Showing papers by "Hospital for Sick Children published in 1990"

Very mild muscular dystrophy associated with the deletion of 46% of dystrophin.

Abstract: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene, a 14 kilobase (kb) transcript which is spread over more than 2 megabases of the human X chromosome. The corresponding protein, dystrophin, has a relative molecular mass of 400,000. Most mutations causing DMD and BMD are deletions and deletions associated with both phenotypes are observed throughout the gene sequence. This observation led to the suggestion that DMD patients possess deletions that disrupt the reading frame of the protein, whereas BMD patients have deletions that retain the translational reading frame and enable the muscle cells to produce altered dystrophin products. This theory is supported by immunoblotting studies, which show that DMD patients lack dystrophin in their muscle cells or that dystrophin is present at very low levels, whereas BMD patients produce a protein with reduced abundance or abnormal size. Here we describe a deletion of the dystrophin gene in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the dystrophin gene encompassing 5,106 base pairs of coding sequence, almost half the coding information. Immunological analysis of muscle from one of the patients demonstrates that this mutation results in the production of a truncated polypeptide localized correctly in the muscle cell. These results are particularly significant in the context of gene therapy which, if it is ever envisaged, would be facilitated by the replacement of the very large dystrophin gene with a more manipulatable mini-gene construct.

Chronic Illness in Infancy and Parenting Stress: A Comparison of Three Groups of Parents

Abstract: Compared responses of parents of infants with cystic fibrosis, those with congenital heart disease, and those with healthy babies on the Parenting Stress Index. Diagnostic group differences were found mainly in the Child Domain with parents of ill infants reporting greater stress. Differences between mothers and fathers were found mainly in the Parent Domain. The groups did not differ in reports of stress arising from life events other than the target child's illness.

Multiple cerebral arteriovenous malformations (AVMs). Review of our experience from 203 patients with cerebral vascular lesions.

Abstract: From our series of 203 patients with cerebral vascular lesions, 18 (9%) could be included in the multiple arteriovenous malformation category. There were five patients with Rendu-Osler-Weber, one with Wyburn-Mason syndromes and two with concurrent arteriovenous malformations. The remaining ten patients (4%) had multiple brain arteriovenous malformations. Careful angiography with magnification is necessary to try to diagnose multiple brain AVMs, since these sometimes become apparent only after embolization of a larger dominant AVM. The incidence, of multiple brain arteriovenous malformations is likely to have been underestimated due to the failure to recognize microarteriovenous malformations associated with larger arteriovenous malformations.

Wilms tumor locus on 11p13 defined by multiple CpG island-associated transcripts.

Abstract: Wilms tumor is an embryonal kidney tumor involving complex pathology and genetics. The Wilms tumor locus on chromosome 11p13 is defined by the region of overlap of constitutional and tumor-associated deletions. Chromosome walking and yeast artificial chromosome (YAC) cloning were used to clone and map 850 kilobases of DNA. Nine CpG islands, constituting a "CpG island archipelago," were identified, including three islands that were not apparent by conventional pulsed-field mapping, and thus were at least partially methylated. Three distinct transcriptional units were found closely associated with a CpG island within the boundaries of a homozygous DNA deletion in a Wilms tumor.

Intravenous gamma globulin therapy in systemic juvenile rheumatoid arthritis.

Abstract: Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.

Developmental expression of the endogenous TIMP gene and a TIMP-lacZ fusion gene in transgenic mice.

Abstract: We determined the expression pattern of the tissue inhibitor of metalloproteinase (TIMP) in the development of the mouse embryo using in situ hybridization and transgenesis. Localized TIMP RNA was first detected at 13.5 days post conceptus (p.c.) in tissues undergoing osteogenesis, such as the mandible, ribs, and calvaria. As development proceeded, TIMP RNA could be detected at additional sites, including the tooth buds, vertebrae, and long bones. To define the sequences regulating TIMP expression, we generated transgenic mice that expressed the Escherichia coli beta-galactosidase gene under control of a 5' region of the mouse TIMP gene containing -2158 to -58 bp upstream of the initiator ATG. By use of an in situ assay for beta-galactosidase activity, the TIMP-lacZ fusion gene product was localized to tissues that also expressed the endogenous TIMP gene, such as the mandible, calvaria, and vertebrae. The localization of TIMP to regions of intramembranous and endochondral bone is similar to that previously reported for TGF-beta, a growth modulator believed to be involved in regulation of extracellular matrix (ECM) formation. Thus, the expression of TIMP in these regions is consistent with it playing a role in ECM deposition and turnover in development.

Prediction of behavior problems in 4-year-olds born prematurely

Abstract: Longitudinal follow-up data for 69 very low birthweight preterm infants were used to assess the influence of four factors (neonatal medical complications, infant temperament, mother-child relationships, and family environment) on mother and teacher reports of behavior problems at 4 years. The proposed model of such influences being tested assumed that (1) the effects of neonatal medical factors would be indirect, and (2) each of the other three factors would show high stability from 1 to 4 years and would have a direct influence on behavior problem outcomes. Neither neonatal medical data nor infant-mother attachment were good predictors of behavior problems at age 4. With these exceptions, teacher report of behavior problems was predicted in a fashion consistent with the preliminary model. However, mother reports of behavior problems was predicted only by prior mother reports of child temperament. Discussion focuses on reasons for discrepancies in these pathways of influence.

Intellectual Characteristics of Diabetic Children at Diagnosis and One Year Later

Abstract: Examined neurocognitive functions in 63 newly diagnosed pediatric patients with insulin-dependent diabetes mellitus (DM) at onset of illness (T0) and 1 year postdiagnosis (T1). Siblings (S) serving as controls were assessed at T0 only. Subjects were given age-appropriate tests of verbal and visuospatial abilities. In addition, DM were interviewed regularly during diabetes clinic to determine current diabetic control and different intervening glycemic-related events. Results revealed no differences between DM and S at T0, nor any specific impairment in DM predating illness. Also, DM did not demonstrate any acquired impairment after 1 year of illness. Children with early onset DM (less than 5 years) scored lower in spatial ability at T0 and T1 than children with later onset DM, who scored lower in verbal ability. Episodes of asymptomatic and mild chronic hypoglycemia correlated positively, not negatively, with improved outcome over time. There were no adverse effects of severe hypoglycemia. Ketonuria and hospitalizations were associated with lower performance IQs 1 year after onset, as was diabetic ketoacidosis at onset. Results are discussed in terms of critical periods of sensitivity of different brain regions to the effects of diabetes and the need for longer follow-up of these children.

A Preliminary Report of the Collaborative Study of Maternal Phenylketonuria in the United States and Canada

Abstract: The Maternal Phenylketonuria Collaborative Study (MPKUCS), encompassing all the United States and provinces of Canada, is a prospective, longitudinal investigation designed to ascertain the efficacy of phenylalanine-restricted therapy in protecting the fetus from high maternal phenylalanine concentrations in women with hyperphenylalaninaemia.

The role of interferon and tumor necrosis factor in the pathogenesis of AIDS.

Abstract: Cytokines including interferon (IFN) and tumor necrosis factor (TNF) are potent modulators of immune processes. They are synthesized in response to microbial infections and inflammation. TNF and IFN interact with other cytokines to elicit differentiation and cellular responses of specific target cells. In view of their multiple biological effects, we have postulated that dysregulation of IFN and TNF may contribute to the pathogenesis of HIV infection. Here, we review data showing that the expression of IFN-alpha receptors is down-regulated in patients with AIDS. As a consequence, HIV-infected cultured cells and cells from AIDS patients show hyporesponsiveness to IFN action. This could contribute to mechanisms by which HIV evades the antiviral activity of IFN-alpha in HIV-infected cells and raise the question of the usefulness of IFN-alpha in the treatment of end-stage AIDS. TNF is a major mediator of inflammation and sepsis and also is capable of inducing the replication of HIV. TNF synthesis and its receptor expression are upregulated by the acid-labile IFN-alpha subtype present in the sera of HIV-infected individuals. In addition, the acid-labile IFN present in AIDS sera may contribute to the pathophysiological changes in sepsis by rendering the cells from AIDS patients hypersensitive to endotoxin stimulation resulting in further synthesis of TNF. Thus aberrant regulation of these cytokines and their cognate receptors are likely contributing factors to the pathogenesis of AIDS.

Ultrasound in the diagnosis of diaphragmatic paralysis after operation for congenital heart disease.

Abstract: Phrenic nerve palsy is a recognised complication of operation for congenital heart disease in children. The accuracy of ultrasound in assessing diaphragmatic motion was prospectively compared with fluoroscopy in 16 patients in whom phrenic nerve palsy was suspected. Ultrasound successfully identified the five patients with phrenic nerve palsy; there were no false positive or false negative diagnoses. Ultrasound was as effective as fluoroscopy in the diagnosis of abnormalities of diaphragmatic motion.

Swelling of astroglia in vitro and the effect of arginine vasopressin and atrial natriuretic peptide.

Abstract: Numerous neuropathological conditions are accompanied by astroglial swelling which may contribute to secondary neuronal damage. From 4–27 days in vitro,swelling of astroglial cells was induced by hypo-osmolar solutions and high K+ solutions and the cells were examined by microscopy and flow cytometry. Regulatory volume decrease was observed beginning after approximately 30 minutes and was accompanied by increased membrane activity. Arginine vasopressin caused gradual persistent astroglial swelling. Atrial natriuretic peptide caused retraction of the astroglial cell processes but did not significantly alter the swelling induced by hypo-osmolar or elevated K+ solutions. The membrane mechanisms responsible for the control of astroglial cell volume did not appear to be specific for mature astroglia, rather they are present at all developmental stages.

Influences on Maternal Responsiveness to Developmentally Delayed Preschoolers.

Abstract: Forty preschoolers with Down syndrome, 29 with a neurological impairment, and 40 with delays of unknown etiology were videotaped in a free play situation with their mothers. A composite rating of maternal behavior, indexing maternal responsiveness, was treated as the outcome measure in a series of regression analyses to assess the effects of maternal and paternal well-being and psychosocial support, and child characteristics and behavior, on maternal responsiveness. Parental age, mother's support, and child responsiveness contributed to maternal responsiveness. Families with older parents, better maternal support, and more responsive children had more responsive mothers.

Group Psychotherapy in Psychiatric Residency Training

Abstract: Residents (n=114) in the department of psychiatry at the University of Toronto were surveyed in the spring of 1987 about their training in and attitudes about group psychotherapy. Significant interest in group psychotherapy was correlated positively with a perception that one’s group psychotherapy training was good, more hours of experience leading groups, a belief in the usefulness of group therapy in one’s future practice, and an appreciation of opportunities to refer patients to group therapy. Confidence in one’s ability as a group leader and knowledge about group therapy were correlated with the number of hours spent leading groups. The implications for planners of group psychotherapy training curricula and faculty are discussed and recommendations are made concerning the principles of group psychotherapy training programs.

Body compartment changes in sick children.

Abstract: The body composition of children changes with growth and development (Pencharz, 1985). It is also affected by disease and the nutritional status of the child. Our group has been particularly interested in the changes due to disease and nutritional perturbations (Pencharz, 1988). A powerful motivation for this interest has come from our clinical responsibilities in practising nutritional medicine. Being able to assess the body composition of children is a key component of assessing and Monitoring their nutritional status. Traditionally, paediatricians have measured anthropometric variables like weight and height. By taking serial measurements it was possible to monitor not only the weight of the child but also to measure growth rates. These measurements, although useful, are not sufficient in themselves. It is necessary to be able to measure changes in the lean body mass of children in response to disease and treatment. Further, it is necessary to be able to monitor body cell mass (i.e. intracellular mass) as related to extracellular mass. The two components when summed make up lean body mass. Within body cell mass there are important constituents like protein, water, and the major intracellular cation potassium. The ratio of these Constituents do vary from tissue to tissue, but are relatively constant in a healthy individual of a given gender and age.

Design and evaluation of a new respiratory monitor.

Abstract: was happening to my patient when the anaesthetic supply appeared to be correct. The oxygen flush control was not released after its use at the end of the previous case and I did not see this. There is no obvious indication that the oxygen flush control is operating on a Cape Waine Mk3, and it may not release if it is partially rotated when it is depressed. A settlement of f20000, with costs, was made within 3 months, and I, not the hospital, accepted full liability for the incident. A ’Safety Information Bulletin” was issued by the Department of Health in Northern Ireland. The assistance of the Safety Committee of the Association of Anasthetists of Great Britain and Ireland was required before a similar Bulletin could be issued in the remainder of the UK. This potential hazard was first described in mid-19793 and most recently in late 1988.4 When this incident occurred, the manufacturer had available an off-the-shelf modification kit. The hazard was known, the modification was available, however no contact was made with the enduser. A ‘yellow card‘ system might speed up the process of hazard reporting ‘and correction. I met and talked with the patient and her husband for some time after the settlement. I explained how I had failed in my responsibility towards her to keep her asleep and pain-free, and the particular circumstances involved. She wrote to me shortly afterwards, and near the end of the letter writes: ‘I can only say now that seeing you was a help to me and I hope that in some way it helped you.’ It certainly did. She is a very brave woman.

Detection of truncated dystrophin in fetal DMD myotubes.

Abstract: Duchenne muscular dystrophy (DMD) is the most common of all muscular dystrophies (1 in 3000 live male births). It is an X-linked recessive lethal disorder, characterized by a progressive muscle degeneration. The application of DNA technology has made it possible to carry out reliable DNA diagnosis with more than 99% certainty in most familial DMD cases1,2,3.

Assessment of the Role of Calcium in Neutrophil Activation Using Electropermeabilized Cells

Abstract: Neutrophils are one of the first lines of defense against invading microorganisms. When exposed to bacteria or to chemoattractant peptides derived thereof, neutrophils undergo a complex series of coordinated responses intended to eliminate the microorganisms, thereby preventing infection. The neutrophils initially approach the site of infection by a migratory process called chemotaxis. The bacteria are then phagocytosed and killing results from the generation of superoxide and the secretion of lytic enzymes into the phagosomal space. Chemotaxis as well as phagocytosis are thought to involve extensive cytoskeletal reorganization, requiring conversion of actin from its monomeric, globular (G) form, to a polymeric, filamentous (F) form. Superoxide radicals are generated by reduction of molecular oxygen, with NADPH as the electron donor. This reaction, known as the respiratory burst, is catalyzed by the NADPH-oxidase, a multimeric plasma membrane membrane enzyme that is quiescent before stimulation, but is greatly activated by chemotactic peptides and other stimuli.