Sickle cell disease. Do you doubt your patient's pain?
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Adult↗
Biomedical subjects
K Gorman
Publications and source records attributed to K Gorman.
Cloned cytotoxic T lymphocytes as target cells. II. Polarity of lysis revisited.
The original polarity of lysis experiments suggested that CTL are themselves sensitive to whatever mechanism it is that CTL use to lyse their targets. This concept has placed certain limitations on possible mechanisms of lysis by CTL. Recently, we found in studies with cloned CTL as targets that cloned CTL are in fact highly resistant to lysis by other CTL, as well as to their cytotoxic granule proteins. We show here that although cloned CTL are extremely resistant to lysis by primary and cloned CTL, they are readily inactivated functionally by all primary CTL and by at least one CTL clone. Moreover, cloned CTL are also functionally inactivated by cytotoxic granule proteins. The activation of CTL, which we call inhibitin, is Ca2+ insensitive and distinct from hemolytic activity, and is, thus, unlikely to be perforin. These experiments suggest a possible alternative interpretation of the original polarity of lysis experiments.
Animals↗
Cloned cytotoxic T lymphocyte target cells fail to induce early activation events in effector cytotoxic T lymphocytes.
We have explored further the basis for resistance of cloned cytotoxic T lymphocytes (CTLs) to cell-mediated cytotoxicity. We find that most cloned CTLs recognized as specific target cells by other cloned CTLs used as effector cells fail to activate three early events that may be critical in triggering lysis in the effector CTLs: Ca2+ influx, microtubule organizing center (MTOC) reorientation, and serine esterase release. To the extent that any or all of these events are involved in activation or expression of the lytic pathway in effector CTLs, our results suggest that in addition to being inherently resistant to cytotoxic granule extracts, many CTLs are also unable to induce lytic function in other (effector) CTLs. We have found one CTL clone that can respond to recognizable cloned CTL target cells with at least MTOC reorientation and serine esterase release, although the target CTLs are still not lysed. In this case, the resistance of the target CTL to lysis may be due solely to its resistance to cytoplasmic granule contents.
Animals↗
Molecular mechanisms of CTL-mediated lysis: a cellular perspective.
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Animals↗
Cocaine self-administration in rats influenced by environmental conditions: implications for the etiology of drug abuse.
The present study investigated the possibility of environmental factors as an explanation for between-subject differences in cocaine self-administration. Weaning rats (21 days) were housed in isolated or aggregated conditions for 6 weeks and were tested for intravenous cocaine self-administration (0.1-1.0 mg/kg/infusion). Rats housed in groups failed to reliably self-administer this drug whereas isolated rats readily acquired an operant to receive infusions of cocaine. These data suggest that environmental factors play a major role in determining individual differences in the propensity to self-administer cocaine and that, as such, they should be considered more seriously by those interested in the basis and treatment of drug abuse.
Animals↗
Resistance of cloned cytotoxic T lymphocytes to cell-mediated cytotoxicity.
Cloned CTLs show an unusually high resistance to lysis by effector CTLs. Several cloned CTL lines in our laboratories are absolutely refractory to lysis by other cloned CTLs, either (a) directly, (b) in the presence of lectin, or (c) by PMA-induced CTLs. They can be lysed to some extent by primary CTL, although they are less than 5% as sensitive as target cells normally used to assay primary CTL lytic activity. Lysis of cloned CTLs by primary CTL effector cells is not enhanced by the presence of lectin, and cloned T cells are also highly resistant to lysis by primary lymphokine-activated killer cells. Cloned CTLs are highly resistant to lysis by isolated CTL granules that contain the membranolytic pore-forming protein (PFP or perforin), while non-CTL targets are highly susceptible to granule-mediated killing, indicating that cloned CTLs resist lysis not only at the intact effector cell level but also when soluble effector proteins are used. This resistance mechanism may explain how CTLs kill but spare themselves from being killed during the cytolytic event.
Animals↗
Age-dependent effects of isolation housing on the self-administration of ethanol in laboratory rats.
Studies of the influence of housing conditions on ethanol self-administration have been inconsistent, with findings that isolation housing increases, decreases or produces no effects on ethanol intake. One possible explanation for these discrepant findings is that the effects of housing are dependent on the age at which the manipulation is performed. In the present experiment rats were housed from weaning or from age 65 days in either an isolated or grouped condition. After 12 weeks, they were tested for the voluntary oral self-administration of ethanol. Although all rats consumed comparable quantities of ethanol when lower concentrations were available, the rats isolated from weaning consumed significantly greater amounts of more concentrated ethanol than their group-housed counterparts. In contrast, there was no difference in ethanol consumption between isolated and grouped rats when they were differentially housed at maturity. These data suggest that an important determinant of ethanol intake in rats is related to environmental factors and that the influence of these factors is age-dependent.
Aging↗
Nerve and tendon gliding exercises and the conservative management of carpal tunnel syndrome.
While developments continue in the surgical management of carpal tunnel syndrome, little emphasis has been placed on the evaluation of a comprehensive non-surgical treatment. In this study, 197 patients (240 hands) presenting for treatment of carpal tunnel syndrome were divided into two groups. Patients in both groups were treated by standard conservative methods, and those in one group were also treated with a program of nerve and tendon gliding exercises. Of those who did not perform the nerve and tendon gliding exercises, 71.2% underwent surgery compared with only 43.0% of patients who did perform them. Patients in the experimental group who did not undergo surgery were interviewed at an average follow-up time of 23 months (range, 14-38 months). Of these 53 patients, 47 (89%) responded to this detailed interview. Of the 47 who responded, 70.2% reported good or excellent results, 19.2% remained symptomatic, and 10.6% were non-compliant. Thus, a significant number of patients who would otherwise have undergone surgery for failure of traditional conservative treatment were spared the surgical morbidity of a carpal tunnel release (p = 0.0001).
Adult↗
Complement activation in patients undergoing mechanical circulatory support.
Contact of blood with artificial surfaces activates pro-inflammatory responses and the complement cascade. This may have broad implications on the post implantation fate of patients needing mechanical circulatory support. Therefore, we investigated the course and prognostic value of complement factors C3a and C5a in 66 patients supported with pulsatile ventricular assist devices. All patients were in severe cardiogenic shock, i.e., catecholamine dependent and in the intensive care unit, before implementation of mechanical circulatory support. Isolated left ventricular support (Novacor [Oakland, CA] or Thermo Cardiosystems, Inc. [TCI; Woburn, MA]) was used in 28 patients, and biventricular support (Berlin Heart [Mediport, Berlin, Germany]) in 38 patients. Before initiation of mechanical circulatory support, no statistically significant differences in C3a or C5a between surviving and nonsurviving patients with left ventricular assist devices (LVADs) were found. Patients with biventricular assist devices (BVADs) had significantly higher C3a (804 +/- 364 ng/L) levels than patients with LVADs (536 +/- 204 ng/L, p = 0.02) before mechanical circulatory support. Only C5a, only in the BVAD group, was able to predict patients' post implantation course before implantation of a ventricular assist device (p = 0.02). Three weeks after initiation of mechanical circulatory support, complement factors remained increased in all groups. There was no difference, however, in complement activation between patients with LVADs and those with BVADs. Patients not reaching transplantation had significantly higher C3a levels at this point than those successfully supported (p = 0.007). The degree of complement activation mainly depends on the severity of cardiogenic shock before initiation of mechanical circulatory support, and not on the device used. Patients with extremely high levels of complement activation before implantation of the device could be saved with BVAD rather than LVAD support. Patients who continued to have highly elevated complement levels 3 weeks after initiation of mechanical circulatory support had unfavorable prognoses. Complement activation indicates the severity of cardiogenic shock before implementation of mechanical circulatory support and the degree of recovery from secondary organ dysfunction while on the device. It is fairly independent of the system used for mechanical circulatory support, and therefore can be applied to predict patients' post implantation course and outcome.
Adolescent↗
Orbital involvement in Wegener granulomatosis: MR findings in 12 patients.
PURPOSE: Our goal was to characterize the MR features of orbital Wegener granulomatosis (WG). METHOD: Twelve patients with pathologically proven WG were studied with MRI. Enhanced and unenhanced T1-weighted sequences with conventional and fat-suppressed techniques were used. T2-weighted images were also obtained. Signal intensity measurements were made in each orbital lesion on the T2-weighted images and compared with that of normal fat. The degree of enhancement was also evaluated by measuring the change in signal intensity of each lesion between the unenhanced and enhanced studies. RESULTS: Seventeen orbital lesions were identified in the 12 patients. Fifteen of the lesions examined by T2-weighted sequences demonstrated a marked decrease in signal intensity. The unenhanced, non-fat-suppressed T1-weighted sequences provided the best contrast between lesion and normal structures. All of the WG lesions enhanced, but the degree of enhancement varied. The enhancement characteristics were best appreciated on the fat-suppressed T1-weighted technique. CONCLUSION: MRI is an excellent imaging modality to evaluate orbital involvement in WG. A marked decrease in the T2 signal is a characteristic feature of this entity. The unenhanced, non-fat-suppressed T1-weighted sequence is the preferred method for lesion detection and for definition of the pattern of anatomic involvement when utilizing MRI.
Adult↗