Differential effects of monoclonal antibodies to tumor necrosis factor alpha and gamma interferon on induction of hepatic nitric oxide synthase in experimental gram-negative sepsis.

To investigate the stimuli required for the induction of nitric oxide synthase (NOS) in sepsis, we have analyzed the levels of this enzyme in the livers of mice infected with a 90% lethal dose of Escherichia coli in a model of gram-negative sepsis. Hepatic NOS levels are markedly induced in this model, with peak values occurring 12 to 22 h following infection. Treatment with TN3-19.12, a neutralizing monoclonal antibody to tumor necrosis factor alpha (TNF-alpha), resulted in complete protection from death in this model of sepsis but had no significant effect on the level of induction of hepatic NOS. Treatment with H22, a monoclonal antibody to gamma interferon (IFN-gamma), also gave significant protection against death and, in addition, did lead to a decrease in the level of induction of the hepatic NOS. Treatment of mice with pure TNF-alpha (0.2 microgram), IFN-gamma (2,000 U), or a combination of the two did not induce the hepatic NOS, but treatment with the combination led to significant mortality (probability of survival at 22 h, 0.32). Thus, the level of induction of NOS within the liver either in sepsis or by the coadministration of TNF-alpha and IFN-gamma does not correlate with death.     

Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31

We studied 10 members of a 4 generation Missouri kindred with a dominant mental retardation syndrome with increasing severity in males. The 21 year-old propositus presented with severe mental retardation, microcephaly, asymmetric face, exotropia, hypogonadism, joint hypermobility, rocker bottom feet, and 10 low digital arches. Two brothers and a male cousin had similar features. The mother, sister, niece, maternal aunt, female cousin, and grandmother were examined and each had 8 to 10 low digital arches. Five of the women had exotropia and one had pes cavus feet. Chromosome analysis for fragile X in multiple relatives was normal. To determine the likelihood that this was an X-linked syndrome. DNA from relatives was hybridized to probes which detect 13 different loci spanning the X-chromosome. A peak LOD score of 2.78 at theta equal to 0.0 was calculated for the syndrome locus and DXYS1 (pDP34). The more distal Xq loci showed increasing recombination with the syndrome locus. These results are consistent with location for this syndrome near Xq21.31, the chromosomal locus for DXYSI.     

Effects of inorganic and triethyl lead and inorganic mercury on the voltage activated calcium channel of Aplysia neurons.

Using conventional two electrode voltage clamp techniques we have studied the effects of Pb2+, triethyl lead (TEL) and Hg2+ on voltage-activated calcium channels of Aplysia neurons and found that all three metals are potent inhibitors at micromolar concentrations. However, the time course of current reduction or block and its reversibility vary when comparing Pb2+ to TEL and Hg2+. With application of Pb2+ the calcium current decreases immediately and a steady state is reached within three to seven minutes, depending upon the concentration of Pb2+ (IC50 = 61 microM). The block was easily reversed upon wash out of Pb2+ with a time course similar to that of onset. Perfusion with either TEL (5 to 50 microM) or Hg2+ (5 to 200 microM) resulted only in a small reduction of current when the substances reached the cell membrane but with clear reduction within 2 min. The decrease continued at about the same speed for the total duration of the application. Upon washing there was no recovery of the response. At the onset of washing the rate of current decline stopped for several minutes, but then the current continued to decline at a slower rate in the absence of toxicant. Our data suggest that Pb2+ acts by a direct and reversible blockade of the calcium channel. In contrast TEL and Hg2+ act slowly and irreversibly to block calcium channels at concentrations which do not greatly affect membrane potential or resistance. In spite of the slow time course these substances are probably acting directly on the calcium channel.     

Gingival cyst of the adult. Case report of a bilateral presentation

The gingival cyst of the adult (GCA) constitutes a pathologic developmental process that the dentist must be prepared to diagnose and treat. The GCA has been infrequently reported in the past as a unilateral phenomenon, but this case constitutes the first known report of synchronously occurring, bilateral GCA in the dental literature.     

The heterogeneity of the long-term course of schizophrenia

Research has demonstrated considerable heterogeneity in the long-term course of schizophrenia. In the period preceding the onset of frank psychosis (onset), patients vary relative to the rapidity of onset, the presence or absence of associality, and the presence or absence of semipsychotic symptoms. Following the onset of psychosis (middle course), patients may suffer from episodic or unremitting psychosis, and may or may not exhibit the deficit syndrome. In late adult life (late course), patients vary relative to the presence or absence of an improvement in psychosis and social capability. The usual approach to the study of putative course subtypes is to define a subtype by a number of features; they may include features of more than one epoch. In addition, the course of psychosis has not been distinguished from enduring personality impairments in these subtypes. Another approach to defining putative course subtypes would be based on dichotomizing patients according to the presence or absence of a particular feature of a single epoch. This second approach has important advantages: the availability of larger study populations and a diminished liability for confounding due to the correlates of features other than those under scrutiny.     

Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease.

BACKGROUND. Bypass grafting to arteries of the lower leg has become standard surgical management of advanced peripheral vascular disease. Its success depends on identifying suitable distal vessels. Preoperative preparation includes imaging of the arteries of the lower leg, usually by conventional contrast arteriography. An alternative procedure, magnetic resonance (MR) angiography, has been successfully employed in patients with various cardiovascular diseases, but its possible value in patients with peripheral vascular disease has received little attention. METHODS. We used both conventional and MR angiography in preoperative studies of the lower-leg vessels of 23 patients (25 legs) with peripheral arteriosclerosis and arterial insufficiency, and developed independent therapeutic plans based on the information provided by each technique. When the plans differed, the interventional procedure judged more likely to save the limb was performed. The findings of conventional and MR angiography were verified by intraoperative arteriography, postinterventional arteriography, or direct operative exploration. RESULTS. MR angiography detected all vessels identified by conventional angiography, whereas conventional arteriography failed to detect 22 percent of the runoff vessels identified by MR angiography. The detection by MR angiography of vessels not identified by conventional angiography altered the surgical management of the disorders of four patients (17 percent) and guided successful bypass procedures. CONCLUSIONS. MR angiography is a noninvasive technique with greater sensitivity than conventional contrast arteriography for detecting distal runoff vessels in patients with peripheral arterial occlusive disease.     

Elevated membrane association of phospholipase C-gamma 1 in MDA-468 mammary tumor cells.

We have examined the distribution of phospholipase C-gamma 1 (PLC-gamma 1) between membrane and cytosolic fractions in several cell lines. In MDA-468 cells, which are derived from a human breast tumor, greater than one-half of the total PLC-gamma 1 is associated with the membrane fraction of the cell. Unlike the situation in A-431 cells [G. Todderud, M. I. Wahl, S. G. Ree, and G. Carpenter, Science, 248: 296-298, 1990], epidermal growth factor (EGF) stimulation of MDA-468 cells does not result in significantly increased PLC-gamma 1 association with membranes. Immunoblot analysis reveals low levels of phosphotyrosine in PLC-gamma 1 and EGF receptors in unstimulated MDA-468 cells and greatly increased phosphotyrosine levels in these proteins as a result of EGF stimulation of the cells. We conclude that autocrine activation of EGF receptors is not responsible for the elevated association of PLC-gamma 1 with membranes in these cells.     

Synthesis and transport of GAP-43 in entorhinal cortex neurons and perforant pathway during lesion-induced sprouting and reactive synaptogenesis.

Metabolic labeling and quantitative 2D gel autoradiography were used to assess changes in the synthesis and transport of GAP-43 in entorhinal cortex (EC) neurons and perforant pathway during lesion-induced sprouting and reactive synaptogenesis. In normal adult rats, there is a high constitutive level of GAP-43 synthesis and transport in EC neurons projecting to the hippocampus. Following unilateral EC lesions, there is a 2-fold (100%) increase in the transport of newly synthesized GAP-43 to the contralateral or 'sprouting' hippocampus. The timing of this upregulation (between 6 and 15 days) suggests that changes in GAP-43 expression occur in response to the growth of presynaptic terminals during sprouting.