bluuebunny/crossref_metadata_2025 huggingface dataset:
Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4
Authors: Ihanus Eveliina , Uotila Liisa M. , Toivanen Anne , Varis Minna , Gahmberg Carl G.
Published: September 2006

Intercellular adhesion molecule 4 (ICAM-4) is a unique member of the ICAM family because of its specific expression on erythroid cells and ability to interact with several types of integrins expressed on blood and endothelial cells. The first reported receptors for ICAM-4 were CD11a/CD18 and CD11b/CD18. In contrast to these 2, the cellular ligands and the functional role of the third β2 integrin, CD11c/CD18, have not been well defined. Here, we show that ICAM-4 functions as a ligand for the monocyte/macrophage-specific CD11c/CD18. Deletion of the individual immunoglobulin domains of ICAM-4 demonstrated that both its domains contain binding sites for CD11c/CD18. Analysis of a panel of ICAM-4 point mutants identified residues that affected binding to the integrin. By molecular modeling the important residues were predicted to cluster in 2 distinct but spatially close regions of the first domain with an extension to the second domain spatially distant from the other residues. We also identified 2 peptides derived from sequences of ICAM-4 that are capable of modulating the binding to CD11c/CD18. CD11c/CD18 is expressed on macrophages in spleen and bone marrow. Inhibition of erythrophagocytosis by anti–ICAM-4 and anti-integrin antibodies suggests a role for these interactions in removal of senescent red cells.
Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)
Authors: Goodeve Anne , Eikenboom Jeroen , Castaman Giancarlo , Rodeghiero Francesco , Federici Augusto B. , Batlle Javier , Meyer Dominique , Mazurier Claudine , Goudemand Jenny , Schneppenheim Reinhard , Budde Ulrich , Ingerslev Jorgen , Habart David , Vorlova Zdena , Holmberg Lars , Lethagen Stefan , Pasi John , Hill Frank , Soteh Mohammad Hashemi , Baronciani Luciano , Hallden Christer , Guilliatt Andrea , Lester Will , Peake Ian
Published: September 2006

Type 1 von Willebrand disease (VWD) is characterized by a personal and family history of bleeding coincident with reduced levels of normal plasma von Willebrand factor (VWF). The molecular basis of the disorder is poorly understood. The aims of this study were to determine phenotype and genotype and their relationship in patients historically diagnosed with type 1 VWD. Families were recruited in 9 European countries based on previous type 1 VWD diagnosis. Bleeding symptoms were recorded, plasma phenotype analyzed, and VWF mutation analysis performed in all index cases (ICs). Phenotypic and molecular analysis stratified patients into those with or without phenotypes suggestive of qualitative VWF defects (abnormal multimers) and with or without mutations. A total of 105 of 150 ICs (70%) had mutations identified. A subgroup with abnormal multimers (38% of ICs, 57 of 150) showed a high prevalence of VWF gene mutations (95% of ICs, 54 of 57), whereas in those with qualitatively normal VWF, fewer mutations were identified (55% of ICs, 51 of 93). About one third of the type 1 VWD cases recruited could be reconsidered as type 2. The remaining group could be considered “true” type 1 VWD, although mutations were found in only 55%.
Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis
Authors: Amé-Thomas Patricia , Maby-El Hajjami Hélène , Monvoisin Céline , Jean Rachel , Monnier Delphine , Caulet-Maugendre Sylvie , Guillaudeux Thierry , Lamy Thierry , Fest Thierry , Tarte Karin
Published: September 2006

Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow–derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-α and lymphotoxin-α1β2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.
End expiratory oxygen concentrations to predict central venous oxygen saturation: an observational pilot study
Authors: Jones Alan E , Kuehne Karl , Steuerwald Michael , Kline Jeffrey A
Published: September 2006

Background

A non-invasive surrogate measurement for central venous oxygen saturation (ScVO2) would be useful in the ED for assessing therapeutic interventions in critically ill patients. We hypothesized that either linear or nonlinear mathematical manipulation of the partial pressure of oxygen in breath at end expiration (EtO2) would accurately predict ScVO2.

Methods

Prospective observational study of a convenience sample of hemodialysis patients age > 17 years with existing upper extremity central venous catheters were enrolled. Using a portable respiratory device, we collected both tidal breathing and end expiratory oxygen and carbon dioxide concentrations, volume and flow on each patient. Simultaneous ScVO2 measurements were obtained via blood samples collected from the hemodialysis catheter. Two models were used to predict ScVO2: 1) Best-fit multivariate linear regression equation incorporating all respiratory variables; 2) MathCAD to model the decay curve of EtO2 versus expiratory volume using the least squares method to estimate the pO2 that would occur at <20% of total lung capacity.

Results

From 21 patients, the correlation between EtO2 and measured ScVO2 yielded R2 = 0.11. The best fit multivariate equation included EtCO2 and EtO2 and when solved for ScVO2, the equation yielded a mean absolute difference from the measured ScVO2 of 8 ± 6% (range -18 to +17%). The predicted ScVO2 value was within 10% of the actual value for 57% of the patients. Modeling of the EtO2 curve did not accurately predict ScVO2 at any lung volume.

Conclusion

We found no significant correlation between EtO2 and ScVO2. A linear equation incorporating EtCO2 and EtO2 had at best modest predictive accuracy for ScVO2.
RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts
Authors: Iovino Flora , Lentini Laura , Amato Angela , Di Leonardo Aldo
Published: September 2006

Background

Incorrect segregation of whole chromosomes or parts of chromosome leads to aneuploidy commonly observed in cancer. The correct centrosome duplication, assuring assembly of a bipolar mitotic spindle, is essential for chromosome segregation fidelity and preventing aneuploidy. Alteration of p53 and pRb functions by expression of HPV16-E6 and E7 oncoproteins has been associated with centrosome amplification. However, these last findings could be the result of targeting cellular proteins in addition to pRb by HPV16-E7 oncoprotein. To get a more detailed picture on the role of pRb in chromosomal instability and centrosome amplification, we analyzed the effects of the acute loss of retinoblastoma gene function in primary conditionalRbdeficient mouse embryonic fibroblasts (MEFs). Moreover, since pRb is a transcriptional repressor, microarray analysis was done on pRb-competent and pRb-deficient MEFs to evaluate changes in expression of genes for centrosome homeostasis and for correct mitosis.

Results

Acute loss of pRb induces centrosome amplification and aneuploidy in the vast majority of cells analyzed. A time course analysis shows a decrease of cells with amplified centrosomes after 40 days from the adenoviral infection. At this time only 12% of cells still show amplified centrosomes. Interestingly, cells with pRb constitutive loss show a similar percentage of cells with amplified centrosomes. DNA-Chip analyses in MEFs wt (mock infected) and pRb depleted (Ad-Cre infected) cells reveal differential expression of genes controlling both centrosome duplication and mitotic progression.

Conclusion

Our findings suggest a direct link between pRb status, centrosome amplification and chromosomal instability, and define specific mitotic genes as targets whose gene expression has to be altered to achieve or maintain aneuploidy.
Collision tumor of the thyroid: follicular variant of papillary carcinoma and squamous carcinoma
Authors: Walvekar Rohan R , Kane Subhadra V , D'Cruz Anil K
Published: September 2006

Background

Collision tumors of the thyroid gland are a rare entity. We present a case of a follicular variant of papillary carcinoma and squamous carcinoma in the thyroid. To the best of our knowledge, this is the first documentation of a collision tumor with a papillary carcinoma and a squamous carcinoma within the thyroid gland. The clinicopathological features and immunohistochemical profile are reported. The theories of origin, epidemiology and management are discussed with a literature review.

Case presentation

A 65 year old woman presented with a large thyroid swelling of 10 years duration and with swellings on the back and scalp which were diagnosed to be a follicular variant of papillary thyroid carcinoma with metastasis. Clinical examination, radiology and endoscopy ruled out any other abnormality of the upper aerodigestive tract. The patient was treated surgically with a total thyroidectomy with central compartment clearance and bilateral selective neck dissections. The histopathology revealed a collision tumor with components of both a follicular variant of papillary carcinoma and a squamous carcinoma. Immunohistochemical analysis confirmed the independent origin of these two primary tumors. Adjuvant radio iodine therapy directed toward the follicular derived component of the thyroid tumor and external beam radiotherapy for the squamous component was planned.

Conclusion

Collision tumors of the thyroid gland pose a diagnostic as well as therapeutic challenge. Metastasis from distant organs and contiguous primary tumors should be excluded. The origins of squamous cancer in the thyroid gland must be established to support the true evolution of a collision tumor and to plan treatment. Treatment for collision tumors depends upon the combination of primary tumors involved and each component of the combination should be treated like an independent primary. The reporting of similar cases with longer follow-up will help define the epidemiology, biology and establish standardized protocols for treatment of these extremely rare tumors.
Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study
Authors: van Halm Vokko P , Nurmohamed Michael T , Twisk Jos WR , Dijkmans Ben AC , Voskuyl Alexandre E
Published: September 2006

Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
Expression and Localization of δ-, κ-, and μ-Opioid Receptors in Human Spermatozoa and Implications for Sperm Motility
Authors: Agirregoitia Ekaitz , Valdivia Asier , Carracedo Arkaitz , Casis Luis , Gil Javier , Subiran Nerea , Ochoa Carmen , Irazusta Jon
Published: September 2006

Context: Endogenous opioid peptides signal through δ-, κ-, and μ-opioid receptors. Some of these peptides such as endorphins and enkephalins are present in the male reproductive tract, but the presence of the corresponding receptors in human sperm cells has not yet been reported.

Objective: Our objective was to study the expression and localization of δ-, κ-, and μ-opioid receptors on human spermatozoa and the implication in sperm motility.

Methods: The expression of receptors was studied by RT-PCR, Western blot, and immunofluorescence techniques. We evaluated the effects of activation of each opioid receptor by specific agonist and antagonist.

Results: Human spermatozoa express δ-, κ-, and μ-opioid receptors. These receptors were located in different parts of the head, in the middle region, and in the tail of the sperm. Progressive motility of spermatozoa, an important parameter to evaluate male fertility, was found to be significantly reduced after incubation with the μ-receptor agonist morphine, whereas this effect was antagonized in the presence of the corresponding antagonist naloxone. The δ-receptor antagonist naltrindole significantly reduced progressive motility immediately after its addition. However, the δ-receptor agonist DPDPE had no significant effect. Finally, neither the κ-receptor agonist U50488 nor its antagonist nor-binaltorphimine significantly affected the progressive motility of human spermatozoa.

Conclusion: We report for first time the presence of functional δ-, κ-, and μ-opioid receptors in human sperm membranes. These findings are indicative of a role for the opioid system in the regulation of sperm physiology.
β-Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation
Authors: Birkenfeld Andreas L. , Boschmann Michael , Moro Cedric , Adams Frauke , Heusser Karsten , Tank Jens , Diedrich André , Schroeder Christoph , Franke Gabi , Berlan Michel , Luft Friedrich C. , Lafontan Max , Jordan Jens
Published: September 2006

Context: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans.

Objective: The objective of the study was to determine the metabolic and cardiovascular interaction of β-adrenergic receptors and ANP.

Design: This was a crossover study, conducted 2004–2005.

Setting: The study was conducted at an academic clinical research center.

Patients: Patients included 10 healthy young male subjects (body mass index 24 ± 1 kg/m2).

Intervention: We infused iv incremental ANP doses (6.25, 12.5, and 25 ng/kg·min) with and without propranolol (0.20 mg/kg in divided doses followed by 0.033 mg/kg·h infusion). Metabolism was monitored through venous blood sampling, im, and sc microdialysis and indirect calorimetry. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings.

Main Outcome Measures: Venous nonesterified fatty acid, glycerol, glucose, and insulin; and microdialysate glucose, glycerol, lactate, and pyruvate were measured.

Results: ANP increased heart rate dose dependently. β-Adrenergic receptor blockade abolished the response. ANP elicited a dose-dependent increase in serum nonesterified fatty acid and glycerol concentrations. The response was not suppressed with propranolol. Venous glucose and insulin concentrations increased with ANP, both without or with propranolol. ANP induced lipid mobilization in sc adipose tissue. In skeletal muscle, microdialysate lactate increased, whereas the lactate to pyruvate ratio decreased, both with and without propranolol. Higher ANP doses increased lipid oxidation, whereas energy expenditure remained unchanged. Propranolol tended to attenuate the increase in lipid oxidation.

Conclusions: Selected cardiovascular ANP effects are at least partly mediated by β-adrenergic receptor stimulation. ANP-induced changes in lipid mobilization and glycolysis are mediated by another mechanism, presumably stimulation of natriuretic peptide receptors, whereas substrate oxidation might be modulated through adrenergic mechanisms.
Spontaneous Hypothyroidism in Adult Women Is Predicted by Small Body Size at Birth and during Childhood
Authors: Kajantie Eero , Phillips David I. W. , Osmond Clive , Barker David J. P. , Forsén Tom , Eriksson Johan G.
Published: September 2006

Background: The relationships of early growth with coronary heart disease and type 2 diabetes have received considerable attention. It is not known whether fetal or childhood growth is linked with autoimmune disorders.

Objective: Our objective was to assess whether the risk of adult-onset spontaneous hypothyroidism is predicted by body size at birth and during childhood.

Design and Setting: We conducted a birth cohort study in Helsinki, Finland.

Participants: A total of 293 women who were born between 1934 and 1944 and had their heights and weights recorded at birth and during childhood participated in the study.

Measurements: We measured spontaneous hypothyroidism, defined as: 1) a disease history confirmed from medical records, or 2) previously undiagnosed hypothyroidism (TSH > 10 mU/liter).

Results: Twenty women (6.8%) had spontaneous hypothyroidism; 18 had been diagnosed previously, between 43 and 65 yr of age, and two had undiagnosed subclinical hypothyroidism. In addition, 59 women were thyroid peroxidase antibody positive. Compared with the 214 thyroid peroxidase antibody-negative women with no thyroid disorder, those with spontaneous hypothyroidism had on average 252 g [95% confidence interval (CI), 61 to 443 g; P = 0.01] lower birth weight and 1.2 cm (95% CI, 0.5 to 2.0 cm; P = 0.002) shorter length at birth. The odds of developing hypothyroidism increased 4.4-fold per kilogram decrease in birth weight (95% CI, 1.4 to 14.1). Hypothyroid subjects had been shorter in early childhood and had lower body mass index during later childhood.

Conclusions: Small body size at birth and during childhood increases the risk of spontaneous hypothyroidism in adult women.
Impact of Type 2 Diabetes on Myocardial Insulin Sensitivity to Glucose Uptake and Perfusion in Patients with Coronary Artery Disease
Authors: Søndergaard Hanne M. , Bøttcher Morten , Marie Madsen Mette , Schmitz Ole , Hansen Søren B. , Nielsen Torsten T. , Bøtker Hans Erik
Published: September 2006

Background and Hypothesis: Myocardial insulin resistance (IR) is a feature of coronary artery disease (CAD) with reduced left ventricular ejection fraction (LVEF). Whether type 2 diabetes mellitus (T2DM) with CAD and preserved LVEF induces myocardial IR and whether insulin in these patients acts as a myocardial vasodilator is debated.

Methods: We studied 27 CAD patients (LVEF > 50%): 12 with T2DM (CAD+DM), 15 without T2DM (CAD-NoDM). Regional myocardial and skeletal glucose uptake, myocardial and skeletal muscle perfusion were measured with positron emission tomography. Myocardial muscle perfusion was measured at rest and during hyperemia in nonstenotic and stenotic regions with and without acute hyperinsulinemia.

Results: Myocardial glucose uptake was similar in CAD+DM and CAD-NoDM in both nonstenotic and stenotic regions [0.38 ± 0.08 and 0.36 ± 0.11 μmol/g·min; P value nonsignificant (NS)] and (0.35 ± 0.09 and 0.37 ± 0.13 μmol/g·min; P = NS). Skeletal glucose uptake was reduced in CAD+DM (0.05 ± 0.04 vs. 0.10 ± 0.05 μmol/g·min; P = 0.02), and likewise, whole-body glucose uptake was reduced in CAD+DM (4.0 ± 2.8 vs. 7.0 ± 2.4 mg/kg·min; P = 0.01). Insulin did not alter myocardial muscle perfusion at rest or during hyperemia. Insulin increased skeletal muscle perfusion in CAD-NoDM (0.11 ± 0.03 vs. 0.06 ± 0.03 ml/g·min; P = 0.02), but not in CAD+DM (0.08 ± 0.04 and 0.09 ± 0.05 ml/g·min; P = NS).

Conclusion: Myocardial IR to glucose uptake is not an inherent feature in T2DM patients with preserved LVEF. Acute physiological insulin exposure exerts no coronary vasodilation in CAD patients irrespective of T2DM.
A more comprehensive complementary theorem for the analysis of Poisson point processes
Authors: Cowan Richard
Published: September 2006

In this paper we discuss the complementary theorem applied to the typical n-tuple of a Poisson point process. The theorem was first presented by Miles in 1970 and discussed by Santaló in 1976 and, within a Palm measure framework, by Møller and Zuyev in 1996. The theorems put forward by these authors are not correct for all the examples that they present, suggesting that further consideration of their work is needed if one wishes to bring all those examples within the ambit of the complementary theorem. We give alternative analyses of the errant examples and, with a modification of the technicalities in the work of the above authors, move toward a more comprehensive complementary theorem. Some open issues still remain.
Dynamic load balancing with flexible workers
Authors: Ahn Hyun-Soo , Righter Rhonda
Published: September 2006

We study the problem of dynamically allocating flexible workers to stations in tandem or serial manufacturing systems. Workers are trained to do a subset of consecutive tasks. We show that the optimal policy is often LBFS (last buffer first-served) or FBFS (first buffer first-served). These results generalize earlier results on the optimality of the pick-and-run, expedite, and bucket brigade-type policies. We also show that, for exponential processing times and general manufacturing networks, the optimal policy will tend to have several workers assigned to the same station.
A note on long-term optimal portfolios under drawdown constraints
Authors: Sekine Jun
Published: September 2006

The maximization of the long-term growth rate of expected utility is considered under drawdown constraints. In a general situation, the value and the optimal strategy of the problem are related to those of another ‘standard’ risk-sensitive-type portfolio optimization problem. Furthermore, an upside-chance maximization problem of a large deviation probability is stated as a ‘dual’ optimization problem. As an example, a ‘linear-quadratic’ model is studied in detail: the conditions to ensure the solvabilities of the problems are discussed and explicit expressions for the solutions are presented.
An iterative method for multiple stopping: convergence and stability
Authors: Bender Christian , Schoenmakers John
Published: September 2006

We present a new iterative procedure for solving the multiple stopping problem in discrete time and discuss the stability of the algorithm. The algorithm produces monotonically increasing approximations of the Snell envelope which coincide with the Snell envelope after finitely many steps. Unlike backward dynamic programming, the algorithm allows us to calculate approximative solutions with only a few nestings of conditional expectations and is, therefore, tailor-made for a plain Monte Carlo implementation.
On the number of segregating sites for populations with large family sizes
Authors: Möhle M
Published: September 2006

We present recursions for the total number,Sn, of mutations in a sample ofnindividuals, when the underlying genealogical tree of the sample is modelled by a coalescent process with mutation rater>0. The coalescent is allowed to have simultaneous multiple collisions of ancestral lineages, which corresponds to the existence of large families in the underlying population model. For the subclass of Λ-coalescent processes allowing for multiple collisions, such that the measure Λ(dx)/xis finite, we prove thatSn/(nr) converges in distribution to a limiting variable,S, characterized via an exponential integral of a certain subordinator. When the measure Λ(dx)/x2is finite, the distribution ofScoincides with the stationary distribution of an autoregressive process of order 1 and is uniquely determined via a stochastic fixed-point equation of the formwith specific independent random coefficientsAandB. Examples are presented in which explicit representations for (the density of)Sare available. We conjecture thatSn/E(Sn)→1 in probability if the measure Λ(dx)/xis infinite.
On the exact asymptotics of the busy period in GI/G/1 queues
Authors: Palmowski Zbigniew , Rolski Tomasz
Published: September 2006

In this paper we study the busy period in GI/G/1 work-conserving queues. We give the exact asymptotics of the tail distribution of the busy period under the light tail assumptions. We also study the workload process in the M/G/1 system conditioned to stay positive.
Parallel matching for ranking all teams in a tournament
Authors: Kobayashi Kei , Kawasaki Hideki , Takemura Akimichi
Published: September 2006

We propose a simple and efficient scheme for ranking all teams in a tournament where matches can be played simultaneously. We show that the distribution of the number of rounds of the proposed scheme can be derived using lattice path counting techniques used in ballot problems. We also discuss our method from the viewpoint of parallel sorting algorithms.
Large deviations-based upper bounds on the expected relative length of longest common subsequences
Authors: Hauser Raphael , Martínez Servet , Matzinger Heinrich
Published: September 2006

Consider the random variable Ln defined as the length of a longest common subsequence of two random strings of length n and whose random characters are independent and identically distributed over a finite alphabet. Chvátal and Sankoff showed that the limit γ=limn→∞E[Ln]/n is well defined. The exact value of this constant is not known, but various methods for the computation of upper and lower bounds have been discussed in the literature. Even so, high-precision bounds are hard to come by. In this paper we discuss how large deviation theory can be used to derive a consistent sequence of upper bounds, (qm)m∈ℕ, on γ, and how Monte Carlo simulation can be used in theory to compute estimates, q̂m, of the qm such that, for given Ξ > 0 and Λ ∈ (0,1), we have P[γ < q̂ < γ + Ξ] ≥ Λ. In other words, with high probability the result is an upper bound that approximates γ to high precision. We establish O((1 − Λ)−1Ξ−(4+ε)) as a theoretical upper bound on the complexity of computing q̂m to the given level of accuracy and confidence. Finally, we discuss a practical heuristic based on our theoretical approach and discuss its empirical behavior.
In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion
Authors: Chimienti Fabrice , Devergnas Séverine , Pattou François , Schuit Frans , Garcia-Cuenca Rachel , Vandewalle Brigitte , Kerr-Conte Julie , Van Lommel Leentje , Grunwald Didier , Favier Alain , Seve Michel
Published: September 2006

Insulin-secreting pancreatic beta cells are exceptionally rich in zinc. In these cells, zinc is required for zinc-insulin crystallization within secretory vesicles. Secreted zinc has also been proposed to be a paracrine and autocrine modulator of glucagon and insulin secretion in pancreatic alpha and beta cells, respectively. However, little is known about the molecular mechanisms underlying zinc accumulation in insulin-containing vesicles. We previously identified a pancreas-specific zinc transporter, ZnT-8, which colocalized with insulin in cultured beta cells. In this paper we studied its localization in human pancreatic islet cells, and its effect on cellular zinc content and insulin secretion. In human pancreatic islet cells, ZnT-8 was exclusively expressed in insulin-producing beta cells, and colocalized with insulin in these cells. ZnT-8 overexpression stimulated zinc accumulation and increased total intracellular zinc in insulin-secreting INS-1E cells. Furthermore, ZnT-8-overexpressing cells display enhanced glucose-stimulated insulin secretion compared with control cells, only for a high glucose challenge, i.e. >10 mM glucose. Altogether, these data strongly suggest that the zinc transporter ZnT-8 is a key protein for both zinc accumulation and regulation of insulin secretion in pancreatic beta cells.
Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage
Authors: Triolo Daniela , Dina Giorgia , Lorenzetti Isabella , Malaguti MariaChiara , Morana Paolo , Del Carro Ubaldo , Comi Giancarlo , Messing Albee , Quattrini Angelo , Previtali Stefano C.
Published: September 2006

Axonal loss causes disabling and permanent deficits in many peripheral neuropathies, and may result from inefficient nerve regeneration due to a defective relationship between Schwann cells, axons and the extracellular matrix. These interactions are mediated by surface receptors and transduced by cytoskeletal molecules. We investigated whether peripheral nerve regeneration is perturbed in mice that lack glial fibrillary acidic protein (GFAP), a Schwann-cell-specific cytoskeleton constituent upregulated after damage. Peripheral nerves develop and function normally in GFAP-null mice. However, axonal regeneration after damage was delayed. Mutant Schwann cells maintained the ability to dedifferentiate but showed defective proliferation, a key event for successful nerve regeneration. We also showed that GFAP and the other Schwann-cell-intermediate filament vimentin physically interact in two distinct signaling pathways involved in proliferation and nerve regeneration. GFAP binds integrin αvβ8, which initiates mitotic signals soon after damage by interacting with fibrin. Consistently, ERK phosphorylation was reduced in crushed GFAP-null nerves. Vimentin instead binds integrin α5β1, which regulates proliferation and differentiation later in regeneration, and may compensate for the absence of GFAP in mutant mice. GFAP might contribute to form macro-complexes to initiate mitogenic and differentiating signaling for efficient nerve regeneration.
A novel domain on HLA-DRβ chain regulates the chaperone role of the invariant chain
Authors: Neumann Jürgen , Koch Norbert
Published: September 2006

The human lymphocyte antigen (HLA) class II region encodes highly polymorphic peptide receptors, which associate in the ER to the chaperone invariant chain (Ii). Ii facilitates assembly of class II subunits to functional peptide receptors. We searched for a conserved structure on HLA-DR polypeptides that mediates contact to a previously identified proline-rich class-II-binding sequence of Ii. Major histocompatibility complex (MHC) class II β chain sequences exhibit two conserved tryptophan residues separated by 22 amino acids. Inspection of this motif in the X-ray structure of DR3 showed TrpTyr residues in the vicinity of the Ii-derived fragment CLIP. Five DRβ mutants were produced. Mutation at Tyr123, Trp153 and Asp152 residues abolished interaction to the proline-rich sequence of Ii. All mutants formed heterodimers with DRα, were capable of binding an antigenic sequence and were expressed on the cell surface of transfected cells. In the presence of endogenous DRβ chain however, the TyrAspTrp mutant was not cell-surface exposed and did not co-isolate with Ii or DRα. The competition of the mutant with the endogenous DRβ for binding to DRα indicates that a structure on DRβ chain regulates assembly of DR subunits. Hence, the chaperone function of Ii is mediated through a conserved region on the β2 domain of class II.
Real-time analysis of cAMP-mediated regulation of ciliary motility in single primary human airway epithelial cells
Authors: Schmid Andreas , Bai Ge , Schmid Nathalie , Zaccolo Manuela , Ostrowski Lawrence E. , Conner Gregory E. , Fregien Nevis , Salathe Matthias
Published: September 2006

Airway ciliary beat frequency regulation is complex but in part influenced by cyclic adenosine monophosphate (cAMP)-mediated changes in cAMP-dependent kinase activity, yet the cAMP concentration required for increases in ciliary beat frequency and the temporal relationship between ciliary beat frequency and cAMP changes are unknown. A lentiviral gene transfer system was developed to express a fluorescence resonance energy transfer (FRET)-based cAMP sensor in ciliated cells. Expression of fluorescently tagged cAMP-dependent kinase subunits from the ciliated-cell-specific foxj1 promoter enhanced expression in fully differentiated ciliated human airway epithelial cells, and permitted simultaneous measurements of ciliary beat frequency and cAMP (represented by the FRET ratio). Apical application of forskolin (1 μM, 10 μM, 20 μM) and, in permeabilized cells, basolateral cAMP (20 μM, 50 μM, 100 μM) caused dose-dependent, albeit similar and simultaneous–increases in cAMP and ciliary beat frequency. However, decreases in cAMP preceded decreases in ciliary beat frequency, suggesting that either cellular cAMP decreases before ciliary cAMP or the dephosphorylation of target proteins by phosphatases occur at a rate slower than the rate of cAMP hydrolysis.
Dynamics and anchoring of heterochromatic loci during development
Authors: Thakar Rajika , Gordon Geoff , Csink Amy K.
Published: September 2006

Positioning a euchromatic gene near heterochromatin can influence its expression. To better understand expression-relevant changes in locus positioning, we monitored in vivo movement of centromeres and a euchromatic locus (with and without a nearby insertion of heterochromatin) in developing Drosophila tissue. In most undifferentiated nuclei, the rate of diffusion and step size of the locus is unaffected by the heterochromatic insertion. Interestingly, although the movement observed here is non directional, the heterochromatic insertion allows the flanking euchromatic region to enter and move within the heterochromatic compartment. This study also finds that a constraint on chromatin movement is imposed which is a factor of distance from the centric heterochromatic compartment. This restraint prevents the heterochromatic locus from moving away from the centric heterochromatin compartment. Therefore, because of the constraint, even distinct and non-random nuclear organizations can be attained from random chromatin movements. We also find a general constraint on chromatin movement is imposed during differentiation, which stabilizes changes in nuclear organization in differentiated nuclei.
The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH
Authors: Maurer Meghan E. , Cooper Jonathan A.
Published: September 2006

Clathrin-mediated endocytosis requires cargo-specific adaptor proteins that recognize specific receptors and recruit them into coated pits. ARH [also called low-density lipoprotein receptor (LDLR) adaptor protein] serves as an adaptor for LDLR endocytosis in liver. However, ARH is dispensable for LDL uptake by some other cell types. Here, we show that the adaptor Dab2 plays a major role in LDLR internalization in HeLa cells and fibroblasts. Dab2 mediates internalization of LDLRs but not transferrin receptors independently of ARH and the classic clathrin adaptor AP-2. If Dab2 is absent, ARH can mediate LDLR endocytosis, but its action requires AP-2. Furthermore, the rate of LDLR endocytosis is decreased when Dab2 is absent and Dab2, but not ARH, catalyzes the efficient clustering of LDLR into coated pits. Dab2 activity requires its binding to clathrin, LDLR and phospholipids. Dab2 is also involved in moving LDLRs off filopodia. We suggest that Dab2 is a cargo-specific endocytic adaptor protein, stably associating with phospholipids and clathrin to sort LDLR to nascent-coated pits, whereas ARH might accelerate later steps in LDLR endocytosis in cooperation with AP-2.
Lucky 13 - microtubule depolymerisation by kinesin-13 motors
Authors: Moores Carolyn A. , Milligan Ronald A.
Published: September 2006

The kinesin-13 class of motors catalyses microtubule depolymerisation by bending tubulins at microtubule ends. Depolymerisation activity is intrinsic to the kinesin-13 motor core but the activity of the core alone is very low compared with that of constructs that also contain a conserved neck sequence. The full-length dimeric motor is an efficient depolymeriser and also diffuses along the microtubule lattice, which helps it to find microtubule ends. Current evidence supports the idea of a generic mechanism for kinesin-13-catalysed depolymerisation. However, the activity of kinesin-13 motors is precisely localised and regulated in vivo to enable a wide range of cellular roles. The proteins are involved in global control of microtubule dynamics. They also localise to mitotic and meiotic spindles, where they contribute to formation and maintenance of spindle bipolarity, chromosomal congression, attachment correction and chromatid separation. In interphase cells, intricate and subtle mechanisms appear to allow kinesin-13 motors to act on specific populations of microtubules. Such carefully controlled localisation and regulation makes these kinesins efficient, multi-tasking molecular motors.
Cladribine: An Investigational Immunomodulatory Agent for Multiple Sclerosis
Authors: Brousil Julie A , Roberts Russel J , Schlein Amanda L
Published: September 2006

Objective:

To review the pharmacology, pharmacokinetics, efficacy, and safety of cladribine, a purine analog undergoing Phase III trials for approval of its use in the treatment of multiple sclerosis (MS).

Data Sources:

A MEDLINE search (1966–September 2006) was conducted using the key words cladribine and multiple sclerosis. No limits were placed on the search.

Study Selection and Data Extraction:

Studies and review articles related to cladribine and MS were reviewed. The trials examining the role of cladribine in MS were analyzed.

Data Synthesis:

Cladribine is a purine analog that demonstrates lymphocytotoxic activity. Recent data suggest that cladribine may have a role in the treatment of relapsing–remitting and the progressive forms of MS. In these studies, cladribine has shown mixed results in decreasing neurologic disability, as measured by various rating scales, but has consistently shown positive results in reducing the number of enhancing lesions, which reflects a measure of disease activity. To date, there is one ongoing study examining the role of oral cladribine in the treatment of relapsing–remitting MS. The incidence of adverse effects with cladribine has been significantly greater than with placebo, with the most common being myelosuppression.

Conclusions:

While data do not support its use as a first-line MS treatment, cladribine may be a promising agent for refractory patients with secondary progressive MS. Further studies are warranted.
Novel Therapies for Crohn's Disease: Focus on Immunomodulators and Antibiotics
Authors: Wilhelm Sheila M , Taylor Jason D , Osiecki Lisa L , Kale-Pradhan Pramodini B
Published: September 2006

Objective:

To review the literature on novel immunomodulators such as tumor necrosis factor alpha (TNF-α)- and interleukin (IL)-related agents, 6-thioguanine (6-TG), tacrolimus, and leflunomide, and antibiotics such as ornidazole, rifaximin, and ciprofloxacin for the treatment of Crohn's disease.

Data Sources:

Literature was accessed through MEDLINE (1966–January 2006) using the terms Crohn's disease, novel therapies, immunomodulators, and antibiotics. Article references were hand-searched for additional relevant articles and abstracts.

Study Selection and Data Extraction:

All articles in English identified from the data sources were evaluated. Studies including greater than 5 patients with primarly adult populations were included in the review.

Data Synthesis:

There are a number of new TNF-α and IL-related agents that may be useful for management of Crohn's disease. They include CDP 571, CDP 870, etanercept, onercept, thalidomide, IL-10, and IL-11. Several studies have shown that CDP 571 decreases the Crohn's Disease Activity Index score and is promising, especially in patients with refractory disease. 6-TG, tacrolimus, and leflunomide are among other immunomodulators that appear to have a role in refractory/severe disease. Finally, ornidazole, rifaximin, and ciprofloxacin are antimicrobials that may be used in patients who have failed other therapies or as adjunctive therapies.

Conclusions:

A number of new treatment modalities are being investigated for Crohn's disease. Many of them are promising, and some of these agents may be considered in treatment-refractory patients in the future. However, some of the agents reviewed here are not available in the US. Future studies need to be double-blinded and placebo- or other treatment-controlled in a more homogeneous patient population.
Use of Non-Aspirin Nonsteroidal Antiinflammatory Drugs and the Risk of Cardiovascular Events
Authors: Cheng Judy WM
Published: September 2006

Objective:

To review published evidence on the use of nonselective, non-aspirin nonsteroidal antiinflammatory drugs (NANSAIDs) and the risks of cardiovascular events and examine the justification for Food and Drug Administration (FDA) in recommending that a cardiovascular risk warning statement be included in all NANSAIDs' product information inserts.

Data Sources:

Peer-reviewed articles in MEDLINE (1966–August 2006) and Current Contents were identified using the key words NSAID, naproxen, ibuprofen, heart diseases, myocardial infarction, and cardiovascular events. Citations from available articles and related FDA Web sites were reviewed for additional references.

Study Selection and Data Extraction:

No randomized, placebo-controlled studies have been published evaluating this subject. Epidemiologic evidence published in English was examined. Sixteen relevant studies were identified (5 cohort, 3 nested case–control, 8 case–control).

Data Synthesis:

Six of the 16 studies demonstrated increased risk for one or more NANSAIDs (rate or ORs varied from 1.13 to 3.08). Five studies demonstrated cardioprotective effect for one or more NANSAIDs used (rate or ORs varied from 0.48 to 0.84). None of the other studies demonstrated an association between use of NANSAIDs and risk of cardiovascular events.

Conclusions:

After adjustment of baseline risk factors for cardiovascular events, epidemiologic studies demonstrated conflicting results regarding the risk of cardiovascular events with long-term use of nonselective NANSAIDs. However, considering the large number of patients consuming NANSAIDs and the potential public health impact, until data from long-term, randomized, controlled trials become available, the FDA's recommendation that a warning statement be included in all nonselective NANSAIDs product package inserts is justified.
Cilomilast: Orally Active Selective Phosphodiesterase-4 Inhibitor for Treatment of Chronic Obstructive Pulmonary Disease
Authors: Martina Shaunta' D , Ismail Maha S , Vesta Kimi S
Published: September 2006

Objective:

To review available literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of cilomilast, a selective phosphodiesterase-4 (PDE4) inhibitor.

Data Sources:

Literature was accessed through MEDLINE (1966–May 2006), Current Contents Clinical Medicine (1998–May 2006), and The Cochrane Library Database (1st quarter 2006) using the terms cilomilast, Ariflo, and SB 207 499. Reference lists from retrieved articles and information from the manufacturer were manually reviewed.

Study Selection and Data Extraction:

All clinical trials evaluating cilomilast and published in English were included in this review. In addition, articles evaluating the pharmacology, pharmacokinetics, and safety of cilomilast in humans were reviewed.

Data Synthesis:

Cilomilast is a second-generation PDE4 inhibitor with antiinflammatory effects that target bronchoconstriction, mucus hypersecretion, and airway remodeling associated with chronic obstructive pulmonary disease (COPD). Selective PDE4 inhibition is proposed to maximize the antiinflammatory effects of PDE inhibition while minimizing the adverse effects of nonselective agents. To date, 4 clinical trials have evaluated the efficacy of cilomilast and demonstrated improvement in lung function (forced expiratory volume in 1 second) and quality of life and reduction in the occurrence of COPD exacerbations compared with placebo. Cilomilast is generally well tolerated, with adverse effects being overall mild and self-limiting.

Conclusions:

COPD is a progressive disease, and available treatment options provide limited efficacy. Given its unique mechanism of action and improved adverse effect profile compared with previous agents, cilomilast may have a promising role for the management of COPD.
Relationships Between Beliefs about Medications and Nonadherence to Prescribed Chronic Medications
Authors: Phatak Hemant M , Thomas Joseph
Published: September 2006

Background:

Medication beliefs of patients with a specific medical condition have been associated with nonadherence to drugs used to treat that condition. However, associations between medication beliefs and nonadherence of individuals on chronic, multiple medications have not been studied.

Objective:

To investigate associations between patients' medication beliefs and nonadherence to chronic drug therapy.

Methods:

A cross-sectional, self-administered survey of patients waiting to see pharmacists at an outpatient pharmacy in a primary care clinic was conducted. Participants' medication beliefs were assessed using the Beliefs about Medicines Questionnaire, and nonadherence was assessed using the Morisky Medication Adherence Scale. Pearson correlation analysis was used to assess bivariate associations between medication beliefs and nonadherence. Regression was used to assess relative strength of associations between various medication beliefs and nonadherence and also to assess the significance of the interactions between those beliefs and nonadherence.

Results:

There were positive bivariate associations between specific concerns about medications (p < 0.001), perceived general harmful effects of medications (p < 0.001), and perceived overprescribing of medications by physicians (p < 0.001) and medication nonadherence. When relative strength of associations between each medication belief and nonadherence was assessed, while controlling for other medication beliefs, specific–necessity (p = 0.02) and specific–concerns (p = 0.01) exhibited significant negative and positive associations with nonadherence, respectively. All two-way interactions between variables in the model were insignificant. A model consisting of age, total number of drugs used, and medication beliefs, that is, specific–necessity, specific–concerns, general–overuse, and general–harm, accounted for 26.5% of variance. Medication beliefs alone explained 22.4% of variation in nonadherence to chronic drug therapy.

Conclusions:

Patients' medication beliefs explained a significant portion of variation in medication nonadherence.