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Biomedical subjects

David J Weber

Publications and source records attributed to David J Weber.

At least 37 records · Page 2Linked to original sources
PubMed2005

Influenza vaccination of healthcare workers and vaccine allocation for healthcare workers during vaccine shortages.

Influenza causes substantial morbidity and mortality annually, particularly in high-risk groups such as the elderly, young children, immunosuppressed individuals, and individuals with chronic illnesses. Healthcare-associated transmission of influenza contributes to this burden but is often under-recognized except in the setting of large outbreaks. The Centers for Disease Control and Prevention has recommended annual influenza vaccination for healthcare workers (HCWs) with direct patient contact since 1984 and for all HCWs since 1993. The rationale for these recommendations is to reduce the chance that HCWs serve as vectors for healthcare-associated influenza due to their close contact with high-risk patients and to enhance both HCW and patient safety. Despite these recommendations as well as the effectiveness of interventions designed to increase HCW vaccination rates, the percentage of HCWs vaccinated annually remains unacceptably low. Ironically, at the same time that campaigns have sought to increase HCW vaccination rates, vaccine shortages, such as the shortage during the 2004-2005 influenza season, present challenges regarding allocation of available vaccine supplies to both patients and HCWs. This two-part document outlines the position of the Society for Healthcare Epidemiology of America on influenza vaccination for HCWs and provides guidance for the allocation of influenza vaccine to HCWs during a vaccine shortage based on influenza transmission routes and the essential need for a practical and adaptive strategy for allocation. These recommendations apply to all types of healthcare facilities, including acute care hospitals, long-term-care facilities, and ambulatory care settings.

Communicable Disease Control↗
PubMed2005

Design of Inhibitors for S100B.

S100B interacts with the p53 protein in a calcium-dependent manner and down-regulates its function as a tumor suppressor. Therefore, inhibiting the S100B-p53 interaction represents a new approach for restoring functional wild-type p53 in cancers with elevated S100B such as found in malignant melanoma. A discussion of the biological rational for targeting S100B and a description of methodologies relevant to the discovery of compounds that inhibit S100B-p53 binding, including computational techniques, structural biology techniques, and cellular assays, is presented.

Biomarkers, Tumor↗
PubMed2004

Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction.

The binding of S100B to p53 down-regulates wild-type p53 tumor suppressor activity in cancer cells such as malignant melanoma, so a search for small molecules that bind S100B and prevent S100B-p53 complex formation was undertaken. Chemical databases were computationally searched for potential inhibitors of S100B, and 60 compounds were selected for testing on the basis of energy scoring, commercial availability, and chemical similarity clustering. Seven of these compounds bound to S100B as determined by steady state fluorescence spectroscopy (1.0 microM < or = K(D) < or = 120 microM) and five inhibited the growth of primary malignant melanoma cells (C8146A) at comparable concentrations (1.0 microM < or = IC(50) < or = 50 microM). Additionally, saturation transfer difference (STD) NMR experiments confirmed binding and qualitatively identified protons from the small molecule at the small molecule-S100B interface. Heteronuclear single quantum coherence (HSQC) NMR titrations indicate that these compounds interact with the p53 binding site on S100B. An NMR-docked model of one such inhibitor, pentamidine, bound to Ca(2+)-loaded S100B was calculated using intermolecular NOE data between S100B and the drug, and indicates that pentamidine binds into the p53 binding site on S100B defined by helices 3 and 4 and loop 2 (termed the hinge region).

Antineoplastic Agents↗
PubMed2004

Disinfection and sterilization in health care facilities: what clinicians need to know.

All invasive procedures involve contact between a medical device or surgical instrument and a patient's sterile tissue or mucous membranes. A major risk of all such procedures is the introduction of pathogenic microbes that could lead to infection. Failure to properly disinfect or sterilize reusable medical equipment carries a risk associated with breach of the host barriers. The level of disinfection or sterilization is dependent on the intended use of the object: critical items (such as surgical instruments, which contact sterile tissue), semicritical items (such as endoscopes, which contact mucous membranes), and noncritical items (such as stethoscopes, which contact only intact skin) require sterilization, high-level disinfection, and low-level disinfection, respectively. Cleaning must always precede high-level disinfection and sterilization. Users must consider the advantages and disadvantages of specific methods when choosing a disinfection or sterilization process. Adherence to these recommendations should improve disinfection and sterilization practices in health care facilities, thereby reducing infections associated with contaminated patient-care items.

Cross Infection↗
PubMed2004

Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells.

S100 calcium-binding proteins such as S100B are elevated in primary malignant melanoma and are used as markers for this and numerous other cancers. Wild-type p53 protein levels are relatively low in these cancer cells (i.e. when compared with cells without S100B) but are elevated when RNA antisense to S100B is introduced. This result implicates S100B in the down-regulation of p53 and is consistent with the large decreases in p53 protein levels observed previously in transient co-transfections of p53 and S100B (Lin, J., Blake, M., Tang, C., Zimmer, D., Rustandi, R. R., Weber, D. J., and Carrier, F. (2001) J. Biol. Chem. 276, 35037-35041). Down-regulation of p53 in primary malignant melanoma cells is likely the result of a direct interaction with S100B, which was observed by co-immunoprecipitation experiments. Furthermore, p53 binds regions of the S100B promoter, one of which matches the 20-nucleotide p53-binding consensus DNA sequence perfectly. Therefore, when p53 levels increase, it contributes to its own demise by up-regulating the transcription of S100B as part of a negative feedback loop. This is analogous to what is found for another protein that down-regulates p53, namely hdm2 (human double mutant 2).

Binding Sites↗
PubMed2004

Virulence associated with outbreak-related strains of Burkholderia cepacia complex among a cohort of patients with bacteremia.

The Burkholderia cepacia complex includes 9 genomovars. The relative virulence of each is unknown. Host and pathogen features associated with mortality were evaluated among patients with B. cepacia complex bacteremia. Cases were ascertained through review of blood culture results for the period of May 1996 through May 2002. Isolates were identified to species level with 16S rDNA and recA-based species-specific polymerase chain reaction analyses and recA restriction fragment-length polymorphism. Strain typing was performed with pulsed-field gel electrophoresis. Fifty-three patients with B. cepacia complex bacteremia were identified; only 9 (17%) had cystic fibrosis. Twenty-five patients (47%) died within 14 days of bacteremia. After controlling for comorbid conditions and therapeutic interventions, 2 outbreak-related strains of Burkholderia cenocepacia (genomovar III) were associated with 14-day mortality (odds ratio, 5.5; 95% confidence interval, 1.20-25.02). B. cenocepacia is an emerging nosocomial pathogen. Certain strains are associated with an enhanced capacity for interpatient spread and poor outcome.

Adolescent↗
PubMed2004

The effects of test variables on the efficacy of hand hygiene agents.

BACKGROUND: Hand hygiene is essential to interrupting disease transmission in health care facilities. Multiple hand hygiene agents are currently available for use in the health care setting. To evaluate the utility of these agents, both the user acceptability and the efficacy need to be evaluated. Different hand hygiene test methodologies have been used to measure the efficacy of these agents, but efficacy results vary depending on variations to key parameters in these methodologies. The purpose of this study was to evaluate the effect of test variables on the efficacy of hand hygiene agents. METHODS: Both a comprehensive literature review and original hand hygiene efficacy studies were undertaken. The literature review was conducted using a Medline search, and hand hygiene efficacy studies were conducted under the American Society for Testing and Materials (ASTM). E 1174 Standard Test Method for Evaluation of the Effectiveness of Health Care Personnel Handwash Formulation. RESULTS: The literature review and our original data showed that the following variables affected the hand hygiene efficacy measurements: hand jewelry, experimental contamination versus normal flora, method of application of test organism, hand hygiene agent, concentration of active ingredient, volume of hand hygiene agent, duration of application of hand hygiene agent, method of application of hand hygiene agent, and study method (human challenge trial versus in vitro suspension test). CONCLUSIONS: Although many methodological variables affect efficacy results, infection control professionals in their analysis of product information should always assess the results in light of the following key variables: concentration and type of active ingredient, duration of exposure to hand hygiene agent, volume of hand hygiene agent applied, test organism, and study method (ie, human challenge vs. in vitro suspension test).

Anti-Infective Agents, Local↗
PubMed2004

Human challenge pilot study with Cyclospora cayetanensis.

We describe a pilot study that attempted to infect human volunteers with Cyclospora cayetanensis. Seven healthy volunteers ingested an inoculum of Cyclospora oocysts (approximately 200-49,000 oocysts). The volunteers did not experience symptoms of gastroenteritis, and no oocysts were detected in any stool samples during the 16 weeks volunteers were monitored.

Adult↗
PubMed2003

Location of the Zn(2+)-binding site on S100B as determined by NMR spectroscopy and site-directed mutagenesis.

In addition to binding Ca(2+), the S100 protein S100B binds Zn(2+) with relatively high affinity as confirmed using isothermal titration calorimetry (ITC; K(d) = 94 +/- 17 nM). The Zn(2+)-binding site on Ca(2+)-bound S100B was examined further using NMR spectroscopy and site-directed mutagenesis. Specifically, ITC measurements of S100B mutants (helix 1, H15A and H25A; helix 4, C84A, H85A, and H90A) were found to bind Zn(2+) with lower affinity than wild-type S100B (from 2- to >25-fold). Thus, His-15, His-25, Cys-84, His-85, and perhaps His-90 of S100B are involved in coordinating Zn(2+), which was confirmed by NMR spectroscopy. Previous studies indicate that the binding of Zn(2+) enhances calcium and target protein-binding affinities, which may contribute to its biological function. Thus, chemical shift perturbations observed here for residues in both EF-hand domains of S100B during Zn(2+) titrations could be detecting structural changes in the Ca(2+)-binding domains of S100B that are pertinent to its increase in Ca(2+)-binding affinity in the presence of Zn(2+). Furthermore, Zn(2+) binding causes helix 4 to extend by one full turn when compared to Ca(2+)-bound S100B. This change in secondary structure likely contributes to the increased binding affinity that S100B has for target peptides (i.e., TRTK peptide) in the presence of Zn(2+).

Amino Acid Sequence↗
PubMed2003

A comparison of height and weight velocity as a part of the composite endpoint in pediatric HIV.

BACKGROUND: HIV adversely affects growth in children. Pediatric AIDS Clinical Trial Group (PACTG) protocols often use weight velocity [changes in weight z-score for age (WAZ)] as a part of the composite endpoint for phase II and III clinical trials. However, WAZ and height velocity (HAZ) have not been critically compared for their utility as part of the composite endpoint. METHODS: HAZ and WAZ were compared to predict laboratory and clinical progression of HIV in a retrospective cohort study of HIV-infected children with data from PACTG Protocol 300. RESULTS: In both bivariable and multivariable analyses, changes in HAZ were more closely linked to subsequent progression than WAZ. Children with improved HAZ were somewhat less likely to exhibit virological failure [odds ratio (OR), 0.76; 95% confidence interval (CI) 0.51-1.14], than children with improved WAZ (OR, 1.45; 95% CI, 0.99,2.11). Children who had improved HAZ were less likely to exhibit immunological failure (OR, 0.7; 95% CI, 0.49-1.00), than children with improved WAZ (OR, 1.13; 95% CI, 0.82-1.57). Children who had improved HAZ were less likely to have other forms of clinical progression of HIV (OR, 0.55; 95% CI, 0.31-0.99), than children who had improved WAZ (OR, 1.0; 95% CI, 1.58-1.94). CONCLUSIONS: Increases in HAZ were associated with reduced risk of subsequent clinical progression and subsequent immune reconstitution and weakly associated with declines in HIV RNA. Changes in WAZ were not associated with laboratory outcomes relevant to pediatric HIV infection. Height velocity should be considered as a component of a composite clinical endpoint in future PACTG trials.

Adolescent↗
PubMed2003

Molecular mechanisms of S100-target protein interactions.

S100 proteins have no known enzymatic activity and exert their intracellular effects via interaction with and regulation of the activity of other proteins, termed target proteins, in both a Ca(2+)-dependent and Ca(2+)-independent manner. Structural studies have identified the linker region between the two EF-hand Ca(2+) binding domains and the C-terminus as Ca(2+)-dependent target protein binding sites in several S100 family members. In fact, C-terminal aromatic residues are obligatory for interaction of S100A1 with several of its Ca(2+)-dependent target proteins. Pharmacological studies suggest the presence of additional Ca(2+)-dependent binding motifs on some family members. A minimum of seven family members interact with and regulate the activity of aldolase A in a Ca(2+)-independent manner. In the case of S100A1, Ca(2+)-independent target protein interactions utilize a binding motif distinct from the C-terminal Ca(2+)-dependent target protein binding site. Several studies suggest that ionic interactions participate in the interaction of S100 family members with Ca(2+)-independent target proteins. While some target proteins are activated by multiple family members, other target proteins exhibit family member-specific activation, i.e., they are activated by a single family member. As predicted, family member specific interactions appear to be mediated by regions that exhibit the most divergence in amino acid sequence among family members, the linker or "hinge" region and the C terminus. Further specificity in S100-target protein interactions may arise from the different biochemical/biophysical properties of the individual family members, including affinity for metal ions (Ca(2+), Zn(2+), and Cu(2+)), oligomerization properties, heterodimerization, post-translational modifications, and lipid-binding. Delineation of the structural motifs that mediate S100-target protein interactions and determination of the in vivo relevance of these interactions are needed to fully understand the role of S100 proteins in normal and diseased cells.

Amino Acid Sequence↗
PubMed2003

Efficacy of selected hand hygiene agents used to remove Bacillus atrophaeus (a surrogate of Bacillus anthracis) from contaminated hands.

CONTEXT: The intentional use of Bacillus anthracis transmitted via the US mail in October-November 2001 resulted in 22 people developing inhalation or cutaneous anthrax. Glove use with handwashing prior to and after contact with potential contaminated environmental surfaces and cutaneous lesions has been recommended. However, only limited data are available on the susceptibility of B anthracis to antiseptics. OBJECTIVE: To evaluate the efficacy of several hand antiseptics (interventions) and soap and water (control) against Bacillus atrophaeus, a surrogate of B anthracis. DESIGN, SETTING, AND PARTICIPANTS: Challenge study conducted among healthy adult volunteers, using the Standard Test Method for Evaluation of the Effectiveness of Health Care Professional Handwash Formulations (American Society for Testing and Materials E 1174-94) to determine the efficacy of various hand hygiene products at wash times of 10, 30, and 60 seconds. Volunteers were excluded if they had eczema, psoriasis, or other chronic skin conditions; nonintact skin; or allergies to any study agent. Study agents were a waterless rub containing 61% ethyl alcohol, a 2% chlorhexidine gluconate preparation, and an antibacterial microfiber towel that releases hypochlorite. A nonantimicrobial soap was used as a control. MAIN OUTCOME MEASURE: Reduction of B atrophaeus spores (log10 CFU/mL) on contaminated hands. RESULTS: Washes of 10, 30, and 60 seconds with either soap and water or 2% chlorhexidine gluconate eliminated 1.5 to 2.0 log10 CFUs/mL of B atrophaeus spores at wash 3. Mean reductions (95% confidence intervals) with 10-, 30-, and 60-second washes with soap and water were 2.4 (2.2-2.5), 2.3 (2.2-2.4), and 2.1 (1.9-2.4) log(10) CFUs/mL, respectively; and with 2% chlorhexidine gluconate, 2.1 (2.0-2.3), 1.8 (1.5-2.0), and 1.7 (1.5-1.9) log10 CFUs/mL, respectively. Handwashing with chlorine-containing towels was increasingly effective as the wipe time increased; reductions at 10, 30, and 60 seconds were 1.3 (1.1-1.5), 1.6 (1.2-2.0), and 2.2 (2.1-2.2) log10 CFUs/mL, respectively. A waterless rub containing 61% ethyl alcohol was ineffective in eliminating B atrophaeus spores at all times tested (0 [-0.1 to 0.1], -0.2 [-0.3 to -0.1], and 0 [-0.2 to 0.2] log10 CFUs/mL). CONCLUSIONS: In this evaluation of hand hygiene agents, handwashing with soap and water, 2% chlorhexidine gluconate, or chlorine-containing towels reduced the amount of B atrophaeus spore contamination, whereas use of a waterless rub containing ethyl alcohol was not effective in removing spores.

Adult↗
PubMed2003

Immunization of immunocompromised persons.

Advances in medicine, science, and technology have led to increasing numbers of people in the general population with altered host defenses. The risk for clinical infection in an immunocompromised host, such as a person who has received a solid organ transplant, is determined largely by the interaction between two factors: the epidemiologic exposures the person encounters and the person's net state of immunosuppresson. Vaccination represents a crucial approach for preventing infection in the general public and immunocompromised persons. This article reviews the benefits of and risks for immunization in immunocompromised persons and provides recommendations for the use of specific vaccines.

Adolescent↗
PubMed2003

Assessment by meta-analysis of PCR for diagnosis of smear-negative pulmonary tuberculosis.

We conducted a meta-analysis to assess the performance of PCR for the diagnosis of smear-negative pulmonary tuberculosis (SPT) and to identify factors that account for differences in the diagnostic accuracy of different studies. Studies published before February 2002 were included if sensitivity and specificity of PCR in smear-negative respiratory or gastric-aspirate specimens could be calculated. Analysis was conducted by using summary receiver operating characteristics models. Sensitivity and specificity ranged from 9 to 100% and from 25 to 100%, respectively. Fewer than 40% of the 50 studies reported results by number of patients, reported clinical characteristics of patients, or used as a reference standard combined culture and clinical criteria. Studies that included bronchial specimens showed higher accuracy than studies that evaluated only sputum specimens or included gastric aspirates. Studies that did not report that tests were applied blindly showed higher accuracy than those reporting blind testing. Increased sensitivity due to the use of DNA purification methods was associated with decreased specificity. Studies published after 1995, using Amplicor or dUTP-UNG, were associated with an increase in specificity at the expense of lower sensitivity. We concluded that PCR is not consistently accurate enough to be routinely recommended for the diagnosis of SPT. However, PCR of bronchial specimens could be useful in highly suspicious SPT cases. Studies not reporting blind testing are likely to overestimate accuracy of PCR. Future evaluation of PCR accuracy should be conducted by patient and type of respiratory specimen, blindly, by using a reference standard that combines culture and clinical criteria and addresses the issue of how patient characteristics affect PCR accuracy.

Humans↗