The relationship between uric acid levels and graft function in renal transplant patients who discontinued steroid therapy / Relación entre niveles de ácido úrico y función del injerto en pacientes de trasplante renal que interrumpieron la terapia con esteroides

ABSTRACT Introduction: High uric acid levels are commonly encountered in kidney transplant recipients, and can be associated with allograft dysfunction. Our study aims to examine the relationship between UA levels and graft function in patients discontinuing steroids. Methods: In this single-center-retrospective study, 56 patients discontinued steroid therapy from among 678 RT patients transplanted from living donors between 1999-2020 were included. The mean age of the study group was 45.8±8.8 years. Causes of steroid discontinuation, creatinine levels concurrent with uric acid levels before and after steroid discontinuation (mean 3.9 ± 2.1 years), acute rejection numbers, demographics, durations of dialysis and transplantation, medications, laboratory data, human leukocyte antigen (HLA) mismatch numbers, blood-pressure (BP), body mass index, delayed acute rejection (DAR) numbers (3 months post-transplantation) were all recorded. Results: Creatinine and uric acid levels were seen to have increased after steroid discontinuation, there was a significant relationship between them (p<0.001). Statistically significant correlation was found between increased creatinine levels after steroid discontinuation and graft survival with higher HLA mismatch; 39 (69.6%) patients with mismatch ≥2, and 17 patients with mismatch <2 (30.4%) (p=0.049) . No significant relationship was found between DAR numbers before and after steroid discontinuation, and creatinine levels after steroid discontinuation. Conclusion: Per model obtained as a result of multivariate linear analysis, hyperuricemia and HLA mismatch numbers (p= 0.048 and p= 0.044, respectively) are independent predictive factors for graft dysfunction in patients discontinuing steroids. Accordingly, negative effects of modeling should be kept in mind for long-term graft survival in patients who plan to continue with steroid-sparing regimens.

RESUMEN Introducción: Con frecuencia se registran niveles elevados de ácido úrico en receptores de trasplantes renales que pueden estar asociados a disfunción de aloinjerto. El presente estudio tiene por objeto examinar la relación entre los niveles de AU y la función del injerto en pacientes que interrumpieron la terapia con esteroides. Métodos: En este estudio retrospectivo en un solo centro participaron 56 pacientes con interrupción de la terapia con esteroides de un total de 678 pacientes con TR receptores de trasplante de donantes vivos en el período 1999-2020. La edad promedio de la población de estudio fue de 45,8 ± 8,8 años. En el estudio se registraron causas de la interrupción de la terapia con esteroides, niveles de creatinina concurrentes con niveles de ácido úrico antes y después de la interrupción de la terapia con esteroides (promedio de 3,9 ± 2,1 años), números de rechazo agudo, datos demográficos, duraciones del período de diálisis y trasplante, medicación (uso de inmunosupresores, antihipertensivos), datos de laboratorio, números de desajuste del antígeno leucocitario humano (HLA), presión arterial (PA), índice de masa corporal, números de rechazo agudo retardado (DAR) (3 meses después del trasplante). Resultados: Se observó que los niveles de creatinina y ácido úrico aumentaron tras interrumpir la administración de esteroides, con una relación significativa entre ambos (p<0,001). Se identificó una correlación estadísticamente significativa entre el aumento en los niveles de creatinina tras la interrupción de la terapia de esteroides y la supervivencia del injerto con un mayor desajuste de HLA: 39 pacientes (el 69,6%) con desajuste ≥2 y 17 (el 30,4%) pacientes con desajuste <2 (p=0,049). No se encontró una relación significativa entre el número de DAR antes y después de la interrupción del tratamiento con esteroides, así como en los niveles de creatinina tras la interrupción de la terapia con esteroides. Conclusión: De acuerdo con el modelo obtenido como resultado del análisis lineal multivariable, la hiperuricemia y los números de desajuste de HLA (p=0,048 y p=0,044, respectivamente) constituyen factores predictivos independientes para la disfunción del injerto en pacientes que interrumpen la terapia con esteroides. En consecuencia, se deben tener en cuenta los efectos negativos del modelado para la supervivencia del injerto a largo plazo en pacientes que planean proseguir con regímenes con reducción de la administración esteroides.

Effect of bone marrow and adipose tissue-derived mesenchymal stem cells on the natural course of corneal scarring after penetrating injury.

In the present study, we investigate and compare the efficacy of bone marrow- and adipose tissue-derived mesenchymal stem cell (MSCs) in corneal wound healing. A penetrating injury was created in the right corneas of Wistar rats (n = 40). Ten microliters of phosphate-buffered solution (PBS) containing 2 × 10(5) green fluorescent protein (GFP) labeled bone-marrow-derived MSCs to group 1 (n = 15), 10 µl of PBS containing 2 × 10(5) GFP-labeled adipose-tissue-derived MSCs to group 2 (n = 15), 10 µl PBS was injected into anterior chamber in group 3 (n = 10, control). Corneal opacity scoring, in vivo confocal microscopy, and histopathological evaluation were done at the end of 8 weeks. Immunofluorescence sections were evaluated to detect transplanted cells. Immune staining was performed to measure the expression levels of keratocan, aldehyde dehydrogenase (ALDH) and CD34. The gene expression levels of tumor necrosis factor (TNF-α), the interleukin 6 receptor (IL-6R), interleukin 12b (IL-12b), and transforming growth factor beta (TGF-ß1) was measured on corneas. The establishment of stem cells in the corneas of the transplanted groups was confirmed by immunofluorescence staining. The expression of keratocan, ALDH, and CD34 increased in the transplanted groups (p < 0.05). The density of keratocytes increased significantly in both transplanted groups according to the in vivo confocal microscopy data (p < 0.05). The expression of TNF-α, IL-6R, and IL-12b decreased significantly in the transplanted groups (p < 0.05). Based on our findings, we consider that allogeneic stem cells facilitate the regeneration of corneal stroma and can be a cell source for stromal repopulation in diseased cornea.

Resveratrol can prevent CCl4-induced liver injury by inhibiting Notch signaling pathway.

We investigated whether Notch signaling was increased in an experimental liver fibrosis model and examined the effects of resveratrol on Notch expression. Rats were divided into four groups: the control group, injected with physiological saline; the CCl4 group; the CCl4 plus resveratrol group; and the resveratrol group. After treatment, immunostaining was performed to detect Notch1, Notch3, Notch4, transforming growth factor (TGF)-beta, alpha-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and proliferating cell nuclear antigen (PCNA), and TUNEL assays were performed to evaluate apoptosis. Sirius red staining was used to detect fibrosis. Samples were also biochemically evaluated for glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), lipid peroxidation, and protein oxidation. GSH, GPx, and catalase activities were significantly decreased (p⟨0.001) in the CCl4 group. Distinct collagen accumulation was detected around the central vein and portal areas, and numbers of Notch1-, Notch3-, and Notch4-positive cells were significantly increased (p⟨0.001) in fibrotic areas in the CCl4 group. Increased expression of Notch proteins in fibrotic areas may support the role of Notch in mediating signaling associated with liver fibrosis through activation of hepatic stellate and progenitor cells. In contrast, resveratrol prevented liver fibrosis by decreasing lipid peroxidation and may be effective for inhibiting Notch signaling.

Immunomodulatory properties of pancreatic islet-derived stem cells co-cultured with T cells: Does it contribute to the pathogenesis of type 1 diabetes?

BACKGROUND: Previously, we isolated stem cells from rat pancreatic islets (rPI-SCs) with similar characteristics of bone-marrow derived-mesenchymal stem cells (MSCs). We aimed to investigate the immunomodulatory effects of them on stimulated T-cells. METHODS: Following in vitro co-culturing directly and indirectly, the response of T-cells stimulated by concanavalin-A and immunosuppressive activity of rPI-SCs were evaluated by analysing in terms of cell viability, proliferation and apoptosis, cell cycle, differentiation of Treg, cytokines and some regulatory factors produced from T and SCs. RESULTS: Our results have firstly demonstrated that rPI-SCs like MSCs could regulate stimulated T-cell responses by altering their cell-cycle and cytokine profile, inhibiting the cell proliferation, and inducing the apoptosis and differentiation of Treg. Direct and indirect in vitro co-cultures of rPI-SCs with stimulated T-cells showed immunosuppressive effects. CONCLUSION: Therefore, we are introducing a novel type of stem cell with immunomodulatory properties. On the other hand, it is questionable why PI-SCs cannot protect the insulin producing cells from attacks of autoreactive T-cells in the developing of type1 diabetes. For this purpose, further molecular researches in vitro and in vivo are needed to clarify why PI-SCs may not suppress attacks of autoreactive-immune-cells towards PIs. PI-SCs from diseased people should be compared with pancreas of healthy ones at both genomic and proteomic levels.

In vitro protection of adipose tissue-derived mesenchymal stem cells by erythropoietin.

Mobilization of stem cells and their differentiation into cardiomyocytes are known to have protective effects after myocardial infarction. The integrity of transplanted mesenchymal stem cells for cardiac regeneration is dependent on cell-cell or cell-matrix interaction, which is adversely affected by reactive oxygen species in an ischemic environment. Treatment with erythropoietin was shown to protect human adipose tissue derived mesenchymal stem cells in an ischemic injury in vitro model. The analyses indicated that expression of erythropoietin receptors played a pivotal role in erythropoietin mediated cell survival. In this study, the anti-apoptotic effect of erythropoietin on stem cells was analyzed in apoptosis-induced human mesenchymal stem cells. Apoptosis was induced in cultured adult human adipose tissue derived mesenchymal stem cells by hydrogen peroxide. A group of cultured cells was also treated with recombinant human erythropoietin in a concentration of 50 ng mL(-1). The degree of apoptosis was analyzed by flow-cytometry and immunohistochemical staining for Caspase 3. The average percentages of apoptotic cells were significantly higher in H2O2-induced stem cells than in cells co-cultured with erythropoietin (63.03 ± 4.96% vs 29 ± 3.41%, p<0.01). We conclude that preconditioning with erythropoietin suppresses apoptosis of mesenchymal stem cells and enhances their survival.

Visual evoked potential abnormalities in migraine patients.

BACKGROUND: Visual processing in migraine has been targeted indicating that the visual pathways are involved in the migraine pathophysiology. We aimed to assess the nature of visual evoked potential (VEP) changes in migraine patients and to evaluate the role of VEP in the diagnosis of migraine. MATERIALS AND METHODS: We examined 31 female and 10 male patients with a migraine headache diagnosis according to the criteria of the International Headache Society. Control subjects had neither migraine and other types of primary headache nor familial history. VEP were elicited using a checkerboard by monocular and binocular pattern reversal stimulation. The latencies of N75, P100 and N145 and peak-to-peak amplitude of N75-P100 were measured. We compared VEP latencies and amplitudes of the monocular and binocular stimulation within each population. RESULTS: The N75 and P100 latencies were found to be significantly longer in the study group than the control group (p = 0.014 and p = 0.034, respectively) while the amplitudes in the study group were lower (p = 0.014). N145 latency was found to be longer in patients with longer duration of disease (p < 0.05). P100 latency was found to be significantly longer in patients with aura than the patients without aura (p = 0.029). N75 latency, recorded by left monocular stimulation, was elongated and the amplitude was diminished with left hemicranial headache. CONCLUSION: Measurement of VEP latency and amplitude is a valuable and reliable test for the diagnosis of migraine. Our results reflect a persisting dysfunction of precortical visual processing which might be relevant in the pathogenesis of migraine.

Increased gray matter density in the parietal cortex of mathematicians: a voxel-based morphometry study.

BACKGROUND AND PURPOSE: The training to acquire or practicing to perform a skill, which may lead to structural changes in the brain, is called experience-dependent structural plasticity. The main purpose of this cross-sectional study was to investigate the presence of experience-dependent structural plasticity in mathematicians' brains, which may develop after long-term practice of mathematic thinking. MATERIALS AND METHODS: Twenty-six volunteer mathematicians, who have been working as academicians, were enrolled in the study. We applied an optimized method of voxel-based morphometry in the mathematicians and the age- and sex-matched control subjects. We assessed the gray and white matter density differences in mathematicians and the control subjects. Moreover, the correlation between the cortical density and the time spent as an academician was investigated. RESULTS: We found that cortical gray matter density in the left inferior frontal and bilateral inferior parietal lobules of the mathematicians were significantly increased compared with the control subjects. Furthermore, increase in gray matter density in the right inferior parietal lobule of the mathematicians was strongly correlated with the time spent as an academician (r = 0.84; P < .01). Left-inferior frontal and bilateral parietal regions are involved in arithmetic processing. Inferior parietal regions are also involved in high-level mathematic thinking, which requires visuospatial imagery, such as mental creation and manipulation of 3D objects. CONCLUSION: The voxel-based morphometric analysis of mathematicians' brains revealed increased gray matter density in the cortical regions related to mathematic thinking. The correlation between cortical density increase and the time spent as an academician suggests experience-dependent structural plasticity in mathematicians' brains.

Quantification of neurometabolites in subacute sclerosing panencephalitis by 1H-MRS.

The authors studied 20 patients with subacute sclerosing panencephalitis (SSPE) to investigate the correlations between MRI, magnetic resonance spectroscopy (MRS), and clinical status. MRI findings did not correlate with clinical status. By contrast, all patients had reductions in N-acetyl aspartate (NAA) and increase in myoinositol (mI) (p < 0.01), and NAA and mI concentrations correlated with clinical severity (p < 0.05). During follow-up, NAA continued to decline. (1)H-MRS may be a useful measure of disease severity and progression in SSPE.