraded by the deadenylation-dependent pathway at some rate. In addition to this default pathway, another layer of complexity would come from degradation mechanisms specific to individual mRNAs or to classes of mRNAs. Such mRNA-specific mechanisms would include sequence-specific endonuclease cleavage and deadenylation-independent decapping. Thus, the overall decay rate of an individual transcript will be a function of its susceptibility to these turnover pathways. In addition, cis-acting sequences that specify mRNA decay rate, as well as regulatory inputs that control mRNA turnover, are likely to affect all the steps of these decay pathways. One important goal in future work will be to identify the gene products that are responsible for the nucleolytic events in these pathways and to delineate how specific mRNA features act to affect the function of these degradative activities. The identification of distinct mRNA decay pathways should allow, genetic and biochemical approaches that can be designed to identify these gene products. A second important goal is to understand the nature of the interaction between the 5' and 3' termini, which may also be critical for efficient translation.
OBJECTIVE: Our purpose was to analyze (1) the effects of prevalent lower reproductive tract infections and (2) the effect of systematic diagnosis and treatment to reduce risks of early pregnancy loss (< 22 weeks), preterm premature rupture of membrances, and overall preterm birth. STUDY DESIGN: A prospective, controlled treatment trial was conducted on 1260 women. During the first 7 months of the program (observation, phase I), women were examined at initiation of prenatal care for a panel of lower genital tract microorganisms and bacterial vaginosis. Women were followed up with reexaminations at 22 to 29 weeks and after 32 weeks' gestation. The recommended treatments of the Centers for Disease Control (i.e., 300 mg of clindamycin orally twice daily for 7 days for bacterial vaginosis) were used for infected women during the second 8 months of the study (treatment, phase II). Data were analyzed according to intent to treat by means of univariate and multivariate methods. RESULTS: Overall, presence of bacterial vaginosis (32.5%) at enrollment was associated with pregnancy loss at < 22 weeks' gestation (relative risk 3.1, 95% confidence interval 1.4 to 6.9). Among women in the observation phase bacterial vaginosis was associated with increased risk of both preterm birth (relative risk 1.9, 95% confidence interval 1.2 to 3.0) and preterm premature rupture of membranes (relative risk 3.5, 95% confidence interval 1.4 to 8.9). Within this population (phase I) 21.9% of preterm birth overall (43.8% premature rupture of membranes) is estimated as attributable to bacterial vaginosis. Among women with bacterial vaginosis phase II (treatment) was associated with reduced preterm birth (relative risk 0.5, 95% confidence interval 0.3 to 0.9); there was a similar reduction for women with preterm premature rupture of membranes (relative risk 0.5, 95% confidence interval 0.2 to 1.4). Women with both bacterial vaginosis and trichomoniasis were at highest risk of preterm birth (28%); treatment of both conditions (phase II) reduced preterm birth (17%) but did not eliminate this risk. Earlier patient enrollment and oral antibiotic treatment were associated with reduced preterm birth. CONCLUSIONS: This prospective, controlled trial confirms that the presence of bacterial vaginosis is associated with increased risks of pregnancy loss at < 22 weeks, preterm premature rupture of membranes, and preterm birth. Orally administered clindamycin treatment is associated with a 50% reduction of bacterial vaginosis-linked preterm birth and preterm premature rupture of membranes. Women at risk for preterm birth or preterm premature rupture of membranes because of bacterial vaginosis or common genital tract infections should be screened, treated, reevaluated for cure, and re-treated if necessary.
Submitral left ventricular aneurysms typically affect young adults of African ancestry. These aneurysms are characterized by heart failure and mitral insufficiency, and occur in the absence of coronary disease. We report a rare case of symptomatic ventricular tachycardia in association with submitral left ventricular aneurysm (and no mitral insufficiency). Ventricular tachycardia was abolished by aneurysm resection and ventricular reconstruction. We suggest surgical management is indicated for ventricular tachycardia associated with this unusual condition, and may be curative.
The glass-transition behaviour of four hydrated wheat gluten proteins (alpha-gliadin, gamma-gliadin, omega-gliadin and high-molecular-weight (HMW) subunits of glutenin) was studied using differential scanning calorimetry (DSC). By fitting the data to the Gordon-Taylor equation, which has previously been used to describe the plasticization of polymers by diluents, the glass-transition temperatures (Tg) for the dry proteins were found by extrapolation. The values for Tg were within the range 397-418 K. Values for the heat capacity increment delta Cp at Tg for the plasticized proteins were also determined and ranged from 0.29-0.47 J g-1 K-1 with no dependence on water content. The differences in glass-transition behaviour of the proteins are discussed in relation to their secondary structure.