Biomedical subjects

D Boyle

Publications and source records attributed to D Boyle.

At least 19 recordsLinked to original sources

PubMed2001

Tioman virus, a novel paramyxovirus isolated from fruit bats in Malaysia.

A search for the natural host of Nipah virus has led to the isolation of a previously unknown member of the family Paramyxoviridae. Tioman virus (TiV) was isolated from the urine of fruit bats (Pteropus hypomelanus) found on the island of the same name off the eastern coast of peninsular Malaysia. An electron microscopic study of TiV-infected cells revealed spherical and pleomorphic-enveloped viral particles (100--500 nm in size) with a single fringe of embedded peplomers. Virus morphogenesis occurred at the plasma membrane of infected cells and morphological features of negative-stained ribonucleoprotein complexes were compatible with that of viruses in the family Paramyxoviridae. Serological studies revealed no cross-reactivity with antibodies against a number of known Paramyxoviridae members except for the newly described Menangle virus (MenV), isolated in Australia in 1997. Failure of PCR amplification using MenV-specific primers suggested that this new virus is related to but different from MenV. For molecular characterization of the virus, a cDNA subtraction strategy was employed to isolate virus-specific cDNA from virus-infected cells. Complete gene sequences for the nucleocapsid protein (N) and phosphoprotein (P/V) have been determined and recombinant N and V proteins produced in baculovirus. The recombinant N and V proteins reacted with porcine anti-MenV sera in Western blot, confirming the serological cross-reactivity observed during initial virus characterization. The lack of a C protein-coding region in the P/V gene, the creation of P mRNA by insertion of 2-G residues, and the results of phylogenetic analyses all indicated that TiV is a novel member of the genus Rubulavirus.

Amino Acid Sequence↗

PubMed2001

NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritis synoviocytes.

IkappaB kinase-1 and IkappaB kinase-2 (IKK1 and IKK2; also called IKKalpha and IKKbeta, respectively) are part of the signal complex that regulates NF-kappaB activity in many cell types, including fibroblast-like synoviocytes (FLS). We determined which of these two kinases is responsible for cytokine-induced NF-kappaB activation in synoviocytes and assessed the functional consequences of IKK1 or IKK2 overexpression and inhibition. FLS were infected with adenovirus constructs encoding either wild-type (wt) IKK1 or IKK2, the dominant negative (dn) mutant of both kinases, or a control construct encoding green fluorescence protein. Analysis of the NF-kappaB pathway revealed that cytokine-induced IKK activation, IkappaB degradation, and NF-kappaB activation was prevented in cells expressing the IKK2 dn mutant, whereas baseline NF-kappaB activity was increased by IKK2 wt. In addition, synthesis of IL-6 and IL-8, as well as expression of ICAM-1 and collagenase, was only increased by IKK2 wt, and their cytokine-induced production was abrogated by IKK2 dn mutant. However, the IKK1 dn mutant did not inhibit cytokine-mediated activation of NF-kappaB or any of the functional assays. These data indicate that IKK2 is the key convergence pathway for cytokine-induced NF-kappaB activation. Furthermore, IKK2 regulates adhesion molecule, matrix metalloproteinase, and cytokine production in FLS.

Adenoviridae↗

PubMed2001

Mechanism of asparagine deamidation during human senile cataractogenesis.

Previous studies have demonstrated that asparagine-143 of gammaS crystallin is preferentially deamidated in human cataractous lenses. A possible mechanism of nonenzymatic deamidation involves the initial formation of L -succinimidyl and D -succinimidyl intermediates, followed by ring cleavage and production of the respective L - and D - forms of beta-aspartate and alpha-aspartate. To determine if this mechanism occurs during cataractogenesis of the human lens, synthetic peptide standards together with reverse phase HPLC were used to purify and quantitate tryptic peptides from cataractous lenses that contained the beta-aspartate and alpha-aspartate forms of residue 143. For all lenses analysed, the ratios of beta-aspartate/alpha-aspartate produced were consistent with a mechanism of deamidation involving succinimide intermediates. Surprisingly, the D / L ratios for all beta- and alpha-aspartates produced were very low, suggesting that the mechanism of deamidation preferentially involves the L -succinimidyl intermediate, with formation of the D -succinimidyl intermediate almost completely blocked by steric hindrance. Together, the results demonstrate that deamidation of asparagine-143 from gammaS crystallin of different human cataracts undergoes the same mechanism, which due to higher ordered structure of the native protein, results in the preferential production of one of two possible succinimidyl intermediates.

Asparagine↗

PubMed2001

Preference comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg tablet in migraine.

OBJECTIVE: To compare the proportion of patients who prefer rizatriptan orally disintegrating tablet (ODT) 10-mg to sumatriptan 50-mg tablet. BACKGROUND: Migraineurs express treatment preference based on a variety of attributes including the speed of pain relief and medication formulation. Rizatriptan ODT is an orally disintegrating formulation of rizatriptan, a selective 5-HT1B/1D receptor agonist. This study was conducted to determine patient preference between rizatriptan ODT 10-mg and sumatriptan 50-mg tablet for the acute treatment of migraine. METHODS: This was a multicenter, randomized, open-label, two-period crossover study conducted in the United States with 524 enrolled patients. Patients treated a single moderate or severe headache in each treatment period. Patients treated one migraine with either rizatriptan ODT 10-mg or sumatriptan 50-mg tablet, then treated a second migraine with the alternate therapy. Patients completed diary assessments at baseline, and 30, 45, 60, 90, and 120 minutes postdose and rated headache severity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). At the final study visit following treatment of their second migraine, patients expressed preference for one of the two study medications by completing an interviewer-administered Global Preference Question and then responded to a self-administered series of questions to capture their most important reason for preferring one study medication over the other. Safety measurements were recorded through standard adverse experience reporting. RESULTS: Three hundred eighty-six patients treated two migraine attacks. For those patients who expressed a preference for either rizatriptan ODT or sumatriptan (n = 374), the percentage of patients who preferred rizatriptan ODT 10-mg (57%, n = 213) was significantly greater than those who preferred sumatriptan 50-mg tablet (43%, n = 161) (P<.01). For those patients who treated two migraine attacks and had drug severity measures for both attacks (n = 384), a significantly greater percentage of patients reported pain relief after taking rizatriptan ODT than sumatriptan at the 45- and 60-minute time points (38% versus 29% and 58% versus 49%, respectively) (P<.01). In addition, a significantly greater percentage of patients taking rizatriptan ODT reported a pain-free status at the 60- and 120-minute time points (23% versus 17% [P<.05] and 60% versus 52% [P<.01], respectively). Both rizatriptan ODT and sumatriptan were well tolerated. CONCLUSIONS: A significantly greater proportion of patients preferred rizatriptan ODT 10-mg to sumatriptan 50-mg tablet for the acute treatment of migraine. Efficacy and safety data are consistent with the preference findings.

Adult↗

PubMed2001

Predictors of left ventricular function after acute myocardial infarction: effects of time to treatment, patency, and body mass index: the GUSTO-I angiographic experience.

BACKGROUND: Despite the significant survival benefit associated with successful reperfusion therapy for acute myocardial infarction, global indices of outcome left ventricular function, such as ejection fraction, have often demonstrated little or no improvement. Although these measurements are confounded by numerous clinical, physiologic, and angiographic variables, no comprehensive analysis of this issue in a large series of patients is available. We used the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) database to better understand this phenomenon by determining independent predictors of left ventricular function and their interplay with regard to outcome ventricular function and improvement in function during the initial postinfarction week. METHODS: Ninety-minute and 5- to 7-day posttreatment global and regional indices derived from left ventriculograms were analyzed from a population of 676 patients. These observations were combined with clinical data to describe independent determinants of ventricular function outcome. RESULTS: Clinical factors predictive of global and regional ventricular function as well as improvement in function between 90 minutes and 5 to 7 days included time to treatment, early infarct-related artery flow grade, and body mass index. These same factors contribute significantly to compensatory hyperkinesis of the noninfarct zone, which is critical to maintenance of global ventricular function during this time period. CONCLUSIONS: The ventricular function benefits of early complete reperfusion after myocardial infarction are readily demonstrable after adjustment for multiple covariables and include (1) maintenance of global ventricular function and (2) prevention or delay in ventricular dilatation.

Aged↗

PubMed2001

Adenosine kinase inhibitor GP515 improves experimental colitis in mice.

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.

Adenosine Kinase↗

PubMed2001

Comparison of time spent writing orders on paper with computerized physician order entry.

Computerized physician order entry (CPOE) has been shown to improve quality, and to reduce resource utilization, but most available data suggest that it takes longer to enter orders using CPOE. We had previously implemented a CPOE system, and elected to evaluate its impact on physician time in the new setting. To do this, we performed a prospective study using random reminder methodology. Key findings were that interns spent 9.0% of their time ordering with CPOE, compared to 2.1% before, although CPOE saved them an additional 2% of time, so that the net difference was 5% of their total time. However, this is counterbalanced by decreased time for other personnel such as nursing and pharmacy, and by the quality and efficiency changes. We conclude that while CPOE has many benefits, it represents a major process change, and organizations must factor this in when they implement it.

Hospital Information Systems↗

PubMed2001

Family Caregivers' Motives for Helping Scale derived from motivation-to-help theory.

The literature does not contain a measure of family caregivers' motives for helping provide daily complex home care. Such a measure will permit nurses to assess and provide interventions specific to each caregiver's motivation for helping. The purpose of this study was to apply Batson's empirically derived helping pathway theory to the measurement of caregiver motives for helping and develop a short form that does not add to the burden of caregiving. A Principal Components factor analysis (N = 93) of Family Caregivers' Motives for Helping Scale is used. Criterion-related validity is ascertained using a triangulated, independent validation procedure with qualitative data from a subsample (N = 41). Subsample subjects' interview data were categorized, based on Batson's theoretical pathway definitions, by coders blinded to caregiver Motives for Helping Scale scores. Three of Batson's four helping pathways (reward seeking, altruism, and punishment-avoidance) were extracted during factor analysis. This three-factor solution explained 66.6% of the variance and was confirmed by a 97% agreement between three of Batson's pathways and caregivers' helping motive score. The content analyses of the descriptive interview data also coincide with the 3-factor solution. The scale items representing Batson's fourth helping pathway, distress reaction, were not retained due to cross loading. The Family Caregivers' Motives for Helping Scale accurately measures three of four theoretically derived motivations for helping another. The scale should be reanalyzed in a larger sample of caregivers. Aligning nursing interventions to caregiver motives for helping can provide reinforcement for caregivers and potentially enhance home care outcomes.

Caregivers↗

PubMed2000

Comparison of d-aspartic acid contents in alpha A-crystallin from normal and age-matched cataractous human lenses.

We have previously shown that biologically uncommon d-beta-aspartic acids (Asp) were localized with very high contents at Asp-151 and Asp-58 of alpha A-crystallin from aged human lenses. The amounts increased with age, and we have proposed the mechanism of this reaction. In the present study, in order to elucidate the possible relationship between the formation of d-beta-aspartic acids in alpha A-crystallin and cataract formation, we measured the d/l ratio of beta-Asp-151 of alpha A-crystallin from both cataractous and age-matched normal human lenses. alpha A-crystallin from total proteins of cataractous and age-matched normal lenses was prepared, followed by tryptic digestion and quantification of d/l ratios for tryptic fragments containing the alpha- and beta-aspartate forms of Asp-151 residues. The results demonstrate that the d/l ratio of beta-Asp-151 of alpha A-crystallin from normal lenses is not statistically significant from that of alpha A-crystallin from cataractous lenses, suggesting that formation of this biologically uncommon amino acid may not play a role in human cataractogenesis.

Amino Acid Sequence↗

PubMed2000

Case studies, practical issues and observations on population and individual bioequivalence.

The FDA has proposed replacing the 1992 average bioequivalence (ABE) with population and individual bioequivalence (PBE and IBE). This has led to considerable public discussion between regulatory, academic and industry experts. At the heart of the discussion has been the relatively modest amount of available data to examine the behaviour of the PBE and IBE criteria. A retrospective analysis of 22 data sets from 15 replicate cross-over bioequivalence studies has been conducted (n=12-74). AUC and C(max) parameters from these studies were analysed using ABE, PBE and IBE methods. Of the 22 data sets for AUC, 19 pass ABE, all pass PBE and 20 pass IBE. Of the three data sets that failed ABE, all passed PBE and one passed IBE. The results for C(max) are more variable. Of the 16 data sets where ABE is demonstrated, one data set failed both PBE and IBE. Of the six data sets that failed ABE, two passed both PBE and IBE, three passed PBE but not IBE and one failed all three criteria. There were five data sets that passed ABE and PBE but not IBE. Additional practical issues involving the behaviour of the new criteria and its expected impact on sample size for highly variable drug products will be presented. The characterization of key parameters and their interrelationships will also be discussed with particular emphasis on the subject by formulation term in the IBE criteria. It is concluded that more studies and simulations are desirable before full-scale implementation of PBE and IBE criteria.

Area Under Curve↗

PubMed2000

Relationship of infarct artery patency and left ventricular ejection fraction to health-related quality of life after myocardial infarction: the GUSTO-I Angiographic Study experience.

BACKGROUND: Post-myocardial infarction global ejection fraction and infarct-related artery patency might be expected to be associated with health-related quality-of-life (HRQOL) outcomes, but this association has not been previously shown. The GUSTO-I Angiographic Study cohort 2-year follow-up afforded an examination of such potential relationships. METHODS AND RESULTS: A total of 1848 patients (87.7% response rate) who were enrolled in the GUSTO-I Angiographic Study were contacted for a telephone interview regarding their current HRQOL (physical function, psychological well-being, perceived health status, and social function) 2 years after MI. In multivariable models, left ventricular ejection fraction (EF) was significantly related to physical (P:=0.021) and social (P:=0.014) function, psychological well-being (P:=0.042), and perceived health status (P:=0.024). Infarct-related artery patency was not directly related to any HRQOL outcome. A decreasing EF was predictive of poorer outcomes in each HRQOL dimension. Men consistently had better outcomes in all HRQOL dimension with the exception of perceived health status. Increasing age was predictive of poorer outcomes in all dimensions of HRQOL except for psychological well-being where the inverse occurred; younger patients experienced greater depression, anxiety and worry than their older counterparts. The presence of comorbidities increased the likelihood of worse outcomes in all dimensions. CONCLUSIONS: This is the first study to demonstrate a significant relationship between EF and long-term HRQOL outcomes. This advantage in left ventricular function preservation should be added to the mortality advantage when considering the impact of treatment strategies for myocardial infarction.

Aged↗

PubMed2000

Increased deamidation of asparagine during human senile cataractogenesis.

PURPOSE: To identify and quantitate deamidation of a specific asparagine residue of gammaS-crystallin that preferentially undergoes deamidation during the process of human senile cataractogenesis. METHODS: Reverse phase chromatography, together with synthetic peptide standards, was used to resolve the amidated and deamidated forms of asparagine-143 in the gammaS-crystallin sequence 131-145 from total tryptic digests of the central, nuclear region of human cataractous and normal lenses. Identities of the resolved peptides co-eluting with synthetic peptide standards were confirmed by mass spectral analysis. The synthetic peptide standards were also used to quantitate the amount of deamidation occurring in individual cataractous and normal lenses. RESULTS: In all lenses analyzed, there was greater deamidation of asparagine-143 in cataractous lenses, as compared with age-matched normal lenses. CONCLUSIONS: The results demonstrate, for the first time, that increased deamidation of a specific asparagine residue is present in proteins from the human cataractous lens.

Aged↗

PubMed2000

Specific glutamine and asparagine residues of gamma-S crystallin are resistant to in vivo deamidation.

It has been hypothesized that resistance to nonenzymatic deamidation of asparagine and glutamine residues may be an important determinant of protein stability in vivo. As a test of this hypothesis, we analyzed the central region of old human lenses, which contain proteins such as gamma-S crystallin that were synthesized during the fetal-embryonic periods of development. Total protein from the fetal-embryonic region of old human lenses was digested with trypsin, followed by resolution of tryptic fragments containing amidated and deamidated forms using high pressure liquid chromatography-reverse phase chromatography together with synthetic peptide standards and mass spectral analysis. The results demonstrate no detectable deamidation of glutamine 92, glutamine 96, asparagine 143, and glutamine 170 from gamma-S crystallin from old human lenses, consistent with the hypothesis that very long-lived proteins can contain asparagine and glutamine residues that are extremely resistant to in vivo deamidation.

Aged↗

PubMed2000

The effect of a T cell-specific NF-kappa B inhibitor on in vitro cytokine production and collagen-induced arthritis.

NF-kappa B plays a key role in the production of cytokines in inflammatory diseases. The effects of a novel T cell-specific NF-kappa B inhibitor, SP100030, were evaluated in cultured Jurkat cells and in murine collagen-induced arthritis (CIA). Chemical libraries were screened for NF-kappa B-inhibitory activity. SP100030, a compound identified in this process, inhibited NF-kappa B activation in PMA/PHA-activated Jurkat cells by EMSA at a concentration of 1 microM. Jurkat cells and the monocytic cell line THP-1 were transfected with an NF-kappa B promotor/luciferase construct and activated. SP100030 inhibited luciferase production in the Jurkat cells (IC50 = 30 nM). ELISA and RT-PCR confirmed that IL-2, IL-8, and TNF-alpha production by activated Jurkat and other T cell lines were inhibited by SP100030. However, cytokine expression was not blocked by the compound in THP-1 cells, fibroblasts, endothelial cells, or epithelial cells. Subsequently, DBA/1J mice were immunized with type II collagen. Treatment with SP100030 (10 mg/kg/day i.p. beginning on day 21) significantly decreased arthritis severity from onset of clinical signs to the end of the study on day 34 (arthritis score, 5.6 +/- 1.7 for SP100030 and 9.8 +/- 1.5 for control; p < 0.001). Histologic evaluation demonstrated a trend toward improvement in SP100030-treated animals. EMSA of arthritic mouse ankles in CIA showed that synovial NF-kappa B binding was suppressed in the SP100030-treated mice. SP100030 inhibits NF-kappa B activation in T cells, resulting in reduced NF-kappa B-regulated gene expression and decreased CIA. Its selectivity for T cells could provide potent immunosuppression with less toxicity than other NF-kappa B inhibitors.

Animals↗

PubMed2000

Nature, incidence, and cause of work-related amputations in Minnesota.

BACKGROUND: The Minnesota Sentinel Event Notification System for Occupational Risks (SENSOR) has collected data on the nature, incidence, and cause of work-related amputation injuries that have taken place since 1992. METHODS: SENSOR defined an amputation as any finger amputation or the loss of any other body part; 832 workers were identified as having amputation injuries between 1994 and 1995 and 72% of these workers completed telephone interviews. RESULTS: The amputation injury rate for Minnesota workers was 39 per 100,000 workers, with agriculture and manufacturing having the highest rates. Sixty-six percent of the injuries involved one finger; 14% involved two or more fingers. Persons working with machinery reported 73% of the injuries. CONCLUSIONS: A closer examination of the incidence and causes for amputation injuries shows that these were not random events. Reliance on human reactions to prevent injury is inadequate; therefore, additional research needs to be conducted.

Accidents, Occupational↗

PubMed2000

Medical, personal, and occupational outcomes for work-related amputations in Minnesota.

BACKGROUND: The Minnesota Sentinel Event Notification System for Occupational Risks (SENSOR) surveillance system has collected data on the medical, personal, and occupational outcomes associated with work-related amputations since 1992. METHODS: SENSOR defined amputations as any finger amputation or the loss of any other body part; 832 workers were identified as having amputation injuries between 1994 and 1995 and 72% of these workers completed a telephone interview. RESULTS: Twenty percent of those injured required overnight hospitalization. Ninety-one percent of the cases reported having missed work, with 56% reporting missing ten or more days. Individuals working on their usual jobs at the time of injury were more likely to report less serious medical and occupational outcomes. CONCLUSIONS: Severe injuries were significantly associated with worse medical, personal, and occupational outcomes. Two groups of machines, material handling, and powered handtools were associated with a higher proportion of severe injuries.

Absenteeism↗

PubMed2000

Professional liability in a neonatal intensive care unit: a review of 20 years' experience.

OBJECTIVE: To examine neonatal intensive care unit (NICU) malpractice claims and identify common characteristics likely to result in malpractice. STUDY DESIGN: A retrospective study (1972 to 1992) at a tertiary care children's hospital examining malpractice claims involving NICU infants. RESULTS: A total of 31 cases of malpractice out of 9367 NICU admissions (incidence 0.33%) were found. Although not statistically significant, the incidence of legal action increased with NICU growth from 0.19% (1972 to 1974) to 0.39% (1980 to 1992). Infants who were significantly over-represented in malpractice cases compared with the general NICU population included those who were full-term, white, privately insured, and those with neurologic conditions. Families' motives for legal action included (1) treatment error/delay (48%), (2) missed/delayed diagnosis (16%), (3) equipment malfunction/misuse (6%), and (4) general improper care (30%). CONCLUSION: Based on this research, three factors may be associated with increased risk of malpractice in the NICU: (1) increased unit growth, (2) parental perceptions of negligence, and (3) full-term infants with diagnoses associated with neurologic conditions.

Adult↗

PubMed2000

Caregiver quality of life after autologous bone marrow transplantation.

Bone marrow transplantation (BMT) is a unique cancer therapy characterized by its novelty, intensity, and toxicity. Although families have been identified as having a critical influence on patient adaptation during the acute phase of BMT, minimal attention has been paid to their experiences during extended survivorship. This article reviews findings from a descriptive study on quality of life in primary caregivers of adult autologous bone marrow transplantation (AuBMT) survivors after acute hospitalization. Caregiver perceptions of their survival are delineated in an effort to characterize the dynamics of family recovery after BMT. Specifically, caregivers of AuBMT survivors require ongoing assistance to maintain their primary support role after BMT.

Adaptation, Psychological↗