Fluctuating dynamics of nematic liquid crystals using the stochastic method of lines.

We construct Langevin equations describing the fluctuations of the tensor order parameter Q(alphabeta) in nematic liquid crystals by adding noise terms to time-dependent variational equations that follow from the Ginzburg-Landau-de Gennes free energy. The noise is required to preserve the symmetry and tracelessness of the tensor order parameter and must satisfy a fluctuation-dissipation relation at thermal equilibrium. We construct a noise with these properties in a basis of symmetric traceless matrices and show that the Langevin equations can be solved numerically in this basis using a stochastic version of the method of lines. The numerical method is validated by comparing equilibrium probability distributions, structure factors, and dynamic correlations obtained from these numerical solutions with analytic predictions. We demonstrate excellent agreement between numerics and theory. This methodology can be applied to the study of phenomena where fluctuations in both the magnitude and direction of nematic order are important, as for instance, in the nematic swarms which produce enhanced opalescence near the isotropic-nematic transition or the problem of nucleation of the nematic from the isotropic phase.

Quantitative structure-activity relationship studies of antimalarial compounds from their calculated mathematical descriptors.

A wide range of mathematical descriptors that can be calculated without the use of any other experimental data except molecular structure were used to develop models to predict binary (+/-) antimalarial activity of a set of 86 4(1H)-quinolones in two strains of parasite: D6 and TM90-C2B (chloroquine and atovaquone susceptible). The quantitative structure-activity relationship for each strain was of high quality and showed good ability in predicting activity versus inactivity when applied to a data set containing well-known antimalarial drugs.

Biaxiality at the isotropic-nematic interface with planar anchoring.

We revisit the classic problem of the structure of the isotropic-nematic interface within Ginzburg-Landau-de Gennes theory, refining previous analytic treatments of biaxiality at the interface. We compare our analysis with numerical results obtained through a highly accurate spectral collocation scheme for the solution of the Landau-Ginzburg-de Gennes equations. In comparison to earlier work, we obtain improved agreement with numerics for both the uniaxial and biaxial profiles, accurate asymptotic results for the decay of biaxial order on both nematic and isotropic sides of the interface, and accurate fits to data from density-functional approaches to this problem.

The isotropic-nematic interface with an oblique anchoring condition.

We present numerical and analytic results for uniaxial and biaxial orders at the isotropic-nematic interface within Ginzburg-Landau-de Gennes theory. We study the case where an oblique anchoring condition is imposed asymptotically on the nematic side of the interface, reproducing results of previous work when this condition reduces to planar or homeotropic anchoring. We construct physically motivated and computationally flexible variational profiles for uniaxial and biaxial orders, comparing our variational results to numerical results obtained from a minimization of the Ginzburg-Landau-de Gennes free energy. While spatial variations of the scalar uniaxial and biaxial order parameters are confined to the neighborhood of the interface, nematic elasticity requires that the director orientation interpolate linearly between either planar or homeotropic anchoring at the location of the interface and the imposed boundary condition at infinity. The selection of planar or homeotropic anchoring at the interface is governed by the sign of the Ginzburg-Landau-de Gennes elastic coefficient L(2). Our variational calculations are in close agreement with our numerics and agree qualitatively with results from density functional theory and molecular simulations.

Numerical method of lines for the relaxational dynamics of nematic liquid crystals.

We propose an efficient numerical scheme, based on the method of lines, for solving the Landau-de Gennes equations describing the relaxational dynamics of nematic liquid crystals. Our method is computationally easy to implement, balancing requirements of efficiency and accuracy. We benchmark our method through the study of the following problems: the isotropic-nematic interface, growth of nematic droplets in the isotropic phase, and the kinetics of coarsening following a quench into the nematic phase. Our results, obtained through solutions of the full coarse-grained equations of motion with no approximations, provide a stringent test of the de Gennes ansatz for the isotropic-nematic interface, illustrate the anisotropic character of droplets in the nucleation regime, and validate dynamical scaling in the coarsening regime.

A study on the use of male animal models for developing a live vaccine for brucellosis.

To study the safety of Brucella melitensis WR201, a live vaccine candidate, we compared the course of infection of this strain with that of virulent 16M in male BALB/c mice. At various times after oral immunization with strains WR201 or 16M, lungs, liver, spleen, testis, epididymis, inguinal and cervical lymph nodes were removed. Tissues were divided for microbiologic culture and histopathological examination. WR201 infection in male BALB/c mice had lower intensity and shorter duration than infection caused by virulent 16M. Pathological examination of testis and epididymis revealed no inflammation following strain WR201 immunization. In contrast, animals given virulent 16M strain had substantial inflammation in infected tissues. These data confirm the marked attenuation of WR201 relative to 16M. In addition, these studies suggest that male mice may be useful to assess the safety of live, attenuated Brucella vaccine candidates.

An in silico 3D pharmacophore model of chalcones useful in the design of novel antimalarial agents.

Malaria, the most important of the human parasitic diseases, causes about 500 million infections worldwide and over 1 million deaths every year. The search for novel drug candidates against specific parasitic targets is an important goal for antimalarial drug discovery. Recently the antimalarial activity of chalcones has generated great interest. These compounds are small non-chiral molecules with relative high lipophilicity (clogP approximately 5-7), have molecular weights in the range of 300 to 600 g/mol, and possess in vivo efficacy against both P. berghei and P. yeolii. Preliminary data on our on-going chalcone synthesis project indicate that these compounds are active in vitro against P. falciparum, but are rapidly metabolized in liver microsome assays. Structurally-related compounds not including the enone linker are found to be much more metabolically stable and yet have comparable in vitro efficacy. In this study, we have utilized the efficacy data from an in-house on-going chalcone project to develop a 3D pharmacophore for antimalarial activity and used it to conduct virtual screening (in silico search) of a chemical library which resulted in identification of several potent chalcone-like antimalarials. The pharmacophore is found to contain an aromatic and an aliphatic hydrophobic site, one hydrogen bond donor site, and a ring aromatic feature distributed over a 3D space. The identified compounds were not only found to be potent in vitro against several drug resistant and susceptible strains of P. falciparum and have better metabolic stability, but included one with good in vivo efficacy in a mouse model of malaria.

Antileishmanial and antimalarial chalcones: synthesis, efficacy and cytotoxicity of pyridinyl and naphthalenyl analogs.

The antileishmanial and antimalarial activity of methoxy-substituted chalcones (1,3-diphenyl-2-propen-1-ones) is well established. The few analogs prepared to date where the 3-phenyl group is replaced by either a pyridine or naphthalene suggest these modifications are potency enhancing. To explore this hypothesis, sixteen 3-naphthalenyl-1-phenyl-2-prop-1-enones and ten 1-phenyl-3-pyridinyl-2-prop-1-enones were synthesized and their in vitro efficacies against Leishmania donovani and Plasmodium falciparum determined. One inhibitor with submicromolar efficacy against L. donovani was identified (IC50 = 0.95 microM), along with three other potent compounds (IC50 < 5 microM), all of which were 3-pyridin-2-yl derivatives. No inhibitors with submicromolar efficacy against P. falciparum were identified, though several potent compounds were found (IC50 < 5 microM). The cytotoxicity of the five most active L. donovani inhibitors was assessed. At best the IC50 against a primary kidney cell line was around two-fold higher than against L. donovani. Being more active than pentamidine, the 1-phenyl-3-pyridin-2-yl-2-propen-1-ones have potential for further development against leishmaniasis; however it will be essential in such a program to address not only efficacy but also their potential for toxicity.

Utility of alkylaminoquinolinyl methanols as new antimalarial drugs.

Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.

Management of vasospasm in a neurosurgical center / Management of vasospasm in a neurosurgical center

Background: Cerebral vasospasm after subarachnoid hemorrhage remains a major source of morbidity and mortality. Various agents have come into vogue to deal with this complication but none has shown any absolute results. We conducted this study to asses the effectiveness of intracisternal lavage of papavarine both prophylactically and therapeutically in a simple cost effective way. Methods: This is a retrospective analysis of patients who were admitted at our institution between January 2002 and July 2003. Eighty five patients with anterior circulation aneurysmal bleed who underwent microsurgical clipping were divided into two groups. Group A: patients who received papavarine through a reservoir and Group B patients who did not receive papavarine. The location of aneurysm, timing of surgery , incidence and outcome of vasospasm were assessed in the patients in two comparable groups. Results: 13 por ciento of patients in Group A developed vasospasm whereas 38 por ciento of patients in Group B developed vasospasm. Symptoms of vasospasm reversed in all patients in Group A. There were 3 deaths in Group A but none where attributed to vasospasm. Four of seven deaths in Group B were attributed to consequence of vasospasm. Eleven patients who survived in Group B in spite of vasospasm had significant morbidity at the time of discharge. Conclusion: Intracisternal lavage with papavarine both prophylactically and theraputically can prevent and reverse vasospasm and this can be achieved by installing a simple reservoir. It is a cost effective and rapid bedside procedure for dealing with vasospasm

Management of vasospasm in a neurosurgical center / Management of vasospasm in a neurosurgical center

Background: Cerebral vasospasm after subarachnoid hemorrhage remains a major source of morbidity and mortality. Various agents have come into vogue to deal with this complication but none has shown any absolute results. We conducted this study to asses the effectiveness of intracisternal lavage of papavarine both prophylactically and therapeutically in a simple cost effective way. Methods: This is a retrospective analysis of patients who were admitted at our institution between January 2002 and July 2003. Eighty five patients with anterior circulation aneurysmal bleed who underwent microsurgical clipping were divided into two groups. Group A: patients who received papavarine through a reservoir and Group B patients who did not receive papavarine. The location of aneurysm, timing of surgery , incidence and outcome of vasospasm were assessed in the patients in two comparable groups. Results: 13 por ciento of patients in Group A developed vasospasm whereas 38 por ciento of patients in Group B developed vasospasm. Symptoms of vasospasm reversed in all patients in Group A. There were 3 deaths in Group A but none where attributed to vasospasm. Four of seven deaths in Group B were attributed to consequence of vasospasm. Eleven patients who survived in Group B in spite of vasospasm had significant morbidity at the time of discharge. Conclusion: Intracisternal lavage with papavarine both prophylactically and theraputically can prevent and reverse vasospasm and this can be achieved by installing a simple reservoir. It is a cost effective and rapid bedside procedure for dealing with vasospasm (AU)

Diphtheria: the patch remains.

This study analysed the number of patients admitted with diphtheria to a teaching hospital in the state of Assam in India over a period of five years and compared the disease characteristics and management with outcomes and incidences of diphtheria reported in the literature. It was a retrospective analysis of data elicited from clinical records of patients admitted to hospital. A total of 101 admissions were recorded during a five-year period between March 1997 to March 2002, mostly with pharyngeal diphtheria (90 per cent). The majority of patients had no history of immunization (70 per cent). Significant presenting features were a tonsillar patch, sore throat, respiratory distress and fever. All patients were treated with anti-diphtheritic serum and intravenous antibiotics. Steroids were given to 81 per cent of patients and tracheostomy was carried out in 10 per cent of cases. The mortality was 16 per cent. Diphtheria of the respiratory tract remains a potentially fatal disease commonly presenting with membranous pharyngitis. Early diagnosis and treatment with anti-diphtheritic serum and antibiotics remain the cornerstone of treatment. Inadequate immunization cover is deemed responsible for the continued menace of diphtheria.

Quantitative analysis of hyperosmotic and hypothermic blood-brain barrier opening.

Hyperosmotic opening of the blood-brain barrier (BBB) by mannitol is being used to enhance drug transport in human brains. Recently, cooling of the solution has been reported to have potential to open the BBB. However, the mechanism in barrier opening and closure remains elusive. We studied the rapid changes in cerebrovascular permeability after hyperosmotic and hypothermic BBB opening in rats, and then demonstrated that the Na+/Ca++ exchange blocker (KB-R7943) prolongs opening. BBB opening was attained by using intra-arterial infusion of hyperosmotic mannitol (1.6 M) and 1.1 M mannitol (which is less hyperosmotic than commonly used mannitol) at 4 degrees in Sprague-Dawley (SD) rats. To measure the changes in cerebrovascular permeability, perfusate-containing [14C]-sucrose was infused intra-arterially at different time points following hyperosmotic and hypothermic stress. Cerebrovascular permeability was then measured with the in situ brain perfusion technique. 1.6 M Mannitol produced opening of the BBB but the duration of the opening was less than 30 minutes. Use of 1.1 M Mannitol at 4 degrees indicated the same results. We then investigated the effect of a Na/Ca ion exchange blocker (KB-R7943) in both hyperosmotic and hypothermic BBB opening. KB-R7943 extended BBB opening up to 30 min without affecting the peak level of BBB permeability at 5 minutes. Our findings represent important experimental information regarding pharmacological manipulation of BBB opening. The possibility of prolonging the transient opening of the BBB has major clinical implications.

Light-induced transformation of tribenuron-methyl on glass, soil, and plant surface.

Photolysis of tribenuron-methyl (methyl 2-[[[[N-(4-methoxy-6-methyl-1,3,5triazin-2-yl)methylamino]carbonyl]amino]sulfonyl]benzoate), a sulfonylurea herbicide, was studied as thin film on glass surface, soil surface, and plant surface. A number of photoproducts such as 4-methoxy-6-methyl-2-aminomethyl-1,3,5-triazine; methyl-2-(aminosulfonyl) benzoate; N-(2-carbomethoxyphenyl)-N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-N'-methylurea; N-(2-carbomethoxyphenyl sulfonyl)-N-methyl urea; o-benzoic sulfimide and 4-methoxy-6-methyl-2-amino-1,3,5-triazine were identified by comparison of their GC-MS with the authentic standards. The rate of degradation in all the cases followed first-order kinetics with a statistically significant correlation coefficient. Rate of photodegradation was greater on glass surface than on soil surface.

Quantitative analysis of papaverine-mediated blood-brain barrier disruption in rats.

The blood-brain barrier (BBB) is a permeability barrier of interconnected brain capillary endothelial cells. Intraarterial infusion of papaverine relieves cerebral vasospasms by inhibiting smooth muscle contractions and it may simultaneously lead to a disruption of BBB permeability. To date, the mechanism underlying this phenomenon and the quantification of BBB disruption remains elusive. We first examined the changes in cerebrovascular permeability after an intracarotid infusion of papaverine (0.20%) in rats by an in situ brain perfusion technique. We then demonstrated that changes in cerebrovascular permeability depend on the concentration of papaverine. This is the first study in which the degree of BBB disruption was accurately quantified in terms of [(14)C]sucrose and it was demonstrated that papaverine has a prolonged effect on cerebrovascular permeability. This result suggests the importance of in vivo experiments for a precise evaluation of permeability for many other agents, particularly for the central nervous system.

Quantification of early blood-brain barrier disruption by in situ brain perfusion technique.

Osmotic disruption is currently being used to circumvent the blood-brain barrier (BBB) and enhance the delivery of therapeutic molecules in human brains. To date, however, the time course during the early phase of disruption has not been clarified. In order to demonstrate the rapid change in cerebrovascular permeability after BBB disruption in rats, we developed a method of in situ brain perfusion to demonstrate the earliest reversibility in cerebrovascular permeability. Osmotic BBB disruption was attained by intracarotid infusion of hypertonic mannitol. Perfusate containing [14C]-sucrose was infused at different time points following osmotic stress followed by measuring cerebrovascular permeability. The earliest BBB disruption was seen to occur 5 min after osmotic stress, after which the exact time course of cerebrovascular reversibility was studied. The protocol reported here, in contrast with those reported in previous studies, was shown to be qualitative, simple, and fast. In addition, the method can be applied to measure any low BBB permeability molecules. This protocol should be helpful for any research focused on enhancing drug delivery into the brain following osmotic BBB disruption.

Structural analysis of chloroquine resistance reversal by imipramine analogs.

For imipramine, desipramine, and eight analogs of these well-known drugs, an N-5-aminoalkyl substitution was a minimum but insufficient structural feature associated with chloroquine resistance reversal. Although a second distal aliphatic nitrogen atom was unnecessary for resistance reversal, the direction of the dipole moment vector was critical.

The effects of the Na(+)/Ca(++) exchange blocker on osmotic blood-brain barrier disruption.

Osmotic disruption of the blood-brain barrier (BBB) by mannitol is currently being used to enhance drug delivery in human brains. Despite clinical and experimental interest, to date the time course in the early phase of disruption has not been accurately identified. The mechanism in barrier closure also remains elusive. We first studied the rapid change in cerebrovascular permeability after BBB disruption in rats, and then demonstrated that the Na(+)/Ca(++) exchange blocker (KB-R7943) prolongs osmotic disruption. Osmotic BBB disruption was attained by using intra-arterial infusion of hypertonic mannitol in Sprague-Dawley (SD) rats. To measure the changes in cerebrovascular permeability, perfusate containing [14C]-sucrose was infused intra-arterially at different time points following osmotic stress. Cerebrovascular permeability was then measured with the in situ brain perfusion technique. This is the first in vivo study demonstrating that osmotic disruption is prolonged by the Na(+)/Ca(++) exchange blocker, which did not affect the peak level of BBB disruption. The exact time course of cerebrovascular reversibility was studied and the earliest BBB disruption was seen to occur 5 min after osmotic stress. Histopathological examination after osmotic disruption with the Na(+)/Ca(++) exchange blocker showed no neuronal damage in rat brains. Our findings represent important experimental information regarding pharmacological manipulation of BBB disruption. The possibility of prolonging the transient opening of the BBB has major clinical implications.

Bacteriologic and histologic features in mice after intranasal inoculation of Brucella melitensis.

OBJECTIVE: To characterize effects of intranasal inoculation of virulent Brucella melitensis strain 16M in mice. ANIMALS: Female Balb/c mice, 6 to 8 weeks old. PROCEDURE: Studies were designed to elucidate gross morphologic lesions, bacterial burden in target organs, and histologic changes in tissues following experimental intranasal inoculation of mice with B melitensis 16M, which could be used to characterize a model for testing vaccine efficacy. RESULTS: Measurable splenomegaly was evident at 3 and 7 weeks after inoculation. A demonstrable increase in splenic colony-forming units (CFU) from infected mice increased over time with increasing dose when comparing inocula of 10(3), 10(4), and 10(5) CFU. Recovery of brucellae from the lungs was possible early in infection with 10(1), 10(3), and 10(5) CFU, but only the group inoculated with 10(5) CFU consistently yielded quantifiable bacteria. At a dose of 10 CFU, few organisms were located in the spleen. Bacteria were recovered up to 140 days after inoculation in mice given 10(3) CFU. At an inoculum of 10(5) CFU, bacterial counts were highest early in infection. Histologic examination of tissues revealed an increase in white pulp and marginal zone in the spleen and lymphohistiocytic hepatitis. CONCLUSION AND CLINICAL RELEVANCE: Changes in the spleen and liver increased with increases in dose and with increased time following intranasal inoculation with B melitensis 16M. Surprisingly, histologic changes were not observed in the lungs of inoculated mice.