Serological specificity of phenolic glycolipid I from Mycobacterium leprae and use in serodiagnosis of leprosy

The serological activities of the specific phenolic glycolipid I from Mycobacterium leprae, its dissected parts, and related glycolipids from other mycobacteria were examined by enzyme-linked immunosorbent assay against hyperimmune anti-M. leprae rabbit antiserum and sera from patients with leprosy and other mycobacterial diseases. High anti-phenolic glycolipid I immunoglobulin M antibodies were found in 23 of 24 (96%) of lepromatous leprosy patients on short term chemotherapy and in 8 of 13 tuberculoid leprosy patients (62%). Sera from patients with tuberculosis or atypical mycobacterial infections were devoid of anti-phenolic glycolipid I activity. The structurally related phenolic glycolipids from Mycobacterium kansasii and Mycobacterium bovis and the aglycone segments of the M. leprae product showed no significant activity. Thus, the trisaccharide determinant of phenolic glycolipid I is specific in its structure, serological activity, and, to a lesser extent, the antibody class it evokes.     

Metabolic depression and myocardial potassium

Summary The action potential duration (APD) of guinea pig atrial muscle responded qualitatively to metabolic depression and altered glucose concentration as shown previously for papillary muscle. Both preparations lost potassium and gained sodium during 8 h anoxic incubations and these changes were partially prevented by 50 mM glucose. Experiments with potassium⁴² indicated that anoxia-induced loss of potassium was not primarily due to an increased efflux but to a decreased influx. Stimulation did not increase potassium⁴² efflux from atria but caused some increase in potassium loss. The ATP content of atria and ventricular muscle decreased rapidly during anoxic incubation but was maintained at a significantly higher level in the presence of 50 mM glucose. Since muscle potassium levels following 8 h of anoxic incubation were incompatible with observed resting potentials, the results support the concept of either an electrogenic sodium pump or the intracellular compartmentalization of potassium. In addition, the anoxia-induced reduction of action potential duration does not appear to be associated with an increase in potassium⁴² efflux.This work was supported by grants from the Medical Research Council of Canada and the Canadian Heart Foundation.     

Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas

We compared hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas to incidental hyperplastic polyps to identify distinguishing morphologic criteria. The study group included 106 hyperplastic-like, nonadenomatous, serrated polyps, most from the ascending colon in 91 patients; the control group included 106 rectosigmoid hyperplastic polyps from 106 patients in whom adenocarcinoma did not develop. Study group polyps had an expanded crypt proliferative zone, a serrated architectural outline that became apparent in the basilar crypt regions, basilar crypt dilation, inverted crypts, and a predominance of dysmaturational crypts (crypts with minimal cell maturation). In contrast, control group polyps had a proliferative zone confined to the basal crypt region, serrated architecture that became apparent in the superficial crypt region, rare to no basilar crypt dilation, and rare or no dysmaturational crypts. Hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas had a distinctive constellation of morphologic features related to altered and decreased cell function and control that resulted in dysmaturational crypts. Dysmaturation constitutes a range of morphologic alterations, some of which overlap with incidental-type innocuous hyperplastic polyps. The morphologic features described herein provide initial guidelines to identify this potentially important subset of premalignant serrated-like polyps.     

Mechanical Contribution of Endocardium During Finite Extension and Torsion Experiments on Papillary Muscles

Finite extension and torsion tests on cardiac papillary muscles are presently the best way to directly measure the response to shear along myocardial fibers. Quantifying this response is necessary for determining the complete three-dimensional constitutive behavior of myocardium as a transversely isotropic material. Analysis of such tests is complicated, however, since papillary muscles are materially inhomogeneous, consisting of a myocardial core surrounded by an endocardial sheath that is rich in collagen. In this article, we show that the papillary muscle response to extension and torsion additively decouples into the response of the bare myocardial core plus the response of an endocardial sheath filled with fluid (assuming the muscle is a radially inhomogeneous and incompressible continuum with cylindrical symmetry). This result allows the endocardial response to be subtracted from the intact papillary muscle response to obtain the response of the bare myocardial core. An initial estimate suggests that the endocardial sheath affects the axial moment significantly (50% of torque for all twists at low stretch) but affects the axial force only slightly (<10% at moderate twists). © 1999 Biomedical Engineering Society. PAC99: 8719Hh, 8719Rr, 8719Ff     

Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients

The dorsolateral prefrontal cortex (DLPFC) plays an essential role in mood regulation and integration of cognitive functions that are abnormal in major depressive disorder (MDD). Few neuroimaging studies have evaluated the still maturing DLPFC in depressed children and adolescents. We conducted single voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left DLPFC in 14 depressed children and adolescents (13.3 +/- 2.3 years old, 10 males) and 22 matched healthy controls (13.6 +/- 2.8 years old, 13 males). Depressed subjects had significantly lower levels of glycerophosphocholine plus phosphocholine (GPC + PC; or choline-containing compounds) and higher myo-inositol levels in the left DLPFC compared to healthy controls. In the depressed subjects, we found significant inverse correlations between glutamate levels and both duration of illness and number of episodes. In healthy controls there was a significant direct correlation between age and glutamine levels, which was not present in the patient group. Lower GPC + PC levels in pediatric MDD may reflect lower cell membrane content per volume in the DLPFC. Increased myo-inositol levels in MDD may represent a disturbed secondary messenger system. GPC + PC and myo-inositol abnormalities further demonstrate the involvement of DLPFC in pediatric MDD.     

Studies on the role of interleukin-12 in acute murine toxoplasmosis.

Interleukin-12 (IL-12) is important in the regulation of resistance to Toxoplasma gondii in mice with severe combined immunodeficiency (SCID). The protective ability of IL-12 in SCID mice appears to be through its activity on natural killer (NK) cells to induce production of interferon-gamma (IFN-gamma). In this study we assessed the role of IL-12 in the acute stage of toxoplasmosis in immunocompetent mice. Administration of IL-12 to BALB/c mice infected with the virulent C56 strain of T. gondii remarkably delayed time to death. The protective activity of IL-12 was abrogated by administration of monoclonal antibodies to IFN-gamma or tumour necrosis factor-alpha (TNF-alpha), and by depletion of NK cells using an antisera against asialoGM1. Whereas BALB/c mice infected with the ME49 strain of T. gondii survived infection, administration of anti-IL-12 to infected mice resulted in 100% mortality accompanied by decreased serum levels of IFN-gamma. Furthermore, this treatment significantly reversed the suppression of spleen cell proliferation to concanavalin A (Con A), which is associated with the acute stage of infection, and resulted in decreased ex vivo production of IFN-gamma, IL-2, IL-4 and IL-10 in response to Con A. Our results indicate an important role for IL-12 in mediating resistance to T. gondii during acute infection in immunocompetent mice, that NK cells are required for this protective activity, and that IL-12 is involved in the immunosuppression which accompanies this infection.     

Integration from proteins to organs: the IUPS Physiome Project

The IUPS Physiome Project is an internationally collaborative open source project intended to provide a public domain framework for computational physiology, including the development of modeling standards, computational tools and web-accessible databases of models of structure and function at all spatial scales and across all organ systems. Here, we illustrate the application of this multi-scale modeling approach to three organ systems: the heart, the lungs and the musculo-skeletal system, and in each case we show how the organ level models incorporate tissue and cell-level physiology. Although the computational physiology framework presented here does not yet incorporate models of ageing processes, the model-based approach is certainly capable of describing ageing and disease-related processes both via parameter changes within the models of normal physiological processes and via models of additional processes added to the framework.     

Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-O-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine

A new lipophilic muramyl dipeptide analog, 6-O-stearoyl-N-acetylmuramyl-L--aminobutyryl-D-isoglutamine, when incorporated in liposomes, was effective in both the prevention and eradication of experimental pulmonary metastases in mice. Multilamellar vesicles composed of synthetic phospholipids (phosphatidylglycerol and phosphatidylcholine) containing saturated myristoyl or unsaturated dioleoyl acyl chains were found to potentiate the antimetastatic activity of this glycopeptide. Prophylactic and therapeutic efficacy was observed against the three murine tumors tested: FSa, an immunogenic fibrosarcoma; NFSa, a nonimmunogenic fibrosarcoma; and B16 melanoma. Neither the administration of empty liposomes or free glycopeptide, nor their coadministration, had a significant antimetastatic effect. This approach is promising for the therapy of cancer metastases in humans, particularly in the prevention of metastatic seeding and in the treatment of micrometastases.This is contribution No. 180 from the Institute of Bio-Organic Chemistry, Syntex Research.     

Dynamic relationship between EMG and torque at the human ankle: Variation with contraction level and modulation

Stochastic system identification techniques were used to determine the dynamic relationship between the electromyogram (EMG) and torque in the ankle muscles of normal human subjects. EMG and torque were recorded while subjects modulated ankle torque by tracking a computer-generated stochastic waveform. Nonparametric impulse response functions (IRFs) relating EMG to ankle torque were computed and parameterised by determining the parameters of the second-order system which provided the best least-squares fit. Two sets of experiments were carried out. In the first, the mean level of torque was varied from 5 per cent of the maximum voluntary contraction (MVC) to 30 per cent MVC while the depth of modulation was held constant at ±5 per cent of MVC. In the second series of experiments the mean torque was held constant at 25 per cent MVC while the depth of modulation was varied from ±2.5 per cent to ±25 per cent. The major findings were: (1) A second-order, low-pass filter provided a good quasilinear model of the EMG/force dynamics under all conditions; (2) The model parameters depended only weakly on the mean level of torque; (3) In contrast, the model parameters depended strongly on the amplitude with which the contraction was modulated; the natural frequency increased significantly with the depth of modulation.     

Increased central adiposity is associated with pro-inflammatory immunoglobulin G N-glycans

Background

Increased body fat may be associated with an increased risk of developing an underlying pro-inflammatory state, thus leading to greater risk of developing certain chronic conditions. Immunoglobulin G has the ability to exert both anti- and pro-inflammatory effects, and the N-glycosylation of the fragment crystallisable portion is involved in mediating this process. Body mass index, a rudimentary yet gold standard indication for body fat, has been shown to be associated with agalactosylated immunoglobulin G N-glycans.