Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase

In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation, and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system, as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge, were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in nonhuman primates.     

Abnormalities of iron metabolism and erythropoiesis in vitamin E- deficient rabbits

Rabbits fed a vitamin E-deficient diet developed severe muscular dystrophy in 3-4 wk, but they did not become anemic. Nevertheless, reticulocyte counts increased in deficient rabbits (3.2%) compared to control rabbits (0.9%), and erythroid hyperplasia was evident in the bone marrow. Comparing deficient rabbits to controls, the plasma iron concentration was lower (134.4 versus 206.6 microgram/dl); the TIBC was higher (335.9 versus 228.3 microgram/dl); the whole blood protoporphyrin concentration was higher (131.6 versus 81.7 microgram/dl); and the total iron content was lower in spleen (71 versus 153 microgram), higher in skeletal muscle (4956 versus 3054 microgram), and unchanged in bone marrow, liver, and heart. Studies of iron absorption and excretion using 59Fe showed no abnormalities in deficient rabbits. There were abnormalities of ferrokinetics, however. The half-time of disappearance of 59Fe was shorter (100.6 versus 169.4 min), the plasma iron turnover was greater (1.25 versus 0.95 mg/dl blood/day), and the reappearance of 59Fe in circulating erythrocytes at day 9 was greater (77.2% versus 57.2%) in deficient rabbits. Anemia induced by phlebotomy accentuated the abnormal iron metabolism of deficient rabbits, and the animals were unable to correct the anemia. These findings show that vitamin E deficiency in rabbits causes abnormal erythropoiesis associated with abnormal iron metabolism and sequestration of iron in skeletal muscle.     

Hemophilia A: carrier detection and prenatal diagnosis by DNA analysis

In this study, we used DNA polymorphisms for carrier detection and prenatal diagnosis of hemophilia A in a large group of Italian families. The restriction fragment length polymorphisms (RFLPs) investigated were the intragenic polymorphic Bc/I site within the factor VIII gene; the extragenic multiallelic Taq I system at the St14 locus; and the extragenic Bg/II site at the DX13 locus. The factor VIII probe was informative in 30%, St14 in 82%, and DX13 in 60% of obligate carriers. The combination of factor VIII-Bc/I and St14-Taq I showed that 91% of obligate carriers were heterozygotes for one or both; with all three probes, only 4% of obligate carriers were noninformative. In families clearly segregating for hemophilia A, RFLP analysis allowed us to define the carrier status for the hemophilia A gene in all 27 women tested. RFLP analysis allowed us to exclude the carrier status in 39 of 45 female relatives of sporadic patients. The combination of RFLP analysis and biological assay of factor VIII allowed us to identify a de novo mutation in the maternal grandfather in 7 of 12 of the families with sporadic cases, for which members of three generations were available for study. Nine of 10 couples requesting prenatal diagnosis provided informative RFLP DNA pattern. Carrier status was excluded in two women, two fetuses were shown to be female, and prenatal diagnosis was carried out in five pregnancies by DNA analysis. Prenatal testing was successful in three instances and failed in two because a sufficient amount of chorionic villous DNA was not obtained for the analysis.     

Nonhomogeneous distribution of leukemia in the bone marrow during minimal residual disease

In a rat model (BNML) for human acute myelocytic leukemia the distribution of leukemic cells in bone marrow samples from various sites was investigated, using monoclonal antibodies (MoAbs) and flow cytometry. Rats were studied before chemotherapy as well as thereafter, ie, in the "minimal residual disease" (MRD) phase. Bone marrow from different types of bones was analyzed from each animal. Before treatment, the ratio of the measured extreme values (ie, highest/lowest value) for leukemic cell frequencies in bones from individual rats ranged from 3.7 to 11.7. During the MRD phase the ratios of the extremes ranged from a factor of 36 to more than 13,000 from one rat to another. The variability between bones of comparable size was estimated by studying the ribs from each individual animal. Within individuals the extremes differed by a factor of 1.2 to 4.0 before chemotherapy and from 2.4 to greater than 320 after chemotherapy. The variability within the marrow cavity of a single bone was determined by analyzing multiple samples from femoral bones cut into slices. The leukemic cell frequency appeared to vary considerably, ie, before treatment from 1.7 to 7.3 and during MRD from 4 to 28,000. The presented data may contribute to understanding the sometimes conflicting observations in leukemic patients. Improvement of methods for detecting MRD will not automatically lead to a more accurate estimation of the total tumor burden. The reliability of diagnoses based on the analysis of single bone marrow aspirates appears to be highly questionable.     

Pathology of human intestinal transplantation

BACKGROUND & AIMS: Intestinal transplantation is a developing therapeutic option for patients with irreversible intestinal failure or short bowel syndrome. The aim of this study was to delineate the histopathology of human intestinal allografts and to define the features of intestinal rejection. METHODS: The histological features of 3015 endoscopic biopsy specimens and 23 allograft specimens from 62 intestinal recipients were analyzed retrospectively and correlated with clinical findings. RESULTS: Acute allograft rejection was characterized by a varying combination of crypt injury, mucosal infiltration primarily by mononuclear cells (including blastic lymphocytes), and increased crypt cell apoptosis (more than 2 per 10 crypts). It represented a patchy, often ileal-centered process that could progress to mucosal ulceration; later episodes (more than 100 days posttransplant) tended to show lesser cellular infiltration and greater apoptosis than earlier episodes. Correlation with clinical rejection was good (false-positive rate of 9%; false-negative rate of 26%). Two resected specimens showed obliterative arteriopathy indicative of chronic rejection. In other specimens, preservation injury, cytomegalovirus infection, post-transplant lymphoproliferative disorder, and nonspecific features of active or past mucosal injury could be recognized. CONCLUSIONS: Mucosal biopsy specimens are a useful means of monitoring intestinal allografts. Based on features validated by clinical correlation, acute rejection can be identified reliably and can be differentiated from the other pathological processes affecting the intestinal allograft. (Gastroenterology 1996 Jun;110(6):1820-34)     

Delayed presentation of vernix caseosa peritonitis

INTRODUCTION

Vernix caseosa peritonitis (VCP) is a rare and poorly recognised condition resulting from a sustained foreign body reaction to the vernix caseosa of the baby. This case-based review aims to highlight its importance for any medical team managing patients with peritonitis who have undergone a recent Caesarean section.

CASE REPORT

A 31-year-old woman presented 5 weeks after a Caesarean section with symptoms and signs of peritonitis.

CONCLUSIONS

Laparotomy and peritoneal lavage is the mainstay of treatment for VCP. Knowledge of the condition may stop inadvertent resection of normal intra-abdominal organs. Greater awareness of VCP is required to ensure earlier recognition as patients can recover well following timely operative intervention.     

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],     

Impact of Early Initiation of Enteral Nutrition on Survival During Pediatric Extracorporeal Membrane Oxygenation

Introduction: Pediatric data related to safety, tolerance, and outcomes of enteral nutrition (EN) for patients requiring extracorporeal membrane oxygenation (ECMO) are lacking. The objectives of this study were to evaluate early nutrition status and timing of EN initiation on survival during pediatric ECMO. Methods: A single center institutional review board–approved retrospective chart review was performed on all pediatric patients requiring ECMO from October 2008 through December 2013. Demographics, ECMO variables, laboratory values, vasoactive inotropic score (VIS), and nutrition data on day 5 (d5) were collected. Patients receiving parenteral nutrition (PN) were compared with those receiving any EN on d5. Analyses were conducted to identify factors influencing survival to completion of ECMO and to discharge. Results: Forty‐nine patients aged 53 ± 76 months met inclusion criteria. Kaplan‐Meier curves demonstrated greater survival to discharge in patients receiving any EN, compared with only receiving PN (P = .031). EN on d5 of ECMO support (P = .040) and a higher percentage of daily energy intake achieved (P = .013) were protective, whereas a higher VIS was associated with increased mortality (P = .010). Multivariable analysis demonstrated EN was no longer associated with survival to discharge (P = .139), whereas energy intake (P = .021) and VIS (P = .013) remained significant. Conclusions: Pediatric patients who received nutrition that was closer to goal energy intake, as well as those who received any EN early during ECMO, had improved survival to hospital discharge.     

A locus for autosomal dominant anterior polar cataract on chromosome 17p

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.