Obese children with steatohepatitis can develop cirrhosis in childhood

Nonalcoholic steatohepatitis, in which fatty change and inflammation of the liver occur in the absence of excess alcohol intake, is increasingly recognized in obese children. Although fibrosis is common in pediatric nonalcoholic steatohepatitis, cirrhosis has been reported rarely. The two boys reported here developed cirrhosis from nonalcoholic steatohepatitis at ages 10 and 14 yr. One child progressed to cirrhosis with symptomatic portal hypertension within a 2-yr period.     

Effect of dose on response to adrenocorticotropin in extremely low birth weight infants

CONTEXT: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. OBJECTIVE: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. DESIGN: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. SETTING: The setting was nine newborn intensive care units. PATIENTS: The patients included infants with 500-999 g birth weight. INTERVENTION: The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth. MAIN OUTCOME MEASURE: We measured the cortisol response to cosyntropin. RESULTS: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P < 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P < 0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. CONCLUSIONS: A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.     

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.     

Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pre-transplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy ( P  = 0.0001). All seven patients developing MDS post-transplantation belonged to group 2 ( P  = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38–86) and 24 months (range 9–39), respectively. Our findings provide evidence that prolonged standard-dose alkylating agent therapy prior to transplantation, rather than autotransplant-supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment-related MDS/AML.     

Endoscopic biopsy diagnosis of acute gastrointestinal graft-versus-host disease: rectosigmoid biopsies are more sensitive than upper gastrointestinal biopsies

OBJECTIVES: The diagnosis of gastrointestinal (GI) graft- versus -host disease (GVHD) is based upon histologic findings in endoscopic mucosal biopsy specimens. The portion of the GI tract with the highest diagnostic yield is a topic of debate. Our aim was to evaluate the sensitivity of simultaneous biopsy of the stomach, duodenum, and rectosigmoid in establishing the diagnosis of GI GVHD.
METHODS: We identified 112 patients who had simultaneous endoscopic biopsies of the stomach, duodenum, and rectosigmoid within the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT). GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. The patient was diagnosed with GI GVHD if at least one biopsy site was positive.
RESULTS: Overall, 81% of the patients had GI GVHD. Of these, 66% had involvement at all three biopsy sites. Rectosigmoid biopsies had the highest sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing GI GVHD, at 95.6%, 100%, 100%, and 84%, respectively. The sensitivities of gastric and duodenal biopsies were 72.5% ( P < 0.0001 vs rectosigmoid) and 79.2% ( P = 0.0018), respectively. The negative predictive values of gastric and duodenal biopsies were 45.6% ( P = 0.0039 vs rectosigmoid) and 52.5% ( P = 0.0205), respectively. Rectosigmoid biopsies had a higher sensitivity and negative predictive value than biopsies at other sites whether the patient presented with diarrhea or nausea/vomiting. No association between the degree of mucosal injury and the presence of GVHD was found at any site.
CONCLUSIONS: Biopsy of the rectosigmoid is the single best test for diagnosing GI GVHD.     

Development of cardiovascular drugs: the U.S. regulatory milieu from the perspective of a participating nonregulator

The Food and Drug Administration (FDA) is responsible for assuring that drugs, devices, and biologicals available in the U.S. are effective and acceptably safe for their intended uses. Both law and regulation define the procedures to be followed by the FDA in judging the effectiveness and safety of therapies. The FDA comprises a cadre of highly skilled public servants who receive and evaluate all data collected by the manufacturer during therapy, not just the portion that reaches publication. To assist in reaching final conclusions about approvability, the FDA can empanel legally constituted advisory committees and external consultants when the need is perceived for additional specific scientific/technical expertise and substantial experience in clinical practice. Evidentiary standards for marketing approval of drugs, biologicals, and devices generally require direct demonstration of clinical benefit, rather than inferences drawn from "surrogate" pharmacologic/device-mediated effects, sufficient exposure to enable a reasonable assessment of countervailing risk, consideration of specific design elements in the pivotal clinical trials (including prespecified hypotheses [implicitly incorporated in "primary end points"], rigorous plans for statistical analyses, and so on), and assessment of persistence of effectiveness and associated stability of safety over time. Finally, sufficient information must be available so that practitioners can receive written instructions for use (the label) adequate to support the likelihood that recipients of the therapy will receive the expected benefits within the envelope of the stated risks. This article will discuss and expand on these issues, with examples.     

Perimount® Bovine Pericardial Valve to Restore Pulmonary Valve Competence Late after Right Ventricular Outflow Tract Repair

Objective. No ideal option exists for restoring pulmonary valve competence late after repair of the congenitally abnormal right ventricular outflow tract (RVOT). This has driven a continued search for new alternatives. Texas Children’s Hospital has recently used the Carpentier‐Edwards Perimount RSR Pericardial Aortic Prosthesis (Edwards Lifesciences, Irvine, Calif, USA) for this indication and reports the initial experience. Design. Retrospective chart review. Setting. Academically affiliated tertiary‐care pediatric hospital. Patients. Twenty‐six patients who underwent pulmonary valve replacement with the Perimount^® valve late after RVOT reconstruction between June 2002 and November 2005. Interventions. No prospective interventions. Outcomes Measures. Hospital morbidity and mortality. Valve function assessed by follow‐up visits and echocardiograms. Results. Mean age and weight of the patients were 20.3 ± 9.8 years (range 7.0–45.1 years) and 56.2 ± 18.1 kg (range 35.8–109 kg). Twenty‐two patients (85%) had severe pulmonary insufficiency (PI), 23 (89%) had symptomatic right heart failure, and 14 (54%) had moderate to severe right ventricular dysfunction. Average prosthetic valve size was 23 mm (range 19–27 mm). Twenty‐one (88%) patients were extubated within 24 hours. There was no hospital mortality. Median length of stay for all patients from day of surgery was 6 days (range 3–56 days). Median length of last echocardiography follow‐up was 12.4 months (range 0.1–37.6 months). At that time, 16 of the 26 (62%) patients had improved right ventricular function, no patient demonstrated significant RVOT obstruction, and 24 patients (92%) have no PI or mild PI. Freedom from death, reintervention, or reoperation on the pulmonary valve is 100% at 2.5 years. Conclusion. Initial results with the Perimount^® bovine pericardial tissue prosthesis for pulmonary valve replacement are encouraging. Further follow‐up is required to define long‐term function and durability.