A Research Protocol: Mixed-Mode Designs to Optimize Engagement in Clinical Informatics Research.

To introduce a research protocol that utilizes mixed-mode methodology (i.e., delayed concurrent and sequential approaches) to optimize response rates of two surveys being administered to U.S. nursing homes (NHs). This protocol is being employed in a cross-sectional survey to assess for HIT maturity and nurse practitioners (NP) care environments. Survey recruitment from 3,000 NHs will be conducted from June 2023 to July 2025. Respondents included NH administrators evaluating facility-wide HIT and NPs in each NH rating their care environment.

alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues.

BACKGROUND AND PURPOSE: The alpha7 nicotinic acetylcholine receptor (nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha7-selective agonist and characterizes analogues developed from this lead. EXPERIMENTAL APPROACH: Activity and selectivity were determined from rat brain alpha7 and alpha4beta2 nAChR binding, recombinant nAChR activation, and native alpha7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. KEY RESULTS: Tilorone bound alpha7 nAChR (IC(50) 110 nM) with high selectivity relative to alpha4beta2 (IC(50) 70 000 nM), activated human alpha7 nAChR with an EC(50) value of 2.5 microM and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha3beta4 or alpha4beta2 nAChRs. However, the rat alpha7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one (A-844606) with improved binding (alpha7 IC(50) 11 nM, alpha4beta2 IC(50)>30 000 nM) and activity at both human and rat alpha7 nAChR (EC(50)s 1.4 and 2.2 microM and apparent efficacies 61 and 63%, respectively). These compounds also activated native alpha7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. CONCLUSIONS AND IMPLICATIONS: Tilorone, known as an interferon inducer, is a selective alpha7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of alpha7 nAChR selective agonists. Whether alpha7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of alpha7 nAChR agonists remains to be elucidated.

[Human biomonitoring investigations of organochlorine compounds -- PCB, DDE, HCB, beta- and gamma-HCH, PCDD/PCDF, Dioxin-like PCB's and polybrominated biphenyl ethers]. / Humanbiomonitoring-Untersuchungen von Organohalogenverbindungen -- PCB, DDE; HCB, beta- und gamma-HCH, PCDD/PCDF, koplanaren PCB sowie polybromierten Biphenylethern.

Although PCB and PCB-containing materials are not processed for a long time, PCB is under discussion again and again caused by the pollution of indoor environments. To objectify the discussion, the dates of the PCB-biomonitoring, the organochlorine-compounds (DDE, HCB, beta-/gamma -HCH, PCDD/PCDF) and the polybrominated biphenyl ethers concerning the investigations within the project "Sentinel Health Departments" in Baden-Wurttemberg are represented. Additionally results from children from Kazakhstan (Aral-Sea area) and from teachers which are working in PCB polluted schools as well as from a long term investigated test person are reported. Blood concentrations of the following compounds decreased from 1996/97 to 2002/03: the sum of the concentration of PCB 138,153 and 180 decreased from 0.46 microg/L to 0.20 microg/L, DDE from 0.32 microg/L to 0.17 microg/, HCB from 0.20 microg/L to 0.08 microg/L, beta-HCH below the level of detection, I-TEQ NATO to 4.8 pg/g blood fat, TEQ WHO (without PCB) to 5.5 pg/g blood fat, PCB 126 to 18,8,pg/g blood fat and PCB 169 to 12.8 pg/g blood fat. The influence of breast feeding and the gender on the level of the pollution is conspicious. No local correlations were found in Baden-Wurttemberg, but they were found in comparison with the results of Kazakhstan (Aral-Sea area). The difficulty to produce time series while the analyzing pollutants are more and more decreasing, as well as the change of the calculation base of the summation of parameters like I-TEQ NATO to TEQ WHO are discussed.

[Determination of mold concentrations in homes and schools in Baden-Württemberg]. / Bestimmung der Schimmelpilzkonzentration in Wohnungen und Schulen Baden-Württembergs.

So far there have been rather few reliable and comparable data available on indoor pollution with mould. Following the publication of the Federal Environmental Agency and the Health Agency Baden-Württemberg which supports the assessment of mould pollution of indoor air, it seemed advisable to investigate as to how far these criteria can be used for the assessing the mould pollution in daily practice. The results of investigations of 130 homes and 117 classrooms in Baden-Württemberg. will be represented.

[Exposition and sensitisation to indoor allergens, house dust mite allergen and cat allergens]. / Exposition und Sensibilisierung gegenüber Milben- und Katzenallergenen bei Kindern in Baden-Württemberg.

The study examined the exposure to biological indoor air agents and their possible role for allergies and respiratory tract illnesses of children. It was conducted as a case control study (atopic vs non-atopic children) at the four surveillance public health departments in Baden-Württemberg in the winter season 1999/2000 and included 379 children of the fourth class. The concentrations of the house dust mite antigens Der F1, Der p1, and Der Gr2 as well as cat allergen Fel d1 were determined in the children's bedrooms on the ground and in the mattress. Specific IgE-antibodies against allergens from house dust, mites and cat were determined in the serum of the children. For mite allergens the following medians ( micro g/g) were estimated in floor dust: Der p1 = 0.6, Der f1 = 2.3, Gr2 = 0.1; in mattresses: Der p1 = 1.2, Der f1 = 3.4, Gr2 = 0.3. The median of Fel d1 in floor dust was 0.2 microg/g, in mattresses 0.1 microg/g. Sensitisation to dust mite allergen was found to be more prevalent than sensitisation to cat. The distribution of sensitisation among the cases and controls is different. Among the cases, more subjects were sensitised to dust mites (32.9 %) and cat (13.1 %). Among the controls, 17.1 % were sensitised to dust mites and 4.1 % to cat. The results showed no direct association between the prevalence of allergies or respiratory tract illnesses and the indoor concentrations of the allergens. Possible reasons for these findings are discussed.

[10 years of observation by public health offices in Baden-Württemberg--assessment of human biomonitoring for mercury due to dental amalgam fillings and other sources]. / 10 Jahre Beobachtungsgesundheitsämter in Baden-Württemberg--Beurteilung der Human-Biomonitoring-Untersuchungen bezüglich der Quecksilber-Belastung durch Amalgamfüllungen und andere Quellen.

Since 1992, in Baden-Württemberg, ten-year old children have been surveyed in the project "Sentinel Health Departments" to study their exposure to environmental pollutants and possible health effects. In the four study areas 1200 children have been investigated every year initially, since 1996 every second year. The data for mercury in body fluids are reported here. The decrease in the body burden of mercury as a result of the declining usage of dental amalgam fillings, was been verified. In 1992/93, of all the children who had been surveyed, the 95 percentile for the body burden of mercury was 3.1 microg/l and in 2000/01 1.35 microg/l. Also to be discussed is the reason why mercury-based cosmetic ointments seriously exceed the HBM-II-intervention-value. Because of using these ointments, concentrations of mercury in urine up to 1400 microg/l were found. A study within the project "Sentinel Health Departments" compared the concentrations of mercury in the urine of adults with those in blood and salvia. The results support the opinion that mercury in urine is appropriate for estimating the mercury uptake from dental amalgam fillings. It can be assumed that these results reflect the situation in the entire Federal Republic of Germany. The ten years' experience confirms that the concept of the "Sentinel Health Departments" is excellently suited to obtain data relevant for environmental health of children. Environmental health protection and the essential gathering of data for future health observation in Baden-Württemberg.

Structural aspects of high affinity ligands for the alpha 4 beta 2 neuronal nicotinic receptor.

Neuronal nicotinic acetylcholine receptors (nAChRs) are a heterogeneous family of related ion channels that are widely distributed throughout the central and peripheral nervous systems. They all share a common architecture of five subunit proteins that combine at the cell surface to create a ligand-gated cation permeable pore. Significant effort is currently being expended by medicinal chemistry teams to synthesize ligands that exhibit selectivity for central over peripheral nAChR subtypes. Within the CNS, multiple nAChR subtypes are recognized, and the discovery of ligands exhibiting selectivity among these subtypes offers an opportunity for the development of novel therapeutic agents. The alpha 4 beta 2 subtype is one of the most abundant nAChR subtypes within the CNS, and has been the primary focus of high affinity ligand design. Nicotine (1), and more recently, epibatidine (2) have served as structural templates for the design of the majority of active compounds. Although the diversity of nAChR ligands is growing, the structural requirements necessary for high affinity binding with the alpha 4 beta 2 receptor remain poorly understood. The putative pharmacophoric elements common to all potent alpha 4 beta 2 ligands include (1) a basic or quaternized nitrogen atom, and (2) a less basic nitrogen or a carbonyl oxygen that presumably interact with electron rich and electron deficient sites on the receptor, respectively. The family of currently known high affinity analogs consists of a diverse array of azacycles containing a basic amine. Several additional basic amine fragments have been identified, including the pyrrolizidine nucleus (exemplified by 8) and the 2-azabicyclo[2.2.1]heptane skeleton (exemplified by 9). In addition, we have found that the furo[2,3-b]pyridine heterocycle (compound 10) serves as useful bioisosteric replacement for the pyridyl substituent of nicotine. A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the alpha 4 beta 2 nAChR reported herein may be accommodated.

Metabolism and distribution of [2,3-14C]acrolein in Sprague-Dawley rats. II. Identification of urinary and fecal metabolites.

The metabolites of [2,3-14C]acrolein in the urine and feces of Sprague-Dawley rats were identified after either intravenous administration in saline at 2.5 mg/kg or oral administration by gavage as an aqueous solution as either single or multiple doses at 2.5 mg/kg or as a single dose of 15 mg/kg. Selected urine and feces samples were pooled by sex and collection interval and profiled by combinations of reverse-phase, anion-exchange, cation-exchange, and ion-exclusion high-performance liquid chromatography (HPLC). Feces were also profiled by size-exclusion chromatography. Metabolites were identified by comparison with well-characterized standards by HPLC and by mass spectrometry. The urinary metabolites were identified as oxalic acid, malonic acid, N-acetyl-S-2-carboxy-2-hydroxyethylcysteine, N-acetyl-S-3-hydroxypropylcysteine, N-acetyl-S-2-carboxyethylcysteine, and 3-hydroxypropionic acid. The fecal radioactivity from the oral dose groups was partitioned into methanol-soluble, water-soluble, and insoluble radioactivity, some of which could be liberated by dilute acid hydrolysis. HPLC analysis of these extracts revealed no discrete metabolites. Size-exclusion chromatography indicated a molecular weight range of 2,000 to 20,000 Da for the radioactivity, which was unaffected by hydrolysis at reflux with 6 M acid or base. This radio-activity was thought to be a homopolymer of acrolein, which was apparently formed in the gastrointestinal tract. The pathways of acrolein metabolism were epoxidation followed by conjugation with glutathione, Michael addition of water followed by oxidative degradation, and glutathione addition to the double bond either following or preceding oxidation or reduction of the aldehyde. The glutathione adducts were further metabolized to the mercapturic acids.