Biomedical subjects

David White

Publications and source records attributed to David White.

At least 19 recordsLinked to original sources

PubMed2006

Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults.

BACKGROUND: Some patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) experience excessive sleepiness (ES) that might not resolve with nasal continuous positive airway pressure (nCPAP) treatment. OBJECTIVE: The aim of the present study was to assess the efficacy and tolerability of armodafinil 150 or 250 mg QD when used as adjunctive treatment for residual ES associated with OSA/HS in patients who are adherent to nCPAP therapy. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled study was conducted at 37 centers in the United States and Canada. Male and female patients aged 18 to 65 years with residual ES associated with OSA/HS were enrolled. Patients were randomly assigned to receive armodafinil 150 or 250 mg or placebo PO QD for 12 weeks. Assessments were conducted at baseline and study weeks 4, 8, and 12 and included the Maintenance of Wakefulness Test (MWT) to determine wakefulness, the Clinical Global Impression of Change (CGI-C) to determine improvement in clinical condition, the Epworth Sleepiness Scale (ESS) to determine patient-estimated wakefulness, the Brief Fatigue Inventory (BFI) to determine global fatigue, and the Cognitive Drug Research computerized assessment battery. To distinguish between earlier and later effects, sleep latencies, assessed using the MWT, were averaged across the first 4 (9 and 11 AM, and 1 and 3 PM) and last 3 (3, 5, and 7 PM) tests. Tolerability assessments included monitoring of adverse events (AEs), clinical laboratory tests, vital sign measurements, and electrocardiography. RESULTS: A total of 395 patients were enrolled in the study (armodafinil 150 mg/d, 133; armodafinil 250 mg/d, 131; placebo, 131); 392 received >or=1 dose of study drug (armodafinil 150 mg/d, 131; armodafinil 250 mg/d, 131; placebo, 130). The armodafinil and placebo groups were well matched with regard to age (mean [SD], 49.2 [8.9] vs 50.1 [9.4] years), sex (71 vs 69% men), race (84% vs 87% white), and body weight (mean [SD], 110.3 [24.9] vs 111.9 [24.0] kg). At the final visit, the mean (SD) change from baseline in MWT sleep latency across the morning and afternoon was significantly greater in the armodafinil combined group compared with the placebo group (+1.9 [7.3] vs 1.7 [8.6] minutes; P < 0.001). Also at the final visit, the proportions of patients who showed at least minimal improvement on the CGI-C, and the mean (SD) changes from baseline in ESS and BFI scores, were significantly greater in the armodafinil group compared with those in the placebo group (72% vs 37%, -5.5 [5.0] vs -3.3 [4.7], and -1.2 [2.2] vs -0.6 [2.0], respectively; P < 0.001, P < 0.001, and P < 0.01, respectively). No significant effects on nighttime sleep, as assessed using polysomnography, were found with armodafinil. AEs reported in the armodafinil combined and placebo groups were headache, nausea, insomnia, anxiety, and dizziness. Serious AEs (ulcerative colitis, migraine, worsening of Axis II and mood disorder, and duodenal ulcer) were reported in 4 (1.5%) patients receiving armodafinil and were considered by the investigator not or unlikely to be drug related. CONCLUSIONS: In this selected population of patients with OSA/HS and residual ES despite effective treatment with nCPAP, armodafinil QD used as an adjunct to nCPAP treatment was associated with improved wakefulness and overall clinical condition. Clinical benefit was shown at the first assessment and maintained for the 12-week duration of the study. Armodafinil was also associated with significantly reduced interference of ES with daily activities and global fatigue. Armodafinil was well tolerated, with no adverse effect on nighttime sleep or nCPAP use.

Benzhydryl Compounds↗

PubMed2006

Creative partnerships for community health improvement: a qualitative evaluation of the Healthy Carolinians community micro-grant project.

This qualitative study evaluated a recent innovative strategy used to involve community-based organizations (CBOs) in implementing health-related projects through locally administered microgrants. The purpose of this study was to identify key elements that enabled the success of the CBO projects, barriers and challenges to project success, and ways to effectively engage CBOs as partners in local health initiatives. In addition, this study sought to identify aspects of this approach that can be replicated. Study findings revealed that microfinancing CBOs aided in building partnerships, developing local leadership and expertise, and providing resources that enabled progress toward CBO missions and goals. These positive outcomes far out-weighed barriers and challenges faced by CBOs. Furthermore, the results of this study revealed ideas and information that provide useful guidelines for establishing and administering microgrant projects through local organizations that encourage community groups to design and implement community based health initiatives.

Advisory Committees↗

PubMed2006

The effect of altitude descent on obstructive sleep apnea.

BACKGROUND: The present requirement for "at facility" polysomnograms requires many residents in mountain communities to descend in elevation for sleep testing, which may cause misleading results regarding the severity of obstructive sleep apnea (OSA). DESIGN: Eleven patients with previously undiagnosed sleep apnea living at an altitude > 2,400 m (7,900 feet) in Colorado underwent diagnostic sleep studies at their home elevation and at 1,370 m (4,500 feet), and 5 of the 11 patients were also studied at sea level. RESULTS: The mean (SE) apnea-hypopnea index (AHI) fell from 49.1 (10.5)/h to 37.0 (11.2)/h on descent to 1,370 m (p = 0.022). In the five patients who traveled to sea level, the AHI dropped from 53.8 (13.2)/h at home elevation to 47.1 (14.8)/h at 1,370 m, and to 33.1 (12.6)/h at sea level (p = 0.018). The reduction in AHI was predominantly a reduction in hypopneas and central apneas, with little change in the frequency of obstructive apneas. Duration of the obstructive apneas lengthened with descent. Of eight patients with an AHI < 50/h at their home elevation, two patients had their AHI fall to < 5/h at 1,370 m, and a third patient dropped to < 5/h at sea level, ie, below many physicians' threshold for providing therapy. Patients with the most severe OSA had the least improvement with descent. CONCLUSIONS: Because AHI decreases significantly with descent in altitude, polysomnography is most accurately done at the home elevation of the patient. Descent to a sleep laboratory at a lower elevation may yield false-negative results in patients with mild or moderate sleep apnea.

Adult↗

PubMed2005

Genetic transformation of Ascochyta rabiei using Agrobacterium-mediated transformation.

In order to study pathogenic mechanisms of the plant pathogen Ascochyta rabiei, conditions for efficient transformation using Agrobacterium-mediated transformation were investigated. Hygromycin B resistance (hph) was superior to geneticin resistance (nptII) for selecting transformants, and the hph gene was more efficiently expressed by the Aspergillus nidulans trpC promoter than by the Cauliflower mosaic virus 35S promoter CaMV35S. Co-cultivation on solid media for 72 h was optimal for generating transformants, but increasing the ratio of bacterial cells to conidia did not affect transformation efficiency. All hygromycin B-resistant transformants carried transfer-DNA (T-DNA) as determined by polymerase chain reaction (PCR) and the T-DNA integrations appeared to be random and in single copy as detected by Southern hybridization. Transformants remained resistant to hygromycin B in the absence of selection. Variations in colony morphology were observed in the presence of hygromycin B under different culture conditions, and a variety of altered phenotypes including reduced virulence were observed among 550 transformants. Inverse PCR was more efficient than TAIL-PCR in identifying flanking genomic sequences from T-DNA borders, and the possible causes are discussed. This transformation technique and recovery of flanking DNA using inverse PCR will provide a useful tool for genetic studies of A. rabiei.

Ascomycota↗

PubMed2005

Robust representations for face recognition: the power of averages.

We are able to recognise familiar faces easily across large variations in image quality, though our ability to match unfamiliar faces is strikingly poor. Here we ask how the representation of a face changes as we become familiar with it. We use a simple image-averaging technique to derive abstract representations of known faces. Using Principal Components Analysis, we show that computational systems based on these averages consistently outperform systems based on collections of instances. Furthermore, the quality of the average improves as more images are used to derive it. These simulations are carried out with famous faces, over which we had no control of superficial image characteristics. We then present data from three experiments demonstrating that image averaging can also improve recognition by human observers. Finally, we describe how PCA on image averages appears to preserve identity-specific face information, while eliminating non-diagnostic pictorial information. We therefore suggest that this is a good candidate for a robust face representation.

Face↗

PubMed2005

Adenomatoid odontogenic tumor mimicking a dentigerous cyst.

Adenomatoid odontogenic tumor (AOT) is a slow-growing, asymptomatic and uncommon lesion that arises from odontogenic epithelium with inductive effects on connective tissue. The more common variant is the follicular type, which involves an unerupted tooth and is often mistaken for a dentigerous cyst. Histopathologic examination demonstrates cuboidal or spindle-shaped epithelial cells forming aggregates or rosette-like structures with minimal connective tissue, and cuboidal or low columnar cells forming glandular duct-like structures. Treatment is complete enucleation, and recurrences are rare. We presented a case of AOT in a 14-year-old male presenting as a cystic mass around an unerupted tooth.

Adolescent↗

PubMed2005

After-hours coverage: national survey of policies and guidelines for primary care physicians.

OBJECTIVE: To determine the prevalence and content of existing or developing policies and guidelines of medical associations and colleges regarding after-hours care by family physicians and general practitioners, especially legal requirements. DESIGN: Telephone survey in fall 2002, updated in fall 2004. SETTING: Canada. PARTICIPANTS: All national and provincial medical associations, Colleges of Family Physicians, Colleges of Physicians and Surgeons, local government offices for the north, and the Canadian Medical Protective Association (CMPA). MAIN OUTCOME MEASURE: RESPONSE TO THE QUESTION: "Does your agency have a policy in place regarding after-hours health care coverage by FPs/GPs, or are there active discussions regarding such a policy?" RESULTS: The College of Physicians and Surgeons of British Columbia was the first to institute a policy, in 1995, requiring physicians to make "specific arrangements" for after-hours care of their patients. The College of Physicians and Surgeons of Alberta adopted a similar policy in 1996 along with a guideline to aid implementation. In 2002, the College of Physicians and Surgeons of Nova Scotia approved a guideline on the Availability of Physicians After Hours. The Saskatchewan Medical Association and the College of Physicians and Surgeons of Saskatchewan formulated a joint policy on medical practice coverage that was released in 2003. Many agencies actively discussed the topic. Provincial and national Colleges of Family Physicians did not have any policies in place. The CMPA does not generate guidelines but released in an information letter in May 2000 a section entitled "Reducing your risk when you're not available." CONCLUSION: There is increasing interest Canada-wide in setting policy for after-hours care. While provincial Colleges of Physicians and Surgeons have traditionally led the way, a trend toward more collaboration between associations was identified. The effect of policy implementation on physicians' coverage of patients is unclear.

After-Hours Care↗

PubMed2005

Medical errors in primary care: results of an international study of family practice.

OBJECTIVE: To describe errors Canadian family physicians found in their practices and reported to study investigators. To compare errors reported by Canadian family physicians with those reported by physicians in five other countries. DESIGN: Analytical study of reports of errors. The Linnaeus Collaboration was formed to study medical errors in primary care. General practitioners in six countries, including a new Canadian family practice research network (Nortren), anonymously reported errors in their practices between June and December 2001. An evolving taxonomy was used to describe the types of errors reported. SETTING: Practices in Canada, Australia, England, the Netherlands, New Zealand, and the United States. PARTICIPANTS: Family physicians in the six countries. MAIN OUTCOME MEASURES: Types of errors reported. Differences in errors reported in different countries. RESULTS: In Canada, 15 family doctors reported 95 errors. In the other five countries, 64 doctors reported 413 errors. Although the absence of a denominator made it impossible to calculate rates of errors, Canadian doctors and doctors from the other countries reported similar proportions of errors arising from health system dysfunction and gaps in knowledge or skills. All countries reported similar proportions of laboratory and prescribing errors. Canadian doctors reported harm to patients from 39.3% of errors; other countries reported harm from 29.3% of errors. Canadian physicians considered errors "very serious" in 5.8% of instances; other countries thought them very serious in 7.1% of instances. Hospital admissions and death were among the consequences of errors reported in other countries, but these consequences were not reported in Canada. CONCLUSION: Serious errors occur in family practice and affect patients in similar ways in Canada and other countries. Validated studies that analyze errors and record error rates are needed to better understand ways of improving patient safety in family practice.

Adolescent↗

PubMed2005

Angina on the Palm: randomized controlled pilot trial of Palm PDA software for referrals for cardiac testing.

OBJECTIVE: Personal digital assistants (PDAs) are popular with physicians: in 2003, 33% of Canadian doctors reported using them in their practices. We do not know, however, whether using a PDA changes the behaviour of practising physicians. We studied the effectiveness of a PDA software application to help family physicians diagnose angina among patients with chest pain. DESIGN: Prospective randomized controlled pilot trial using a cluster design. SETTING: Primary care practices in the Toronto area. PARTICIPANTS: Eighteen family physicians belonging to the North Toronto Primary Care Research Network (Nortren) or recruited from a local hospital. INTERVENTIONS: We randomized physicians to receive a Palm PDA (which included the angina diagnosis software) or to continue conventional care. Physicians prospectively recorded the process of care for patients aged 30 to 75 presenting with suspected angina, over 7 months. MAIN OUTCOME MEASURES: Did the process of care for patients with suspected angina improve when their physicians had PDAs and software? The primary outcomes we looked at were frequency of cardiac stress test orders for suspected angina, and the appropriateness of referral for cardiac stress testing at presentation and for nuclear cardiology testing after cardiac stress testing. Secondary outcome was referrals to cardiologists. RESULTS: The software led to more overall use of cardiac stress testing (81% vs 50%). The absolute increase was 31% (P = .007, 95% confidence interval [CI] 8% to 58%). There was a trend toward more appropriate use of stress testing (48.6% with the PDA vs 28.6% control), an increase of 20% (P = .284, 95% CI -11.54% to 51.4%). There was also a trend toward more appropriate use of nuclear cardiology following cardiac stress testing (63.0% vs 45.5%), an absolute increase of 17.5% (P =.400, 95% CI -13.9% to 48.9%). Referrals to cardiologists did not increase (38.2% with the PDA vs 40.9%, P =.869). CONCLUSION: A PDA-based software application can lead to improved care for patients with suspected angina seen in family practices; this finding requires confirmation in a larger study.

Adult↗

PubMed2005

After-hours care in Canada: analysis of the 2001 National Family Physician Workforce Survey.

OBJECTIVE: To determine family physicians' availability to their general practice patients after hours and to explore the characteristics and determinants of after-hours services. DESIGN: Secondary analysis of the 2001 National Family Physician Workforce Survey. SETTING: Canada. PARTICIPANTS: Canadian family physicians and general practitioners currently in practice (n = 10,553). MAIN OUTCOME MEASURES: Provision of after-hours care, defined as providing care to all practice patients outside of normal office hours. RESULTS: Sixty-two percent of Canadian family physicians reported providing after-hours service. The lowest rates were found in Quebec (34%) and the highest in Alberta and Saskatchewan (88%). Respondents practising in academic and community clinics, offering selective medical services (emergency care, palliative care, housecalls, after-hours care), or living outside of Ontario or Quebec were more likely to provide after-hours care. Women physicians, those practising in walk-in clinics, or physicians primarily paid by fee-for-service were less likely to do so. Urban versus rural location, organization of practice (solo or group), age of physician, country of graduation, and physician satisfaction were not found to significantly affect the likelihood of providing after-hours services. CONCLUSION: Knowledge of these factors can be used to inform policy development for after-hours service arrangements, which is particularly relevant today, given provincial governments' interests in exploring alternative payment plans and primary care reform options.

Adult↗

PubMed2004

Long-term persistence of primary genotypic resistance after HIV-1 seroconversion.

Primary infection with drug-resistant HIV-1 is well documented. We have followed up patients infected with such viruses to determine the stability of resistance-associated mutations. Fourteen patients who experienced primary infection with genotypic evidence of resistance were followed for up to 3 years. Drug resistance-associated mutations persisted over time in most patients studied. In particular, M41L, T69N, K103N, and T215 variants within reverse transcriptase (RT) and multidrug resistance demonstrated little reversion to wild-type virus. By contrast, Y181C and K219Q in RT, occurring alone, disappeared within 25 and 9 months, respectively. Multidrug resistance in 2 patients was found to be stable for up to 18 months, the maximum period studied. We conclude that certain resistance-associated mutations are highly stable and these data support the recommendation that all new HIV diagnoses in areas where primary resistance may occur should undergo genotyping irrespective of whether the date of seroconversion is known.

Anti-HIV Agents↗

PubMed2004

Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000.

OBJECTIVES: To establish a surveillance programme for HIV drug resistance within the UK covering the years from 1998 to 2000, following the introduction of triple combination antiretroviral therapy. METHODS: Sentinel sites included large, medium sized and small clinical centres. Data were analysed until December 2000. RESULTS: Of nearly 300 samples tested, results from 91, 92 and 92 patients, respectively in 1998, 1999 and 2000, who were receiving HIV therapy with a viral load >2000 copies/mL, the majority had viruses with some degree of drug resistance. Overall, the presence of any resistance increased between 1998 and 1999, and fell again in 2000 (69% versus 88% versus 55%). However, major differences were observed between drug classes, such that non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) resistance rose dramatically over the period studied. We show that this correlated with increased NNRTI prescribing. Furthermore, an overall increase in prevalence of viruses with resistance to one or more drugs within all three available classes was observed. A higher prevalence of drug resistance was observed in patients from smaller clinical centres. CONCLUSIONS: This is the first such sentinel surveillance dataset from the UK, and is unique in correlating these data with national antiretroviral prescribing patterns. Our findings are relevant to the increased transmission of HIV drug resistance observed over this period.

Anti-HIV Agents↗

PubMed2004

RNA interference: a potent tool for gene-specific therapeutics.

RNA interference (RNAi) is a process through which double-stranded RNA induces the activation of cellular pathways, leading to potent and selective silencing of genes with homology to the double strand. Much excitement surrounding small interfering RNA (siRNA)-mediated therapeutics arises from the fact that this approach overcomes many of the shortcomings previously experienced with approaches such as antibodies, antisense oligonucleotides and pharmacological inhibitors. Induction of RNAi through administration of siRNA has been successfully used in treatment of hepatitis, viral infections, and cancer. In this review we will present a brief history of RNAi, methods of inducing RNAi, application of RNAi in the therapeutic setting, and the possibilities of using this highly promising approach in the context of transplantation.

Animals↗

PubMed2004

Induction of RNA interference in dendritic cells.

Dendritic cells (DC) reside at the center of the immunological universe, possessing the ability both to stimulate and inhibit various types of responses. Tolerogenic/regulatory DC with therapeutic properties can be generated through various means of manipulations in vitro and in vivo. Here we describe several attractive strategies for manipulation of DC using the novel technique of RNA interference (RNAi). Additionally, we overview some of our data regarding yet undescribed characteristics of RNAi in DC such as specific transfection strategies, persistence of gene silencing, and multi-gene silencing. The advantages of using RNAi for DC genetic manipulation gives rise to the promise of generating tailor-made DC that can be used effectively to treat a variety of immunologically mediated diseases.

Animals↗

PubMed2003

Inhibition of human p53 basal transcription by down-regulation of protein kinase Cdelta.

In response to DNA damage, signal transduction pathways are activated that result in the increase of p53 protein levels, leading to either growth arrest or apoptosis. Protein kinase C (PKC) delta has been implicated as a tumor suppressor that is down-regulated by tumor-promoting phorbol esters in both mouse skin and cell culture models. We report here that the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate prevents DNA damage-induced up-regulation of p53 by down-regulating PKC delta. Regulation of p53 in response to stress most commonly occurs by preventing ubiquitination and degradation of the p53 protein. Surprisingly, suppression of p53 expression by inhibition of PKC delta was caused by the inhibition of p53 synthesis, not increased degradation of p53 protein. Inhibiting PKC delta blocked both basal transcription of the human p53 gene and initiation of transcription from the human p53 promoter. Therefore, the tumor-suppressing effects of PKC delta are mediated at least in part through activating p53 transcription.

Apoptosis↗

PubMed2003

Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance.

An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4(+)CD25(+) T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4(+)CD25(+) Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.

Animals↗

PubMed2003

Detailed gene copy number and RNA expression analysis of the 17q12-23 region in primary breast cancers.

Chromosome region 17q12-23 commonly shows an increase in DNA copy number in breast cancers, suggesting that several oncogenes are located at this site. We performed a high-resolution expression array and comparative genomic hybridization analysis of genes mapped to the entire 17q12-23 region, to identify novel candidate oncogenes. We identified 24 genes that showed significant overexpression in breast cancers with gain of 17q12-23, compared to cancers without gain. These genes included previously identified oncogenes, together with several novel candidate oncogenes. FISH analysis using specific gene probes hybridized to tissue arrays confirmed the underlying amplification of overexpressed genes. This high-resolution analysis of the 17q12-23 region indicates that several established and novel candidate oncogenes, including a Wnt-signaling pathway member, are amplified and overexpressed within individual primary breast cancer samples. We were also able to confirm the presence of two apparently separate and reciprocally amplified groups of genes within this region. Investigation of these genes and their functional interactions will facilitate our understanding of breast oncogenesis and optimal management of this disease.

Breast Neoplasms↗

PubMed2003

Uses of MAC.

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Age Factors↗