Margaret E. Ginn-Pease

Redox Signals and NF-κB Activation in T Cells

Abstract Accumulating data from a number of laboratories have recently indicated that the response of transcription factor NF-κB to alterations in the redox homeostasis of cells may play an important role in modulating immune function. The activation of NF-κB has been recognized to regulate a number of genes necessary for normal T cell responses including IL-2, IL-6, IL-8, and several T cell surface receptors. Diminished NF-κB activity has been shown to occur in T cells with aging, suggesting that impaired activation of NF-κB might occur during cellular senescence. In addition, aberrancies in NF-κB activity have been implicated in the immunopathogenesis of diseases involving immune or inflammatory processes such as atherosclerosis and HIV-1 infection. The role of H2O2 and other reactive oxygen species (ROS) as an integratory secondary messenger for divergent T cell signals has been complicated by the fact that various T cell lines and peripheral blood T cells differ markedly in the levels of NF-κB activation induced by oxidant stress. Additionally, proposed pathways of NF-κB activation have been based on indirect evidence provided by experiments which used antioxidants to inhibit active NF-κB formation. Further, complete activation of T cells requires at least two signals, one that stimulates an increase in intracellular calcium and one that stimulates enzymatic processes including kinases. Similarly, substantial evidence indicates that full activation of NF-κB requires dual signals. The ability of H2O2 or other ROS to induce T cell signals and functional responses by these two mechanisms is reviewed and the specific response of NF-κB to redox changes in T cells is examined. Data are also presented to suggest that the redox regulation in NF-κB activation may be relevant to immune-related diseases and to aging.

Pediatric Head Injuries: Can Clinical Factors Reliably Predict an Abnormality on Computed Tomography?

STUDY OBJECTIVE To assess clinical features that might reliably predict the need for computed tomography (CT) imaging in pediatric head trauma. DESIGN/SETTING/TYPE OF PARTICIPANT: Prospective cohort of 324 head CT scans performed on 322 consecutive trauma patients at an urban childrens hospital. RESULTS Sixty-two percent of patients were male. The mean age was 7.1 years (10 days to 20.6 years); half were less than 5 years of age. The two most frequent mechanisms of injury were falls (32%) and motor vehicle accidents (25%). Abnormalities were detected in 74 scans. Intracranial injuries were apparent in 39 patients (12%); 16 had a concomitant fracture. An isolated cranial abnormality was observed on 35 scans (11%). Loss of consciousness, amnesia for the event, a Glasgow Coma Scale (GCS) of less than 15, and the presence of a neurologic deficit were more common in children with intracranial injury (P < .05). Vomiting, seizures, and headache were not discriminating clinical features. No single characteristic consistently identified the children with an intracranial injury. Of the 195 children who were neurologically intact (GCS, 15) at the time of presentation, 11 (5%) had evidence of intracranial pathology on CT scan. CONCLUSION This study demonstrates a poor correlation between the clinical symptoms of significant traumatic brain injury and findings on CT.

Sequelae of antireflux surgery in profoundly disabled children

Between 1976 and 1989 an antireflux operation (193 Nissen; 5 Thal) was performed in 198 children with profound neurological impairment (NI). Etiology of the NI was a syndrome in 24%, congenital in 30%, and acquired in 46%. The most frequent symptoms of gastroesophageal reflux (GER), vomiting and pneumonia, were significantly reduced (P less than .05) after the antireflux operation. Postoperatively, 141 children (71%) developed return of one or more symptoms that had been preoperatively associated with GER, whereas 57 patients (29%) remained asymptomatic. Of the children with symptoms, 86 (61%) underwent diagnostic testing to exclude recurrent GER and 55 (39%) had no diagnostic evaluation. Recurrent GER was documented in 31 patients and a mechanical problem with the fundoplication in 18 children, an operative failure rate of 25%. The symptom-free interval following the antireflux operation averaged 11 months postoperatively; return of symptoms showed no statistical relationship to the etiology of NI, presence of seizures, or degree of muscle tone. The majority of children required multiple outpatient or emergency department visits for evaluation of these symptoms or assessment of gastrostomy tube problems. Survival of all children was 71% at an average postoperative follow-up of 3.5 years.

Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal–Like Sequences for Nuclear Import Mediated by Major Vault Protein

Although phosphatase and tensin homologue deleted on chromosome 10 (PTEN) localization in the nucleus and cytoplasm is established, the mechanism is unknown. PTEN is a tumor suppressor phosphatase that causes cell cycle arrest and/or apoptosis. Nuclear-cytoplasmic compartmentalization may be a novel mechanism in regulating these events. PTEN does not contain a traditional nuclear localization sequence (NLS); however, we identified putative NLS-like sequences, which we analyzed by site-directed mutagenesis and localization studies in MCF-7 cells. Two double site mutations exhibited nuclear localization defects. Furthermore, unlike wild-type PTEN, double NLS mutant PTEN did not interact with major vault protein (MVP), a previously hypothesized nuclear-cytoplasmic transport protein. We conclude that these two NLS-like sequences are required for PTEN nuclear import that is mediated by MVP. Further, we show that this MVP-mediated nuclear import is independent of PTEN phosphorylation and of the lipid and protein phosphatase activities of PTEN.

Broviac catheter sepsis: The natural history of an iatrogenic infection

Between January 1982 and December 1983, 335 Broviac catheters placed in 270 infants and children were prospectively evaluated. The average duration of catheter life was 99.7 days, yielding a total accumulated experience of 33,394 catheter days. Blood culture-proven bacteremia occurred on 77 occasions (23%), an average of one spetic episode for every 434 days of catheter use. Temperature elevation was the only consistent clinical sign of infection occurring in 91% of the children. White blood cell counts remained within the normal range in the majority of patients. The differential counts were most helpful, however, documenting a significant increase in the number of immature neutrophils. The rise in band forms was frequently observed 24 to 48 hours before the onset of clinically evident sepsis. Platelet counts did not change significantly. Eighty-eight microorganisms were identified on blood culture. Eighty-three bacterial isolates were recovered (94%) and five fungi. The vast majority of patients (86%) had a single organism on blood culture but polymicrobial sepsis was observed on 11 occasions. Staphylococcus sp (38%) and Streptococcus sp (25%) species were most common. Of particular importance, 48% of coagulase negative staphylococci were nafcillin-resistant. Of the gram negative bacteria, Klebsiella (10%) and Pseudomonas (6%) species were most frequent. In 53 patients, antibiotic therapy was administered in an attempt to salvage the catheter. Bacteremia was controlled successfully in 39 (74%), and in the other 14 children, persistent sepsis dictated catheter removal. One patient (0.4%) died as a result of catheter-related sepsis.

Pediatric cervical spine fractures: Predominately subtle presentation☆

Previous description of cervical spine fractures in children have emphasized high mortality injuries to the upper cervical vertebra. Our experience suggests a much wider spectrum of injury. The medical records of all children with cervical spine fractures admitted to Childrens Hospital between January 1, 1985 and December 31, 1989 were reviewed. The average age of the 50 patients was 11 years (range, 2.7 to 18.8 years) and 62% were boys. Motor vehicle-related accidents (54%), sports injuries (18%), and falls (12%) accounted for the majority of the fractures. Twenty-nine patients (58%) had an associated head injury. Fifty percent of the patients were transported from the accident scene and 44% were interhospital transfers. All patients receiving medical care prior to referral had appropriate cervical spine stabilization. On admission 30% of the patients were unresponsive. Thirty-one children were alert and verbal at the time of evaluation and 30 complained of neck pain and tenderness (97%). Twenty-five of the 31 patients (83%) had no demonstrable neurological deficit on initial physical examination. Lateral cervical spine radiographs were diagnostic in 49 children (98%). A relatively even distribution of fractures occurred at all levels of the cervical spine. The anatomic site of the injury did not correlate with age. Sixteen patients (32%) died. Of the 34 who survived, only 6 had a persistent neurological deficit. Children with cervical spine fractures have two distinct patterns of presentation: lethal or intact. The majority of children with cervical spine fractures presented with no complaints of neck pain and/or tenderness need a complete radiographic evaluation of their cervical spine.

Pediatric cervical-spine immobilization : achieving neutral position ?

This study was designed to evaluate prospectively the ability of current spine-immobilization devices to achieve radiographic-neutral positioning of the cervical spine in pediatric trauma patients. All trauma patients who required spinal immobilization and a lateral cervical spine radiograph were included in the study. A lateral cervical spine radiograph was obtained while the child was immobilized. The Cobb angle (C2-C6) was measured using a handheld goniometer. The method of immobilization, age at injury, and Cobb angle were compared. One hundred and eighteen patients with an average age of 7.9 years were enrolled. The majority were males (71%). The most frequent mechanisms of injury included motor vehicle accidents (35%) and falls (32%). The average Glascow Coma Scale score was 14. Although 31% of the children complained of neck pain, 92% were without neurologic deficits. The Cobb angles ranged from 27 degree kyphosis to 27 degree lordosis, and only 12 of the patients presented in a neutral position (0 degrees). Greater than 5 degrees of kyphosis or lordosis was observed in 60% of the children. Thirty-seven percent of the patients had 10 degrees or greater angulation. The most frequent methods of immobilization included a collar, backboard, and towels (40%), and a collar, backboard, and blocks (20%), but these techniques provided < 5 degrees kyphosis or lordosis in only 45% and 26% of the children respectively. No single method or combination of methods of immobilization consistently placed the children in the neutral position.(ABSTRACT TRUNCATED AT 250 WORDS)

An individualized approach to the management of gastroschisis

A 93% survival rate was achieved in 80 neonates treated for gastroschisis between 1979 and 1986. Uncomplicated gastroschisis occurred in 70 infants (88%); 51% underwent staged silo reduction and 49% had primary fascial closure. Gastroschisis associated with intestinal atresia or volvulus was present in 10 neonates (12%), half of whom had a residual jejunoileum between 10 and 55 cm. Major postoperative complications included gastrointestinal problems (infarction, obstruction, and prolonged dysfunction), wound infection, and catheter-associated difficulties (sepsis, infiltration, and malposition). Three of the six deaths were related to associated conditions (extreme prematurity, trisomy 13, and multiple anomalies) and three were caused by intraoperative hemorrhage, necrotizing enterocolitis, and extensive short-bowel syndrome. No statistical difference in morbidity, mortality, and length of hospitalization was demonstrated between infants treated by silo reduction and primary closure. Safe management of gastroschisis should include an individualized assessment of visceroabdominal disproportion and degree of intraabdominal tension. Vigilant expectation of potentially life-threatening complications is required to decrease postoperative morbidity, irrespective of the technique of abdominal wall closure.

Recognition of recurrent gastroesophageal reflux following antireflux surgery in the neurologically disabled child: High index of suspicion and definitive evaluation

Multiple symptoms suggestive of gastroesophageal reflux (GER) developed in 181 of 240 children (75%) with profound neurological impairment (NI) following operative management of GER. Diagnostic testing was performed in 102 children, 56% of patients with symptoms. Recurrent GER was evident on one or more diagnostic studies in 46% of children evaluated. Significant differences (P less than .05) were found in the testing protocols of children with studies positive for GER and those individuals with negative tests. Children with study-documented recurrent GER: (1) had testing conducted at a more remote time postoperatively; (2) received a greater number of total tests; (3) were evaluated by more than one type of diagnostic test; and (4) underwent upper endoscopy and pH monitoring more frequently. No single clinical symptom was predictive of study-documented recurrent GER. These results suggest that recognition of recurrent GER after an antireflux operation in a child with profound NI requires a high index of suspicion. Definitive evaluation of children with postoperative symptoms demands repeated testing over time and the use of more than one type of diagnostic test. A contrast study should be used to evaluate the mechanical properties of the fundoplication and esophagoscopy and/or esophageal pH monitoring to assess the physiological control of GER.

Pulmonary function is compromised in children with mediastinal lymphoma.

PURPOSE Lymphomas account for nearly 20% of the malignancies in childhood and the majority of patients with Hodgkins Disease (HD) and non-Hodgkins lymphoma (NHL) have radiological evidence of mediastinal involvement at presentation. Children with mediastinal tumors are at risk for the development of lethal airway obstruction during general anesthesia. This study quantitates the degree of the airway obstruction and the functional significance of tracheal compression in a cohort of 51 children with HD and NHL. RESULTS Thirty patients with HD (mean age, 14.6 years) and 21 with NHL (mean age, 9.2 years) were included in this study. Twenty-five children (49%) had respiratory symptoms at the time of presentation. Respiratory complaints were much more common in children with NHL (76%) when compared with those with HD (30%). Pulmonary function was also significantly worse in the NHL patients who had a mean upright forced vital capacity (FVC) of 66 +/- 21%. The comparable value for the children with HD was 85 +/- 15% (P = .031). Patients with respiratory symptoms at presentation had both obstructive and restrictive deficits of pulmonary function. Their mean upright forced expiratory volume in 1 second (FEV1) was 69 +/- 22% and the FVC was 69 +/- 18%. Children with large mediastinal masses also had significantly decreased pulmonary function compared with those with small tumors. The upright FEV1 for these two groups was 72 +/- 18% versus 98 +/- 15% (P = .016). Their FVC values were 68 +/- 20% and 91 +/- 17%, respectively (P = .049). Mean tracheal compression was measured at 44% in the children with large tumors versus 27% for those with small lesions (P = .048). CONCLUSION Children with mediastinal lymphomas have both obstructive and restrictive deficits on pulmonary function testing. Pulmonary function is significantly decreased in patients with NHL, children who present with respiratory symptoms, and those with very large mediastinal masses (mediastinal mass ratio > 45%). The extent of tracheal compression correlates with the size of the mediastinal mass.