The effect of growth hormone on the development of diabetic kidney disease in rats.

BACKGROUND: Nephropathy is the most severe complication of diabetes mellitus. We investigated the effect of exogenous growth hormone (GH) administration on renal function and matrix deposition in the streptozotocin (STZ) model of type I-diabetic rat. METHODS: Adult female STZ-diabetic rats (D), non-diabetic control rats injected with saline (C) and control and diabetic rats injected with bovine GH for 3 months (CGH and DGH, respectively) were used. RESULTS: The usual renal hypertrophy seen in D animals was more pronounced in the DGH group. Creatinine clearance increased only in the D rats, but not in the other groups, including DGH. Albuminuria was observed in the D animals but was significantly elevated in the DGH group. Glomeruli from DGH animals showed more extensive matrix accumulation (manifested as an increase in mesangial/glomerular area ratio). Renal extractable insulin-like growth factor (IGF-I) mRNA was decreased in the D and DGH groups, but renal IGF-I protein was not significantly increased. Renal IGF binding protein-1 was increased in the D groups and further increased in the DGH group, at both the mRNA and protein levels. CONCLUSIONS: GH-treated diabetic rats had less hyperfiltration and more albuminuria, concomitant with more glomerular matrix deposition, when compared with regular diabetic animals. This was associated with a significant increase in renal IGFBP-1, and dissociated from IGF-I changes. Thus, in this model, GH exacerbates the course of diabetic kidney disease.     

Are Prenatal Ultrasound Scans Associated with the Autism Phenotype? Follow-up of a Randomised Controlled Trial

An existing randomised controlled trial was used to investigate whether multiple ultrasound scans may be associated with the autism phenotype. From 2,834 single pregnancies, 1,415 were selected at random to receive ultrasound imaging and continuous wave Doppler flow studies at five points throughout pregnancy (Intensive) and 1,419 to receive a single imaging scan at 18?weeks (Regular), with further scans only as indicated on clinical grounds. There was no significant difference in the rate of Autism Spectrum Disorder between the Regular (9/1,125, 0.8?%) and Intensive (7/1,167, 0.6?%) groups, nor a difference between groups in the level of autistic-like traits in early adulthood. There is no clear link between the frequency and timing of prenatal ultrasound scans and the autism phenotype.     

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines.

Farnesyl transferase inhibitors (FTIs) target signal-transduction pathways responsible for the proliferation and survival of hematologic malignancies, including acute myelogenous leukemias (AML). Lonafarnib has been shown to be a potent inhibitor of Pgp-mediated drug efflux. On the basis of these findings, we examined the Pgp-inhibitory properties of tipifarnib and assessed its activity when combined with anthracyclines. The effects of tipifarnib on cell proliferation, induction of apoptosis and inhibition of Pgp-mediated anthracycline efflux were analyzed in two human leukemia cell lines overexpressing Pgp (CCRF-CEM and KG1a). Measurement of residual daunorubicin (DNR)-mediated fluorescence after incubation with DNR and tipifarnib demonstrated that tipifarnib significantly inhibited DNR efflux in CCRF-CEM with an IC(50) value less than 0.5 microM. Proliferation and apoptosis assays after exposure to DNR in the presence or absence of tipifarnib demonstrated synergistic inhibition of cellular proliferation, and induction of apoptosis with the combination of tipifarnib and DNR. Similar data was obtained with an enantiomer of tipifarnib that possesses no FTI activity. Incubation with tipifarnib and DNR did not interfere with inhibition of the post-translational processing of HDJ-2. These data suggest that tipifarnib possesses Pgp-inhibitory activity in addition to its FTI activity. In high risk and refractory patients these properties may be exploited as a dual targeting mechanism in the therapy of AML.     

Lung function, airway responsiveness, and respiratory symptoms before and after bronchiolitis

Acute viral respiratory illness during infancy has been implicated as a precursor for subsequent lower respiratory morbidity in childhood. A prospective, longitudinal study of respiratory function, airway responsiveness, and lower respiratory illness during early childhood was performed in a cohort of 253 healthy infants to characterise those who experienced bronchiolitis. Seventeen infants (7% of the cohort), were given a diagnosis of bronchiolitis during the first two years of life with two (1%) requiring hospital admission. Seventy one per cent of those infants with bronchiolitis had a family history of atopy, 53% of asthma, and 29% had a mother who smoked cigarettes. These family history characteristics in this group with bronchiolitis were not different from the rest of the cohort. There were also no differences in the number of older siblings, the number breast fed, the duration of breast feeding, or socioeconomic status of the families between those that did and did not get bronchiolitis. Respiratory function was assessed at 1, 6, and 12 months of age. Maximum flow at functional residual capacity (VmaxFRC) was measured using the rapid thoracic compression technique. Resistance (Rrs) and size corrected compliance (Crs/kg) were obtained from a single brief occlusion at end inspiration. Airway responsiveness was assessed by histamine inhalation challenge and the provocation concentration of histamine resulting in a 40% fall on VmaxFRC from baseline (PC40) was determined. Respiratory measurements were ranked into terciles to assess the distribution of infants who developed bronchiolitis through the cohort. Cough and wheeze were noted to be frequent before the episode of bronchiolitis. This study has demonstrated that infants who develop bronchiolitis have evidence of pre-existing reduced respiratory function and lower respiratory symptoms. It is proposed that bronchiolitis, although potentially contributory, is not usually causative of subsequent lower respiratory morbidity.