Plasma lipids in kidney transplanted children and adolescents: influence of pubertal development, dietary intake and steroid therapy

Abstract. Plasma triglycerides and/or cholesterol were significantly increased in twenty-four of thirty kidney transplanted children and adolescents with stable renal function, at least one year after the last rejection crisis who received low dose prednisone therapy. The cholesterol increment was related to both low density and high density lipoproteins. However, similar to findings in adult allograft recipients, these increases were very variable: six subjects had normal levels, eight had increased triglycerides, five increased triglycerides and cholesterol, and eleven increased cholesterol. No influence of renal function was found in this series of patients all of whom had plasma creatinine below 160 μmol/1. Subjects who had achieved sexual development had lower cholesterol values. An insignificant difference was observed between patients receiving daily and alternate-day steroid therapy, but a significant negative correlation was found between plasma triglycerides and fractional urinary excretion of 17 OH corticosteroids in the first 6 h after an oral dose of prednisone. Finally, no correlation was found between energy intake and triglycerides; but a significant correlation was observed between protein intake and plasma cholesterol.
In conclusion, some patients show a high level of triglycerides and/or cholesterol after renal transplantation, possibly due to a different individual response to steroid therapy.     

Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells

Transient spinal cord ischemia in humans can lead to the development of permanent paraplegia with prominent spasticity and rigidity. Histopathological analyses of spinal cords in animals with ischemic spastic paraplegia show a selective loss of small inhibitory interneurons in previously ischemic segments but with a continuing presence of ventral alpha-motoneurons and descending cortico-spinal and rubro-spinal projections. The aim of the present study was to examine the effect of human spinal stem cells (hSSCs) implanted spinally in rats with fully developed ischemic paraplegia on the recovery of motor function and corresponding changes in motor evoked potentials. In addition the optimal time frame for cell grafting after ischemia and the optimal dosing of grafted cells were also studied. Spinal cord ischemia was induced for 10 min using aortic occlusion and systemic hypotension. In the functional recovery study, hSSCs (10,000-30,000 cells/0.5 mul/injection) were grafted into spinal central gray matter of L2-L5 segments at 21 days after ischemia. Animals were immunosuppressed with Prograf (1 mg/kg or 3 mg/kg) for the duration of the study. After cell grafting the recovery of motor function was assessed periodically using the Basso, Beattie and Bresnahan (BBB) scoring system and correlated with the recovery of motor evoked potentials. At predetermined times after grafting (2-12 weeks), animals were perfusion-fixed and the survival, and maturation of implanted cells were analyzed using antibodies recognizing human-specific antigens: nuclear protein (hNUMA), neural cell adhesion molecule (hMOC), neuron-specific enolase (hNSE) and synapthophysin (hSYN) as well as the non-human specific antibodies TUJ1, GFAP, GABA, GAD65 and GLYT2. After cell grafting a time-dependent improvement in motor function and suppression of spasticity and rigidity was seen and this improvement correlated with the recovery of motor evoked potentials. Immunohistochemical analysis of grafted lumbar segments at 8 and 12 weeks after grafting revealed intense hNSE immunoreactivity, an extensive axo-dendritic outgrowth as well as rostrocaudal and dorsoventral migration of implanted hNUMA-positive cells. An intense hSYN immunoreactivity was identified within the grafts and in the vicinity of persisting alpha-motoneurons. On average, 64% of hSYN terminals were GAD65 immunoreactive which corresponded to GABA immunoreactivity identified in 40-45% of hNUMA-positive grafted cells. The most robust survival of grafted cells was seen when cells were grafted 21 days after ischemia. As defined by cell survival and laminar distribution, the optimal dose of injected cells was 10,000-30,000 cells per injection. These data indicate that spinal grafting of hSSCs can represent an effective therapy for patients with spinal ischemic paraplegia.     

Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis

Tactile allodynia can be modeled in experimental animals by acutely blocking spinal glycine or GABA(A) receptors with intrathecal (i.t.) strychnine (STR) or bicuculline (BIC), respectively. To test the hypothesis that glycine and GABA effect cooperative (supra-additive) inhibition of touch-evoked responses in the spinal cord, male Sprague-Dawley rats, fitted with chronic i.t. catheters, were used. Following i.t. STR, BIC, or STR + BIC, hair deflection evoked cardiovascular (increased blood pressure and heart rate), motor (scratching, kicking and rippling of the affected dermatomes), and cortical encephalographic responses. Hair deflection was without effect in i.t. saline-treated rats. Isobolographic analysis of STR (ED(50) = 25.1-36.9 microg), BIC (ED(50) = 0.5-0.6 microg), and BIC:STR combination (ED(50) = 0.026-0.034:2.6-3.4 microg) dose-response curves confirmed a supra-additive interaction between BIC and STR in this model. BIC-allodynia was reproduced by i.t. picrotoxin. Pretreatment with i.t. scopolamine, or i.t. muscarine had no effect. STR-allodynia was dose dependently inhibited by i.t. muscimol but not baclofen. The results of this study indicate that 1) glycine and GABA effect cooperative inhibition of low-threshold mechanical input in the spinal cord of the rat; and 2) BIC-allodynia arises from the blockade of GABA(A) receptors and is unrelated to any secondary anticholinesterase activity. The allodynic state induced by the blockade of glycine or GABA receptors is clearly exacerbated by the removal of both inhibitory systems. Their combined loss after neural injury may explain the exaggerated sensitivity to and subsequent miscoding of tactile information as pain.     

Transplantation of rat synapsin-EGFP-labeled embryonic neurons into the intact and ischemic CA1 hippocampal region: distribution, phenotype, and axodendritic sprouting

A major limitation of neural transplantation studies is assessing the degree of host-graft interaction. In the present study, rat hippocampal/cortical embryonic neurons (E18) were infected with a lentivirus encoding enhanced green fluorescent protein (GFP) under control of the neuron-specific synapsin promoter, thus permitting robust identification of labeled neurons after in vivo grafting. Two weeks after transient forebrain ischemia or sham-surgery, GFP-expressing neurons were transplanted into CA1 hippocampal regions in immunosuppressed adult Wistar rats. The survival, distribution, phenotype, and axonal projections of GFP-immunoreactive (IR) positive transplanted neurons were evaluated in the sham-operated and ischemia- damaged CA1 hippocampal regions 4, 8, and 12 weeks after transplantation. In both experimental groups, we observed that the main phenotype of host-derived afferents projecting towards grafted GFP-IR neurons as well as transplant-derived GFP-IR efferents were glutamatergic in both animal groups. GFP axonal projections were seen in the nucleus accumbens, septal nuclei, and subiculum-known target areas of CA1 pyramidal neurons. Compared to sham-operated animals, GFP-IR neurons grafted into the ischemia-damaged CA1 migrated more extensively throughout a larger volume of host tissue, particularly in the stratum radiatum. Moreover, enhanced axonal sprouting and neuronal plasticity of grafted cells were evident in the hippocampus, subiculum, septal nuclei, and nucleus accumbens of the ischemia-damaged rats. Our study suggests that the adult rat brain retains some capacity to direct newly sprouting axons of transplanted embryonic neurons to the correct targets and that this capacity is enhanced in previously ischemia-injured forebrain.     

The circulating platelet count is not dictated by the liver,but may be determined in part by the bone marrow: analyses from human liver and stem cell transplantations

Summary. Background: The platelet count varies considerably between individuals, but within an individual the platelet count is remarkably stable over time. Mechanisms controlling the platelet count are not yet established. Objective: In the present study, we tested the hypothesis that the liver is important in controlling the circulating platelet count, as the liver is the main producer of thrombopoietin. Methods: We compared the platelet count prior to and after liver transplantation in > 250 patients transplanted for familial amyloidotic polyneuropathy (FAP). In contrast to most patients undergoing liver transplantation, patients with FAP have normal liver function before transplantation. Furthermore, we compared platelet counts in 89 living liver donors with the platelet count in the recipients of these grafts. Finally we compared platelet counts in donor‐recipient pairs of hematopoietic stem cells. Results and conclusions: The platelet count prior to transplantation correlated with the platelet count at 3 or 12 months after transplantation in patients with FAP (r = 0.48, P < 0.0001 at 3 months, r = 0.39, P < 0.0001 at 12 months), whereas the platelet count in a living liver donor did not correlate with the platelet count in the recipient at 3 or 12 months after transplantation (r = 0.16, P = 0.26 at 3 months, r = 0.11, P = 0.30 at 12 months). The platelet count of related donors of hematopoietic stem cells correlated with the platelet count in the recipient after transplantation (r = 0.25, P = 0.011). Conclusions: These results suggest that the liver, in spite of being the prime producer of thrombopoietin, does not dictate the circulating platelet count, whereas the bone marrow does appear to play a role.