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Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eµ-Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite 'on-target' IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.

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Differential expression of fucosylated glycoproteins has been correlated with malignancy and metastatic potential in various types of neoplasia. Utilizing glycoproteomics techniques, changes in fucosylated serum peptides associated with naturally occurring canine lymphoma and transitional cell carcinoma (TCC) have been evaluated. In both types of neoplasia, the majority of the fucosylated peptides that changed increased with the cancer. In one lymphoma case that was examined over the course of the disease, the same fucosylated peptides that increased during pre-chemotherapy decreased during post-chemotherapy, and then subsequently increased upon recurrence of the lymphoma. When comparing all the fucosylated peptides that increased in both types of cancer, there were only two peptides in common allowing discrimination between lymphoma and TCC based on their peptide profiles. These results emphasize the prospect of glycopeptide profiling in proteomics for use in discovering a panel of non-invasive, diagnostic or prognostic biomarkers of cancer.

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Recent meta-analyses have documented considerable evidence demonstrating that correctional treatment programs are indeed effective for reducing recidivism in offender populations. The effect of client risk, an issue that has received extensive coverage in the extant literature from an assessment perspective, has been relatively ignored in these efforts. The present study marks the first exhaustive meta-analytic investigation of the risk principle and its effects on correctional treatment program effectiveness. The results reveal moderate support for its utility, although the magnitude of the findings are affected by the reporting practices used in the primary studies. Finally, the evidence supporting the risk principle is much stronger for female offenders and young offenders and within programs that are deemed appropriate according to the principles of need and responsivity. It should be noted that justice interventions that did not include elements of human service (e.g., increased sanctions) yielded negative results regardless of level of client risk.

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Several meta-analyses have rendered strong support for the clinically relevant and psychologically informed principles of human service, risk, need, and general responsivity. However, each of these reviews has focused on specific program components and not on the characteristics of the staff or the specific techniques used to deliver the program. This meta-analytic review examines the role of core correctional practices in reducing recidivism and provides strong preliminary evidence regarding their effectiveness. Staff characteristics and training in core skills must be addressed to ensure the maximum therapeutic impact of correctional treatment programs.

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Although relapse prevention models have been applied within offender treatment, there has been little controlled outcome research evaluating their effectiveness. This meta-analysis of 40 tests of relapse prevention treatment revealed moderate mean reductions in recidivism (0.15), and certain elements of the relapse prevention model (i.e., training significant others in the program model and identifying the offense chain) yielded stronger effects than others (i.e., provision of booster/aftercare sessions and developing coping skills). Further analyses revealed that the clinically relevant and psychologically informed principles of risk, need, and general responsivity yielded the strongest reductions in recidivism. The implications for future research and treatment are discussed.

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Nonoperative management of solid organ injury in children with blunt abdominal trauma represents the standard of care. In rare cases, a major duct injury with persistent bile leakage may result from blunt trauma to the liver. This injury is of concern in patients treated nonoperatively because it generally must be treated with major abdominal surgery. The authors describe a case of hepatic duct injury from blunt trauma in which healing occurred without surgical repair or resection.

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Lysophosphatidic acid (LPA) is a lipid-derived second messenger that mobilizes many cells of the circulatory and vascular systems to assist in thrombus development and wound healing. LPA, however, has not been tested on human erythrocytes, largely because erythrocytes are considered to be both biologically inert and inactive in intercellular communication. To test this presumption, we have examined the impact of LPA on signaling reactions within the human red blood cell (RBC). Using both (45)Ca(++) and a Ca(++)-sensitive fluorescent probe (Fluo-3), we demonstrated that LPA, but not phosphatidic acid or the closely related sphingosine-1-phosphate, stimulates the influx of micromolar quantities of extracellular Ca(++) into fresh RBCs. This Ca(++) influx was shown to be channel mediated rather than leak promoted because the influx was observed at LPA concentrations too low to perturb membrane integrity, it was inhibited by P-type but not L-type Ca(++) channel blockers, it was inhibited by broad-specificity protein kinase inhibitors, and it was not induced by inactive analogues of LPA. Further characterization reveals that only approximately 25% of the RBCs participate in LPA-induced Ca(++) entry and that within this active population, Ca(++) gating occurs in an all-or-nothing manner. Because the stimulation of Ca(++) uptake occurs at LPA concentrations (1-5 micromol/L) known to occur near a developing thrombus and because the internalized Ca(++) can potentially promote prothrombic properties in the stimulated RBCs, we conclude that RBCs are not insensitive to signals released from other cells.

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Most biomedical textbooks teach that coagulation and thrombosis are primarily a function of endothelial cells, platelets, and soluble coagulation factors. Red blood cells, in contrast, are generally regarded as innocent bystanders, passively entrapped in a developing thrombus as they flow through the vasculature. This review summarizes evidence that demonstrates an active role for red cells in normal and pathologic hemostasis. We then evaluate the possible molecular mechanisms whereby a usually inert erythrocyte can actively contribute to the processes of clot formation.

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Esophageal stenosis caused by an intrinsic congenital deformity is uncommon in infants and children. The main forms of stenosis are congenital esophageal web congenital stricture caused by tracheobronchial remnants, and congenital idiopathic muscular hypertrophy. The authors report on two patients who were successfully treated and managed after being diagnosed as having upper esophageal stenosis. One patient underwent resection of the web and primary anastomosis of the esophagus and was discharged 6 days after surgery. After 1 year, this patient has had no symptoms of dysphagia or other postoperative difficulties. The second patient underwent balloon dilatation of the esophageal stricture and was discharged on the day of surgery; however, this patient required numerous repeat dilatations.

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Long gap esophageal atresia occurs in approximately 5% of patients with tracheoesophageal anomalies. A small group of such patients have a rudimentary or diverticular distal esophagus that is not amenable to primary repair. These children usually require staged procedures and esophageal replacement using other parts of the intestinal tract. To circumvent the morbidity and delayed repair associated with cervical esophagostomy, colon interposition, or delayed gastric tube interposition, the authors propose the use of a primary gastric tube for early establishment of esophageal continuity in the neonate. Three cases of early esophageal replacement using a gastric tube are described. All three patients were born prematurely, with comorbid conditions, and had a rudimentary distal esophagus. The results of the operation were successful. The authors believe that primary repair of the esophagus, when possible, is the gold standard.

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The study explored a set of potential risk and protective factors in relation to criminal activity and adjustment with a group of delinquent youths. The results indicated, first, that risk variables reflecting family relationship and parenting problems were associated with heightened rates of re-offending and lower overall adjustment. Second, the presence of protective factors relating to positive peer relations, good school achievement, positive response to authority and effective use of leisure time was associated with more positive outcomes with controls for the risk variables. Third, there was no evidence of interaction between risk and protective factors; the latter operated similarly at low and high levels of risk. These results are discussed in terms of their theoretical and applied significance.

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Three hypotheses regarding the predictors of criminal activity in children and adolescents were assessed. These dealt with family, peer, and attitudinal variables, and they were explored in relation to indices based on seriousness of criminal activity and reoffending. The data were based on a sample of 338 youths who had been convicted of crimes and received probation or custody dispositions. The results provided general support for a model implicating family, peer, and attitudinal variables in youthful criminal activity. They did not, however, provide support for hypothesized interactions between family relationship and family structuring dimensions or between family relationship and peer association variables. The results did support an hypothesis regarding the independent contribution of an antisocial attitudes variable to the prediction of criminal activity.

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Previous descriptions of hereditary high-phosphatidylcholine hemolytic anemia (HPCHA) have highlighted the association of increased erythrocyte membrane phosphatidylcholine with abnormal membrane cation permeability. We studied the function and composition of erythrocyte membranes from three individuals with HPCHA to characterize further the membrane abnormalities in this disorder. Despite significant macrocytosis, HPCHA red cells were dehydrated and showed an increased surface area to volume ratio compared to normal red cells. The passive efflux of K+ from HPCHA erythrocytes was increased fourfold at 37 degrees C. Total membrane phospholipid was increased 7-42%, largely due to excess phosphatidylcholine, which made up 35.8-37.2% of total phospholipid. Membrane cholesterol:phospholipid ratios were in the normal range. It appears that the excess phosphatidylcholine was not acquired during circulation, since plasma lipids were normal and all subpopulations of density-separated HPCHA erythrocytes were similarly abnormal. The ratio of total protein to phospholipid in white ghosts was increased, indicating that membrane protein was increased to an even greater extent than membrane lipids. No abnormal membrane proteins were identified by Coomassie or periodic acid Schiff (PAS) staining. Quantitation of the major membrane proteins indicated that the total protein excess in HPCHA membranes was due to a proportional increase in all major proteins. We conclude that HPCHA erythrocytes have excess membrane proteins and hypothesize that the changes in lipid composition and cation permeability are secondary to underlying protein abnormalities, which remain to be defined.

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Necrotizing enterocolitis (NEC) is usually a disease of premature infants, but occasionally it affects the term neonate. A 5-year review of NEC at Children's Hospital and Medical Center identified the unique features of this disease in the term neonate. Eighty-one patients with NEC were treated between January 1984 and May 1989. Ten full-term neonates with gestational age greater than 38 weeks were identified for study. Charts were reviewed for recognized risk factors, clinical course, surgical intervention, and outcome. Ninety percent had a birth weight greater than or equal to 2.7 kg, and all were above 2.1 kg. NEC developed early in this group, with onset of disease in the first 48 hours of life in 50% of the group and within the first 4 days of life in 90%. The recognized risk factors of asphyxia, hypoglycemia, polycythemia, and respiratory distress were absent in 60%. Seven of 10 patients required exploratory laparotomy, whereas 3 of 10 required only medical treatment. Indications for operation were perforation in three patients, peritonitis in three patients, and mass in one patient. All patients requiring operations had severe colonic disease, with perforation of the colon in five of seven and full-thickness necrosis without perforation in two of seven. Two patients required total abdominal colectomy. Only one patient with perforated meconium ileus and associated NEC had small bowel involvement. This patient was the only mortality of the group. Subsequent intestinal continuity was restored in all surviving patients with no late complications. Two patients required resection of additional NEC strictures prior to reanastomosis. Of the three medically treated patients, none required subsequent operation for colonic stricture. Our experience indicates that the presentation, clinical course, and operative findings in full-term neonates with NEC differ from those encountered in the premature infant with NEC.

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The Family Relationship Index (FRI) is a self-report measure that provides an overall index of the quality of the family environment, as well as subscores that reflect family cohesion, expressiveness, and conflict. The current study is based on 53 families who had approached a family service agency for counseling and who had completed an FRI measure prior to intake. The construct validity of the FRI scores was evaluated by comparing them to measures of family functioning provided by experienced family therapists as part of the intake process. Support for the construct validity of the composite index and two of the subscores, Family Cohesion and Family Conflict, was obtained.

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The construct validity of family therapists' assessments of client functioning was evaluated with data collected in a clinical setting (N = 1,165). The assessments were provided by the therapists in the context of the intake interview. The convergent and discriminant validities of various dimensions of client functioning were evaluated through analyses conducted within the therapist-generated judgments and with data collected directly from clients. The analyses were generally supportive of the construct validity of the assessments. A factor analysis of the client functioning data also is reported.

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