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Biomedical subjects

A L Wilson

Publications and source records attributed to A L Wilson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Prenylation of a Rab1B mutant with altered GTPase activity is impaired in cell-free systems but not in intact mammalian cells.

Previous studies have reached differing conclusions as to whether or not guanine-nucleotide-dependent conformational changes affect the ability of Rab proteins to undergo post-translational modification by Rab:geranylgeranyltransferase (Rab-GGTase). We now show that the ability of a Rab1B mutant [Q67L (Gln-67-->Leu)] with reduced intrinsic GTPase activity to undergo geranylgeranylation in cell-free assays depends on the guanine nucleotide composition of the system. When GTP is the predominant nucleotide in the assay, Rab1BQ67L is a poor substrate. However, when GDP is present and GTP is omitted, prenylation of the Q67L mutant is comparable with that of the wild-type (WT) protein. These studies, coupled with the poor prenylation of Rab1BWT in the presence of the non-hydrolysable GTP analogue guanosine 5'-[gamma-thio]triphosphate, support the notion that Rab-GGTase prefers substrates in the GDP conformation. When the abilities of Rab1BQ67L and Rab1BWT to undergo prenylation were compared by metabolic labelling of transiently expressed proteins in cultured human 293 cells, we did not observe a decline in prenylation of the mutant protein as predicted on the basis of the cell-free assays. Moreover, the Q67L mutant was comparable with the wild-type Rab1B in its ability to associate with co-expressed Rab GDP dissociation inhibitors in 293 cells. These findings raise the possibility that unidentified proteins present in intact cells may compensate for the reduced intrinsic GTPase activity of the Q67L mutant, allowing a significant proportion of the nascent Rab1BQ67L to assume a GDP conformation. The differential prenylation of Rab1BQ67L in cell-free systems versus intact cells underscores the importance of evaluating the post-translational modification of specific Rab mutants in vivo, where poorly characterized regulatory proteins may have a significant effect on GTPase activity or nucleotide exchange rates.

Amino Acid Sequence↗
PubMed1996

Association of Rab1B with GDP-dissociation inhibitor (GDI) is required for recycling but not initial membrane targeting of the Rab protein.

We have identified the Rab1B effector-domain mutant (D44N) that, when geranylgeranylated by Rab:geranylgeranyltransferase (GGTase II) in cell-free systems or intact cells, fails to form detectable complexes with GDP-dissociation inhibitors (GDIs). GDI-Rab complexes were collected on anti-FLAG affinity beads after incubating recombinant geranylgeranylated Rab1B with FLAG epitope-tagged GDI in vitro, or transiently coexpressing Myc-tagged Rab1B with FLAG-GDI-alpha or FLAG-GDI-2 in human embryonal kidney 293 cells. [3H]Mevalonate labeling and immunoprecipitation studies confirmed that the inability of Myc-Rab1BD44N to associate with GDI in vivo was not due to failure of the mutant to undergo geranylgeranylation. Immunofluorescence localization and immunoblot analysis of subcellular fractions indicated that expressed Myc-Rab1BD44N was efficiently delivered to intracellular membranes in 293 cells. This was confirmed when the fate of the prenylated pool of Rab1BD44N in 293 cells was traced by labeling the geranylgeranyl groups attached to the nascent protein with [3H]meval onate. However, in contrast to the prenylated Rab1BWT, which was distributed in both the membrane and soluble fractions, the prenylated Rab1BD44N was completely absent from the cytosol. Overexpression of Myc-Rab1BD44N did not impair ER --> Golgi glycoprotein trafficking in 293 cells, which was assessed by monitoring the Golgi-dependent processing of coexpressed beta-amyloid precursor protein. The current findings suggest that nascent prenylated Rab1B can be delivered to intracellular membranes in intact cells without forming a stable complex with GDI, but that recycling of prenylated Rab1B to the cytosolic compartment is absolutely dependent on GDI interaction.

Amino Acid Sequence↗
PubMed1996

State of South Dakota's child: 1995.

The total number of births in South Dakota declined again in 1994 to 10,504 with a .6% decrease in white babies and a 11% decrease in American Indian babies. The percent of low birth weight (LBW) newborns in South Dakota is lower than that observed nationally yet, increased in 1994 to 5.9%, the highest percent reported since 1974. These LBW newborns contributed to 79% of South Dakota's 1994 neonatal (less than 28 day mortality). Although there was a decrease in the total number of infant deaths in South Dakota, the infant mortality rate remained at 9.5 compared to the US rate of 7.9. The neonatal mortality rate was also higher than the US rate (5.4 versus 5.0) as was the post neonatal rate (4.1 versus 2.9). The post neonatal mortality rate in 1994 for infants of color (8.1) was the lowest ever recorded. In recent years the state's perinatal mortality rate that combines the fetal and neonatal mortality rates has shown a decline, possibly reflecting advances in care available during pregnancy. Recognizing the importance of prenatal care to perinatal outcome, the prevention of alcohol-related birth defects is considered in this year's report. Several screening instruments are presented with a discussion of the complex inter and intrapersonal dynamics that must be considered when women with drinking problems are identified and helped during pregnancy.

Cause of Death↗
PubMed1995

Pegaspargase versus asparaginase in adult ALL: a pharmacoeconomic assessment.

Asparaginase is an effective treatment for patients with acute lymphocytic leukemia (ALL). Unfortunately, asparaginase therapy is associated with a high incidence of hypersensitivity reactions (up to 73%), including life-threatening anaphylaxis, and its half-life of approximately 20 hours necessitates daily administration. Pegaspargase, a modification of L-asparaginase, has a longer half-life (357 hours), a decreased incidence of hypersensitivity reactions, and when doses every 14 days, provides comparable efficacy to asparaginase; however, it is much more expensive per single-dose vial ($980.00 vs $52.38). To determine the pharmacoeconomic impact of the two agents, we conducted a cost-minimization analysis for three common adult ALL protocols. Results showed that pegaspargase was significantly less costly to payers on an inpatient or outpatient basis and warranted addition to our formulary.

Adult↗
PubMed1995

The state of South Dakota's child: 1994.

This annual report reviews natality and infant mortality data and also reviews teenage pregnancy in South Dakota. Data for 1993 again document a declining rate of birth for South Dakota with a 3% decline in the number of births since 1990 and an 18% decline since 1980. An identical number of infants (102) died in 1993 as 1992 with neonatal mortality slightly declining and post neonatal mortality slightly increasing for the state. Rates of perinatal causes of infant death are lower in South Dakota than they are nation-wide, but are higher for congenital anomalies, sudden infant death, pneumonia/influenza, and injuries/homicide. The 1993 birth rate per 1,000 teenagers 15-19 years of age in South Dakota was 44.5 compared to the 1992 rate of 60.7 for the United States. In South Dakota the rate of teen births for American Indian mothers is over four times higher than that for whites. The American Indian rate is also higher than that observed for Indians nation-wide. Alternately, the South Dakota white rate of birth to this age group is lower than the national rate. For all babies born to teenage mothers, 69% of the fathers are beyond their teen years. The need to examine teen pregnancy as a societal, and not just an adolescent problem, is emphasized.

Adolescent↗
PubMed1994

Certification program in antineoplastic drug preparation for pharmacy technicians and pharmacists.

A formal training program for technicians who prepare cytotoxic agents and pharmacists who check the doses is described. To handle an overwhelming workload in an oncology satellite pharmacy and to enable the pharmacists there to increase their clinical involvement, a program was developed to train technicians to prepare antineoplastic doses and pharmacists to check the technicians' work. The program consists of two days of classroom instruction, three weeks of hands-on training, and a written examination. In addition to handling and preparation of antineoplastic drugs, other topics related to oncology are covered to give the participants a better understanding of cancer and its treatment. The technicians must complete a refresher program annually. From 1991 to 1993, 15 pharmacists and 14 technicians and pharmacy students completed the program. The technicians have taken on additional responsibilities in the satellite pharmacy, including managing the inventory of oncology drugs. Implementation of a comprehensive cancer chemotherapy training class for technicians and pharmacists has benefited the pharmacy in terms of labor and inventory control.

Antineoplastic Agents↗
PubMed1994

Personal exposure to nitrogen dioxide in the Los Angeles Basin.

A large scale study of human exposure to nitrogen dioxide (NO2) was conducted in the Los Angeles Basin, the only metropolitan area in the United States that exceeds the NO2 NAAQS. Data are available for a population representative sample of 482 households and 682 individuals. Personal exposures, as well as indoor and outdoor home levels, were monitored using passive time-integrating filter badges. Monitoring extended over a one-year period (May 1987 to May 1988), with each individual providing two consecutive days of data. Information was also collected on activity patterns, household and personal characteristics, and spatial and temporal variables. This paper describes the study design, summarizes the sample characteristics and representativeness, and presents the distribution of personal, indoor, and outdoor NO2 concentrations recorded by the monitors. Over the entire sample, median personal and outdoor levels were 35 ppb; median indoor levels were 24 ppb. Personal exposures for those in homes with gas ranges with pilot lights average 10 ppb greater than those with electric ranges, and 4 ppb greater than those with gas ranges without pilot lights. Forty percent of the variation in indoor concentrations is explained by outdoor levels; 59 percent of the variation in personal exposures is explained by indoor levels; and 48 percent of the variation in personal exposures is explained by outdoor levels.

Adolescent↗
PubMed1994

Influencing prescribers.

Appropriate drug therapy is centered on the acts of selection and dosing of pharmaceuticals. Prescribing drugs has been the exclusive province of physicians until recently. Pharmacists and others who seek to encourage physicians to prescribe specific drugs or therapies or to use pharmaceuticals in a particular manner have addressed their concerns through influence. The article examines direct and indirect methods of influencing prescribers. The changing goals of providers, payers, pharmacists, and patients are discussed, and the effectiveness of various methods of influencing prescribers are reviewed, including financial incentives, drug use evaluation, persuasion, collaboration, and computer-aided information delivery.

Clinical Protocols↗
PubMed1994

Virtue and longitudinal ethics education in medical school.

This article advances the argument that the inherent virtue/character of the caregiver is an important element in clinical ethical decision making. Virtue should be promoted as an essential component of professional behavior, and specifically emphasized in both medical student education and professional practice.

Bioethics↗
PubMed1994

Women voicing their autonomy: the changing picture of women's health care.

In recent years women's health concerns have received considerable attention. Both women and the medical establishment have recognized how biases of the past have affected clinical decision making and research affecting women's health. This article explores potential responses to these deficiencies. It suggests that training for health professionals that helps them become more attentive to patient's concerns and respectful of their autonomy will benefit all patients, regardless of gender. In addition, research that focuses upon women's health will benefit all of society.

Female↗
PubMed1994

The state of South Dakota's child: 1993.

This annual report on South Dakota's children highlights 1992 natality and mortality data and discusses the state's effort to improve its rate of childhood immunizations. In 1992 there was a slight increase over the previous year in total births (11,007) with 15% of these American Indians and 2% of other ethnic backgrounds. The state's 1992 infant mortality rate of 9.3 is the lowest ever recorded by South Dakota but represents a rate that is 9% higher than that of the United States. Analyses show that the post neonatal rate of death for American Indians remains much higher than that observed by minorities nation-wide. Progress is continuing in decreasing deaths due to perinatal causes, but infant death due to congenital anomalies and Sudden Infant Death are higher for South Dakota's white and minority populations than they are nation-wide. Current data show that only 61% of young children in South Dakota are up to date in their immunizations. The state is one of six sites in the nation to receive special funds to develop innovative strategies to achieve the year 2000 goal of a 90% childhood immunization rate. To achieve this goal there must be a commitment on the part of all health care providers to assure surveillance of children's immunization status and provision of vaccines to protect children and communities from preventable serious diseases.

Child↗
PubMed1993

Isoprenylation of Rab1B is impaired by mutations in its effector domain.

Low molecular mass GTP-binding proteins encoded by the Rab gene family are posttranslationally modified by a specific geranylgeranyltransferase (GGTase II), which catalyzes the thioether linkage of geranylgeranyl isoprenoids to cysteines within one of the following carboxyl-terminal sequence motifs: GGCC, CXC, CCSN. Short peptides containing these sequences are poor substrates for isoprenylation in vitro, suggesting that structural domains remote from the carboxyl terminus are required for interactions between Rab proteins and GGTase II. To begin to define these domains, deletions and point mutations were created within the Rab1B gene, and the ability of the mutant translation products to undergo isoprenylation was evaluated in reticulocyte lysates. Deletion of amino acids 2-9 diminished but did not eliminate isoprenylation of Rab1B, suggesting that the extreme amino-terminal region is not absolutely required for interaction with GGTase II. Longer deletions in the amino-terminal region, which probably disrupt the overall conformation of Rab1B, completely prevented isoprenylation. Site-directed mutations predicted to lie in the amino-terminal variable region (Y5N), the beta 3 strand (Q60E), and Loop 7 (A110D) of the Rab1B structure did not reduce isoprenylation. However, two mutations (I41N, D44N) in the effector domain, which appears to mediate interactions with proteins that stimulate GTP hydrolysis or GDP dissociation, essentially abolished the ability of Rab1B to undergo isoprenylation. These findings imply that the effector domain plays a key role in the isoprenylation of Rab proteins, either by serving as a prenyltransferase binding site or by facilitating interactions with accessory proteins that allow Rab1B to assume a specific guanine nucleotide-dependent conformation that is recognized by GGTase II.

Amino Acids↗