Guideline-concordant therapy and reduced mortality and length of stay in adults with community-acquired pneumonia: playing by the rules.

Background: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Clinical practice guidelines for empirical CAP treatment, formulated jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS), remain controversial and inconsistently applied. We evaluated the impact of guideline-concordant therapy on in-hospital survival and other outcomes using a large database including adults treated for CAP in both community and tertiary care hospitals.

Laboratory-based evaluation of legionellosis epidemiology in Ontario, Canada, 1978 to 2006.

Background: Legionellosis is a common cause of severe community acquired pneumonia and respiratory disease outbreaks. The Ontario Public Health Laboratory (OPHL) has conducted most testing for Legionella species in the Canadian province of Ontario since 1978, and represents a multi-decade repository of population-based data on legionellosis epidemiology. We sought to provide a laboratory-based review of the epidemiology of legionellosis in Ontario over the past 3 decades, with a focus on changing rates of disease and species associated with legionellosis during that time period.

Going with the flow: legionellosis risk in Toronto, Canada is strongly associated with local watershed hydrology.

Legionella species are increasingly recognized as a cause of both healthcare- and community-acquired pneumonia (so-called "Legionnaire's disease"). These pathogens are ubiquitous in the environment, but environmental factors in the occurrence of sporadic legionellosis remain poorly understood. We analyzed all legionellosis cases identified in the Greater Toronto Area of Ontario from 1978 to 2006, and evaluated seasonal and environmental patterns in legionellosis case occurrence by using both negative binomial models and case-crossover analysis.

Rapid identification of herd effects with the introduction of serogroup C meningococcal conjugate vaccine in Ontario, Canada, 2000-2006.

In 2001, Canada's National Advisory Committee on Immunization endorsed a meningococcal serogroup C conjugate vaccine, which appears to provide durable serogroup-specific immunity while reducing nasopharyngeal carriage. With reference to direct and indirect effects on case occurrence, we sought to evaluate recent trends in the incidence of invasive meningococcal disease (IMD) in Ontario. Analyses included all IMD cases reported between 2000 and 2006 to the Ontario Central Public Health Laboratory.

Environmental exposures and invasive meningococcal disease: an evaluation of effects on varying time scales.

Invasive meningococcal disease (IMD) is an important cause of meningitis and bacteremia worldwide. Seasonal variation in IMD incidence has long been recognized, but mechanisms responsible for this phenomenon remain poorly understood. The authors sought to evaluate the effect of environmental factors on IMD risk in Philadelphia, Pennsylvania, a major urban center.

Direct interaction of a small-molecule modulator with G551D-CFTR, a cystic fibrosis-causing mutation associated with severe disease.

CF (cystic fibrosis) is caused by mutations in CFTR (CF transmembrane conductance regulator), which cause its mistrafficking and/or dysfunction as a regulated chloride channel on the apical surface of epithelia. CFTR is a member of the ABC (ATP-binding-cassette) superfamily of membrane proteins and a disease-causing missense mutation within the ABC signature sequence; G551D-CFTR exhibits defective phosphorylation and ATP-dependent channel gating. Studies of the purified and reconstituted G551D-CFTR protein revealed that faulty gating is associated with defective ATP binding and ATPase activity, reflecting the key role of G551 in these functions.

The Philadelphia High-School STD Screening Program: key insights from dynamic transmission modeling.

Background: The Philadelphia high-school STD Screening Program (PHSSP) represents an innovative approach to screening-based control of Chlamydia trachomatis infection. The program has been associated with significant reductions in Chlamydia trachomatis prevalence in young females in Philadelphia. We sought to assess program cost-effectiveness in a manner that allowed us to quantify the impact of including males students in the screened population.

Comparative analysis of metal binding characteristics of copper chaperone proteins, Atx1 and ATOX1.

The metal binding properties of the human copper chaperone ATOXI and its yeast homologue Atxl have been characterized. Complexes of these proteins with Cu(I), Ag (1), Cd(II) and Hg(II) were studied by native gel electrophoresis, chemical cross-linking followed by SDS-PAGE, as well as by size exclusion chromatography, mutagenesis and UV-visible absorption spectroscopy. Results indicate that binding of different metals to either ATOXI or Atxl altered conformation of subunit structure and the oligomerization state of the proteins.

Climate change and infectious diseases in North America: the road ahead.

Global climate change is inevitable--the combustion of fossil fuels has resulted in a buildup of greenhouse gases within the atmosphere, causing unprecedented changes to the earth's climate. The Fourth Assessment Report of the Intergovernmental Panel on Climate Change suggests that North America will experience marked changes in weather patterns in coming decades, including warmer temperatures and increased rainfall, summertime droughts and extreme weather events (e.g.

The intact CFTR protein mediates ATPase rather than adenylate kinase activity.

The two NBDs (nucleotide-binding domains) of ABC (ATP-binding-cassette) proteins function in a complex to mediate ATPase activity and this activity has been linked to their regulated transport activity. A similar model has been proposed for CFTR (cystic fibrosis transmembrane conductance regulator), the chloride channel defective in cystic fibrosis, wherein ATP binding and hydrolysis regulate the channel gate. Recently, it was shown that the individual NBDs isolated from CFTR primarily mediate adenylate kinase activity, raising the possibility that this activity may also contribute to gating of the CFTR channel.

The challenges of quantitative measurement of lung deposition using 99mTc-DTPA from delivery systems with very different delivery times.

In quantifying aerosol delivery, the drug is often mixed with a radiolabel such as (99m)Tc-DTPA whose deposition is used as a proxy for the drug. (99m)Tc-DTPA deposited in the lung is cleared by a combination of absorption into the pulmonary circulation and mucociliary clearance. If administration is not instantaneous, the image will not include that clearance during administration, a problem raised if comparing devices with different administration times.

Characterization and copper binding properties of human COMMD1 (MURR1).

COMMD1 (copper metabolism gene MURR1 (mouse U2af1-rs1 region1) domain) belongs to a family of multifunctional proteins that inhibit nuclear factor NF-kappaB. COMMD1 was implicated as a regulator of copper metabolism by the discovery that a deletion of exon 2 of COMMD1 causes copper toxicosis in Bedlington terriers. Here, we report the detailed characterization and specific copper binding properties of purified recombinant human COMMD1 as well as that of the exon 2 product, COMMD(61-154).

Seasonality of infectious diseases.

Seasonality, a periodic surge in disease incidence corresponding to seasons or other calendar periods, characterizes many infectious diseases of public health importance. The recognition of seasonal patterns in infectious disease occurrence dates back at least as far as the Hippocratic era, but mechanisms underlying seasonality of person-to-person transmitted diseases are not well understood. Improved understanding will enhance understanding of host-pathogen interactions and will improve the accuracy of public health surveillance and forecasting systems.

Short-term daily or weekly administration of micronutrient Sprinkles has high compliance and does not cause iron overload in Chinese schoolchildren: a cluster-randomised trial.

Objectives: To examine consumption rates and serum ferritin (SF) concentrations (as a marker of safety) among schoolchildren (3-6 years) provided with daily and weekly micronutrients.

Design And Methods: Micronutrients were provided for one school term (13 weeks) to a kindergarten in northern China as single-dose Sprinkles sachets containing 30 mg of iron as encapsulated ferrous fumarate, 5 mg zinc gluconate, 50 mg vitamin C, 300 microg vitamin A, 7.5 microg vitamin D3 and 150 microg folic acid.

Evaluation of the membrane-spanning domain of ClC-2.

The ClC family of chloride channels and transporters includes several members in which mutations have been associated with human disease. An understanding of the structure-function relationships of these proteins is essential for defining the molecular mechanisms underlying pathogenesis. To date, the X-ray crystal structures of prokaryotic ClC transporter proteins have been used to model the membrane domains of eukaryotic ClC channel-forming proteins.

Time perception: modality and duration effects in attention-deficit/hyperactivity disorder (ADHD).

Time perception performance was systematically investigated in adolescents with and without attention-deficit/hyperactivity disorder (ADHD). Specifically, the effects of manipulating modality (auditory and visual) and length of duration (200 and 1000 ms) were examined. Forty-six adolescents with ADHD and 44 controls were administered four duration discrimination tasks and two control tasks, and a set of standardized measures.

A method for proteomic identification of membrane-bound proteins containing Asn-linked oligosaccharides.

Glycosylated proteins on the cell surface have been shown to be essential for cell-cell interactions in development and differentiation. Our ultimate goal is to identify Asn-linked oligosaccharides that are directly involved in these critical in vivo functions. Because such oligosaccharides would be expected to reside on the integral plasma membrane proteins, and conventional two-dimensional gel techniques are ineffective at separating such proteins, we have developed a new approach to their identification on a proteomics scale from Caenorhabditis elegans.

Expression of epithelial sodium channel alpha-subunit mRNAs with alternative 5'-untranslated regions in the developing human lung.

In preparation for birth, lung epithelia must switch from net fluid secretion, required for lung development, to net absorption, which prepares the lungs for postnatal gas exchange. The apical membrane amiloride-sensitive epithelial Na channel (ENaC) is the rate-limiting step for Na+ and fluid absorption. Expression of alpha-ENaC mRNA has been detected in human lung as early as the embryonic stage of development.

Differential translational efficiency of ENaC subunits during lung development.

The amiloride-sensitive epithelial Na(+) channel (ENaC), the rate-limiting step in epithelial Na(+) transport, consists of three subunits: alpha, beta, and gamma. The abundance of mRNA encoding the alpha-subunit far surpasses the amount for other subunits, and considerably exceeds the predicted subunit protein stoichiometry. We evaluated 5'-untranslated region (UTR) expression and found that fetal rat lung uses alternative 5'UTRs for alpha-ENaC during development.

Protein disulfide isomerase, a multifunctional protein chaperone, shows copper-binding activity.

Protein disulfide isomerase (PDI) is a 55 kDa multifunctional protein of the endoplasmic reticulum (ER) involved in protein folding and isomerization. In addition to the chaperone and catalytic functions, PDI is a major calcium-binding protein of the ER. Although the active site of PDI has a similar motif CXXC to the Cu-binding motif in Wilson and Menkes proteins and in other copper chaperones, there has been no report on any metal-binding capability of PDI other than calcium binding.

Time perception deficits in attention-deficit/ hyperactivity disorder and comorbid reading difficulties in child and adolescent samples.

Background: Our objective was to investigate time perception in Attention-Deficit/Hyperactivity Disorder (ADHD) with and without comorbid reading difficulties (RD) in child and adolescent participants.

Method: In study 1, 50 children with ADHD (31 ADHD, 19 ADHD+RD) and age-matched healthy controls (n = 50) completed three psychophysical tasks: duration discrimination (target duration of 400 ms versus a foil duration), frequency discrimination (a control condition to evaluate general perceptual ability), and a duration estimation task using the method of reproduction for intervals of 400 ms, 2000 ms, and 6000 ms. Study 2 used the same tasks with an adolescent sample (35 ADHD, 24 ADHD+RD, 39 controls).

Control of synaptic strength, a novel function of Akt.

Akt (also known as PKB), a serine/threonine kinase involved in diverse signal-transduction pathways, is highly expressed in the brain. Akt is known to have a strong antiapoptotic action and thereby to be critically involved in neuronal survival, but its potential role in the dynamic modulation of synaptic transmission is unknown. Here we report that Akt phosphorylates, both in vitro and in vivo, the type A gamma-aminobutyric acid receptor (GABA(A)R), the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain.