Cellular models for the detection and evaluation of drugs that modulate human phagocyte activity

Summary Simple testing models have been developed for the evaluation of chemical or biological compounds that modulate the activity of human phagocytes. Human neutrophils from buffy coats of donor blood are used. They are stimulated with receptor agonists, and the effects of test compounds on exocytosis of different enzymes, the generation of superoxide (respiratory burst), and cytotoxicity are quantified. All assays are performed in microtiter plates and the responses are evaluated by multi-well photometry or fluorimetry. The models are apt to detect compounds acting on phagocytes as agonists or antagonists, signal transduction activators or inhibitors and primers of agonist responses, and to assess cytotoxic effects.     

Mouse models for human intestinal microbiota research: a critical evaluation

Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between intestinal microbiota in mice and humans need to be considered. This is done here with specific attention for the comparative physiology of the intestinal tract, the effect of dietary patterns and differences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the human and murine intestine, these differ strongly in abundance and in total only 4% of the bacterial genes are found to share considerable identity. Moreover, a large variety of murine strains is available yet most of the microbiota research is performed in wild-type, inbred strains and their transgenic derivatives. It has become increasingly clear that the providers, rearing facilities and the genetic background of these mice have a significant impact on the microbial composition and this is illustrated with recent experimental data. This may affect the reproducibility of mouse microbiota studies and their conclusions. Hence, future studies should take these into account to truly show the effect of diet, genotype or environmental factors on the microbial composition.     

Cellular and molecular aspects of drugs of the future: oxaliplatin

Oxaliplatin (Eloxatine) is a third-generation platinum compound which has shown a wide antitumour effect both in vitro and in vivo, a better safety profile than cisplatin and a lack of cross-resistance with cisplatin and carboplatin. In this scenario, oxaliplatin may represent an innovative and challenging drug extending the antitumour activity in diseases such as gastrointestinal cancer that are not usually sensitive to these coordination complexes. Oxaliplatin has a non-hydrolysable diaminocyclohexane (DACH) carrier ligand which is maintained in the final cytotoxic metabolites of the drug. Like cisplatin, oxaliplatin targets DNA producing mainly 1,2-GG intrastrand cross-links. The cellular and molecular aspects of the mechanism of action of oxaliplatin have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of the DACH-platinum adducts appear to contribute to the lack of cross-resistance with cisplatin. To date, mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these agents. Received 15 March 2002; received after revision 13 May 2002; accepted 21 May 2002 RID="*" ID="*"Corresponding author.     

Cellular and molecular aspects of drugs of the future: meropenem

Meropenem, first synthesized in the late eighties, has become one of the most important beta-lactam antibiotics of the carbapenem subclass used for the treatment of a variety of life-threatening infections. Due to its unique chemical structure, meropenem is not inactivated by the kidney dehydropeptidase I and the majority of microbial beta-lactamases. Its antimicrobial activity is based on its high affinity for the majority of cell wall-synthesizing enzymes, the so-called penicillin-binding proteins, of Gram-positive and -negative bacteria. However, bacteria have evolved several approaches to resist meropenem: (i) by reducing the affinity of the penicillin-binding proteins for the antibiotics, (ii) by decreasing the permeability of the outer membrane of Gram-negative bacteria, (iii) by using efflux pumps, and (iv) by activating zinc-dependent carbapenemases. Meropenem has a low toxicity profile and, in contrast to imipenem, no central nervous system toxicity.     

Criteria for the evaluation of the antirheumatic (antiinflammatory drugs in man]

Comparison of 5 antiinflammatory drugs and placebo in a double blind, short term, cross-over trial conducted in patients suffering from rheumatoid arthritis. 15 measurements were used and studied. With classical unidimensional statistical tests it was not possible to discriminate active drugs between them. Multidimensional analysis (correspondance analysis and discriminant analysis) are more sensitive and allow us to distinguish active drugs with only 11 criterion.     

An approach for the in vitro screening of drugs for activity against leprosy

Summary Slow growing strains of mycobacteria isolated from leprous tissues present a characteristic resistance pattern to antibacterial agents that is comparable to drug sensitivity ofM. leprae in man.The Hansen Chair of Research is a foundation of Le Secours aux Lépreux (Canada) Inc..     

Cellular membrane activity in the corneal endothelium of the intact eye

Zusammenfassung Die direkte Beobachtung des Hornhautendothels wird mit einem speziellen Mikroskop möglich. Formveränderungen der Zellen, besonders ihrer Oberflächenmembranen, lassen sich zeigen.     

Comparison of X-prolyl dipeptidyl-aminopeptidase activity in human cerebrospinal fluid with that in serum

Summary X-Prolyl dipeptidyl-aminopeptidase activities in cerebrospinal fluid and serum from the same patients without neurological diseases, undergoing surgery under lumbar anesthesia, were assayed fluorometrically with a newly synthesized fluorogenic substrate, 7-glycylproline-4-methylcoumarinamide; the values were 129.1±19.5 nmoles/min/1 and 54.17±3.11 moles/min/1 (mean±SEM, n=23), respectively, and there was no correlation between both activities (r=0.0894).     

Comparison of X-prolyl dipeptidyl-aminopeptidase activity in human cerebrospinal fluid with that in serum.

X-Prolyl dipeptidyl-aminopeptidase activities in cerebrospinal fluid and serum from the same patients without neurological diseases, undergoing surgery under lumbar anesthesia, were assayed fluorometrically with a newly synthesized fluorogenic substrate, 7-glycylproline-4-methylcoumarinamide; the values were 129.1 +/- 19.5 nmoles/min/l and 54.17 +/- 3.11 mumoles/min/l (mean +/- SEM, n = 23), respectively, and there was no correlation between both activities (r = 0.0894).     

The role of time series analysis in the evaluation of econometric models

This paper compares the properties of a structural model—the London Business School model of the U.K. economy—with a time series model. Information provided by this type of comparison is a useful diagnostic tool for detecting types of model misspecification. This is a more meaningful way of proceeding rather than attempting to establish the superiority of one type of model over another. In lieu of a better structural model, the effects of inappropriate dynamic specification can be reduced by combining the forecasts of both the structural and time series models. For many variables considered here these provide more accurate forecasts than each of the model types alone.     

Molecular models of the open and closed states of the whole human CFTR protein

Cystic fibrosis transmembrane conductance regulator (CFTR), involved in cystic fibrosis (CF), is a chloride channel belonging to the ATP-binding cassette (ABC) superfamily. Using the experimental structure of Sav1866 as template, we previously modeled the human CFTR structure, including membrane-spanning domains (MSD) and nucleotide-binding domains (NBD), in an outward-facing conformation (open channel state). Here, we constructed a model of the CFTR inward-facing conformation (closed channel) on the basis of the recent corrected structures of MsbA and compared the structural features of those two states of the channel. Interestingly, the MSD:NBD coupling interfaces including F508 (ΔF508 being the most common CF mutation) are mainly left unchanged. This prediction, completed by the modeling of the regulatory R domain, is supported by experimental data and provides a molecular basis for a better understanding of the functioning of CFTR, especially of the structural features that make CFTR the unique channel among the ABC transporters.     

Cellular distribution of catalase activity in red cells of homozygous and heterozygous cases of acatalasia

Zusammenfassung Es wird ein Verfahren beschrieben, welches im Blutausstrich katalasehaltige und katalasefreie Erythrocyten zu unterscheiden erlaubt. Dieses beruht auf der sehr ungleichen Methämoglobinbildung bei Inkubierung der Zellen mit Glucose und Glucoseoxidase. Es wird nachgewiesen, dass im Blut homozygoter Defektträger 0,5-1% aller Erythrocyten einen anscheinend normalen Katalasegehalt aufweisen. Im Blut heterozygoter Defektträger konnten keine Anhaltspunkte für das Bestehen zweier Zellpopulationen von verschiedener Katalaseaktivität gefunden werden.     

Performance evaluation of the New Connecticut Leading Employment Index using lead profiles and BVAR models

The leading and coincident employment indexes for the state of Connecticut developed following the recession of the early 1990s fell short of expectations. This paper performs two tasks. First, it describes the process of revising the Connecticut Coincident and Leading Employment Indexes. Second, it analyzes the statistical properties and performance of the new indexes by comparing the lead profiles of the new and old indexes as well as their out‐of‐sample forecasting performance, using the Bayesian Vector Autoregressive (BVAR) method. The new coincident index shows improved performance in dating employment cycle chronologies. The lead profile test demonstrates that superiority in a rigorous, non‐parametric statistic fashion. The mixed evidence on the BVAR forecasting experiments illustrates that leading indexes properly predict cycle turning points and do not necessarily provide accurate forecasts except at turning points, a view that our results support. Copyright © 2006 John Wiley & Sons, Ltd.     

Cumulative record of motor activity. (A new procedure and its use for the study of central stimulant drugs)

Zusammenfassung Eine Methode zur kumulativen Registrierung spontaner motorischer Aktivität kleiner Tiere wird beschrieben. Die Wirksamkeitsbestimmung aus dem kumulativen Rekord und die analytische Bedeutung der Methode für die Wirkungsweise zentralstimulierender Substanzen wird diskutiert.     

Cell culture models and animal models for studying the patho-physiological role of renal aquaporins

Aquaporins (AQPs) are key players regulating urinary-concentrating ability. To date, eight aquaporins have been characterized and localized along the nephron, namely, AQP1 located in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2, AQP3 and AQP4 in collecting duct principal cells; AQP5 in intercalated cell type B; AQP6 in intercalated cells type A in the papilla; AQP7, AQP8 and AQP11 in the proximal tubule. AQP2, whose expression and cellular distribution is dependent on vasopressin stimulation, is involved in hereditary and acquired diseases affecting urine-concentrating mechanisms. Due to the lack of selective aquaporin inhibitors, the patho-physiological role of renal aquaporins has not yet been completely clarified, and despite extensive studies, several questions remain unanswered. Until the recent and large-scale development of genetic manipulation technology, which has led to the generation of transgenic mice models, our knowledge on renal aquaporin regulation was mainly based on in vitro studies with suitable renal cell models. Transgenic and knockout technology approaches are providing pivotal information on the role of aquaporins in health and disease. The main goal of this review is to update and summarize what we can learn from cell and animal models that will shed more light on our understanding of aquaporin-dependent renal water regulation.