Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide.

Islet amyloid polypeptide (IAPP) (amylin), the major component of islet amyloid, is produced by cleavage at the COOH- and NH(2)-termini of its precursor, proIAPP, likely by the beta-cell prohormone convertases (PC) 1/3 and PC2. Mice lacking PC2 can process proIAPP at its COOH- but not its NH(2)-terminal cleavage site, suggesting that PC1/3 is capable of initiating proIAPP cleavage at its COOH-terminus. To determine the precise role of PC1/3 in proIAPP processing, Western blot analysis was performed on islets isolated from mice lacking PC1/3 (PC1/3(-/-)).

A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.

Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3.

Hospitals and academic health sciences centres: leaders or followers in health globalization?

The overall impact of globalization on health outcomes is contentious, but there is no doubt that knowledge transfer and the extension of specific health interventions to developing countries promise extraordinary benefits. It has been suggested that improved information/communications technology and the creation of distributed hospital systems leading a virtual healthcare web will permit realization of the promise of globalization. It is argued in this commentary that such evolution will require a new model of shared governance in the healthcare system.

Lack of islet neogenesis plays a key role in beta-cell depletion in mice infected with a diabetogenic variant of coxsackievirus B4.

Group B coxsackieviruses (CVBs) have a well-established association with type 1 diabetes but the mechanism of depletion of beta-cell mass following infection has not yet been defined. In this report we show that the major difference in pathogenesis between the E2 diabetogenic strain of CVB4 and the prototypic JVB strain in SJL mice is not in tropism for islet cells but in the degree of damage inflicted on the exocrine pancreas and the resulting capacity for regeneration of both acinar and islet tissue by the host. Both strains replicated to a high titre in acinar tissue up to day 3 post-infection (p.

Retroposon compensatory mechanism hypothesis not supported: Zfa knockout mice are fertile.

It is hypothesized that autosomal retroposons compensate for the loss of their inactivated essential X-chromosome progenitors during spermatogenesis. Here we test this Retroposon Compensatory Mechanism (RCM) hypothesis using the Zfy gene family. The mouse autosomal retroposon Zfa is expressed in testes at the same developmental time points at which Zfx levels decline, which correspond to the time of male sex chromosome inactivation, suggesting that Zfa may compensate for the loss of Zfx during spermatogenesis.

Are there developmentally distinct motor indicators of pain in preterm infants?

The aims of this study were to examine preterm infant reactions to pain in detail over prolonged time periods using multiple measures, and to assess the value of including specific body movements of the Neonatal Individualized Developmental Care and Assessment Program (NIDCAP) system to evaluate pain. Ten preterm infants born at 31 weeks mean gestational age (GA) and mean birth weight 1676 g were studied during a routine blood collection in a Level III neonatal intensive care unit (NICU). At 32-week post-conceptional age, computerized physiologic and video recordings were obtained continuously for 60 min (prior to, during and after lance).

Clinical aspects, prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism.

Introduction: Analysis of data from cases of trisomy mosaicism can provide insight for genetic counselling after prenatal diagnosis and for the elucidation of the pathogenesis of trisomy during pregnancy.

Methods: Statistical analysis was carried out on data from 162 cases of pregnancies with prenatal diagnosis of trisomy 16 mosaicism.

Results: The majority of cases resulted in live birth (66%) with an average gestational age of 35.

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice.

Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of multiple immune system intracellular signalling pathways. The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P(2)) and phosphatidylinositol (3,4,5) trisphosphate (PIP(3)), are regulated by inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for Pten, a 3'-inositol phosphatase, develop a progressive lymphoproliferative syndrome with autoimmune features.

Novel Sxr(a) ES cell line offers hope for Y chromosome gene-targeted mice.

A mouse targeted for a Y Chromosome gene has not been reported. Because the Y Chromosome is present in only one copy, and most of its genes are critical for germ cell development, such a mouse would likely be infertile. Thus, we describe a new reproductive strategy to enable transmission of targeted Y Chromosome genes to subsequent generations.

Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci.

Fierce (frc) mice are deleted for nuclear receptor 2e1 (Nr2e1), and exhibit cerebral hypoplasia, blindness, and extreme aggression. To characterize the Nr2e1 locus, which may also contain the mouse kidney disease (kd) allele, we compared sequence from human, mouse, and the puffer fish Fugu rubripes. We identified a novel gene, c222389, containing conserved elements in noncoding regions.

Disruption of a single Pten allele augments the chemotactic response of B lymphocytes to stromal cell-derived factor-1.

The tumor suppressor, Pten, has emerged as a critical negative regulator of phosphatidylinositol-3-kinase-dependent intracellular signaling pathways responsible for phenomena such as cellular adhesion, proliferation, and apoptosis. Herein, we present evidence that Pten regulates chemokine-dependent events in B lymphocytes. Primary B cells isolated from Pten(+/-) mice demonstrated increased responsiveness to stromal cell-derived factor-1-induced chemotaxis.

Pattern of learning disabilities in children with extremely low birth weight and broadly average intelligence.

Objectives: To examine the prevalence and pattern of specific areas of learning disability (LD) in neurologically normal children with extremely low birth weight (ELBW) (< or = 800 g) who have broadly average intelligence compared with full-term children with normal birth weight of comparable sociodemographic background, and to explore concurrent cognitive correlates of the specific LDs.

Design: Longitudinal follow-up; geographically defined region.

Setting: Regional follow-up program.

Meningococcal disease and vaccination in North America.

In North America, meningococcal disease occurs at a rate of I case per 100000 population per year, producing 2725 cases notified in the US in 1998 and 155 laboratory confirmed cases in Canada in the same year. A majority of these cases occur in the winter season and in early childhood, with a case fatality rate of approximately 10%. There has been an increase in the proportion of cases due to serogroup Y meningococci over the past decade: in 1995-98 in the US, 33% of cases were due to serogroup B, 28% were due to serogroup C and 34% were due to serogroup Y; in Canada in 1995-96, 47% of cases were due to serogroup B, 40% were due to serogroup C and 10% were due to serogroup Y.

Relations between behavioral and cardiac autonomic reactivity to acute pain in preterm neonates.

Objective: The purpose of this study was to assess relations and concordance between behavioral and physiologic reactivity to pain in preterm neonates at 32 weeks postconceptional age as a function of gestational age at birth.

Setting: Level III neonatal intensive care unit.

Design/patients: The study group comprised 136 preterm neonates (mean [range] birthweight, 1,020 g [445-1,500 g]: gestational age at birth, 28 weeks [23-32 weeks]) separated into three groups according to gestational age at birth as follows: 23 to 26 weeks (n = 48), 27 to 29 weeks (n = 52), and 30 to 32 weeks (n = 36).

Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase.

Several lines of evidence point to an abnormality in the response of Fanconi anemia cells to reactive oxygen species. To investigate the potential pathologic consequences of an in vivo alteration of redox state in mice lacking one of the Fanconi anemia genes, animals were generated having combined deficiencies of the cytosolic Cu/Zn superoxide dismutase (Sod1) and Fanconi anemia complementation group C (Fancc) genes. Interestingly, hepatocytes of Fancc(-/-)Sod1(-/-) mice exhibited a zonal pattern of microvesicular steatosis, possibly as a result of oxidative stress-induced injury to hepatocyte membranes.

The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site.

Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the beta-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to beta-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2.

Development of natural immunity to Neisseria meningitidis.

Although meningococcal disease is rare in industrialized nations, Neisseria meningitidis holds a prominent position amongst pediatric infections because of the dramatic clinical presentation of the disease, high mortality, epidemic potential and the recent disappearance of many other important infectious diseases in developed countries through improvements in public health and vaccination. The precise nature of natural immunity to meningococci remains unknown, although a complex interaction between the organism and nasopharyngeal mucosal barrier, innate immune mechanisms and acquired immunity is involved. Study of the mechanisms of natural immunity may provide the key to development of vaccines that can reduce the burden of disease in early childhood.

Identification of a heparin binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide. Implications for islet amyloid formation.

Islet amyloid deposits are a characteristic pathologic lesion of the pancreas in type 2 diabetes and are composed primarily of the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin) as well as the basement membrane heparan sulfate proteoglycan perlecan. Impaired processing of the IAPP precursor has been implicated in the mechanism of islet amyloid formation. The N- and C-terminal cleavage sites where pro-IAPP is processed by prohormone convertases contain a series of basic amino acid residues that we hypothesized may interact with heparan sulfate proteoglycans.

Predicting IQ of biologically "at risk" children from age 3 to school entry: sensitivity and specificity of the Stanford-Binet Intelligence Scale IV.

Predictive validity of the Stanford-Binet Intelligence Scale Fourth Edition (S-B IV) from age 3 years to ages 4-5 years was evaluated with biologically "at risk" children without major sensory or motor impairments (n = 236). Using the standard scoring, children with full scale IQ < or = 84 on the Wechsler Preschool and Primary Scale of Intelligence at age 4-5 years were poorly identified (sensitivity 54%) from the composite S-B IV score at age 3. However, sensitivity improved greatly to 78% by including as a predictor the number of subtests the child was actually able to perform at age 3 years.

Recurrent trisomy 21 in a couple with a child presenting trisomy 21 mosaicism and maternal uniparental disomy for chromosome 21 in the euploid cell line.

Recurrence of trisomy 21 was observed in a family in which both parents had a normal chromosome complement. Mosaic trisomy 21 was found in a blood karyotype of the first child, a second pregnancy ended in spontaneous abortion, and a full trisomy 21 was found at prenatal diagnosis of the third pregnancy of this same couple. Although recurrent trisomy 21 may be due to chance, the possibility of germline mosaicism for trisomy 21 in one of the parents has important implications for recurrence risk.

Economics of prematurity in the era of managed care.

Both the acute intensive care of premature infants and the management of their long-term medical and educational sequelae are costly. Because neonatal intensive care is very effective in reducing mortality, however, its cost effectiveness as described previously is actually quite favorable when compared with other well-accepted medical interventions, such as coronary artery bypass grafting and renal dialysis. This article has highlighted the relatively scant literature on which those estimates of costs and cost effectiveness of both neonatal intensive care and its component interventions rest.

Comparative genomic hybridization in combination with flow cytometry improves results of cytogenetic analysis of spontaneous abortions.

More than 50% of spontaneous abortions (SAs) have abnormal chromosomes; the most common abnormalities are trisomy, sex chromosome monosomy, and polyploidy. Conventional cytogenetic analysis of SAs depends on tissue culturing and is associated with a significant tissue culture failure rate and contamination by maternally derived cells. Comparative genomic hybridization (CGH), in combination with flow cytometry (FCM), can detect numerical and unbalanced structural chromosomal abnormalities associated with SAs while avoiding the technical problems associated with tissue culture.

Are twitches, startles, and body movements pain indicators in extremely low birth weight infants?

Objective: The goal of this study was to examine whether body activity such as postural, trunk, and limb movements may be potential pain cues in preterm infants.

Design: Convenience sample.

Setting: Level III neonatal intensive care unit (NICU).

SHPS-1 induces aggregation of Ba/F3 pro-B cells via an interaction with CD47.

SHPS-1 (SH2-domain bearing protein tyrosine phosphatase (SHP) substrate-1), a member of the inhibitory-receptor superfamily that is abundantly expressed in macrophages and neural tissue, appears to regulate intracellular signaling events downstream of receptor protein-tyrosine kinases and integrin-extracellular matrix molecule interactions. To investigate the function of SHPS-1 in a hematopoietic cell line, SHPS-1 was expressed in Ba/F3 cells, an IL-3-dependent pro-B-cell line that lacks endogenous SHPS-1 protein. Interestingly, expression of either SHPS-1, or a mutant lacking the intracellular domain of SHPS-1 (DeltaCT SHPS-1), resulted in the rapid formation of macroscopic Ba/F3 cell aggregates.

Recombinant proteins for genetic disease.

The era of molecular biology has led to the development of powerful tools capable of generating therapeutics for genetic disorders. Although there is much current emphasis placed on the development of 'gene therapy' for human disease, developments in the production and availability of recombinant proteins are likely to have a more substantial impact on genetic disease in the short term. The clinical evaluation of recombinant or purified proteins serves as an initial 'proof of principle' of gene-based therapies and thus should expedite advances in this area.