Role of the CTLA-4 receptor in t cell activation and immunity

Costimulatory molecules of the B7 family regulate the activation of T lymphocytes. T cell activation is promoted by binding of B7 molecules to CD28 and inhibited by binding to CTLA-4 (CD152). The balance between positive signals through CD28 and negative signals through CTLA-4 is critical for the fate of the T cell and is subject to tight regulation. Recent in vitro and in vivo studies have significantly advanced our understanding of the function of the CTLA-4 receptor. The results of these experiments suggest that CTLA-4 is critical for the induction of self-tolerance, and that it may have distinct signaling functions in resting and activated T cells. In resting T cells, CTLA-4 crosslinking leads to cell-cycle arrest, whereas in activated T cells, CTLA-4 crosslinking induces apoptosis. In this article, we will review the physiologic functions of the CTLA-4 receptor.     

MRI of the fingers in patients with systemic scleroderma. Early results of contrast-enhanced examinations on a dedicated MRI system

Purpose. To estimate disease activity in patients with systemic sclerosis using contrast-enhanced MRI of the skin. Material and Methods. In a pre-study, sequences of a low-field (0.2 T) scanner (Artoscan, Esaote, Genova, Italy) were optimized for detection of intravenous contrast (0.1 mmol/l Gd-DTPA) in six patients with the autoimmune disease systemic scleroderma. Based on the results of the pre-study, 17 patients with scleroderma (7 sclerotic/10 active inflammatory disease) were scanned using gradient-spoiled 3D GRE sequences (FA 90 °, TR 100 ms, TE 18 ms), which had been established as most sensitive for intravenous contrast. Contrast enhancement of the skin was determined quantitatively by contrast-to-noise ratios (CNR), comparing post- to pre-contrast and dynamic scans (for 6 min, 1 acquisition/min). Patients in the chronic state with sclerodactylia and active inflammation of the hands were considered separately and compared to a control group (n = 10) matched according to age. Results. CNR increase after intravenous contrast was significantly higher in patients with active disease (86 ± 16 % increase) than sclerosing disease (29 ± 3 %, p < 0.05) and the control group (4 ± 2 %, p < 0.05). The dynamic examination showed a significantly slower decrease after the peak rise in the first minute in patients with active disease (CNR 15.4 ± 0.7 to 14.2 ± 1.4) than in those with chronic disease (14.1 ± 0.5 to 11.3 ± 0.9, p < 0.05). Discussion. Capillary leakage is the most likely explanation for the increased enhancement in patients with active scleroderma. Using sequences optimized for contrast detection, disease activity in the course of scleroderma and response to therapy can be determined by MRI in the future.      

Giving up driving in Alzheimer's disease—an integrative therapeutic approach

For patients with Alzheimer's disease (AD), a recommendation to stop operating a motor vehicle can be a serious event complicated by a loss of self-esteem and personal dignity. Patients are often reluctant to give up an activity so essential, both practically and symbolically, to independent living. We describe here a patient with moderately progressed AD who lacked insight of his need to cease driving. Through an integrative treatment approach, combining behavioral and psychodynamic modalities, we helped him to formulate effective ways of coping with his loss of access to independent transportation. We favor a psychotherapeutic strategy that combines behavioral and managerial measures with dynamic patient interaction, thereby developing the patient's insight of the need to give up driving while fostering his sense of autonomy.     

Endothelin and a Ca2+ ionophore raise cyclic GMP levels in a neuronal cell line via formation of nitric oxide.

1. The vasoconstrictor peptide endothelin-1 caused a fast, transient rise in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in a neuronal cell line (mouse neuroblastoma x rat glioma hybrid cells 108CC15). The mechanism of activation of guanylate cyclase by endothelin-1 was investigated. The endothelin-1-induced rise depended on the release of internal Ca2+. 2. The stimulation of cyclic GMP synthesis induced by endothelin-1 was suppressed after preincubating the cells in medium containing haemoglobin (IC50 3 microM). Similarly, pretreatment of the cells with the L-arginine analogues, L-canavanine (IC50 60 microM) or NG-monomethyl-L-arginine (IC50 2.5 microM), inhibited the cyclic GMP response to endothelin-1. Therefore, endothelin-1 activates guanylate cyclase most probably via formation of nitric oxide, which is released from L-arginine. 3. The Ca2+ ionophore ionomycin induced a transient rise in cyclic GMP levels, which was also suppressed by preincubation in the presence of either haemoglobin or the L-arginine analogues L-canavanine or NG-monomethyl-L-arginine. Therefore, we conclude that ionomycin can activate guanylate cyclase by a mechanism involving nitric oxide formation, similar to that induced by endothelin-1. 4. The alkaloid veratridine, which activates Na+ channels and also causes influx of Ca2+ induced a transient rise of cyclic GMP levels in the neuronal cell line. This stimulation was blocked by pretreating the cells with L-canavanine, NG-monomethyl-L-arginine or haemoglobin. 5. Loading the cells with the Ca2+ chelator BAPTA suppresed the cyclic GMP response to application of endothelin-1, ionomycin, or veratridine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hand and wrist imaging using a low-field dedicated MRI system

Summary Purpose of this study was to evaluate the diagnostic value of a low field dedicated MRI system in hand and wrist imaging. All 308 exams of the hand and wrist, that were performed on a low-field dedicated MRI system (Artoscan, Esaote Biomedica, Italy) in our institution in 1996, and high-field MRI exams performed in addition as part of the diagnostic work-up, were evaluated and correlated to final operative (n = 64) and histologic (n = 12) reports. 90 % of all low-field MRI scans stated a diagnosis according to clinical suspicion. In 62 % the clinical question was answered, and in 26 % additional pathologies were identified. An MR-diagnosis completely different from the clinical suspicion was stated in 2 %. High field exams contributed additional information in 6 of 36 patients. In 3 patients a tumor was not shown completely in the limited field-of-view of the dedicated low-field MRI-system. Frequency-selective fat-suppression pulse sequences and a better spatial resolution were the reasons for the additional information obtained in the other three patients. Low-field dedicated MR-imaging is a valuable method in the extensive work-up of the hand and wrist. Osseous, ligamentous and tendinous pathologies are well depicted. Large or infiltrative tumors should be referred to a high-field system.      

Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Background: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.

Methods: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34[degrees]C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.

Results: Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4[degrees]C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds.     

Compulsive respiratory stereotypies in children with autistic features: Polygraphic recording and treatment with fenfluramine

Syncopes due to compulsive respiratory stereotypies were studied in eight patients with autistic features. Most had been referred for episodes thought to be intractable epileptic seizures. Polygraphic recording showed two types of syncope, one induced by prolonged apnea and the other by a prolonged Valsalva maneuver. Fenfluramine, 1.5–3 mg/kg per day, was given in an open trial. In four of five cases with frequent Valsalva maneuvers, respiratory stereotypies and syncopes were suppressed for 2–18 months. Patients with periodic apneas were more severely retarded and had less clear benefit. Side effects consisted of dose-dependent sedation and mild weight loss which stabilized without interrupting treatment. We suggest that these syncopes are volitional and may be associated with pleasant sensations. A double-blind placebo-controlled trial of fenfluramine seems warranted in such patients.     

Production of toxic shock syndrome toxin 1 by Staphylococcus aureus restricted to endogenous air in tampons.

All types of four brands of tampons were tested in triplicate by a tampon sac method for their effect on production of toxic shock syndrome toxin 1 (TSST-1). In this method the available air is limited to that which is in the tampon sac. Tampons were weighed and inserted into dialysis sacs inoculated with a TSST-1-producing Staphylococcus aureus strain; the sacs were submerged into brain heart infusion agar, which was allowed to harden around the sacs, and were incubated for 18 h at 37 degrees C. The tampons were removed, weighed, and extracted; the CFU of staphylococci and the amount of toxin present in the extracts were determined. Glass wool was used in place of the tampons as one control, and inoculated empty sacs were used as a second control. The total CFU were consistently greater than 2 X 10(11) for the tampons and glass wool and less than or equal to 10(11) for the empty sac control. Total toxin production for all tampons tested and the glass wool was 2 to 10 times higher than the toxin produced with the empty sac control. These results indicate that tampons provide increased surface area for the staphylococci to grow and adequate oxygen for toxin production. No significant inhibition of growth of the staphylococci or TSST-1 production by any of the tampons tested was noted.