What is the role for mycophenolate mofetil in pediatric renal transplantation?

Mycophenolate mofetil (MMF) has gained considerable popularity in pediatric renal transplantation. This popularity is largely a result of data from three large trials of MMF in adult cadaveric transplant patients who demonstrated a decreased rate of acute rejection episodes when treated with cyclosporin A (CsA), prednisone, and MMF compared with those receiving CsA, prednisone, and azathioprine (AZA) or placebo. However, the ability of MMF to reduce acute rejection appears to be limited to the first month post-transplant, and its effectiveness with microemulsion CsA or tacrolimus-based regimens has not been proven. In addition, there are currently no data that convincingly demonstrate that this agent improves graft survival, patient survival, graft function or protects against chronic rejection. Finally, there may be an increased risk for severe cytomegalovirus (CMV) disease and lymphoproliferative disorder with central nervous system involvement in patients treated with MMF. These data call into question the role of MMF in current immunosuppressive regimens.     

Mycophenolate mofetil – is it worth the cost? The in-favor opinion

Since its introduction, mycophenolate mofetil (MMF) has rapidly gained acceptance among renal transplant physicians. Three large multicenter studies have shown that MMF decreased the incidence of acute rejection episodes by 50%. While clinical data supporting the long-term benefits of MMF are not available, there is some experimental evidence which demonstrates that MMF may play a role in the prevention of chronic allograft rejection. Furthermore, MM F is a potent immunosuppressive agent, which could result in a reduction of the dose of cyclosporin A (CsA) required and subsequently reduce its associated toxicity. Despite the fact that MMF is six to seven times more expensive than azathioprine (AZA), its introduction into maintenance immunosuppressive protocols may not increase renal transplant charges during the first year after renal transplant as its cost can be offset by the reduced number of acute rejection episodes (ARE). The long-term societal impact of MMF will need to be evaluated as the data related to graft and patient survival, as well as chronic rejection, become available.     

Trends in immunosuppressive therapy: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data registry has now compiled data for 11 years, and includes data on 6038 renal transplants in 5516 patients. With the availability of new data and immunosuppressive medications, trends in their usage continue to change. NAPRTCS data have previously demonstrated that increased doses of cyclosporin A (CsA) are associated with improved allograft outcomes, and there has been a steady increase in the dose of CsA given post-transplantation. Transplants that occurred in 1987, 1989, 1991, and 1993 received a mean one-year post-transplant dose of 6.5, 7.0, 7.7, and 8.2 mg/kg/d, respectively. In the 1995 cohort, the dose decreased to 7.4 mg/kg/d. Since the introduction of Neoral, its use has steadily increased. Of the 1997 cohort, 81% report Neoral as the formulation of CsA used. The dose of CsA given, however, has not changed. At day 30 post-transplant, the dose was 7.0 mg/kg/d for Sandimmune and 7.4 mg/kg/d for Neoral. Finally, the outcome in black transplant patients is inferior to that of nonblack. Evaluation of CsA blood levels revealed that at 1 year post-transplant, black patients consistently have CsA levels higher than nonblacks, and a lower percentage of black patients have a CsA level < 100 ng/mL. The percentage of patients using triple therapy (prednisone, azathioprine, and CsA) remained stable from 1987 to 1993 at 80-85%. However, in 1996 only 30% of patients were receiving triple therapy. This is probably due to the introduction of mycophenolate mofetil (MMF). Comparing the 1996-97 cohorts, there has been no significant change in the percentage of patients receiving prednisone (96.2% vs. 95.4%) or CsA (83.1% vs. 79.6%). However, during this time, the use of azathioprine has decreased from 50.0% to 35.8%, the use of tacrolimus has increased from 2.5% to 10.8%, and the use of MMF has increased from 6.5% to 35.8%.     

Limited sampling model for area‐under‐the‐curve monitoring in pediatric patients receiving either Sandimmune® or Neoral® cyclosporin A oral formulations

Several limited sampling equations were tested to predict the area under the curve (AUC) of cyclosporin A (CsA) at steady state in 10 children with end-stage renal disease receiving oral CsA 2.5 mg/kg b.i.d. as two different formulations, namely Sandimmune and Neoral, according to a randomized crossover design with a one-month washout period. AUC was significantly correlated with CsA concentration at 5 h. The equation derived from this single concentration time point was able to adequately predict the AUC for Sandimmune but not for Neoral. The equation derived from CsA concentration data, measured at 2 and 12 h, significantly improved predictive performance in terms of bias and precision, allowing adequate AUC predictions in both formulations. CsA concentration at 2 h was also able to predict Cmax, while the concentration at 12 h corresponded to the trough value in a b.i.d. dosing scheme. Therefore, it is concluded that a limited sampling model including concentration data at 2 and 12 h allows the estimation of AUC, Cmax and trough levels, yielding a complete profile in patients exposed to CsA as Sandimmune or Neoral. Hence, this model can be used for therapeutic monitoring of CsA levels in pediatric patients being switched from one formulation to another.     

Influence of external biliary drainage on cyclosporin A (Neoral®) absorption in a pediatric liver transplant recipient

We report on a patient who underwent a liver transplant 8 yr ago at the age of 2. The post-operative course and further follow-up were uneventful, maintaining immunosuppression with cyclosporin A (CsA) (Sandimmune) and prednisone; 1.5 yr ago, the patient was converted to Neoral. The mean +/- SD trough CsA level was 127 +/- 37.2 ng/mL, when the patient was maintained on a daily dose of 180 mg. Following an increase in gamma-GTP levels, a biliary-enteric anastomotic stricture was found. Dilatation was performed and a tube placed for external biliary drainage. Three days later the trough CsA level was at the limit of detection; consequently, the Neoral dose was increased to 480 mg/d. CsA concentration measured 5 days later reached 164 ng/mL. After restoring internal biliary drainage the dose was decreased to 180 mg/d and the CsA level was 142 ng/mL. Later on the CsA dose was further reduced to 160 mg/d (a third of the dose during external biliary drainage) and trough levels were maintained at 90-120 ng/mL. We suggest that CsA dose adjustment and continuous drug monitoring are necessary when bile flow is compromised, in order to prevent rejection of the transplanted liver.     

A comparative analysis of the use of mycophenolate mofetil in pediatric vs. adult renal allograft recipients

Mycophenolate mofetil (MMF) is a new immunosuppressive drug used in combination with cyclosporin A (CsA) or tacrolimus and prednisone to prevent rejection of renal allografts in both adult and pediatric recipients. It has been shown in several large studies that MMF significantly decreases the incidence of acute rejection in adults and has acceptable adverse effects. In this retrospective study, we compare the incidence of adverse events between pediatric and adult renal allograft recipients. Twenty-two children and 37 adult renal allograft recipients were included in the study. The initial dose of MMF was 1.5 g b.i.d. for the adult patients and ranged from 15 to 30 mg/kg/d for the pediatric patients. All patients received p.o. acyclovir as prophylaxis for cytomegalovirus (CMV). The two groups were similar regarding gender distribution and graft source. Acute rejections occurred in 10 of the 22 pediatric patients (45%) and in nine of the 37 adults (24%), p = NS. The incidence of infections was similar in both groups except for the occurrence of CMV (n = 5), which was seen only in adults. The incidence of GI symptoms was significantly higher in the pediatric population (54.5% vs. 21.6%; p = 0.02). Significant weight loss was seen more often in the smaller pediatric patients (weight < or = 15 kg) compared to the larger pediatric patients, 60% vs. 11.7%, p = 0.05. Among the patients who had significant GI symptoms 50% of the adults and 75% of the pediatric recipients required either dose reduction or, most commonly, discontinuation of the MMF. The need to discontinue MMF was significantly higher in the pediatric patients, especially in those that weighed less than 15 kg. We suggest the possibility that the optimum dose, dosing interval or preparation of MMF has not yet been established for pediatric patients. One should therefore monitor pediatric patients closely, especially the small ones, to avoid significant nutritional problems and other adverse GI events.     

Sandimmune to Neoral conversion and value of abbreviated AUC monitoring in stable pediatric kidney transplant recipients

Neoral is a new microemulsion formulation of cyclosporin A (CsA) that has been reported to have better absorption characteristics than sandimmune. We converted 25 long-term pediatric renal transplant recipients with a mean age of 14.1 yr and a mean follow-up period of 6.4 yr from sandimmune (SIM) to neoral (NEO) on a 1:1 basis. The mean dosage of SIM or NEO required to maintain 'therapeutic range' steady-state trough levels between 100 and 200 ng/mL was similar. We compared 6-h CsA pharmacokinetic profiles taken approximately 6 months after the conversion to NEO with the previous SIM profiles of the same patients. Generally, in the NEO profiles the time to reach the maximum concentration was shorter and the maximum concentration was higher, showing a rapid decline towards the trough-level when compared to the previous SIM profiles. During intake of NEO the AUC0-12 h in the 12-h profiles correlates strongly with the AUC0-6 h in the 6-h profiles (r = 0.98), a similar finding to that which we reported previously for SIM. The median AUC0-6 h for NEO demonstrates a 70% increase compared to the median AUC0-6 h for SIM. Despite the increased drug exposure NEO was well tolerated and did not cause any apparent toxicity within the first 6 months after conversion. The CsA blood level 2 h after intake of NEO showed a higher correlation with the AUC0-12 h (r = 0.91) than the trough level (r = 0.64). The abbreviated profile based on three early sampling points and calculated by AUCPRED = 335.9 + 1.1*(C1) + 1.1*(C2) + 5.4*(C4) correlated well with the full AUC (r2 = 0.98, p < 0.0001). Mean prediction error (+/- SD) was 0.16% (+/- 4.32), and in no patients did the calculated values fall outside the 10% prediction error limit. We therefore conclude that NEO exhibits a higher bioavailability in children compared to SIM without causing apparent toxicity. Monitoring of the C2 might be a better alternative for trough level monitoring in daily clinical practice. A strategy of three early sampling points (C1, C2 and C4) allows a reliable AUC0-12 h prediction and can reduce the length of observation, making it a useful and cost-effective tool in clinical practice.     

Changing cyclosporin A formulation: An analysis in paediatric cardiac transplant recipients

Cyclosporin A is the primary immunosuppressive agent used in cardiac transplantation to maintain chronic immunosuppression. Absorption may be erratic and major side-effects include nephrotoxicity. A recently introduced formulation (Neoral) improves absorption in cystic fibrosis heart-lung transplant recipients, but episodes of rejection have been reported on conversion from the oil-based formulation. A retrospective analysis of 21 paediatric cardiac transplant recipients who had been converted from the oil-based formulation to the micro-emulsified formulation was performed. No clinical rejection episodes occurred following conversion. There was a significant reduction in dose following conversion (p < 0.001). The mean trough level was less on the new formulation (p = 0.04), but there was no difference in coefficient of variation or standard deviation. Mean glomerular filtration rate (GFR) was significantly less, but there was no difference in the rate of change of GFR on the new formulation. Erratic absorption and deteriorating renal function remain as significant problems in paediatric cardiac transplant recipients despite conversion to the new formulation.     

Experience of parenteral nutrition for nutritional rescue in children with severe liver disease following failure of enteral nutrition

Nutritional support is often necessary in chronic liver disease in childhood, and when enteral nutrition is insufficient, parenteral nutrition (PN) can be envisaged as a last resort. Pediatric experience is still limited in this indication. Seven children with severe liver disease received PN for a mean duration of 105 d, with additional enteral nutrition. Clinical tolerance was assessed and anthropometric and biological data were compared at the beginning and at the end of the study by the paired non-parametric test of Wilcoxon. Weight change, expressed as weight-for-age or weight-for-height Z-scores, increased. Conjugated bilirubin increased significantly. This retrospective study suggests that PN is a well-tolerated method for maintaining nutritional status in pediatric chronic liver disease when enteral nutrition has failed.     

Long‐term outcomes in pediatric liver recipients: Comparison between cyclosporin A and tacrolimus

In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0% (28/147) of CsA patients had to be switched to TAC for reasons not related to rejection (i.e. side-effects). The overall incidence of histologically proven chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who were on CsA initially developed chronic rejection, which was significantly higher compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0 months; range 1-8 months), whereas the TAC patient has remained clinically stable with normal liver function tests after 23 months of follow-up. One year after liver transplantation, 72.8% (107/147) of CsA patients were still on steroids (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90), 7.0% (5/71) and 12.3% (7/57) for CsA, primary and TAC-converted groups, respectively. The overall incidence of PTLD was 6.9% (15/218). In summary, pediatric liver transplant recipients treated with TAC as primary maintenance immunosuppressive medication experienced significantly fewer episodes of rejection; especially chronic rejection, which lead to graft loss. However, the trade-off is a potential increased incidence of EBV-related PTLD in these patients.     

Auxiliary partial orthotopic liver transplantation for acute liver failure in two children

Acute liver failure in children and adults is associated with a high mortality rate. At present the treatment of choice is orthotopic whole-liver transplantation. However, allogeneic liver transplantation necessitates lifelong immunosuppressive therapy, which is associated with substantial risks to the patient. Temporary auxiliary partial orthotopic liver transplantation has been developed recently as an alternative, enabling the native liver to regenerate while avoiding the risks of long-term immunosuppressive treatment. Here we describe two cases of partial orthotopic liver transplantation in children. Auxiliary partial orthotopic liver transplantation was performed in two boys (5 and 6 years old) suffering from acute liver failure of unknown origin. The native left lateral liver lobes (segment II and II) were removed and replaced by left lateral liver grafts from young blood-group-compatible adults. In the first child the native liver, which was 80% necrotic at time of transplantation, showed regeneration within two weeks and the partially necrotic graft could be surgically removed on day 15 after auxiliary transplantation. Four years after transplantation, the child is in excellent condition with normal liver function and does not require any treatment. In the second case the native liver (90% necrotic at time of transplantation) regenerated within 6 weeks of transplantation, at which time the transplanted liver was removed. The patient developed aplastic anemia and died 2 months after transplantation from candida sepsis. The conclusion was that auxiliary partial liver transplantation in childhood provides a valuable option to maintain liver function in acute liver failure until functional recovery of the native liver. The main advantage over whole-liver transplantation is the chance to avoid lifelong immunosuppression. However, there is a higher surgical risk. Therefore, auxiliary transplantation should be considered carefully in every case of acute liver failure in children.     

Vesico‐ureteral reflux in pediatric kidney transplants: Clinical relevance to graft and patient outcome

From June 1985 to December 1998, 173 pediatric renal transplants were carried out in 170 patients at our center. From this pool, 73 patients (34 males and 39 females) with a follow-up of 48 months were examined. In all patients, ureteroneocystostomy was performed according to the Lich-Grégoire procedure. All patients were treated with cyclosporin A (CsA)-based immunosuppression, including prednisone and sometimes azathioprine (AZA). Six months after transplantation, voiding cystography (VCU) was performed in all patients and reflux was classified from Grade I to Grade IV. The patients were divided into two groups: those with reflux (Group A: 25 patients) and those without (Group B: 48 patients). Grade I reflux was found in four patients, Grade II in seven patients, Grade III in seven patients, and Grade IV in seven patients. All the patients with severe reflux (Grade IV) underwent a corrective surgical procedure. Both groups were examined for immunologic and non-immunologic risk factors and no significant differences were found. Analysis of patient and graft survival rates revealed no statistical differences (NS) between Groups A and B. Mean serum creatinine (mg/dL) was 1.06 +/- 0.28 and 1.12 +/- 0.41 at 4 yr in Groups A and B, respectively (NS). Mean calculated creatinine clearance (cCrC; ml/min) was 76.74 +/- 15.92 and 77.96 +/- 15.66 in Groups A and B, respectively (NS). The analysis was further extended by considering the grade of reflux (I to IV). Again, no significant differences in the above parameters emerged between the reflux sub-groups; only in the Grade IV sub-group was a slight decrease in cCrC detected, although this difference was not statistically significant when compared with the other sub-groups. In conclusion, vesico-ureteral reflux (VUR) does not seem to negatively affect graft function. However, as all severe reflux patients (Grade IV) were surgically corrected, no conclusions can be drawn with regard to the influence of Grade IV reflux on long-term graft function.     

Mycophenolate mofetil and reduced doses of cyclosporine in pediatric liver transplantation with chronic renal dysfunction: changes in the immune responses

The aim of this study was to study the incidence of chronic renal dysfunction in patients with more than 5 yr of follow-up following liver transplantation and to evaluate the benefit of decreasing cyclosporine A (CsA) dose combined with mycophenolate mofetil (MMF) on renal function and immune response in these patients. Between 1988 and 1994, 60 children were transplanted, and 86% survived >5 yr post-liver transplantation. Fourteen patients developed chronic renal dysfunction secondary to CsA toxicity as evaluated by renal biopsy. In 11 patients CsA dose was decreased to 40-90 mg/ml target levels and MMF 600 mg/m(2) twice daily was added to the immunosuppressive regimen. Plasma creatinine decreased (from 1.0 +/- 0.03 to 0.8 +/- 0.03 ng/dl, p < 0.007), creatinine clearance increased (from 66.8 +/- 3.0 to 99.2 +/- 6.3 ml/min/1.73 m(2), p < 0.002) and microalbuminuria decreased (from 21.0 +/- 8.6 to 3.6 +/- 1.1 mg/24 h, p < 0.05) after 12 months of CsA combined with MMF therapy. During combined therapy the proliferative, cytolytic response and cytotoxic antibodies showed no significant changes, whereas CD4/CD8 ratio increased (from 1.2 +/- 0.2 to 1.4 +/- 0.1, p < 0.05). Tumor necrosis factor-alpha secretion increased (p < 0.005) during MMF therapy. The release of interleukin-10 was strikingly augmented under both immunosuppressive regimens, but the release of transforming growth factor-beta and interferon-gamma did not change. Our findings indicate that initiation of MMF combined with reduced doses of CsA allowed the recovery of renal function with minor changes in the immune response.     

Pathological evaluation of steroid withdrawal in pediatric renal transplant recipients

Protocol biopsies were performed to detect and treat subclinical rejection in eight living related pediatric renal transplant recipients who had been withdrawn from steroids. Low-grade tubulitis (t1) and mononuclear cell interstitial inflammation (i1), typical of borderline rejection and low-grade interstitial fibrosis (ci1), and tubular atrophy (ct1), characteristic of chronic rejection, appeared frequently in protocol biopsies more than 3 yr after steroid withdrawal. In contrast, early-type glomerulitis (g), allograft glomerulopathy (cg), arteriolar hyaline thickening (ah), intimal arteritis (v), and fibrous intimal thickening (cv) were not observed in protocol biopsies after steroid withdrawal. Low-dose pulse therapy (methylprednisolone (MP) 250 or 500 mg/d for 3 d) was administered to five patients for borderline and/or acute grade 1a rejection, as determined by protocol biopsies in the absence of clinical rejection. No oral steroids were administered. Renal function in all patients remained satisfactory, without proteinuria, in follow-up periods ranging from 22 to 68 months after steroid withdrawal. Of the eight patients, three grew to almost normal height (> mean -2SD) and four exhibited catch-up growth. Thus, steroid withdrawal can be safe and improves growth in pediatric renal transplant recipients if undertaken with careful clinical follow-up, including protocol biopsies.     

Unusual presentation of graft‐versus‐host disease in pediatric liver transplant recipients: Evidence of late and recurrent disease

Graft-versus-host disease (GvHD) is a multi-organ disease caused by mature donor T cells that are activated by alloantigens expressed by the host antigen-presenting cells. GvHD has been reported after solid organ transplantation with two principal presentations: humoral and cellular. In the cellular type of GvHD after liver transplantation the symptoms are identical to the GvHD after bone marrow transplant, except that the liver is spared because it lacks host antigens. We have described three cases of intestinal GvHD after pediatric liver transplant with an unusual recurrent late presentation in two patients. Two patients were female, and their age at the time of transplant was 8 and 9 months, respectively, and one was an 8-month-old male. They all received reduced liver allografts of identical blood type from three different donors. One patient received two doses of donor bone marrow cell infusion. Two patients received double immunosuppressive therapy constituted by tacrolimus at a dose of 0.05 mg/kg p.o. b.i.d. and steroids 10 mg p.o. daily. One patient received a triple drug immunosuppression with tacrolimus (0.05 mg/kg p.o. b.i.d.), steroids (10 mg p.o. daily) and mycophenolate mofetil (125 mg p.o. b.i.d.). Diagnosis of intestinal GvHD was confirmed histologically on intestinal biopsies performed at the time of presentation of the clinical symptoms or at autopsy.     

Leukocyte‐reduction to prevent transfusion‐transmitted cytomegalovirus infections

Abstract: Certain infectious organisms, including cytomegalovirus, are associated 'exclusively' with blood leukocytes (WBC), and their transmission by transfusion is strikingly diminished by marked WBC‐reduction of cellular blood components. Based on several reports of WBC‐reduction, it is clear that the risk of CMV is nearly eliminated by consistently removing WBC to a level < 1–5 × 10⁶ WBCs/unit (≤ 1 × 10⁶ preferred in Europe; ≤ 5 × 10⁶ in the United States). Alternatively, the rate of CMV infections is reduced by transfusing blood components collected from donors negative for CMV antibody. However, neither technique is perfect, with a failure rate of 1–4%. Although WBC‐reduction is favored by many experts, practitioners must choose the method that they believe to be most efficacious – being mindful that data do not exist to establish additive protection by combining WBC‐reduction and transfusion of blood components collected from antibody negative donors.     

Living related liver transplantation from heterozygote genetic carriers to children with Wilson's disease

We reviewed the outcome of children undergoing living related liver transplantation (LRLT) for Wilson's disease (WD), and specifically addressed the potential risk associated with the use of donors who were heterozygous for the Wilson genetic defect. LRLTs were carried out in 11 children with WD, nine of whom presented with fulminant hepatic failure and two with end-stage hepatic insufficiency. The age of the patients ranged from 6 to 16 yr. Eight patients had hepatic encephalopathy and were plasmapheresed preoperatively. The donors (all parents: six fathers and five mothers) were all one-haplotype matched with their respective recipients, and were all therefore heterozygote carriers of the WD genetic defect. The serum ceruloplasmin levels were within normal limits in all donors (mean: 20.0 +/- 2.85 mg/dL). All recipients but one had low serum ceruloplasmin levels with a mean value of 11.6 +/- 7.36 mg/dL before transplantation. The serum ceruloplasmin levels had increased to an average of 21.0 +/- 3.76 mg/dL after LRLT at the latest evaluation, which ranged between 7 and 75 months after transplantation. A marked reduction in urinary copper excretion was observed in all recipients after transplantation. Of eight recipients presenting preoperatively with Kayser-Fleischer (K-F) rings, this abnormality resolved completely after LRLT in five patients and partially in three. All recipients are alive and remain well, and none have developed signs of recurrent WD after a mean follow-up period of 31 months (range 7-75 months). In conclusion, LRLT is an excellent choice for effective treatment of WD, and grafts chosen from heterozygote carriers of the condition do not appear to confer any risk of recurrence in the recipients.     

Long‐term psychosocial adjustment following pediatric liver transplantation

This study assessed long-term psychosocial adjustment to pediatric liver transplantation in 146 patients aged 4-25 yr, who had received a transplant 2-12 yr previously. Evaluations of psychosocial adjustment and related variables were based on the Harter Self-Perception Profiles for children, Child Behavior Checklist (CBCL), and children's academic level. Up to the age of 8 yr, transplant children as a group did not perceive themselves as less competent than healthy peers. Gender effects were characterized by older girls perceiving significantly less scholastic cognitive competence than their healthy peers. Adolescent and young adult boys had significantly lower global self-worth and lower perceived athletic competence than their healthy peers. In comparison to normative data of healthy children, CBCL parent-reported scores revealed significant deficits in competences for all age groups. Only for the older boys, however, did these deficits reported by the parents reach a pathological level. The majority of transplant children also had significantly higher problem scores, but they remained within the normal range, except for the older boys whose internalizing problems reached a borderline level. Our results suggest that liver transplantation does not substantially affect schooling. Regardless of statistically significant differences in psychosocial adjustment, the majority of the transplant children functioned at a normal level. For adolescent and young adult boys, however, the presence of problems and the lack of competences observed by parents and by the youngsters themselves reached borderline to pathological levels. Our findings stress the importance of psychological post-transplant follow-up with increased attention of caregivers to child and parental concerns about their long-term psychosocial adjustment process.     

Endocrine complications of bone marrow transplantation in children

Eighty-seven patients had a bone marrow transplantation (BMT) at our institution between 1980 and 1992. We wished to study the endocrine complications that accompany this procedure as long-term survival is now much more common. Forty-three patients were retrospectively available for review and their records were examined for evidence of thyroid, pubertal, and growth complications. Fifteen per cent of the patients showed evidence of thyroid involvement. Pubertal delay or gonadal damage was almost universal in pubertal-aged girls treated with busulfan/cyclophosphamide. Gonadal involvement was more frequent in girls than in boys (70% vs. 47%). Sixty per cent of children were shorter or grew at a slower rate. Sixty-five per cent of the children presented with one or more endocrine complications. These are the combined effects of different treatment regimens (chemotherapy, radiotherapy, combined therapy). It is essential to know the natural history of these patients in order to offer proper guidance and treatment as survival rates are increasing.     

自噬在脂多糖诱导的A549细胞炎症反应中的作用及机制研究

目的 探讨自噬在脂多糖(lipopolysaccharide,LPS)诱导的人肺泡上皮A549细胞炎症反应中的作用及机制。方法 用LPS刺激A549细胞建立炎症反应模型,按浓度(0、1、5、10μg/mL)和时间(0、4、8、12、24h)分组(各组n=3)。用自噬抑制剂3-甲基腺嘌呤(3-methyladenine,3-MA)处理细胞,分为对照组、LPS组、3-MA组、3-MA+LPS组(各组n=3);用自噬激动剂雷帕霉素(rapamycin,RAPA)处理细胞,分为对照组、LPS组、RAPA组、RAPA+LPS组(各组n=3)。通过Toll样受体4 (Toll-like receptor 4,TLR4)过表达质粒和siRNA转染A549细胞,实验分为两部分,每部分各分4组(各组n=3):TLR4过表达对照组、TLR4过表达组、TLR4过表达对照+LPS组、TLR4过表达+LPS组;TLR4沉默对照组、TLR4沉默组、TLR4沉默对照+LPS组、TLR4沉默+LPS组。采用CCK-8法检测细胞存活率,免疫印迹法检测炎症指标(NLRP3、Caspase-1、ASC)、自噬指标(LC3B...