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D W Smith

Publications and source records attributed to D W Smith.

At least 19 recordsLinked to original sources
PubMed1999

The amino acid/auxin:proton symport permease family.

Amino acids and their derivatives are transported into and out of cells by a variety of permease types which comprise several distinct protein families. We here present a systematic analysis of a group of homologous transport proteins which together comprise the eukaryotic-specific amino acid/auxin permease (AAAP) family (TC #2. 18). In characterizing this family, we have (1) identified all sequenced members of the family, (2) aligned their sequences, (3) identified regions of striking conservation, (4) derived a family-specific signature sequence, and (5) proposed a topological model that appears to be applicable to all members of the family. We have also constructed AAAP family phylogenetic trees and dendrograms using six different programs that allow us to trace the evolutionary history of the family, estimate the relatedness of proteins from dissimilar organismal phyla, and evaluate the reliability of the different programs available for phylogenetic studies. The TREE and neighbor-joining programs gave fully consistent results while CLUSTAL W gave similar but non-identical results. Other programs gave less consistent results. The phylogenetic analyses reveal (1) that many plant AAAP family proteins arose recently by multiple gene duplication events that occurred within a single organism, (2) that some plant members of the family with strikingly different specificities diverged early in evolutionary history, and (3) that AAAP family proteins from fungi and animals diverged from the plant proteins long ago, possibly when animals, plants and fungi diverged from each other. The Neurospora protein nevertheless exhibits overlapping specificity with those found in plants. Preliminary evidence is presented suggesting that proteins of the AAAP family are distantly related to proteins of the large ubiquitous amino acid/polyamine/choline family (TC #2.3) as well as to those of two small bacterial amino acid transporter families, the ArAAP family (TC #2.42) and the STP family (TC #2.43).

Amino Acid Sequence↗
PubMed1999

Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury.

Gene therapy is a technique that may offer advantages over current methods of cytokine delivery to ligaments. To determine if implanted genes could be expressed in normal and injured knee ligaments, the medial collateral ligament and anterior cruciate ligament were studied in 18 rabbits. A retroviral ex vivo technique using allograft medial collateral ligament and anterior cruciate ligament fibroblasts and an adenoviral in vivo technique were compared as methods for delivering the LacZ marker gene to knee ligaments. Bilateral knee surgeries were performed, and the rabbits were equally divided into three groups. Group 1 received the retrovirus and the medial collateral ligament was ruptured, Group 2 received the adenovirus and the medial collateral ligament was ruptured, and Group 3 received the adenovirus and the medial collateral ligament was not injured. The anterior cruciate ligament was not injured in any group. The medial collateral and anterior cruciate ligaments of the right knees received 10(6) allografted, transduced ligament fibroblasts or 10(9) adenovirus particles, whereas the ligaments of the left knee received a similar volume of saline solution only. Equal numbers of rabbits were killed at 10 days, 3 weeks, and 6 weeks following the procedure. Ligament samples were stained with X-gal to detect the expression of the LacZ gene product, beta-galactosidase. LacZ gene expression was evident in ruptured and uninjured medial collateral ligaments as well as in the anterior cruciate ligament. The expression lasted between 10 days and 3 weeks in the medial collateral and anterior cruciate ligaments with use of the retrovirus and between 3 and 6 weeks in the medial collateral ligament and at least 6 weeks in the anterior cruciate ligament with the adenovirus. The length of gene expression in the ruptured and uninjured medial collateral ligaments did not differ. These preliminary studies indicate that gene transfer to normal and injured knee ligaments is possible.

Adenoviridae↗
PubMed1999

Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein.

Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.

Aging↗
PubMed1999

Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein.

Mutations in the beta-amyloid precursor protein are strongly associated with some cases of familial Alzheimer's disease. The normal physiological role of beta-amyloid precursor protein in the brain was evaluated in a cross-sectional analysis of mice deficient in beta-amyloid precursor protein. Compared with wild-type control mice the beta-amyloid precursor protein-null mice developed age-dependent deficits in cognitive function and also had impairments in long-term potentiation. In addition, the brains of the beta-amyloid precursor protein-null mice had marked reactive gliosis in many areas, especially in the cortex and hippocampus. A subpopulation of mice (n = 15) died prematurely (between three and 18 months of age). Analysis of another six mice from the same population that were showing weight loss and hypolocomotor activity exhibited a marked reactive gliosis as detected by immunoreactivity for glial fibrillary acidic protein and a profound loss of immunoreactivities for the presynaptic terminal vesicle marker proteins synaptophysin and synapsin and the dendritic marker microtubule-associated protein-2 in many brain areas, but most predominantly in the cortex and hippocampus. These results suggest that normal beta-amyloid precursor protein may serve an essential role in the maintenance of synaptic function during ageing. A compromise of this function of the beta-amyloid precursor protein may contribute to the progression of the memory decline and the neurodegenerative changes seen in Alzheimer's disease.

Aging↗
PubMed1999

Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid.

Free radical generation is increasingly implicated in a variety of pathological processes, including drug toxicity. Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of radical species both in vivo and in vitro, which suggests that this process plays an important role in aminoglycoside-induced ototoxicity. Free radical scavengers are compounds capable of inactivating free radicals, thereby attenuating their tissue damaging capacity. In this study we have determined the ability of the powerful free radical scavenger alpha-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by a highly ototoxic regimen of the aminoglycoside amikacin (450 mg/kg/day, i.m.). Experiments were carried out on pigmented guinea pigs initially weighing 200-250 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every 5 days, by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving alpha-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone (P < 0.001; t-test). These results provide further evidence of the recently reported intrinsic role of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of alpha-lipoic acid in the management of patients undergoing aminoglycoside treatment.

Action Potentials↗
PubMed1999

Diagnosis of Chlamydia trachomatis and Neisseria gonorrhoeae. Genitourinary infections in males by the Amplicor PCR assay of urine.

The Amplicor CT/NG polymerase chain reaction (PCR) test on urine specimens from males was prospectively evaluated against established specimens and laboratory methods for diagnosing Chlamydia trachomatis and Neisseria gonorrhoeae genitourinary infections, in patients from a remote region of Western Australia. Seventy-three males who were tested for both C. trachomatis and N. gonorrhoeae by both conventional methodology and Amplicor PCR on urine were enrolled in the study. Established testing comprised enzyme immunoassay/immunofluorescence antigen testing (EIA/IF) for C. trachomatis and microscopy and/or culture for N. gonorrhoeae on urethral swabs. Positive test results were confirmed using a set of criteria that included supplemental PCR testing and clinical history. Overall, 13.7% of patients were resolved as positive for C. trachomatis and 52.1% as positive for N. gonorrhoeae. The sensitivity and specificity of the Amplicor CT/NG PCR on male urine specimens for C. trachomatis were 80.0% (8/10) and 95.2% (60/63), compared with 60.0% (6/10) and 100.0% (63/63) for EIA/IF on urethral swabs. For N. gonorrhoeae, the sensitivity and specificity of the Amplicor CT/NG PCR on male urine specimens were both 100% (38/38 and 35/35, respectively) compared with 86.8% (33/38) and 100% (35/35) for microscopy and/or culture on urethral swabs. The results of this study indicate that the Amplicor CT/NG multiplex PCR test for C. trachomatis and N. gonorrhoeae performed on urine in males provides a highly sensitive, specific, and robust method for the diagnosis of both C. trachomatis and N. gonorrhoeae, for the early detection of both symptomatic and asymptomatic infected individuals.

Chlamydia Infections↗
PubMed1999

Population effects of the bombing of Oklahoma City.

BACKGROUND AND PURPOSE: The explosion at the Murrah Federal Building in Oklahoma City on April 19, 1995, affected many members of the community as well as direct victims. Our goal was to measure the exposure and effects among the general population. METHODS: We conducted surveys of the Oklahoma City metropolitan area and a control area to measure exposure and impact, primarily stress and psychological distress. RESULTS: Of the adults in the Oklahoma City MSA, 61.5 percent (58.5 percent to 64.5 percent with 95 percent confidence) reported experiencing at least one direct result of the bombing. In population terms, about 433 thousand adults (between 412 thousand and 457 thousand, with 95 percent confidence) were exposed to one or more of the consequences of the bombing. Oklahomans reported higher rates (about double) of increased alcohol use, smoking more or starting smoking. They reported more stress (about double), psychological distress (about double), post-traumatic stress-disorder components, and intrusive thoughts (double) related to the bombing than in the control area. Oklahomans also reported higher rates of seeking help for their stress or taking steps to reduce stress. The differences persisted into 1996, more than a year after the bombing. CONCLUSION: The exposure to the bombing was widespread, including more than half the adults in the metropolitan area surrounding Oklahoma City. The psychological effects were high and, while decreasing, persisted more than a year after the bombing. Primary care practitioners should screen their patients, who may normally not be considered victims, for exposure to the effects of a terrorist disaster for an extended period of time.

Adult↗
PubMed1998

A comparison of the diseases caused by Ross River virus and Barmah Forest virus.

Barmah Forest virus (BFV) and Ross River virus (RRV) are mosquito-borne viruses with similar vectors and environmental requirements. They cause diseases characterised by arthralgia, arthritis and myalgia, often accompanied by fever and rash. Arthritis is more common and more prominent in RRV disease and rash is more common and florid with BFV infection, although the diseases cannot be reliably distinguished by their clinical symptoms. Diagnosis is based on serological tests and a definite diagnosis of recent infection requires the demonstration of rising titres of IgG. Arthralgia, myalgia and lethargy may continue for at least six months in up to half of patients with RRV, but in only about 10% of patients with BFV. Both diseases are managed symptomatically.

Alphavirus↗
PubMed1998

Arboviruses in the Australian region, 1990 to 1998.

Arboviruses continue to be major human pathogens in the Australian region. This report provides a summary of the activities of these viruses over the past eight years, and comments on new findings relevant to their respective ecologies. Of particular interest and concern is the propensity of these viruses to spread. The examples discussed include the initiation of dengue epidemics in north Queensland by virus imported in viraemic travellers; the spread of Japanese encephalitis virus to the Australasian region and its probable enzootic establishment in the south-west of Papua New Guinea; the potential spread of Ross River virus to other countries, as demonstrated by the 1979-80 outbreak in the South Pacific, and the recent occurrence in military personnel from the United States of America after an exercise; and the recent spread of Barmah Forest virus into Western Australia.

Animals↗
PubMed1998

Engineering the healing of the rabbit medial collateral ligament.

A biological approach to improve healing of the medial collateral ligament (MCL) was investigated by exploring the use of therapeutic growth factors based on in vitro and in vivo experiments. The in vitro cell culture studies involved screening a variety of growth factors to select those that exhibit the most positive effects on cell proliferation and extracellular matrix synthesis. The selected growth factors were applied in vivo to a rabbit model where the MCL was ruptured. Biomechanical and histological evaluations are performed to determine whether the selected growth factors can enhance the properties of the healed MCL, whether these improvements are dose dependent, and whether combinations of growth factors can enhance MCL healing to a greater extent than individual growth factors. In vitro studies showed that epidermal growth factor (EGF) and platelet derived growth factor-BB (PDGF-BB) have the greatest effect on ligament fibroblast proliferation, whereas transforming growth factor-beta 1 (TGF-beta 1) superiorly promotes extracellular matrix synthesis. These growth factors were then applied in vivo at different dosages, in isolation and in combination, and the ligaments were evaluated six weeks post-operatively. Tensile testing of the femur-MCL-tibia complexes (FMTCs) revealed that the specimens treated with a high dose of PDGF-BB have ultimate load, ultimate elongation and energy absorbed to failure values that are significantly greater than those from the other groups. The high dose of PDGF-BB was more effective than the low dose, indicating a dose dependency. The addition of TGF-beta 1 to PDGF-BB did not lead to any further increases in the structural properties of the FMTC. These encouraging results suggest that PDGF-BB may be a potential growth factor to enhance the quality of the healing ligament.

Animals↗
PubMed1998

Supplemental iron exacerbates aminoglycoside ototoxicity in vivo.

There is increasing evidence to suggest that free radical generation is central to a variety of pathological processes, including drug toxicity. Studies demonstrating the ability of gentamicin to facilitate the generation of radical species suggest that this process plays an important role in aminoglycoside-induced ototoxicity. Because transition metals, particularly iron, play an important role in the production of free radicals and the generation of reactive oxygen species, we sought to determine whether gentamicin-induced ototoxicity is exacerbated by increases in serum iron levels. To this end, we assessed the effects of supplemental iron administration (2 mg/kg/day and 6 mg/kg/day) on changes in auditory function induced by co-administration of gentamicin (100 mg/kg/day for 30 days). Experiments were carried out on pigmented guinea pigs initially weighing 250-300 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every third day throughout the treatment period by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving iron in combination with gentamicin demonstrated a more rapid and profound elevation in CAP thresholds compared with animals receiving gentamicin alone. This effect occurred in a dose-dependent manner. Animals receiving supplemental iron alone maintained normal CAP thresholds throughout the treatment period. There was no statistically significant difference in serum gentamicin levels between groups receiving gentamicin alone or gentamicin plus iron. These results provide further evidence of the recently reported intrinsic role of iron in aminoglycoside ototoxicity, and highlight a potential risk of aminoglycoside administration in patients with elevated serum iron.

Animals↗
PubMed1998

Roles of community organizations in improving cancer prevention instruction in schools.

Health education can be an important factor in the development of appropriate health behaviors in children. Community agencies that have not traditionally supported school health education can be of significant influence in improving school health education. This study examined the relationships between the involvement of the American Cancer Society (ACS) in schools and the degree of implementation of cancer prevention curricula. School health specialists from 41 metropolitan school districts in Texas were surveyed regarding the coverage of topical areas related to cancer prevention, health instructional patterns in districts, and collaborative efforts with the ACS. Tobacco use was widely covered in all levels of schools (elementary, middle, and high school), as was nutrition. Cancer detection and the concepts of cancer as a disease received most extensive coverage in high schools, and there were no significant grade level differences regarding coverage of the risks of sun exposure. School personnel had little training and felt little district support for school health education. Most respondents felt that teachers saw the ACS primarily as a resource for cancer information and resources than as a collaborative partner in health education efforts. Community organizations can play three roles in supporting school health education. First, the organization must certainly provide disease-specific information (in this case, cancer). They must also promote comprehensive school health education in general. Lastly, the study illustrates that community organizations must act as advocates for broader change in schools by supporting the development of organizational capacity within schools and districts to implement quality school health education, enlisting community support for quality school health education, and supporting policy initiatives that strengthen school health education activities.

Adolescent↗
PubMed1998

Effect of behavior modification on patient compliance in orthodontics.

The purpose of this study was to evaluate the effects of a reward system for improving patient compliance in orthodontic treatment. The sample consisted of 144 orthodontic patients (63 male, 81 female, average age 12.8 years), 6 to 12 months into their treatment. The sample was divided into above-average and below-average compliers, based on the orthodontic patient cooperation scale (OPCS). Each group was further divided into three subgroups: (a) a control group, which received only standard instructions; (b) an award group, which received compliance instructions and a written evaluation of compliance; and (c) a reward group, which received compliance instructions, a report card, and eligibility to receive rewards for adherent behavior. Two measurements of patient compliance were used: (1) the OPCS, which divided the sample into high and low compliers and was used to compare compliance before and after the 6-month experimental period; and (2) a clinical evaluation of compliance that was based on oral hygiene, appointment punctuality, appliance wear, and appliance maintenance. Evaluations were completed at each monthly appointment. Average compliance scores of above-average compliers showed no significant improvement with rewards. The average scores of patients with below-average compliance did not improve significantly. Only oral hygiene scores in the low compliance reward group were better than in the low compliance control group. Academic performance in school was found to be correlated (p < 0.001) with compliance. Above-average compliers remained above average in their compliance. The award/reward system may help motivate below-average compliers to comply with prescribed instructions.

Achievement↗
PubMed1998

Finding intron/exon splice junctions using INFO, INterruption Finder and Organizer.

INFO, INterruption Finder and Organizer, has been used to find coding sequence intron-exon splice junctions in human and other DNA by comparing the six conceptual translations of the input DNA sequence with sequences in protein databanks using a similarity matrix and windowing algorithm. Similarities detected both delineate position of the gene and provide clues as to the function of the gene product. In addition to use of a standard similarity matrix and windowing algorithm, INFO uses two novel steps, the MiniLibrary and Reverse Sequence steps, to enhance identification of small exons and to improve precision of junction nucleotide delineation. Exons as small as about 30 bases can be reliably found, and > 90% of junctions are precisely identified when canonical splice junction information is used. With the MiniLibrary and Reverse Sequence steps, INFO parameters need not be optimized by the user. In comparative test runs using 19 human DNA sequences, INFO found 108 of 111 exons, with 0 reported false positives, compared with 111 exons and 51 false positives for BLASTX, 99 exons and 6 false positives for GRAIL II, 77 exons and 24 false positives for GeneMark, 61 exons and 9 false positives for GeneID, and 105 exons and 6 false positives for PROCRUSTES. The correlation coefficient for finding and positioning these 111 exons was greater than 98% for INFO. Comparable results were obtained in test runs of 13 nonhuman DNA sequences. INFO is applicable to DNA from any species, will become more robust as sequence databanks expand, and complements other heuristic approaches.

Algorithms↗
PubMed1998

Attenuation of neomycin ototoxicity by iron chelation.

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential (CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.

Animals↗
PubMed1998

Topical gentamicin and ethacrynic acid: effects on cochlear function.

OBJECTIVE: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. STUDY DESIGN: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. METHODS: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. RESULTS: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. CONCLUSIONS: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.

Action Potentials↗
PubMed1998

Australian encephalitis in the Northern Territory: clinical and epidemiological features, 1987-1996.

BACKGROUND: The last epidemic of Australian encephalitis occurred in 1974. Since then, cases have been reported from the Kimberley of Western Australia (WA). AIMS: To describe the epidemiology and clinical features of Australian encephalitis in the Northern Territory (NT) of Australia. METHODS: Review of cases of Australian encephalitis presenting to Royal Darwin Hospital from 1987-1996 and review of sentinel chicken surveillance for Australian encephalitis viruses. RESULTS: Sixteen patients were identified; ten from the NT and six from WA. Cases occurred in the years 1987, 1988, 1991 and 1993. Infection was acquired throughout northern NT below latitude 20 degrees S in the months March to July. All infections were due to Murray Valley encephalitis (MVE) virus. Eleven of the patients were children. Distinguishing features were spinal cord and brainstem involvement and the absence of seizures in adults. CT scanning was normal and EEG showed no focal activity. Five died (31%) and four (25%) have residual neurological disability. Sentinel chicken surveillance since 1992 shows yearly seroconversion to MVE virus throughout northern NT; human cases occurred simultaneously with chicken seroconversion in 1993. CONCLUSIONS: Australian encephalitis is endemic in the NT; the areas at risk are north of Tennant Creek. Outbreaks are seasonal and occur every few years. Young children are most at risk. Mortality and morbidity are high. Prevention of disease is by avoidance of mosquito exposure and vector control measures.

Adult↗