An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M

The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization.     

Ultrasonic vocalization behavior differs between lines of ethanol-preferring and nonpreferring rats

To further understand the relationship between emotional state and alcohol intake in rats, the tendency to emit ultrasonic vocalizations in response to an aversive, but nonpainful, air puff stimulus was tested in several rat lines. Included in this group were Maudsley Reactive (MR) and Non-Reactive (MNR) rats, and several lines of rats with either high ethanol preference or a low ethanol preference: Preferring, (P), Alko-Alcohol (AA), and Fawn-Hooded (FH) animals; and Non-Preferring (NP), Alko-Non-Alcohol (ANA), and Flinders Resistant Line (FRL). MR rats emitted fewer ultrasonic vocalizations (USVs) and showed less preference for ethanol than did MNR animals. An overall analysis that included the P, NP, FH, FRL, AA, and ANA groups demonstrated a significant negative correlation between the total number of USVs emitted and ethanol consumption. NP, FRL, and especially ANA rats (low ethanol-preferring) emitted the most USVs--to an extent similar to that typically found for normal rats. The duration of vocalizing was higher only in the NP and the FRL rats the relative to their P and FH comparison groups, respectively. In the ethanol-preferring and nonpreferring lines, the numbers of USVs emitted correlated positively with the duration of vocalizing, but not with the latency to vocalize, which in turn did not correlate strongly with ethanol intake. The latency to vocalize did not correlate significantly with ethanol intake across all drinking lines or MR or MNR rats, but was found to be higher in FH and AA rats relative to their nondrinking comparison groups. These associations suggest that the relationship between emotional state and ethanol drinking is complex and cannot be attributed to a simple elevated state of anxiety or emotionality. Further examination of the central nervous system mechanisms mediating the difference in USVs between paired lines of ethanol-preferring and nonpreferring rats may identify neurochemical factors that predict ethanol preference.     

MR imaging of congenital anomalies of the thoracic veins

Congenital anomalies of the thoracic veins are infrequent but important developmental abnormalities. Thoracic venous anomalies can be classified as systemic or pulmonary. Systemic venous anomalies are often incidental findings, whereas pulmonary venous anomalies are more likely to manifest with cyanosis and to be associated with congenital cardiac abnormalities, especially atrial septal defect. Magnetic resonance (MR) imaging provides excellent delineation of the abnormal vessels and associated cardiac defects. Conventional spin-echo (SE) techniques show blood flow as a signal void and are sufficient for demonstrating the aberrant venous anatomy in most cases. Gradient-echo images show flowing blood as high signal intensity and are useful for clarifying the course of anomalous veins when vessel walls are difficult to visualize on SE images. Phase-contrast images are valuable for ascertaining the direction of blood flow and thus provide a physiologic method of distinguishing the vertical vein of anomalous pulmonary venous return from a left superior vena cava. MR imaging is useful for delineating both the thoracic venous and accompanying intracardiac anomalies and is a valuable, complementary technique to echocardiography, angiography, and computed tomography in the evaluation of patients with these abnormalities.     

Red flags and religious coping: identifying some religious warning signs among people in crisis

Particulate and soluble (1-3)-beta-glucans are effective in preventing infections by enhancing macrophage and neutrophil functions. However, the mechanisms triggering these enhanced cellular responses are essentially unknown. We recently demonstrated that zymosan, a particulate (1-3)-beta-glucan receptor agonist, caused an influx of Ca2+ in NR8383 rat alveolar macrophages (AMs) and a resulting increase in intracellular Ca2+ (Zhang et al., J. Leukoc. Biol. 62 (1997) 341-348). Since Ca2+ is important in mediating leukocyte responses, we investigated whether other (1-3)-beta-glucans also alter Ca2+ mobilization in AMs. Particulate and soluble (1-3)-beta-glucans derived from Saccharomyces cerevisiae were used in these studies. Like zymosan, particulate (1-3)-beta-glucan (WGPs) caused a concentration-dependent increase in [Ca2+]i, which was inhibited by removal of extracellular Ca2+ and by SKF96365, an inhibitor of receptor-operated Ca2+ channels. When three different soluble (1-3)-beta-glucans, with molecular weights of approximately 11,000, 150,000, and 1,000,000 Da, were tested alone for effects on Ca2+ responses, the low molecular weight (1-3)-beta-glucan produced no effect and the intermediate and high molecular weight (1-3)-beta-glucans caused only a small increase in [Ca2+]i. Interestingly, however, all three soluble (1-3)-beta-glucans could significantly reduce the Ca2+ responses induced by a subsequent exposure to either WGPs or zymosan. These results demonstrate that: 1) particulate (1-3)-beta-glucan activates Ca2+ influx in NR8383 macrophages through receptor-operated Ca2+ channels; 2) soluble (1-3)-beta-glucans do not strongly activate Ca2+ influx in these cells; and 3) soluble (1-3)-beta-glucans significantly inhibit Ca2+ influx induced by WGPs or zymosan. Soluble (1-3)-beta-glucans are likely to prevent Ca2+ influx by competitively binding to the (1-3)-beta-glucan receptors recognizing zymosan and WGPs. The smaller Ca2+ influx induced by soluble (1-3)-beta-glucans may represent only a partial activation of post-receptor signal transduction pathways necessary for inducing Ca2+ influx.     

Combinatorial chemistry in insects: a library of defensive macrocyclic polyamines

The pupal defensive secretion of the coccinellid beetle Epilachna borealis is composed principally of a combinatorial library of macrocyclic polyamines. These compounds constitute a previously unrecognized family of natural products, characterized by extremely large-ring lactonic structures derived from a small set of (2-hydroxyethylamino)alkanoic acids. The combinatorial assembly of these simple building blocks generates a high degree of structural diversity, which is further increased by slow, spontaneous intramolecular rearrangement of the macrocycles.     

Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches

Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10 patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor (FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS, DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently. IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS associated with IgG-MGUS, but not with IgM-MGUS.     

Early cyclosporine monotherapy in liver transplantation: a 5-year follow-up of a prospective, randomized trial

Maintenance of adequate immunosuppression and avoidance of side-effects are the goals of long-term management of all organ-transplanted patients. We here report the final results of a prospective, randomized trial comparing early cyclosporine monotherapy versus double-drug therapy (cyclosporine and steroids) in adult liver transplantation patients. One hundred four patients were randomized 3 months after transplantation either to continue (Group I = 50 patients) or to stop steroids (Group II = 54 patients). Patients on a double-drug regimen were maintained long term on methylprednisolone at a dose of 0.1 mg/kg/d. Target cyclosporine trough levels were between 150 and 250 ng/mL in both groups. Our main points of interest were the prevalence of acute and chronic rejections and steroid-related side-effects in the two groups of patients. Mean follow-up was 41 +/- 16 months (range, 4-68 months). Patient actuarial survival 2 and 5 years after randomization was similar in the two groups (82% vs. 83% and 82% vs. 77%). The prevalence of acute rejections after randomization was, respectively, 8% and 4%. A single episode of chronic rejection was observed only in a patient on long-term steroid therapy. Side-effects of steroid therapy were less frequent in patients weaned off steroids, and when considering hypertension and diabetes, the differences between the two groups were statistically significant. Early cyclosporine monotherapy is a safe undertaking in liver transplantation because it allows a significant reduction of steroid-related side-effects without increasing the risk of acute and chronic rejection. After 5 years, patient survival was similar in patients with or without steroids.     

Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity

PURPOSE: The goal of this study is to describe asymmetrical forms of primary open angle glaucomas in black african originated patients. MATERIAL AND METHOD: Data of 514 glaucomatous patients (1022 eyes) followed between 1993 and 1997, and attending our hospital eye department are retrospectively analysed. All the participants were diagnosed as primary open angle glaucomas; asymetry was defined as a difference of 0.2 at least between the vertical cup disc ratio of the same patient. RESULTS: The mean age of all 514 glaucoma patients was 34.52 +/- 15.55 years; 254 patients (49.40%) had no differences between cup disc values while 260 remaining others had asymmetric glaucomas (50.58%). Of them, 189 (72.69%) had a difference of 0.2 between both eyes; 49 (18.8%) had 0.3 difference; 7 (2.69%) had 0.4 difference; 4 (1.53%) had 0.5 difference, and 11 (4.23%) a difference of 0.6. Besides, 114 eyes (11.15%) had a vertical ratio of 0.9 at the first diagnosis. CONCLUSION: Carefully recognition of asymmetric cup disc ratios is of great diagnostic value in the the early stages of primary open angle glaucoma because 50% of all patients presented with this clinical form in our experience. This strategy would improve early diagnosis of glaucoma in our areas.