Showing papers by "Boston Children's Hospital published in 1988"

Pediatric risk of mortality (PRISM) score.

Abstract: The Pediatric Risk of Mortality (PRISM) score was developed from the Physiologic Stability Index (PSI) to reduce the number of physiologic variables required for pediatric ICU (PICU) mortality risk assessment and to obtain an objective weighting of the remaining variables. Univariate and multivariate statistical techniques were applied to admission day PSI data (1,415 patients, 116 deaths) from four PICUs. The resulting PRISM score consists of 14 routinely measured, physiologic variables, and 23 variable ranges. The performance of a logistic function estimating PICU mortality risk from the PRISM score, age, and operative status was tested in a different sample from six PICUs (1,227 patients, 105 deaths), each PICU separately, and in diagnostic groups using chi-square goodness-of-fit tests and receiver operating characteristic (ROC) analysis. In all groups, the number and distribution of survivors and nonsurvivors in adjacent mortality risk intervals were accurately predicted: total validation group (chi 2(5) = 0.80; p greater than .95), each PICU separately (chi 2(5) range 0.83 to 7.38; all p greater than .10), operative patients (chi 2(5) = 2.03; p greater than .75), nonoperative patients (chi 2(5) = 2.80, p greater than .50), cardiovascular disease patients (chi 2(5) = 4.72; p greater than .25), respiratory disease patients (chi 2(5) = 5.82; p greater than .25), and neurologic disease patients (chi 2(5) = 7.15; p greater than .10). ROC analysis also demonstrated excellent predictor performance (area index = 0.92 +/- 0.02).

Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease.

Abstract: Amyloid B-protein/amyloid A4 is a peptide present in the neuritic plaques, neurofibrillary tangles and cerebrovascular deposits in patients with Alzheimer's disease and Down's syndrome (trisomy 21)1–4 and may be involved in the pathogenesis of Alzheimer's disease5. Recent molecular genetic studies have indicated that amyloid protein is encoded as part of a larger protein by a gene on human chromosome 21 (refs 6–9). The amyloid protein precursor (APP) gene is expressed in brain and in several peripheral tissues, but the specific biochemical events leading to deposition of amyloid are not known. We have now screened complementary DNA libraries constructed from peripheral tissues to determine whether the messenger RNA encoding APP in these tissues is identical to that expressed in brain, and we identify a second APP mRNA that encodes an additional internal domain with a sequence characteristic of a Kunitz-type serine protease inhibitor. The alternative APP mRNA is present in both brain and peripheral tissues of normal individuals and those with Alzheimer's disease, but its pattern of expression differs from that of the previously reported APP mRNA.

Hypoplasia of Cerebellar Vermal Lobules VI and VII in Autism

Abstract: Autism is a neurologic disorder that severely impairs social, language, and cognitive development. Whether autism involves maldevelopment of neuroanatomical structures is not known. The size of the cerebellar vermis in patients with autism was measured on magnetic resonance scans and compared with its size in controls. The neocerebellar vermal lobules VI and VII were found to be significantly smaller in the patients. This appeared to be a result of developmental hypoplasia rather than shrinkage or deterioration after full development had been achieved. In contrast, the adjacent vermal lobules I to V, which are ontogenetically, developmentally, and anatomically distinct from lobules VI and VII, were found to be of normal size. Maldevelopment of the vermal neocerebellum had occurred in both retarded and nonretarded patients with autism. This localized maldevelopment may serve as a temporal marker to identify the events that damage the brain in autism, as well as other neural structures that may be concomitantly damaged. Our findings suggest that in patients with autism, neocerebellar abnormality may directly impair cognitive functions that some investigators have attributed to the neocerebellum; may indirectly affect, through its connections to the brain stem, hypothalamus, and thalamus, the development and functioning of one or more systems involved in cognitive, sensory, autonomic, and motor activities; or may occur concomitantly with damage to other neural sites whose dysfunction directly underlies the cognitive deficits in autism.

A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane.

Abstract: The basement membranes of bovine cornea are found to contain an angiogenic endothelial cell mitogen, basic fibroblast growth factor (FGF), as determined by heparin-affinity chromatography, immunoblotting, immunofluorescence, and stimulation of capillary endothelial cell proliferation. The growth factor appears to be bound to heparan sulfate and is released from the cornea by treatment with heparin, a hexasaccharide heparin fragment, heparan sulfate, or heparanase, but not by chondroitin sulfate or chondroitinase. These findings indicate that basement membranes of the cornea may serve as physiologic storage depots for an angiogenic molecule. Abnormal release of this growth factor could be responsible for corneal neovascularization in a variety of ocular diseases. Physiologic and pathologic neovascularization in other tissues may also be initiated by release of stored angiogenic factors from the basement membrane. The sequestration of angiogenic endothelial mitogens in the basement membrane may be a general mechanism for regulating their accessibility to vascular endothelium.

Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy

Abstract: A deficiency of the protein dystrophin has recently been shown to be the probable cause of Duchenne's muscular dystrophy. We sought to determine the relation between the clinical phenotype and the status of dystrophin in muscle-biopsy specimens from 103 patients with various neuromuscular disorders. We found very low levels (less than 3 percent of normal levels) or no dystrophin in the severe Duchenne phenotype (35 of 38 patients), low concentrations of dystrophin in the intermediate (outlier) phenotype (4 of 7), and dystrophin of abnormal molecular weight in the mild Becker phenotype (12 of 18). Normal levels of dystrophin of normal molecular weight were found in nearly all the patients (38 of 40) with 20 other neuromuscular disorders we studied. These data show the clinical consequences of both quantitative alterations (in Duchenne's and intermediate dystrophy) in a single protein. The biochemical assay for dystrophin should prove helpful in delineating myopathies that overlap clinically with Duchenne's and Becker's dystrophies, and it shows promise as an accurate diagnostic tool.

Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants.

Abstract: The timing and synchronization of postnatal myelination in the human central nervous system (CNS) are complex. We found eight time-related patterns of CNS myelination during the first two postnatal years in autopsied infants. The intensity of myelination was graded in 162 infants with diverse diseases on an ordinal scale of degrees 0-4. The Ayer method for maximum likelihood estimates for censored data was utilized to generate curves of the temporal changes in the percent of infants with degrees 0 through 4 of myelin in 62 white matter sites. These sites fall into eight subgroups determined by the presence or absence of microscopic myelin (degree 1) at birth and the median age at which mature myelin (degree 3) is reached. There is variability in the timing of myelination within and across axonal systems, and early onset of myelination is not always followed by early myelin maturation. We reexamined general rules governing the timing of myelination proposed by previous investigators, and found that those rules are neither complete nor inviolate, and that there is a complex interplay among them. This study specifies distinct periods of maturation in which myelinating pathways are potentially vulnerable to insult during the first two postnatal years.

Elastic stable intramedullary nailing of femoral shaft fractures in children

Abstract: We report the use of elastic stable intramedullary nailing (ESIN) in 123 fractures of the femoral shaft in children. Flexible rods are introduced through the distal metaphyseal area, and the aim is to develop bridging callus. Early weight-bearing is possible and is recommended. There was one case of bone infection and no delayed union. Complications were minimal, the most common being minor skin ulceration caused by the ends of the rods. A surprising feature was the low incidence of growth changes, with a mean lengthening of only 1.2 mm after an average follow-up of 22 months. Compared with conservative treatment, ESIN obviates the need for prolonged bed rest and is thus particularly advantageous for treating children.

Transcatheter closure of ventricular septal defects.

Abstract: Between January and October, 1987, we attempted percutaneous transcatheter closure of seven ventricular septal defects (VSD) in six patients; none of the patients was a candidate for operative management. Patients' ages ranged from 8 months to 82 years (6.0-70 kg); diagnoses included postinfarction VSD (n = 4), congenital VSD (n = 1), and postoperative congenital VSD (n = 2). Indications for VSD closure were shock or respiratory failure (n = 5) or multiple episodes of endocarditis (n = 1). Closure was attempted with a Rashkind double umbrella: VSDs were crossed via the left ventricle and a guide wire was advanced to the right heart, snared with a venous catheter, and used to direct a long sheath (and ultimately the double umbrella) across the VSD. We crossed the VSD in all seven attempts, and a 17-mm double umbrella was successfully placed in each VSD. In the first (postinfarction) patient with the largest (12 mm) VSD, the umbrella embolized after 20 seconds to the pulmonary artery (without reducing flow). The other six umbrellas remained in position, either diminishing or abolishing the left-to-right shunts. Postinfarction patients had increasing VSD shunting over the next several days and died; at postmortem, the umbrellas remained well positioned in the septum, with other VSDs present. All three congenital VSDs had absent or diminished shunts after umbrella closure. These preliminary data indicate that transcatheter VSD closure is feasible in selected cases.

The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs.

Abstract: Duchenne muscular dystrophy (DMD) is the most common and the most severe of the muscular dystrophies in man. It is inherited as an X-linked recessive trait and is characterized by ongoing necrosis of skeletal muscle fibres with regeneration and eventually fibrosis and fatty infiltration. Although the gene and gene product which are defective in DMD have recently been identified, the pathogenesis of the disease is still poorly understood. A myopathy has been described in the dog which has been shown to be inherited as an X-linked trait and which is therefore a potential model of the human disease. We have studied the phenotypic expression of the disease, canine X-linked muscular dystrophy (CXMD), and have examined the molecular relationship between it and DMD. We report here that dogs with CXMD faithfully mimic the phenotype of Duchenne muscular dystrophy and that they lack the Duchenne gene transcript and its protein product, dystrophin.

Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial.

Abstract: The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewing's Sarcoma Study (CESS 81) using a four-drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease-free. Using the Kaplan-Meier life table analysis, the estimated disease-free survival (DFS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty-one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3-year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewing's sarcoma of bone.

Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients.

Abstract: These 62 patients with the Kabuki make-up syndrome (KMS) were collected in a collaborative study among 33 institutions and analyzed clinically, cytogenetically, and epidemiologically to delineate the phenotypic spectrum of KMS and to learn about its cause. Among various manifestations observed, most patients had the following five cardinal manifestations: 1) a peculiar face (100%) characterized by eversion of the lower lateral eyelid; arched eyebrows, with sparse or dispersed lateral one-third; a depressed nasal tip; and prominent ears; 2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; 3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; 4) mild to moderate mental retardation (92%); and 5) postnatal growth deficiency (83%). Thus the core of the phenotypic spectrum of KMS is rather narrow and clearly defined. Many other inconsistent anomalies were observed. Important among them were early breast development in infant girls (23%), and congenital heart defects (31%), such as a single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus, aneurysm of aorta, transposition of great vessels, and right bundle branch block. Of the 62 KMS patients, 58 were Japanese, an indication that the syndrome is fairly common in Japan. It was estimated that its prevalence in Japanese newborn infants is 1/32,000. All the KMS cases in this study were sporadic, the sex ratio was even, there was no correlation with birth order, the consanguinity rate among the parents was not high, and no incriminated agent was found that was taken by the mothers during early pregnancy. Three of the 62 patients had a Y chromosome abnormality involving a possible common breakpoint (Yp11.2). This could indicate another possibility, i.e., that the KMS gene is on Yp11.2 and that the disease is pseudoautosomal dominant. These findings are compatible with an autosomal dominant disorder in which every patient represents a fresh mutation. The mutation rate was calculated at 15.6 X 10(6).

Resilient adolescents whose parents have serious affective and other psychiatric disorders: importance of self-understanding and relationships.

Abstract: Eighteen young men and women whose parents had major affective disorders, often in combination with other serious psychiatric disorders, were selected from a larger sample on the basis of their good behavioral functioning as adolescents at initial assessment. When they were reassessed an average of 2 1/2 years later, 15 of the 18 were still functioning well. Considerable self-understanding, a deep commitment to relationships, and the ability to think and act separately from their parents characterized these young people. Many of them were taking care of their ill parents. The implications of these findings for preventive and clinical intervention are discussed.

Human IL-3 and GM-CSF Act Synergistically in Stimulating Hematopoiesis in Primates

Abstract: Interleukin-3 (IL-3) is a member of a family of growth factors, each of which supports the proliferation and development of hematopoietic precursors in culture. Although the biologic effects of the different hematopoietic growth factors have been well documented in different culture systems, it has only recently become possible to study the activities of these molecules in vivo. In comparison with the later acting hematopoietic growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor, IL-3 elicited a delayed and relatively modest leukocytosis when continuously infused intravenously in primates. The IL-3 infusion, however, greatly potentiated the responsiveness of the animal to subsequent administration of a low dose of GM-CSF. These results suggest that IL-3 expands an early cell population in vivo that subsequently requires the action of a later acting factor such as GM-CSF to complete its development. Optimal stimulation of hematopoiesis may be achieved with combinations of hematopoietic growth factors.

Measurements on radiographs of the foot in normal infants and children.

Abstract: Radiographs were made of the feet of seventy-four normal infants and children who ranged in age from six to 127 months, and various angles were measured. Means and deviations of the measurements were calculated for eleven clinically useful angles. On the anteroposterior radiographs the talocalcaneal, talus-first metatarsal, and calcaneus-fifth metatarsal angles were recorded, and on the lateral radiograph the talocalcaneal, tibiocalcaneal, tibiotalar, talus-first metatarsal, and talohorizontal angles were documented. On lateral radiographs that were made with the foot in maximum dorsiflexion, the talocalcaneal and tibiocalcaneal angles were documented and the talocalcaneal index was recorded. The mean values and the ranges of normal values changed with age. These data provide a standard for assessment of initial and residual deformity in patients who have club foot, vertical talus, metatarsus adductus, or other deformities.

Dendritic spines of rat cerebellar Purkinje cells: serial electron microscopy with reference to their biophysical characteristics.

Abstract: We have used serial electron microscopy and Zd the area of the postsynaptic density (PSD) was measured; the volume of spine smooth endoplasmic reticulum (SER) was computed; and all of the vesicles in the axonal varicosities were counted. Spine head volume and the volume of SER contained in the head are well correlated with the area of the PSD and the number of vesicles in the presynaptic axonal varicosity. Spine neck diameter does not fluctuate with PSD area, head volume, or the vesicle number. These results suggest that the dimensions of the spine head, but not of the spine neck, are likely to reflect differences in synaptic efficacy. Second, does the geometry of cerebellar spine necks reduce the transfer of synaptic charge to the recipient dendrite from the theoretical maximum that could be transferred if the synapse were on a dendritic shaft2 Comparison of volume to surface area showed that the spine heads are approximately spherical and the necks are approximately cylindrical. Application of results from a biophysical model that assumed these geometrical shapes for spines (Wilson, 1984) showed that the cerebellar spine necks are unlikely to reduce transfer of synaptic charge by more than 5-20% even if their SER were to completely block passage of current through the portion of the neck that it occupies. We suggest that the constricted spine neck diameter might serve to isolate metabolic events in the vicinity of activated synapses

Site-directed neovessel formation in vivo

Abstract: Angiogenesis is an important component of organogenesis and wound repair and occurs during the pathology of oncogenesis, atherogenesis, and other disease processes. Thus, it is important to understand the physiological mechanisms that control neovascularization, especially with methods that permit the molecular dissection of the phenomenon in vivo. Heparin-binding growth factor-1 was shown to bind to collagen type I and type IV. When complexed with gelatin, heparin-binding growth factor-1 can induce neovascularization at polypeptide concentrations that are consistent with the biological activity of the mitogen in vitro. The adsorption strategy induces rapid blood vessel formation at and between organ- and tissue-specific sites and permits recovery of the site-specific implant for examination and manipulation by molecular methods.

Linear Accelerator as a Neurosurgical Tool for Stereotactic Radiosurgery

Abstract: A new system has been developed for stereotactically delivering prescribed high doses of radiation to precisely located volumes of approximately 0.6 to 10.0 ml within the brain. A Brown-Roberts-Wells stereotactic apparatus and a 6-MeV linear accelerator equipped with a special collimator (12.5 to 30 mm in diameter) have been adapted. The 20-mm collimator allows treatment of a nearly spherical volume of 2.1 ml. Outside the treatment field, the dosage declines to 80% of the dose prescribed for the periphery of the lesion over a distance of 1.8 mm and to 50% over the next 3.4 mm. Localization can be accomplished via computed tomography or cerebral angiography. Treatment is accomplished with an arcing beam of photon radiation with the turntable (couch) in each of four positions. The entire system has been extensively tested for accuracy in alignment and distribution of radiation. Errors have been measured for the alignment of the apparatus and for the process of localization. Safety of operation was emphasized throughout the design and testing phase.

Duplications of the alimentary tract. Clinical characteristics, preferred treatment, and associated malformations

Abstract: Duplications of the alimentary tract are unusual congenital anomalies that frequently present a diagnostic as well as therapeutic challenge to the surgeon. Because these lesions occur so infrequently, they are often not suspected until encountered intraoperatively. Due to the complicated anatomy and common blood supply shared between the duplication and associated native bowel, appropriate management requires a familiarity with the anatomy and clinical characteristics of this entity. To better define the range of patient characteristics, clinical presentation, and preferred therapy, 20 enteric duplications were reviewed in 17 patients treated at the Children's Hospital Medical Center from 1956 to 1986. Ages of patients ranged from 1 day to 11 years; 60% were less than 2 years of age at initial presentation. Seven duplications in six patients involved alimentary tract structures of foregut derivation (esophagus, stomach, and Parts I and II of duodenum), with a predominance of girls (4 of 6). Most of these patients (67%) presented with moderate to severe acute respiratory distress and a mass present on chest radiograph. In 67% of the patients, the correct diagnosis was established before operation. None required emergency operative intervention. By contrast, 13 duplications in 11 patients were of midgut or hindgut derivation (Parts III and IV of the duodenum, jejunum, ileum, and colon). In this group of patients, 62% of the duplications involved the cecum, 23% involved the ileum, and 16%, the jejunum. Seventy-eight per cent of the patients were boys. The most common symptoms were nausea and vomiting, and the most common sign was a palpable abdominal mass. Emergency operative intervention was required of eight of 11 patients with duplications involving the small bowel and colon. Three patients presented with an intussusception, four with signs and symptoms consistent with acute appendicitis, one with a small bowel obstruction, and two with gastrointestinal hemorrhage due to the presence of ectopic gastric mucosa within the duplication. It was found that two important points must be considered in regard to the management of enteric duplications: (1) the common blood supply shared between the duplication and native bowel must be carefully protected to avoid undue sacrifice of normal bowel, and (2) the presence of heterotopic gastric mucosa in 35% of patients negates internal drainage.(ABSTRACT TRUNCATED AT 400 WORDS)

A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins.

Abstract: Mannose-binding proteins have been isolated from the liver of rats and humans and subsequently been found in the serum of rats, rabbits, and humans. We report the isolation of cDNA clones isolated from a human liver cDNA library that encodes a human mannose-binding protein. The primary structure has three domains: (a) an NH2-terminal cysteine-rich segment of 19 amino acids which appears to be involved in the formation of interchain disulfide bonds that would stabilize multimeric forms of the protein; (b) a collagen-like region consisting of 19 repeats of the sequence Gly-x-y; and (c) a COOH-terminal putative carbohydrate-binding domain consisting of 148 residues. This human mannose-binding protein bears 51% overall homology (allowing three gaps) with a rat mannose-binding protein C and 48% homology (allowing seven gaps) with a rat mannose-binding protein A. Like these homologous rat proteins, the human mannose-binding protein COOH-terminal sequences are homologous to the carbohydrate recognition portion of several other lectin-like proteins including mammalian hepatic receptors, an insect-soluble hemolymph, and a sea urchin lectin found in coelomic fluid. The apoproteins of dog and human surfactant and the human lymphocyte IgE Ec receptor have not been shown to have lectin-like properties, yet by homology are members of this family of lectin-like proteins. The human mannose-binding protein is preceded by a typical hydrophobic signal sequence and its hepatic secretion is induced as part of the acute-phase response consistent with its probable role in host defense.

Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes

Abstract: rIL-4 (B cell stimulatory factor 1) induces the expression of Fc epsilon R2/CD23 on normal human monocytes (Mo). Fc epsilon R2/CD23 induction was detectable both by flow cytometry using anti-CD23 mAbs as well as soluble IgE, and by the immunoprecipitation with CD23-specific mAb or IgE of a 45-kD band from 125I-lactoperoxidase-labeled Mo. Fc epsilon R2/CD23 was fully expressed after a 24-h incubation with rIL-4, and was still detectable after 72 h from the addition of IL-4. This effect was specific, because none of the other rILs tested (IL-1, IL-2, IL-3, IL-5, B cell stimulatory factor 2, granulocyte-macrophage colony stimulating factor, and IFN-gamma) could induce FC epsilon R2/CD23, either alone or in various combinations. No synergism was observed between IL-4 and other ILs. IFN-gamma was not able to inhibit the IL-4-induced expression of Fc epsilon R2/CD23 on Mo, neither when added to the culture together with IL-4, nor when added 36 h earlier.

Pulmonary responses to bronchoconstrictor agonists in the mouse.

Abstract: Mice have been used in studies of the immunology or pathology of several different disorders affecting the lung. However, the value of the mouse for the analysis of pulmonary pathophysiology has been limited by the lack of methods for measuring lung function in the living animal. We report here the first method for measuring pulmonary conductance (GL) and compliance (Cdyn) in tracheostomized mechanically ventilated mice. We used this method to characterize the mouse's pulmonary responses to several putative bronchoconstrictor agonists. GL and Cdyn were decreased by intravenous infusions of methacholine, norepinephrine, or serotonin. Reproducible responses were not detected after infusions of histamine, prostaglandins D2 or F2 alpha, leukotrienes C4 or D4, substance P, or platelet-activating factor. The pattern of airway responsiveness to these agonists in the mouse is similar to that reported for the rat; in contrast to the rat, the mouse has many well-characterized strains or mutants with deficiencies of immunologic or inflammatory cells or mediators. As a result, this model offers unique advantages for identifying the roles of individual inflammatory cell types or mediators in pulmonary processes, including pulmonary anaphylaxis.

Expression of a Distinctive BCR-ABL Oncogene in Ph1-positive Acute Lymphocytic Leukemia (ALL)

Abstract: The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts in Ph1-positive ALL cells. In Ph1-positive ALL, ABL sequences were joined to BCR sequences approximately 1.5 kilobases 5' of the CML junction. P185ALL-ABL represents the product of a BCR-ABL fusion gene in Ph1-positive ALL that is distinct from the BCR-ABL fusion gene of CML.

Partial Correction of the Phagocyte Defect in Patients with X-Linked Chronic Granulomatous Disease by Subcutaneous Interferon Gamma

Abstract: Chronic granulomatous disease, a disorder of host defense, is characterized by an impairment in the killing of microbes that results from a defect in the production of superoxide anion by phagocytes. We examined the efficacy of interferon gamma, a physiologic activator of phagocytic-cell function, in the treatment of the disease. Two subcutaneous injections of recombinant interferon gamma (0.1 mg per square meter of body-surface area per dose) were administered on consecutive days to four patients with the X-linked form of the disease. Treatment resulted in 5- to 10-fold increases in superoxide production by granulocytes and monocytes; the improvement was sustained for more than two weeks. Granulocyte bactericidal activity rose proportionally. In the two most responsive patients, both phagocytic functions reached the normal range of activity. In association with these functional changes, we observed an increase in cellular contents of phagocyte cytochrome b (a critical component of the superoxide-producing oxidase) and immunoreactive cytochrome b heavy chain (the product of the gene that is defective in X-linked chronic granulomatous disease). Levels of cytochrome b detected by spectrophotometry rose from near zero to 10 to 50 percent of normal values. This study demonstrates partial correction of the cellular defects in chronic granulomatous disease by interferon gamma and provides a basis for clinical trials of the agent.