Correlation between lymphocyte-induced donor-specific tolerance and donor cell recirculation. Role of class I and class II major histocompatibility complex

Intravenous infusion of mice with viable allogeneic lymphocytes can produce donor-specific enhancement of skin graft survival, but only if the injected lymphocytes can persist in the host's recirculating lymphocyte pool for at least 3 days. We have investigated the relative roles of class I and class II MHC for C57BL/6 mice infused with lymphoid cells from co-isogenic strains mutated at class I MHC (bm1) or class II MHC (bm12), and for A.TH lymphoid cells infused into C3H (class I different, class II identical) or A.TH (class II different, class I identical). Injected cells differing from the host at class I MHC, but not at class II MHC, can be rapidly removed by host natural immune mechanisms (probably NK cells). Persistence is favored if the injected cells also carry host class I MHC, i.e., tolerance is more readily induced by injecting F1 (A x B) into A rather than B into A, consistent with the "missing self" hypothesis of NK recognition, with class I MHC being the relevant self-marker. Injected cells differing from the host at class II MHC but not at class I MHC always persist for at least 3 days, even when class I-different cells are being actively removed.     

Effects of subject- versus experimenter-selected reinforcers on the behavior of individuals with profound developmental disabilities

Results from a number of studies have shown that individuals with profound developmental disabilities often show differential approach behavior to stimuli presented in a variety of formats, and that such behavior is a reasonably good predictor of reinforcement effects when these "preferred" stimuli are used subsequently in a contingent arrangement. Recent data suggest that reinforcement effects may be enhanced further by allowing individuals to select, just prior to training sessions, which (of several) preferred stimuli would be used as reinforcers, but whether this method is superior to one based on selection by a teacher or therapist has not been adequately addressed. We compared the effects of these two methods of reinforcer selection on rates of responding on a free-operant task, using stimuli previously identified as potential reinforcers. Results obtained with 4 subjects indicated little or no difference in reinforcement effects when stimuli were selected by subjects rather than experimenters. Implications of these results with respect to choice and its relation to reinforcement are discussed.     

Symptomatic subclavian steal syndrome four decades after operation for dysphagia lusoria

Congenital abnormalities of the aortic arch may lead to signs and symptoms of tracheal and esophageal obstruction secondary to a restrictive vascular ring. There are many case reports and monographs concerning the surgical management of dysphagia lusoria. This case provides the first example of long-term follow-up of surgical intervention for relief of dysphagia lusoria. A 45-year-old laborer presented with a several year history of episodic bilateral blindness and a more recent onset of "drop attacks." Notably this patient had presented at the age of 18 months with difficulty breathing and eating since birth. The patient also had frequent upper respiratory infections and episodes of pneumonia. Workup revealed a right-sided aortic arch with a left ligamentum arteriosum. When he was first seen in our clinic, history and physical examination revealed claudication and diminished pulses in the left upper extremity. Arteriography and duplex studies confirmed reversal of flow in the patient's left vertebral artery. The arteriogram demonstrated the presence of a right-sided aortic arch and descending aorta along with the proximal stump of the previously ligated left subclavian artery. He underwent left carotid to left axillary artery bypass for the treatment of symptomatic subclavian steal syndrome. His symptoms have resolved with return of antegrade vertebral flow and the presence of normal pulses in the left arm. Congenital aortic abnormalities that lead to tracheal and esophageal compromise are numerous and varied. Surgical management requires a thorough understanding of the person's anatomy and preoperative planning. The life expectancy of patients with dysphagia lusoria necessitates consideration of the long-term consequences of surgical intervention.     

Virtual planning in patients with frontal lobe lesions

The VIrtual Planning Test (VIP) was developed to investigate the planning and organisational abilities of 25 patients with frontal lobe neurosurgical lesions, comparing their performance with 25 matched control subjects. The task, presented in the form of a board game, simulates planning and execution of a set of target activities that have to take place over a four day period, involving those that are either preparatory for a fictional "trip" abroad, or those that relate to the subject's current environment (context). The frontal lobe patients were impaired overall, tending to select inappropriate activities associated with their current context and showing greater impairment on subtasks requiring only one, rather than two, preparatory acts. The findings are discussed in terms of the validity of the VIP test in identifying executive functioning impairment and the degree to which the pattern of deficits are consistent with neuropsychological models of executive function.     

The impact of employment and serious illness on grandmothers who are raising their grandchildren

Increasing numbers of children are living in families consisting of grandparents and grandchildren. This paper presents findings of a study in which 123 caregiving grandmothers were interviewed. Fifty-eight percent of these grandmothers were "career caregivers," whose homes were always filled with a child or grandchild. Most of them were in good to excellent physical health and their mental health was at least as good as that of a national sample. Regression analyses found that having a life-threatening physical condition, being younger and white explained psychological anxiety; and having a life-threatening physical condition and not being employed explained psychophysiological mental health symptoms. These findings suggest that some grandmothers are at risk for mental health symptoms and raise questions about the implications of caregiving of grandchildren for women.     

NK cells can recognize different forms of class I MHC

NK recognition and lysis of targets are mediated by activation receptor(s) whose effects may be over-ridden by inhibitory receptors recognizing class I MHC on the target. Incubation of normal lymphoblasts with a peptide that can bind to their class I MHC renders them sensitive to lysis by syngeneic NK cells. By binding to class I MHC, the peptide alters or masks the target structure recognized by an inhibitory NK receptor(s). This target structure is most likely an "empty" dimer of class I heavy chain and beta2m as opposed to a "full" class I trimer formed by binding of specific peptide that is recognized by CTL.     

Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.     

Anterior cervical corpectomy for cervical spondylotic myelopathy

OBJECTIVE: To evaluate the efficacy of anterior surgery for the treatment of cervical spondylotic myelopathy, we have reviewed our experience with anterior cervical corpectomy (ACC) at the University of Florida, specifically analyzing neurological outcomes and complications. These results have been compared with historical control subjects receiving laminectomy or "no treatment." METHODS: Between 1982 and 1992, 93 ACC operations were performed for the primary diagnosis of cervical spondylotic myelopathy. This consecutive series of patients was reviewed retrospectively. Age, gender, pre- and postoperative myelopathy severity, number of levels decompressed, and neurological complications were assessed. Myelopathy severity was graded using the Nurick myelopathy grading system. The average follow-up period was 39 months (range, 2-137 mo). RESULTS: Symptomatic improvement was achieved for 92% of patients (F = 28.9, df = 2172, P < 0.001). Nurick scores reflected improvement for 86% of patients, with the conditions of 13% remaining unchanged and only one patient showing worsening. Preoperative myelopathy severity was weakly correlated with age (P < 0.05) but was not correlated with gender or number of levels decompressed. Similarly, postoperative myelopathy severity was not significantly correlated with age, gender, preoperative myelopathy severity, or number of levels decompressed. ACC-treated patients showed an average improvement of 1.24 points on the Nurick scale, compared with an improvement of 0.07 points for patients treated with laminectomy (P < 0.001) and a deterioration of 0.23 points for patients undergoing conservative treatment (P < 0.001). Complications were slightly more likely to occur in older patients (P < 0.05). The number of levels decompressed was not significantly correlated with complications. Only one permanent neurological complication was seen in this series of patients. CONCLUSION: We conclude that ACC is a safe and effective treatment for cervical spondylotic myelopathy. In an average of 39 months, ACC showed improved results in terms of myelopathy scores, compared with historical control subjects receiving either no treatment or laminectomy. Age, gender, preoperative myelopathy severity, and extent of disease were not negative predictors of clinical outcomes.     

Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation

Normal human diploid fibroblasts have a finite replicative lifespan in vitro, which has been postulated to be a cellular manifestation of aging in vivo. Several studies have shown an inverse relationship between donor age and fibroblast culture replicative lifespan; however, in all cases, the correlation was weak, and, with few exceptions, the health status of the donors was unknown. We have determined the replicative lifespans of 124 skin fibroblast cell lines established from donors of different ages as part of the Baltimore Longitudinal Study of Aging. All of the donors were medically examined and were declared "healthy," according to Baltimore Longitudinal Study of Aging protocols, at the time the biopsies were taken. Both long- and short-lived cell lines were observed in all age groups, but no significant correlation between the proliferative potential of the cell lines and donor age was found. A comparison of multiple cell lines established from the same donors at different ages also failed to reveal any significant trends between proliferative potential and donor age. The rate of [3H]thymidine incorporation and the initial rates of growth during the first few subcultivations were examined in a subset of cell lines and were found to be significantly greater in fetal lines than in postnatal lines. Cell lines established from adults did not vary significantly either in initial growth rate or in [3H]thymidine incorporation. These results clearly indicate that, if health status and biopsy conditions are controlled, the replicative lifespan of fibroblasts in culture does not correlate with donor age.     

Fiber-optic transmission of stretched pulses from a Q-switched ruby laser

Fiber-optic transmission of Q-switched ruby laser pulses is limited by fiber damage owing to the high laser-beam intensities. Pulse stretching with a semiconductor-based control circuit for the Pockels cell of the ruby laser to reduce the peak intensities is described. Pulses with durations from 200 ns to 1 μs and a coherence length of ~3 m were generated. These pulses were coupled into multimode optical fibers to investigate the transmission characteristics and the limits of transmittable pulse energies. Stretched pulses can be transmitted in quartz fibers with a 600-μm core diameter to pulse energies of 300 mJ, which is an increase by a factor of 4 compared with standard Q-switched pulses. It is expected that beam guiding of ruby laser pulses by fiber optics will significantly facilitate the use of holographic interferometry in technical applications such as vibration analysis.