Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H(4) receptor antagonists

Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.

Atomic Latin squares of order eleven

A Latin square is pan-Hamiltonian if the permutation which defines row i relative to row j consists of a single cycle for every i j. A Latin square is atomic if all of its conjugates are pan-Hamiltonian. We give a complete enumeration of atomic squares for order 11, the smallest order for which there are examples distinct from the cyclic group. We find that there are seven main classes, including the three that were previously known. A perfect 1-factorization of a graph is a decomposition of that graph into matchings such that the union of any two matchings is a Hamiltonian cycle. Each pan-Hamiltonian Latin square of order n describes a perfect 1-factorization of Kn,n, and vice versa. Perfect 1-factorizations of Kn,n can be constructed from a perfect 1-factorization of Kn+1. Six of the seven main classes of atomic squares of order 11 can be obtained in this way. For each atomic square of order 11, we find the largest set of Mutually Orthogonal Latin Squares (MOLS) involving that square. We discuss algorithms for counting orthogonal mates, and discover the number of orthogonal mates possessed by the cyclic squares of orders up to 11 and by Parker's famous turn-square. We find that the number of atomic orthogonal mates possessed by a Latin square is not a main class invariant. We also define a new sort of Latin square, called a pairing square, which is mapped to its transpose by an involution acting on the symbols. We show that pairing squares are often orthogonal mates for symmetric Latin squares. Finally, we discover connections between our atomic squares and Franklin's diagonally cyclic self-orthogonal squares, and we correct a theorem of Longyear which uses tactical representations to identify self-orthogonal Latin squares in the same main class as a given Latin square.

Least energy solutions of a critical Neumann problem with a weight

We investigate the effect of the coefficient of the critical nonlinearity for the Neumann problem on the existence of least energy solutions. As a by-product we establish a Sobolev inequality with interior norm.

Determination of pore size distributions by regularization and finite element collocation

The problem of extracting pore size distributions from characterization data is solved here with particular reference to adsorption. The technique developed is based on a finite element collocation discretization of the adsorption integral, with fitting of the isotherm data by least squares using regularization. A rapid and simple technique for ensuring non-negativity of the solutions is also developed which modifies the original solution having some negativity. The technique yields stable and converged solutions, and is implemented in a package RIDFEC. The package is demonstrated to be robust, yielding results which are less sensitive to experimental error than conventional methods, with fitting errors matching the known data error. It is shown that the choice of relative or absolute error norm in the least-squares analysis is best based on the kind of error in the data. (C) 1998 Elsevier Science Ltd. All rights reserved.

Comparison of trends in method-specific suicide rates in Australia and England & Wales, 1968-97

Objective: To compare secular trends in method-specific suicide rates among young people in Australia and England & Wales between 1968 and 1997. Methods: Australian data were obtained from the Australian Bureau of Statistics, and for England & Wales from the Office for National Statistics. Overall and method-specific suicide rates for 15-34 year old males and females were calculated using ICD codes E950-9 and E980-9 except E988.8. Results: In both settings, suicide rates have almost doubled in young males over the past 30 years (from 16.8 to 32.9 per 100,000 in Australia and from 10.1 to 19.0 in England & Wales). Overall rates have changed little in young females. In both sexes and in both settings there have been substantial increases in suicide by hanging (5-7 fold increase in Australia and four-fold increase in England & Wales). There have also been smaller increases in gassing in the 1980s and '90s. In females, the impact of these increases on overall rates has been offset by a decline in drug overdose, the most common method in females. Conclusions: Rates of male suicide have increased substantially in both settings in recent years, and hanging has become an increasingly common method of suicide. The similarity in observed trends in both settings supports the view that such changes may have common causes. Research should focus on understanding why hanging has increased in popularity and what measures may be taken to diminish it.

Residence time distributions of gas flowing through rotating drum bioreactors

Residence time distribution studies of gas through a rotating drum bioreactor for solid-state fermentation were performed using carbon monoxide as a tracer gas. The exit concentration as a function of time differed considerably from profiles expected for plug flow, plug flow with axial dispersion, and continuous stirred tank reactor (CSTR) models. The data were then fitted by least-squares analysis to mathematical models describing a central plug flow region surrounded by either one dead region (a three-parameter model) or two dead regions (a five-parameter model). Model parameters were the dispersion coefficient in the central plug flow region, the volumes of the dead regions, and the exchange rates between the different regions. The superficial velocity of the gas through the reactor has a large effect on parameter values. Increased superficial velocity tends to decrease dead region volumes, interregion transfer rates, and axial dispersion. The significant deviation from CSTR, plug flow, and plug flow with axial dispersion of the residence time distribution of gas within small-scale reactors can lead to underestimation of the calculation of mass and heat transfer coefficients and hence has implications for reactor design and scaleup. (C) 2001 John Wiley & Sons, Inc.

An economic evaluation of plasma production via erythroplasmapheresis and whole blood collection

This paper presents cost-effectiveness analyses (CEAs) of plasma collection via two alternative methods: whole blood collection (WBC) and erythroplasmapheresis collection (EPC). The objective of the study is to provide an answer to the question 'What is the least-cost method of plasma production'. This question is answered, both from the viewpoint of the blood collection agency (using financial CEA) and from that of 'society' as a whole (using economic CEA). We employ detailed financial data and economic survey data for collections made by a blood collection agency and to WBC and EPC donors in Brisbane, Australia. The results indicate that, despite the superior yield provided by EPC, WBC is actually more cost-effective. This result is robust to thorough sensitivity analysis and arises regardless of whether an economic or financial perspective is taken. We conclude that, ceteris paribus, the cost of recruiting new plasma donors would need to be quite substantial for marginal investments in EPC to be considered cost-effective. Crown Copyright (C) 2002 Published by Elsevier Science Ltd. All rights reserved.

Age and Method-dependent Variability of Predicted Oxygen Consumption in Congenital Heart Disease

Background and Purpose. There has been a lot of debate about the use of predicted oxygen consumption to calculate pulmonary vascular resistance using the Fick principle. We therefore comparatively analyzed predicted oxygen consumption in infants and children in specific age groups, using different methods (formulas), as an attempt to better understand the usefulness and limitations of predictions. Methods and Results. Four models (LaFarge & Miettinen, Bergstra et al., Lindahl, and Lundell et al.) were used to predict oxygen consumption in 200 acyanotic patients with congenital cardiac defects aged 0-2.0, > 2.0-4.0, > 4.0-6.0, and > 6.0-8.75 years (median 2.04 years). Significant differences were observed between the age groups (P < .001) and between the methods (P < .001), not related to diagnoses. Differences between methods were more impressive in the first age group (P < .01). In patients aged 0-2.0 years, the lowest values of oxygen consumption (corresponding to the highest estimates of pulmonary vascular resistance) were obtained with the method of Lindahl; above this age, any method except that of Lundell et al. Conclusions. Although measuring oxygen consumption is always preferable, a rational use of predictions, using different methods, may be of help in situations where measurements are definitely not possible.

A method for drug infusion into the lateral median eminence and arcuate nucleus of sheep

The role of catecholamines in the control of the GnRH pulse generator is unclear as studies have relied on the use of peripheral or intracerebroventricular injections, which lack specificity in relation to the anatomical site of action. Direct brain site infusions have been used, however, these are limited by the ability to accurately target small brain regions. One such area of interest in the control of GnRH is the median eminence and arcuate nucleus within the medial basal hypothalamus. Here we describe a method of stereotaxically targeting this area in a large animal (sheep) and an infusion system to deliver drugs into unrestrained conscious animals. To test our technique we infused the dopamine agonist, quinpirole or vehicle into the medial basal hypothalamus of ovariectomised ewes. Quinpirole significantly suppressed LH pulsatility only in animals with injectors located close to the lateral median eminence. This in vivo result supports the hypothesis that dopamine inhibits GnRH secretion by presynaptic inhibition in the lateral median eminence. Also infusion of quinpirole into the medial basal hypothalamus suppressed prolactin secretion providing in vivo evidence that is consistent with the hypothesis that there are stimulatory autoreceptors on tubero-infundibular dopamine neurons. (C) 1997 Elsevier Science B.V.

Applying linear time-varying constraints to econometric models: With an application to demand systems

When linear equality constraints are invariant through time they can be incorporated into estimation by restricted least squares. If, however, the constraints are time-varying, this standard methodology cannot be applied. In this paper we show how to incorporate linear time-varying constraints into the estimation of econometric models. The method involves the augmentation of the observation equation of a state-space model prior to estimation by the Kalman filter. Numerical optimisation routines are used for the estimation. A simple example drawn from demand analysis is used to illustrate the method and its application.

Reprint of ""Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury""

Previous studies have suggested that abnormal corneal wound healing in patients after photorefractive keratectomy (PRK) is associated with the appearance of myofibroblasts in the stroma between two and four weeks after surgery. The purpose of this study was to examine potential myofibroblast progenitor cells that might express other filament markers prior to completion of the differentiation pathway that yields alpha-smooth muscle actin (SMA)-expressing myofibroblasts associated with haze localized beneath the epithelial basement membrane after PRK. Twenty-four female rabbits that had -9 diopter PRK were sacrificed at 1 week, 2 weeks, 3 weeks or 4 weeks after surgery. Corneal rims were collected, frozen at -80 degrees C, and analyzed by immunocytochemistry using anti-vimentin, anti-desmin, and anti-SMA antibodies. Double immunostaining was performed for the co-localization of SMA with vimentin or desmin with SMA. An increase in vimentin expression in stromal cells is noted as early as 1 week after PRK in the rabbit cornea. As the healing response continues at two or three weeks after surgery, many stromal cells expressing vimentin also begin to express desmin and SMA. By 4 weeks after the surgery most, if not all, myofibroblasts express vimentin, desmin and SMA. Generalized least squares regression analysis showed that there was strong evidence that each of the marker groups differed in expression over time compared to the other two (p < 0.01). Intermediate filaments - vimentin and desmin co-exist in myofibroblasts along with SMA and may play an important role in corneal remodeling after photorefractive keratectomy. The earliest precursors of myofibroblasts destined to express SMA and desmin are detectible by staining for vimentin at 1 week after surgery. (C) 2009 Elsevier Ltd. All rights reserved.

Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury

Previous studies have suggested that abnormal corneal wound healing in patients after photorefractive keratectomy (PRK) is associated with the appearance of myofibroblasts in the stroma between two and four weeks after surgery. The purpose of this study was to examine potential myofibroblast progenitor cells that might express other filament markers prior to completion of the differentiation pathway that yields a-smooth muscle actin (SMA)-expressing myofibroblasts associated with haze localized beneath the epithelial basement membrane after PRK. Twenty-four female rabbits that had -9 diopter PRK were sacrificed at I week, 2 weeks, 3 weeks or 4 weeks after surgery. Corneal rims were collected, frozen at -80 degrees C, and analyzed by immunocytochemistry using anti-vimentin, anti-desmin, and anti-SMA antibodies. Double immunostaining was performed for the co-localization of SMA with vimentin or desmin with SMA. An increase in vimentin expression in stromal cells is noted as early as 1 week after PRK in the rabbit cornea. As the healing response continues at two or three weeks after surgery, many stromal cells expressing vimentin also begin to express desmin and SMA. By 4 weeks after the surgery most, if not all, myofibroblasts express vimentin, desmin and SMA. Generalized least squares regression analysis showed that there was strong evidence that each of the marker groups differed in expression over time compared to the other two (p < 0.01). Intermediate filaments - vimentin and desmin co-exist in myofibroblasts along with SMA and may play an important role in corneal remodeling after photorefractive keratectomy. The earliest precursors of myofibroblasts destined to express SMA and desmin are detectible by staining for vimentin at I week after surgery. (C) 2009 Elsevier Ltd. All rights reserved.

Safety Profile of Trocar and Insufflation Needle Access Systems in Laparoscopic Surgery

BACKGROUND: The most common laparoscopic complications are associated with trocar insertion. The purpose of this study was to develop an objective method of evaluating the safety profile of various access devices used in laparoscopic surgery. STUDY DESIGN: In 20 swine, 6 bladed and 2 needle access devices were evaluated. A force profile was determined by measuring the force required to drive the trocar or needle through the fascia and into the peritoneum, at 0 and 10 mmHg. The amount Of tissue deformation, the length of blade exposed, and the duration of exposure were measured using a high-speed digital imaging system. RESULTS: The needle system without the sheath required the least driving force and had the most favorable force profile. In contrast, the bladed, nonretractable trocar system required a higher driving force and a rapid loss of resistance. Insertion under a pneumoperitoneum did not significantly alter the force profile of the various access devices except for the amount of tissue deformation. With the bladed system, the blade itself was exposed for an average of 0.5 to 1.0 seconds for a distance of 4.5 to 5.0 cm. In comparison, the needle system was exposed for 0.2 seconds for a distance of 1.8 cm. CONCLUSIONS: We developed a reproducible method of measuring the forces required to place the access systems, their pattern of resistance loss, and the characteristics of the blade exposure. These parameters may provide an adjunctive and objective measurement of safety, allowing for more direct comparison between various trocar designs. (J Am Coll Surg 2009;209:222-232. (C) 2009 by the American College of Surgeons)

Effect of ion exchange on strength and slow crack growth of a dental porcelain

Objectives. To determine the effect of ion exchange on slow crack growth (SCG) parameters (n, stress corrosion susceptibility coefficient, and sigma(f0), scaling parameter) and Weibull parameters (m, Weibull modulus, and sigma(0), characteristic strength) of a dental porcelain. Methods. 160 porcelain discs were fabricated according to manufacturer`s instructions, polished through 1 mu m and divided into two groups: GC (control) and GI (submitted to an ion exchange procedure using a KNO(3) paste at 470 degrees C for 15 min). SCG parameters were determined by biaxial flexural strength test in artificial saliva at 37 degrees C using five constant stress rates (n =10). 20 specimens of each group were tested at 1 MPa/s to determine Weibull parameters. The SPT diagram was constructed using the least-squares fit of the strength data versus probability of failure. Results. Mean values of m and sigma(0) (95% confidence interval), n and sigma(f0) (standard deviation) were, respectively: 13.8 (10.1-18.8) and 60.4 (58.5 - 62.2), 24.1 (2.5) and 58.1 (0.01) for GC and 7.4 (5.3 -10.0) and 136.8 (129.1-144.7), 36.7 (7.3) and 127.9 (0.01) for GI. Fracture stresses (MPa) calculated using the SPT diagram for lifetimes of 1 day, 1 year and 10 years (at a 5% failure probability) were, respectively, 31.8, 24.9 and 22.7 for GC and 71.2, 60.6 and 56.9 for GI. Significance. For the porcelain tested, the ion exchange process improved strength and resistance to SCG, however, the material`s reliability decreased. The predicted fracture stress at 5% failure probability for a lifetime of 10 years was also higher for the ion treated group. (C) 009 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Smallest weak and smallest totally weak critical sets in the latin squares of order at most seven

A critical set in a latin square of order n is a set of entries in a latin square which can be embedded in precisely one latin square of order n. Also, if any element of the critical set is deleted, the remaining set can be embedded in more than one latin square of order n. In this paper we find smallest weak and smallest totally weak critical sets for all the latin squares of orders six and seven. Moreover, we computationally prove that there is no (totally) weak critical set in the back circulant latin square of order five and we find a totally weak critical set of size seven in the other main class of latin squares of order five.