Autoimmune vasculitis in MRL/Mp-lpr/lpr mice: orthochromatic basophils participate in the development of delayed-type hypersensitivity angiitis.

The pathogenesis of autoimmune vasculitis is poorly understood. Understanding the immunologic mechanisms governing this disease requires precise identification of the cells which comprise the lesion. In this report, we have evaluated tissue sections from MRL/lpr mice from 16 to 45 weeks of age, representing all stages of clinical vasculitis. We demonstrate that basophil myelocytes participate in the evolution of the delayed-type hypersensitivity (DTH) response which initiates and perpetuates autoimmune vasculitis in these mice. These findings raise questions regarding the immunologic mechanisms by which basophils develop in this lesion and the interaction of basophils. VSMCs and lymphocytes in vasculitic angiodestruction.     

A multicenter clinical trial of gadolite oral suspension as a contrast agent for MRI

The purpose of this study was to assess the effectiveness and safety of Gadolite Oral Suspension as a gastrointestinal (GI) contrast agent for MRI in a phase II and two phase III multicenter clinical trials. Gadolite was administered to 306 patients with known or suspected abdominal and/or pelvic disease. MRI with T1- and T2-weighted sequences was performed before and after ingestion. Efficacy was evaluated by having two masked readers rate the certainty of their MR diagnosis (0 = uncertain, 1 = probable, 2 = definite) on randomly presented pre- and post-Gadolite Oral Suspension enhanced images. Principal investigators also evaluated the images and established the final diagnosis. Vital signs, clinical chemistries, and adverse events were documented. Blood and urine samples were analyzed for gadolinium content to determine whether Gadolite Oral Suspension was absorbed systemically. Certainty in MR diagnosis increased significantly (P < .001) for both blinded readers between pre- and post-Gadolite images (.49–1.18 for reader 1; .46–1.53 for reader 2). Sensitivity, specificity, and accuracy also increased for both masked readers. No gadolinium was detected in blood or urine samples. There were no serious adverse events and no apparent drug-related trends in mean vital signs or laboratory values. Gadolite is a highly effective, safe, and well tolerated contrast agent for clinical use with MRI.     

Block of the endplate acetylcholine receptor channel by the sympathomimetic agents ephedrine, pseudoephedrine, and albuterol

Recent observations suggest that some patients with congenital myasthenic syndromes respond favorably to ephedrine, pseudoephedrine, or albuterol. Conventional microelectrode studies, however, provide no clear explanation for a beneficial effect of ephedrine in endplate diseases. To gain further insight into how these drugs affect neuromuscular transmission, we investigated their effects on the kinetic properties of the acetylcholine (ACh) receptor. Single channel currents were recorded from rat lumbrical muscles endplates using low concentrations of ACh and 2.5–100 μM of drugs. Between 10–100 μM, each drug progressively increased the rate of channel closure in a concentration dependent manner, consistent with an open-channel block. Albuterol acted as a sequential fast-acting channel blocker, increasing the mean burst duration in a concentration dependent manner without altering the total open time per burst or the duration of intraburst blockages. Increasing concentrations of ephedrine and pseudoephedrine also increased the number of intraburst closures but decreased the total open time per burst. None of the drugs altered single channel conductance. The channel blocking effects of ephedrine and pseudoephedrine might reduce the synaptic overactivity that occurs in the slow-channel myasthenic syndromes or in endplate ACh esterase deficiency, but these effects occur at concentrations not attainable in clinical practice.     

Partial-solubility Parameters of Naproxen and Sodium Diclofenac

The expanded Hansen method was tested for determination of the solubility parameters of two non-steroidal anti-inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility lnX₂ in the solubility models. The solubility of both drugs was measured in pure solvents of several chemical classes and the activity coefficient was obtained from the molar heat and the temperature of fusion. Differential scanning calorimetry was performed on the original powder and on the solid phase after equilibration with the pure solvents, enabling detection of possible changes of the thermal properties of the solid phase that might change the value of the activity coefficient. The molar heat and temperature of fusion of sodium diclofenac could not be determined because this drug decomposed near the fusion temperature. The best results for both drugs were obtained with the dependent variable lnX₂ in association with the four-parameter model which includes the acidic and basic partial-solubility parameters δ_a and δ_b instead of the Hansen hydrogen bonding parameter δ_h. Because the dispersion parameter does not vary greatly from one drug to another, the variation of solubility among solvents is largely a result of the dipolar and hydrogen-bonding parameters, a fact that is being consistently found for other drugs of small molecular weight. These results support earlier findings with citric acid and paracetamol that the expanded Hansen approach is suitable for determining partial-solubility parameters. The modification introduced in the expanded Hansen method, i.e. the use of lnX₂ as the dependent variable, provides better results than the activity coefficient used in the original method. This is advantageous for drugs such as sodium diclofenac for which the ideal solubility cannot be estimated. This paper shows for the first time that the method is suitable for determination of the partial-solubility parameters of a sodium salt of a drug, sodium diclofenac.     

Effect of clonidine on ultrasonic vocalization in preweaning rats

Summary The present study was undertaken to investigate the involvement of the noradrenergic neurotransmission system in the ultra sonic callings emitted by rat pups separated from their mother and exposed to cold stimulation. The investigation was primarily performed by help of agents selectively affecting the -adrenoceptors: the ₂-agonist clonidine, the ₁-antagonist prazosin and the ₂-antagonist idazoxan.Clonidine dose-dependently stimulated the amount of ultra sonic vocalization, an effect not solely dependent upon the effect of clonidine on body temperature. In a developmental study it was found that clonidine uniformly stimulated crying at all ages from 4 days of age up to 18 days of age, that is during the whole preweaning period. Clonidine stimulated ultrasonic crying in rat pups, devoid of presynaptic catecholamine (CA) neurons by combined pretreatment with the monoamine depletor, reserpine, and the inhibitor of CAsynthesis, -methyl-tyrosine. This finding suggested that the stimulating effect of clonidine on ultrasonic vocalization was mediated by postsynaptic adrenoceptors.In pups, 12 days of age, idazoxan blocked the effect of cold stimulation on ultra sonic crying, suggesting that ₂-adrenoceptors, presumably postsynaptic ones, mediated this kind of stimulation. Idazoxan also antagonized the effect of clonidine, but only at a dose effective also in control pups. Prazosin had no effect on cold-stimulated crying, but antagonized the effect of clonidine, suggesting that the effect of clonidine was also mediated by ₁-receptors. At 18 days of age, prazosin no longer antagonized the effect of clonidine, whereas the antagonizing action of idazoxan was reinforced.The age-dependent variation in responsiveness to the adrenergic drugs suggest maturational changes in the function of the CA-system occurring between 12–16 days of age.     

A developmentally regulated chlamydial gene with apparent homology to eukaryotic histone H1.

We have developed a method for the isolation of genes whose expression is developmentally regulated from the murine strain of Chlamydia trachomatis. Here we describe the identification of two developmental stage-specific genes, one of which is predicted to encode a 26-kDa lysine- and alanine-rich protein that appears to be homologous to several eukaryotic histone H1 proteins. A substantial proportion of this homology relates to its distinctive amino acid composition. No sequence homology was observed between this protein and other bacterial "histone-like" chromosomal proteins, but homology does exist with two other recently described prokaryotic proteins. The protein is expressed late in chlamydial development, during the transition from reticulate bodies to elementary bodies. The basic nature of the protein predicts that it could bind DNA, and Southwestern blotting experiments confirm this finding. These properties are consistent with a role either in the regulation of late gene expression or in the compaction of the chlamydial genome.     

Macular disease in related rhesus monkeys

During (January) 1986–(May) 1988, we examined 272 eyes in 136 rhesus monkeys in the closed Cayo Santiago colony of the Caribbean Primate Research Center of the University of Puerto Rico. Seventy-eight eyes were less than 10 years of age. One hundred and ninety-four were aged 10–28 years. The fundi were examined and photographed. Fluorescein angiography was performed in some eyes. Selected cases were evaluated for acuity loss by recording of pattern-evoked retinal and cortical signals. Light and electron microscopy were used to evaluate the pigment epithelium of some animals. Thirty-eight percent of all eyes had posterior pole drusen. Incidence was highly age-related. When late-stage lesions were found, we did not see neovascularization, but late hyperfluorescence was consistent with degenerative scarring and atrophy. Electrophysiology demonstrated moderately reduced acuity in the presence of numerous macular drusen. Electrooculograms were low normal. Histopathology showed changes identical to those reported in human age-related macular degeneration. No eyes less than 10 years of age had confluent drusen or disciform-like lesions. The incidence of drusen in samples of some social groups was much higher than others.