Acute cellular rejection remains a serious and frequent complication during the posttransplant course of small bowel allograft recipients. Currently, small bowel biopsies are the optimal method to ...identify this form of rejection. The morphological criteria for this diagnosis have been known for some time; however, no consensus study has classified these changes. To address issues in bowel transplant pathology, several pathologists experienced in this particular subdiscipline participated in a Pathology Workshop preceding the VIIIth International Small Bowel Transplant Symposium in Miami, Florida. Among the results of this workshop was the development a standardized grading scheme for acute cellular rejection in small bowel transplants.
Nonadherence to medications is a leading cause of morbidity in children and adolescents who have had a transplant, yet there are no published data about the use of different methods for detecting ...whether these children are taking their medications. There are also no published data about the age of transition at which a child assumes responsibility over taking the medications. This information is important if interventions to improve adherence are contemplated.
We present an analysis of data obtained in the first year of the implementation of an adherence assessment protocol at a pediatric liver transplant clinic in a tertiary medical care center. Data were obtained for children and adolescents who had a liver transplant at least 1 year before the assessments took place. We used 5 adherence detection methods. The 4 subjective methods were self-reported, scaled questionnaires answered by nurses, physicians, caregivers, and patients. For the objective method, a standard deviation (SD) was calculated for tacrolimus blood levels obtained from each patient over time. A higher SD suggests increased variation among patients' blood levels and hence more erratic medication taking. We also asked the patients and caregivers who is responsible for taking the medications and what are the reasons for not taking them. The medical outcome measures were biopsy-proven rejection episodes, number of biopsies regardless of the results, number of hospital admissions, and number of in-patient days.
An analysis of 81 cases (258 assessments) revealed that the only method that predicted the medical outcome variables (biopsy-proven rejection and number of biopsies) was the SD of medication blood levels. Patients', clinicians', and caregivers' reports were not predictive. Clinicians' ratings of adherence were not correlated with patients' or caregivers'. The transition of responsibility for medication taking occurred approximately at the age of 12 years. Forgetfulness was cited as the most common reason for nonadherence by patients and caregivers; medication side effects were not frequently cited.
Our results indicate that clinical impression is not sufficient to determine whether children and adolescents are taking their medications after they have had a liver transplant. An objective assessment method should be used. Interventions targeting adherence should address the child's increasing role beginning in early adolescence. A clinical protocol incorporating objective assessments of adherence could potentially be implemented in other settings. It could form the basis for the evaluation of efficacy of interventions seeking to improve adherence to medications.
Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, ...relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown.
We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared ...the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.
Background & Aims
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The mechanisms by which mutations in the familial intrahepatic cholestasis-1 gene cause Byler’s disease (progressive familial intrahepatic cholestasis type 1) are unknown.
Methods
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Interactions among the apical sodium-dependent bile acid transporter, the farnesoid X receptor (FXR), and familial intrahepatic cholestasis-1 were studied in the ileum of children with progressive familial intrahepatic cholestasis type 1 and in Caco-2 cells.
Results
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Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with progressive familial intrahepatic cholestasis type 1. Paradoxically, ileal lipid-binding protein mRNA expression was repressed, suggesting a central defect in bile acid response. Ileal FXR and short heterodimer partner mRNA levels were reduced in the same 3 patients. In Caco-2 cells, antisense-mediated knock-down of endogenous familial intrahepatic cholestasis-1 led to up-regulation of apical sodium-dependent bile acid transporter and down-regulation of FXR, ileal lipid-binding protein, and short heterodimer partner mRNA. In familial intrahepatic cholestasis-1-negative Caco-2 cells, the activity of the human apical sodium-dependent bile acid transporter promoter was enhanced, whereas the human FXR and bile salt excretory pump promoters’ activities were reduced. Overexpression of short heterodimer partner but not of the FXR abrogated the effect of familial intrahepatic cholestasis-1 antisense oligonucleotides. FXR
cis-element binding and FXR protein were reduced primarily in nuclear but not cytoplasmic extracts from familial intrahepatic cholestasis-1-negative Caco-2 cells.
Conclusions
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Loss of familial intrahepatic cholestasis-1 leads to diminished nuclear translocation of the FXR, with the subsequent potential for pathologic alterations in intestinal and hepatic bile acid transporter expression. Marked hypercholanemia and cholestasis are predicted to develop, presumably because of both enhanced ileal uptake of bile salts via up-regulation of the apical sodium-dependent bile acid transporter and diminished canalicular secretion of bile salts secondary to down-regulation of the bile salt excretory pump.
: Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the ...cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision‐making regarding renal transplantation in ARPKD.
Toxoplasmosis prophylaxis is standard following heart and heart lung transplantation, when an increased risk of allograft transmitted Toxoplasma is well-recognized. In contrast, prophylaxis and ...routine serologic evaluation of donors and recipients for Toxoplasma in noncardiac solid organ transplantation (SOT) is not recommended. We report the first case of disseminated toxoplasmosis following small bowel transplantation, presumably transmitted via the transplanted intestine and systematically review reported cases of toxoplasmosis in noncardiac SOT recipients to determine if current guidelines should be reconsidered.
Systematic MEDLINE review was performed for tissue invasive toxoplasmosis in noncardiac SOT recipients and analysis of clinical features, serologic status, and treatment regimens with respect to mortality.
Fifty-two cases of toxoplasmosis in noncardiac SOT recipients were identified. Eighty-six percent developed disease within 90 days of transplantation. Presentation was nonspecific and consisted of fever (77%), respiratory distress (29%), neurologic manifestations (29%), and bone marrow suppression (26%). Multivariate analyses demonstrated that localized disease (odds ratio OR=37.36, 95% CI 1.85-754.85), treatment received (OR=1.814, 95% CI 1.193-3.480) and donor and recipient serostatus (OR=1.39, 95% CI 1.068-1.815) were predictors of survival. High-risk recipients (donor seropositive/recipient seronegative) developed disease earlier (16 days vs. 31 days P=0.002) and were less likely to survive (OR=0.14, 95% CI 0.03-0.69) than standard-risk recipients.
Toxoplasmosis is recognized following noncardiac SOT. Reduction of morbidity and mortality necessitates knowledge of donor and recipient Toxoplasma serostatus, prophylaxis, early diagnosis, and treatment. The findings support a reconsideration of pretransplantation evaluation and prophylaxis strategies in SOT recipients.
We report 2 neonatal deaths caused by cardiac tamponade related to peripherally inserted central catheters (PICCs). A total of 3 deaths were noted for 390 PICCs placed, giving an incidence of 0.76%. ...To determine the magnitude of neonatal death related to PICCs, directors of neonatal intensive care units in the United States were surveyed by means of a questionnaire. Myocardial perforation and pericardial effusion were reported by 29% and 43%, respectively. Deaths were attributed to PICCs by 24% of the respondents. Uniform guidelines need to be formulated to avoid this complication. (J Pediatr 2001;138:599-601)
Recent work has implicated nitric oxide (NO) in several aspects of male genital physiology including erectile function and
androgen secretion, as well as in vitro effects on sperm motility and ...capacitation. The objectives of this study were to characterize
the distribution of endothelial nitric oxide synthase (eNOS) in "normal" human testis, epididymis, and vas deferens and in
testis pathology. Nitric oxide synthase protein was localized immunohistochemically using an eNOS monoclonal antibody. Endothelial
NOS protein co-localized to areas that showed positive NADPH diaphorase activity. Within the testis, eNOS protein was localized
to the cytoplasm of Leydig cells and Sertoli cells at all stages of spermatogenesis. Within the epididymis and vas deferens,
eNOS was localized to the epithelium. Endothelial NOS was also localized to endothelial cells in all tissues; it was not detectable
in normal germ cells. Endothelial NOS and diaphorase activity were, however, detected in degenerating or apoptotic intraepithelial
germ cells. In addition, prematurely shed spermatocytes and spermatids had intense eNOS expression. Previous studies have
suggested a role for NOS in the contractile, hemodynamic, and hormonal aspects of testicular function as well as in epididymal
secretion. The studies reported herein suggest a role for eNOS in spermatogenesis and germ cell degeneration.
The human caliciviruses, which include Norwalk-like viruses (or Noroviruses) and Sapporo viruses, commonly cause epidemic and endemic viral gastroenteritis of short duration in healthy individuals. ...However, the impact of human calicivirus in immunosuppressed populations has not been established. The authors report five pediatric patients who developed human calicivirus enteritis after intestinal transplantation.
Infection was documented with repetitive reverse transcription polymerase chain reaction testing with nucleotide sequencing of tissue and lumen fluid specimens.
A single strain, type Miami Beach, affected all patients in the hospital with an apparent index case. A potential mode of transmission was not defined. Severe osmotic or secretory diarrhea necessitated intravenous fluid therapy for 40 days or more in three of the five infants. Concurrent or recent subclinical allograft infection with adenovirus in two patients was associated with more severe symptoms. Virus excretion exceeded 80 days in two patients. Differentiation of human calicivirus enteritis from allograft rejection was difficult, as both disorders were associated with increased enterocyte apoptosis and inflammation. Intensification of immunosuppressive therapy because of suspected rejection appeared to prolong symptoms.
These findings demonstrate that human calicivirus can be a significant pathogen in intestinal transplant recipients and potentially in other immunocompromised patients.
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