Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.     

46,XX/69,XXX diploid-triploid mixoploidy with hypothyroidism and precocious puberty

We report a 20 month old female patient with diploid-triploid mixoploidy (46,XX/69,XXX) syndrome with hypothyroidism and precocious puberty. The triploid cell line was only expressed in the fibroblast culture and comprised the majority (95%) of the cells. Chromosome analysis of the fetal blood sample and peripheral blood sample were normal. The patient shows typical features of full triploidy (growth and severe mental retardation, cranial and facial dysmorphism, complete syndactyly of fingers 3/4, partial syndactyly of toes 2/3) and facial but no body asymmetry. At the age of 5 months central hypothyroidism and precocious puberty were diagnosed. Thin pigmented streaks were visible on the wrists and legs of the patient at the age of 16 months. This is the first patient reported so far with 46,XX/69,XXX mixoploidy suffering from hypothyroidism and precocious puberty.     

Dynamic simulations of the molecular conformations of wild type and mutant xanthan polymers suggest that conformational differences may contribute to observed differences in viscosity

Xanthan gum is an exopolysaccharide secreted by the bacterium Xanthamonas campestris whose ability to make solutions viscous at low concentrations and over a pH and temperature range have generated much interest in both academic and industrial environments. Mutant Xanthamonas strains have been derived that produce xanthan gums with an altered or variant subunit chemical structure and different measured viscosities when compared with the wild type (wt) form of the polymer. Two variant gums were targeted as potentially interesting in this study, these being the nonacetylated tetramer (natet) and the acetylated tetramer (atet), which both lack a side-chain terminal mannose residue and in one case (natet) lacks an acetate group on an internal mannose residue. Solutions of these tetrameric gums possess viscosities higher (natet) and lower (atet) than the wt gum, and therefore we have attempted to determine whether these molecules possess unique conformational preferences when compared with the wt and with each other. In this manner we can initiate an understanding of how a polysaccharide's conformation contributes to its solution properties. The GEGOP software permits a sampling of the static and dynamic equilibrium states of carbohydrate molecules, and this software was employed to calculate equilibrium states of representative oligosaccharides with chemical structures representative of xanthan-like molecules. Energy minimization techniques revealed similar local minima for all three molecules. Some of these minima are comprised of elongate backbone conformations (A type) in which side chains fold onto backbone surfaces. Other minima with A backbones possessed side chains in less intimate backbone contact especially when calculations were performed with a low dielectric constant. This phenomenon was particularly pronounced in the wt molecule where an increased number of negatively charged side-chain residues experience charge repulsion resulting in reduced side-chain-backbone contact. Metropolis Monte Carlo (MMC) dynamic simulations performed with an elevated temperature factor (1000 K) allowed a better qualitative representation of conformational space than 300 K simulations. Employing a nonhierarchical cluster analysis method (population density profile: PDP) coupled with a classification scheme, it was possible to partition resulting MMC data sets into conformational families. This analysis revealed that in simulations performed with different dielectric constant values (10, 25, and infinity) all molecules possessed primarily A-type backbones. Less elongate, more open helical backbone forms (B, C, D, J, and Flat-a) did occur during the simulations but were populated to a lesser extent. In the natet molecule significantly open helical backbones existed (E, F, G, H, and I) that did not occur in the lower viscosity wt and atet molecules. PDP clustering methods and subsequent conformational classification applied to the first residue (mannose) of the side chain permitted a determination of side-chain orientation. Comparison of all three molecules indicated a larger population of side-chain conformational families in less direct backbone contact for the wt molecule than either of the variant molecules (natet/atet) suggesting that the side chains in the wt are more flexible. Thus, a major conformational difference between the high viscosity natet and the lower viscosities of the wt/atet is the increased amount of open helical backbone in the natet. In addition, the significant difference between the higher viscosity wt and the lower viscosity atet is the increase side-chain flexibility in the wt. We hypothesize that conformational differences of this kind could form a partial explanation of the observed differences in viscosity between these xanthan-like polymers.     

Hepatitis B virus infection, hepatitis B vaccine, and hepatitis B immune globulin

Hepatitis B virus (HBV) infection is a major health problem in the United States; in 1995, approximately 128,000 cases occurred. Transmission of HBV occurs primarily by blood exchange (eg, by shared needles during injection drug use) and by sexual contact. Persons infected early in life are much more likely to become chronically infected than those infected during adulthood: as many as 90% of infants infected perinatally develop chronic infection and up to 25% will die of HBV-related chronic liver disease as adults. Clinical signs of acute hepatitis occur in about 50% of infected adults but in only 5% of infected preschool-aged children. In the United States, hepatitis B vaccine is currently made by recombinant DNA technology using baker's yeast. Preexposure vaccination results in protective antibody levels in almost all infants and children (> 95%) and healthy adults younger than 40 years of age (> 90%). The most common adverse event following administration of hepatitis B vaccine is pain at the injection site, which occurs in 13% to 29% of adult and 3% to 9% of children. A comprehensive hepatitis B vaccination policy is now recommended that includes (1) routine infant vaccination; (2) catch-up vaccination of 11- to 12-year-olds who were not previously vaccinated; (3) catch-up vaccination of young children at high risk for infection; (4) vaccination of adolescents and adults based on lifestyle or environmental, medical, and occupational situations that place them at risk; and (5) prevention of perinatal HBV infection.     

Cortisone-induced osteoporosis: effects on bone adenylate cyclase

The majority of patients with soft tissue or bone sarcomas of the upper extremity can be treated today with limb-saving procedures using combined modality therapies. For patients with a tumor in the shoulder area, sometimes an interscapulothoracic amputation is the only radical surgical treatment. However, in selected cases, in which the tumor does not involve the neurovascular bundle, a limb-sparing alternative might be the Tikhoff-Linberg resection. Normal function of the hand and forearm, with reasonable function of the elbow, can be maintained by this procedure. Four case histories are reported.     

Large reference displacement analysis of composite plates. Part II: Computer implementation

This investigation concerns itself with the computer implementation of the dynamic formulation of thin laminated composite plates consisting of layers of orthotropic laminae that undergo large arbitrary rigid body displacements and small elastic deformations. A finite element preprocessor computer program is developed to automatically generate the invariants of the laminae, which may have arbitrary orientations. The laminae invariants are then used to obtain the invariants of the elements and the composite laminated plate. The consistent and lumped mass formulations of the invariants of motion of composite plates are compared and it is concluded that the two methods are comparable, if a fine enough finite element mesh is used. The structure of the dynamic equations of motion, based on the formulation presented in Part I of this paper, is examined. Non-linear centrifugal and Coriolis forces arising as the result of the finite rotations of the laminae are defined, and the solution schemes of the resulting non-linear differential equations of motion are discussed. Numerical examples illustrating the differences between homogeneous isotropic and laminated composite plates are presented. An RSSR (Revolute-Spherical-Spherical-Revolute) mechanism is used in the numerical examples, with the coupler modelled as a laminated plate flexible body. It is found that the inertia of the plate contributed greatly to the transverse deformation. The effects of laminae orientation is also investigated.