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Biomedical subjects

David L Lewis

Publications and source records attributed to David L Lewis.

At least 19 recordsLinked to original sources
PubMed2007

Prospective study of cross-infection from upper-GI endoscopy in a hepatitis C-prevalent population.

BACKGROUND: A high prevalence of hepatitis C (HCV) in the Egyptian Nile Delta increases the demand for upper-GI endoscopy (UGIE) and the risk of cross-infection with this virus. OBJECTIVE: To assess the potential for UGIE to transmit HCV when endoscopes are reprocessed according to current international standards. DESIGN: A prospective cohort study to detect the incidence of HCV and hepatitis B cross-infections. SETTING: The endoscopic unit of the National Liver Institute, a hospital for patients with chronic liver disease. PATIENTS: A total of 859, including 149 of 249 patients (60%) at risk (HCV-antibody negative) retested 3 to 10 months after UGIE with endoscopes previously used on HCV carriers. INTERVENTIONS: Nurses were trained to process endoscopes according to American Society for Gastrointestinal Endoscopy guidelines, and procedures were observed and recorded. MAIN OUTCOME MEASUREMENTS: Seroconversions were determined by using enzyme immunoassays for anti-HCV; reverse transcriptase-polymerase chain reaction was used to detect HCV-ribonucleic acid (RNA). RESULTS: Four patients, initially negative, tested positive for anti-HCV after UGIE. However, 2 of these had HCV-RNA in their baseline blood sample, and the other 2 did not have HCV-RNA in their follow-up sample. LIMITATIONS: Very-high prevalence of anti-HCV in subjects reduced the proportion at risk of infection, and follow-up was difficult. CONCLUSIONS: There were no cases of proven transmission of HCV when endoscopes were reprocessed by using currently accepted standards. This negative study is encouraging, because patients undergoing UGIE in the Nile Delta of Egypt where HCV-caused liver disease is so pervasive would be at maximum risk of HCV cross-infection from UGIE.

Adult↗
PubMed2007

Do the ABCS 135 short cognitive screen and its subtests discriminate between normal cognition, mild cognitive impairment and dementia?

BACKGROUND: Cognitive screening instruments are either too long for routine clinical use or not sensitive to distinguish mild cognitive impairment (MCI) from normal cognition (NC) or dementia. OBJECTIVE: To evaluate the sensitivity and specificity of the AB Cognitive Screen (ABCS) and its subtests with a view to improving its ability to differentiate between dementia, MCI and NC. The influence of age and education on sensitivity and specificity is also examined. DESIGN: Cross-sectional study. METHODS: Participants with dementia and MCI were recruited from those presenting to four specialty geriatric clinics in southern Ontario. Participants with NC were recruited from the family and friends of patients. A comprehensive geriatric assessment was done including ABCS, SMMSE and 15 point Geriatric Depression Scale. Analysis of variance and receiver operating characteristic (ROC) curves compared test scores. SMMSE scores were also analysed for comparison purposes. RESULTS: Three hundred and two participants had dementia, 166 had MCI and 174 had NC. ABCS total scores were significantly different between NC and MCI (mean difference 7.1, 1.8-12.5 CI, p = 0.000) while SMMSE scores were not (mean difference 0.5, -0.7-1.7, p < 0.628). Of individual ABCS subtests, verbal fluency and delayed recall were most sensitive to differences between NC and MCI. ROC curve analysis, which presents sensitivity and specificity, showed verbal fluency was better than delayed recall in distinguishing between NC and MCI, among participants 75 years of age or older. CONCLUSION: The AB Cognitive Screen (ABCS) can be administered in 3-5 min. The SMMSE and ABCS total and subtests significantly distinguished between dementia and MCI or NC. Verbal fluency and delayed recall were best at distinguishing between MCI and NC. The analysis illustrates how each subtest contributes to the sensitivity of the ABCS and suggests ways that sensitivity might be improved.

Aged↗
PubMed2006

Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice.

RNA interference (RNAi) has great potential as a tool for studying gene function in mammals. However, the specificity and magnitude of the in vivo response to RNAi remains to be fully characterized. A molecular and phenotypic comparison of a genetic knockout mouse and the corresponding knockdown version would help clarify the utility of the RNAi approach. Here, we used hydrodynamic delivery of small interfering RNA (siRNA) to knockdown peroxisome proliferator activated receptor alpha (Ppara), a gene that is central to the regulation of fatty acid metabolism. We found that Ppara knockdown in the liver results in a transcript profile and metabolic phenotype that is comparable to those of Ppara-/- mice. Combining the profiles from mice treated with the PPARalpha agonist fenofibrate, we confirmed the specificity of the RNAi response and identified candidate genes proximal to PPARalpha regulation. Ppara knockdown animals developed hypoglycemia and hypertriglyceridemia, phenotypes observed in Ppara-/- mice. In contrast to Ppara-/- mice, fasting was not required to uncover these phenotypes. Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies.

Animals↗
PubMed2006

Alternate forms of logical memory and verbal fluency tasks for repeated testing in early cognitive changes.

BACKGROUND: Repeat cognitive testing is an essential diagnostic strategy to measure changes in cognition over time when following people with memory problems. Alternate forms may avert practice effects that can mimic improvements in cognition. We evaluated alternate forms of verbal fluency and logical memory (paragraph recall) tasks to evaluate their equivalence for clinical use. METHODS: Participants with mild cognitive impairment (MCI) and dementia were recruited from five outpatient memory clinics and one nursing home. Participants with normal cognition (NC) were recruited from family members or friends. Verbal fluency categories of animals, cities & towns, fruits & vegetables and first names were used. Scores were recorded for 0-30 seconds, 31-60 seconds and errors. For the logical memory task, participants were read one of three different paragraphs and then were asked to recall the story. Immediate recall and delayed recall scores were recorded. The Standardized Mini-mental State Examination, the AB Cognitive Screen and the 15-point Geriatric Depression Scale were administered as part of the assessment. Analyses were performed using means, frequency distributions, t-tests, receiver-operating characteristic curves and effect sizes. RESULTS: There were 46 NC participants, 45 with MCI and 55 with dementia. For verbal fluency, the mean number of animals, cities & towns, names or fruits & vegetables named in 60 seconds did not differ significantly within each cognitive group. First names was an easier category than the others: NC named 16.9-22.3 items, MCI named 11.6-14.4 items and dementia named 8.1-11.4 items. The mean number of items immediately recalled in logical memory was not significantly different for the three paragraphs. The verbal fluency task (in 60 seconds) and logical memory immediate recall were highly sensitive and specific to differences between NC and MCI (areas under the curves 0.87 and 0.76, respectively). CONCLUSIONS: Alternate forms allow serial testing without learning bias. Verbal fluency and logical memory tasks are sensitive to early cognitive changes.

Age of Onset↗
PubMed2006

Mechanism of plasmid delivery by hydrodynamic tail vein injection. I. Hepatocyte uptake of various molecules.

BACKGROUND: The hydrodynamic tail vein (HTV) injection of naked plasmid DNA is a simple yet effective in vivo gene delivery method into hepatocytes. It is increasingly being used as a research tool to elucidate mechanisms of gene expression and the role of genes and their cognate proteins in the pathogenesis of disease in animal models. A greater understanding of its mechanism will aid these efforts and has relevance to macromolecular and nucleic acid delivery in general. METHODS: In an attempt to explore how naked DNA enters hepatocytes the fate of a variety of molecules and particles was followed over a 24-h time frame using fluorescence microscopy. The uptake of some of these compounds was correlated with marker gene expression from a co-injected plasmid DNA. In addition, the uptake of the injected compounds was correlated with the histologic appearance of hepatocytes. RESULTS: Out of the large number of nucleic acids, peptides, proteins, inert polymers and small molecules that we tested, most were efficiently delivered into hepatocytes independently of their size and charge. Even T7 phage and highly charged DNA/protein complexes of 60-100 nm in size were able to enter the cytoplasm. In animals co-injected with an enhanced yellow fluorescent protein (EYFP) expression vector and fluorescently labeled immunoglobulin (IgG), hepatocytes flooded with large amounts of IgG appeared permanently damaged and did not express EYFP-Nuc. Hepatocytes expressing EYFP had only slight IgG uptake. In contrast, when an EYFP expression vector was co-injected with a fluorescently labeled 200-bp linear DNA fragment, both were mostly (in 91% of the observed cells) co-localized to the same hepatocytes 24 h later. CONCLUSIONS: The appearance of permanently damaged cells with increased uptake of some molecules such as endogenous IgG raised the possibility that a molecule could be present in a hepatocyte but its transport would not be indicative of the transport process that can lead to foreign gene expression. The HTV procedure enables the uptake of a variety of molecules (as previous studies also found), but the uptake process for some of these molecules may be associated with a more disruptive process to the hepatocytes that is not compatible with successful gene delivery.

Amino Acid Sequence↗
PubMed2005

Long-term RNA interference from optimized siRNA expression constructs in adult mice.

DNA constructs for small interfering RNA (siRNA) expression in mammalian cells have the potential for longer-term target gene knockdown than synthetic siRNAs. We compared in adult mice the efficacy and longevity of target gene knockdown from siRNA expression cassettes contained in plasmids, PCR-generated linear constructs or PCR constructs containing "dumbbell" ends using the hydrodynamic delivery method. Plasmid siRNA expression constructs were more effective than PCR constructs for target gene knockdown. The efficacy of the PCR constructs was improved by addition of short extensions beyond the transcription termination signal and greatly improved by addition of dumbbell ends. Constructs containing the H1 promoter were significantly less effective in mice than those containing the U6 promoter, whereas both promoters functioned equally well in cultured cells. Target gene knockdown perdured for at least 20 weeks in mice after delivery of either PCR or plasmid siRNA expression cassettes. These results will help guide RNAi vector design.

Animals↗
PubMed2005

Delivery of siRNA and siRNA expression constructs to adult mammals by hydrodynamic intravascular injection.

Extensive use of RNA interference in mammals has been hindered by the inability to effectively deliver small interfering RNAs (siRNAs) or DNA-based constructs designed to express siRNAs. In this chapter, we describe the high-pressure or hydrodynamic intravascular injection technique used to deliver these nucleic acids to mice and nonhuman primates. Emphasis is placed on the use of this technique for delivery to the liver.

Animals↗
PubMed2005

Screening for mild cognitive impairment: comparing the SMMSE and the ABCS.

OBJECTIVE: To compare the sensitivity and specificity of the AB Cognitive Screen (ABCS) with the Standardized Mini-Mental State Examination (SMMSE) to differentiate normal cognition from mild cognitive impairment (MCI), especially when educational level and age are taken into account. METHOD: This cross-sectional study took place at geriatric outpatient memory clinics. Participants were community-dwelling adults, aged 55 years or over, referred from primary care settings (a minority of participants were referred from specialists) for assessment of memory loss and age-matched control subjects with no complaint of memory loss. Each participant had the ABCS and the SMMSE administered in random order on the same day. RESULTS: Participants included 124 patients diagnosed with MCI and 111 with normal cognitive function. The ABCS showed a statistically significant difference between normal cognition and MCI (ABCS score 111.7 and 104.6 points, respectively, P < 0.001) for the whole group. This difference was significant with the ABCS, regardless of participants' age or education. There was a significant difference between normal cognition and MCI for SMMSE scores (SMMSE score 27.8 and 27.2 points, respectively, P = 0.040), but the differences were not significant when age and education were taken into account. Age and education were shown to affect the scores of both instruments except for the ABCS scores of MCI subjects, which were not significantly affected by education (P = 0.059). CONCLUSIONS: The ABCS is more sensitive than the SMMSE in differentiating normal cognition from MCI. The ABCS appears to be less influenced by education. It has improved clinical utility with a wider range of scoring gradations, reduced ceiling effects, and shorter scoring and administration times.

Aged↗
PubMed2005

Translating evidence into practice: the case of dementia guidelines in specialized geriatric services.

This paper describes a process of identifying best practice guidelines for non-pharmacological management for individuals with dementia and disseminating them to a group of frontline practitioners in specialized geriatric services. Our dissemination plan involved early participation of practitioners, development of a chart summarizing five guidelines showing commonalities, contrasts, and gaps in the guidelines, and their interpretation, colour-coded for the strength of the evidence on which they were based. Two sequential workshops were held in which recommendations for action were developed. Outcomes of the process included a resource manual, a network of practitioners, and action recommendations based upon survey data. An early follow-up evaluation showed increased adoption of guidelines.

Aged↗
PubMed2004

A facile nonviral method for delivering genes and siRNAs to skeletal muscle of mammalian limbs.

Delivery is increasingly being recognized as the critical hurdle holding back the tremendous promise of nucleic acid-based therapies that include gene therapy and more recently siRNA-based therapeutics. While numerous candidate genes (and siRNA sequences) with therapeutic potential have been identified, their utility has not yet been realized because of inefficient and/or unsafe delivery technologies. We now describe an intravascular, nonviral methodology that enables efficient and repeatable delivery of nucleic acids to muscle cells (myofibers) throughout the limb muscles of mammals. The procedure involves the injection of naked plasmid DNA or siRNA into a distal vein of a limb that is transiently isolated by a tourniquet or blood pressure cuff. Nucleic acid delivery to myofibers is facilitated by its rapid injection in sufficient volume to enable extravasation of the nucleic acid solution into muscle tissue. High levels of transgene expression in skeletal muscle were achieved in both small and large animals with minimal toxicity. Evidence of siRNA delivery to limb muscle was also obtained. The simplicity, effectiveness, and safety of the procedure make this methodology well suited to limb muscle gene therapy applications.

Animals↗
PubMed2004

A high-level disinfection standard for land applying sewage sludges (biosolids).

Complaints associated with land-applied sewage sludges primarily involve irritation of the skin, mucous membranes, and the respiratory tract accompanied by opportunistic infections. Volatile emissions and organic dusts appear to be the main source of irritation. Occasionally, chronic gastrointestinal problems are reported by affected residents who have private wells. To prevent acute health effects, we recommend that the current system of classifying sludges based on indicator pathogen levels (Class A and Class B) be replaced with a single high-level disinfection standard and that methods used to treat sludges be improved to reduce levels of irritant chemicals, especially endotoxins. A national opinion survey of individuals impacted by or concerned about the safety of land-application practices indicated that most did not consider the practice inherently unsafe but that they lacked confidence in research supported by federal and state agencies.

Disinfection↗
PubMed2002

Efficient delivery of siRNA for inhibition of gene expression in postnatal mice.

It has recently been shown that RNA interference can be induced in cultured mammalian cells by delivery of short interfering RNAs (siRNAs). Here we describe a method for efficient in vivo delivery of siRNAs to organs of postnatal mice and demonstrate effective and specific inhibition of transgene expression in a variety of organs.

Animals↗
PubMed2002

Interactions of pathogens and irritant chemicals in land-applied sewage sludges (biosolids).

BACKGROUND: Fertilisation of land with processed sewage sludges, which often contain low levels of pathogens, endotoxins, and trace amounts of industrial and household chemicals, has become common practice in Western Europe, the US, and Canada. Local governments, however, are increasingly restricting or banning the practice in response to residents reporting adverse health effects. These self-reported illnesses have not been studied and methods for assessing exposures of residential communities to contaminants from processed sewage sludges need to be developed. METHODS: To describe and document adverse effects reported by residents, 48 individuals at ten sites in the US and Canada were questioned about their environmental exposures and symptoms. Information was obtained on five additional cases where an outbreak of staphylococcal infections occurred near a land application site in Robesonia, PA. Medical records were reviewed in cases involving hospitalisation or other medical treatment. Since most complaints were associated with airborne contaminants, an air dispersion model was used as a means for potentially ruling out exposure to sludge as the cause of adverse effects. RESULTS: Affected residents lived within approximately 1 km of land application sites and generally complained of irritation (e.g., skin rashes and burning of the eyes, throat, and lungs) after exposure to winds blowing from treated fields. A prevalence of Staphylococcus aureus infections of the skin and respiratory tract was found. Approximately 1 in 4 of 54 individuals were infected, including 2 mortalities (septicaemia, pneumonia). This result was consistent with the prevalence of S. aureus infections accompanying diaper rashes in which the organism, which is commonly found in the lower human colon, tends to invade irritated or inflamed tissue. CONCLUSIONS: When assessing public health risks from applying sewage sludges in residential areas, potential interactions of chemical contaminants with low levels of pathogens should be considered. An increased risk of infection may occur when allergic and non-allergic reactions to endotoxins and other chemical components irritate skin and mucus membranes and thereby compromise normal barriers to infection.

Air Pollutants↗
PubMed2002

Interactions of pathogens and irritant chemicals in land-applied sewage sludges (biosolids).

UNLABELLED: Fertilization of land with processed sewage sludges, which often contain low levels of pathogens, endotoxins, and trace amounts of industrial and household chemicals, has become common practice in Western Europe, the United States, and Canada. Local governments, however, are increasingly restricting or banning the practice in response to residents reporting adverse health effects. These self-reported illnesses have not been studied and methods for assessing exposures of residential communities to contaminants from processed sewage sludges need to be developed. METHODS: To describe and document adverse effects reported by residents, 48 individuals at ten sites in the United States and Canada were questioned about their environmental exposures and symptoms. Information was obtained on five additional cases where an outbreak of staphylococcal infections occurred near a land application site in Robesonia, Pennsylvania. Medical records were reviewed in cases involving hospitalization or other medical treatment. Since most complaints were associated with airborne contaminants, an air dispersion model was used as a means for potentially ruling out exposure to sludge as the cause of adverse effects. RESULTS: Affected residents lived within approximately 1 km of land-application sites and generally complained of irritation (e.g., skin rashes and burning of the eyes, throat, and lungs) after exposure to winds blowing from treated fields. A prevalence of Staphylococcus aureus infections of the skin and respiratory tract was found. Approximately one in four of 54 individuals were infected, including two mortalities (septicemia, pneumonia). This result was consistent with the prevalence of S. aureus infections accompanying diaper rashes in which the organism, which is occasionally found in the lower human colon, tends to invade irritated or inflamed tissue. CONCLUSIONS: When assessing public health risks from applying sewage sludges in residential areas, potential interactions of chemical contaminants with low levels of pathogens should be considered. An increased risk of infection may occur when allergic and non-allergic reactions to endotoxins and other chemical components irritate skin and mucous membranes and thereby compromise normal barriers to infection.

Journal Article↗