Recruiting and retaining GPs and patients in intervention studies: the DEPS-GP project as a case study

Background  

Recruiting and retaining GPs for research can prove difficult, and may result in sub-optimal patient participation where GPs are required to recruit patients. Low participation rates may affect the validity of research.     

TLR7 and TLR9 trigger distinct neuroinflammatory responses in the CNS

Toll-like receptors (TLRs) 7 and 9 recognize nucleic acid determinants from viruses and bacteria and elicit the production of type I interferons and proinflammatory cytokines. TLR7 and TLR9 are similar regarding localization and signal transduction mechanisms. However, stimulation of these receptors has differing effects in modulating viral pathogenesis and in direct toxicity in the central nervous system (CNS). In the present study, we examined the potential of the TLR7 agonist imiquimod and the TLR9 agonist cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) to induce neuroinflammation after intracerebroventricular inoculation. CpG-ODN induced a more robust inflammatory response than did imiquimod after inoculation into the CNS, with higher levels of several proinflammatory cytokines and chemokines. The increase in cytokines and chemokines correlated with breakdown of the blood-cerebrospinal fluid barrier and recruitment of peripheral cells to the CNS in CpG-ODN-inoculated mice. In contrast, TLR7 agonists induced a strong interferon β response in the CNS but only low levels of other cytokines. The difference in response to these agonists was not due to differences in distribution or longevity of the agonists but rather was correlated with cytokine production by choroid plexus cells. These results indicate that despite the high similarity of TLR7 and TLR9 in binding nucleic acids and inducing similar downstream signaling, the neuroinflammation response induced by these receptors differs dramatically due, at least in part, to activation of cells in the choroid plexus.     

Reproducibility of multiple breath washout indices in the unsedated preterm neonate

Multiple breath inert gas washout (MBW) is gaining popularity for measurements of resting lung volume and ventilation inhomogeneity. Test reproducibility is an important determinant of the clinical applicability of diagnostic tests. The between‐test reproducibility of variables derived from MBW tests in newborn infants is unknown. We aimed to determine the within‐test repeatability and short‐term between‐test reproducibility of MBW variables in unsedated preterm infants. We hypothesized that measurements obtained within a 3‐day interval in clinically stable preterm infants would be reproducible and suitable for use as an objective clinical outcome measurement. In this cross‐sectional observational study, clinically stable hospitalized preterm infants whose parents had given informed consent for MBW studies were tested twice within 72 hr during quiet, unsedated sleep. Functional residual capacity (FRC), lung clearance index (LCI), and the first and second to zeroeth moment ratios (M₁:M₀; M₂:M₀) were computed from MBW traces obtained using a mainstream ultrasonic flowmeter and 4% sulphur hexafluoride (MBW_SF6). Within‐test repeatability and between‐test reproducibility were determined. Within‐test repeatability (expressed as a coefficient of variability (C_v)) for differences between two and four replicate measurements on the same test occasion, were 9.3% (FRC), 9.0% (LCI), 7.6% (M₁:M₀), and 15.6% (M₂:M₀), respectively. The within‐test C_v's were not statistically different to the between‐tests C_v's, which were 7.7% (FRC), 10.3% (LCI), 6.1% (M₁:M₀), and 13.0% (M₂:M₀), respectively. Among unsedated preterm infants, between‐test reproducibility over a 3‐day interval was similar to within‐test repeatability. The wide limits of agreement may limit the application of these measures to detect a clinically significant change in condition in small preterm infants. Pediatr Pulmonol. 2010; 45:62–70. © 2009 Wiley‐Liss, Inc.     

Clinical and molecular study in congenital muscular dystrophy with partial laminin alpha 2 (LAMA2) deficiency

Complete laminin alpha2 (LAMA2) deficiency causes approximately half of congenital muscular dystrophy (CMD) cases. Many loss-of-function mutations have been reported in these severe, neonatal-onset patients, but only single missense mutations have been found in milder CMD with partial laminin alpha2 deficiency. Here, we studied nine patients diagnosed with CMD who showed abnormal white-matter signal at brain MRI and partial deficiency of laminin alpha2 on immunofluorescence of muscle biopsy. We screened the entire 9.5 kb laminin alpha2 mRNA from patient muscle biopsy by direct capillary automated sequencing, single strand conformational polymorphism (SSCP), or denaturing high performance liquid chromatography (DHPLC) of overlapping RT-PCR products followed by direct sequencing of heteroduplexes. We identified laminin alpha2 sequence changes in six of nine CMD patients. Each of the gene changes identified, except one, was novel, including three missense changes and two splice-site mutations. The finding of partial laminin alpha2 deficiency by immunostaining is not specific for laminin alpha2 gene mutation carriers, with only two patients (22%) showing clear causative mutations, and an additional three patients (33%) showing possible mutations. The clinical presentation and disease progression was homogeneous in the laminin alpha2-mutation positive and negative CMD patients.     

Autoimmune myasthenia gravis, immunotherapy and thymectomy in children

Autoimmune myasthenia gravis is a rare condition in children. Identifying antibodies directed against the acetylcholine receptor is helpful in making the diagnosis. However, seronegative cases do exist and need to be distinguished from congenital forms of myasthenia. There is little published experience to inform the judicious management of autoimmune myasthenia gravis in children. In this article, we report our experience in the management of 12 cases of autoimmune myasthenia gravis in children in the modern era of medical immunotherapy and thymectomy.     

The influence of parental offending on the continuity and discontinuity of children’s internalizing and externalizing difficulties from early to middle childhood

Purpose

Although parental criminal offending is a recognized risk factor for conduct problems among offspring, its impact on the continuity and discontinuity of children’s behavioural and emotional difficulties during the early development is less well known. We used data from a large, population-based record-linkage project to examine the relationship between parental offending and the continuity and discontinuity of children’s conduct, attentional, and emotional difficulties from early to middle childhood while also considering the role of timing of the parental offending exposure.

Method

Data for 19,208 children and their parents were drawn from the New South Wales Child Development Study. Multinomial regression analyses tested associations between mother’s and father’s history and timing of any and violent offending, and patterns of continuity or discontinuity in offspring emotional, conduct, and attentional difficulties between ages 5 and 11 years.

Results

Maternal and paternal offending each conferred a significantly increased risk of all the patterns of developmental difficulties, including those limited to age 5 only (remitting problems), to age 11 only (incident problems), and to difficulties present at both ages 5 and 11 years (persisting problems). Greatest odds were observed for persisting conduct problems. Paternal offending that continued through early and middle childhood had the greatest association with child difficulties, while the timing of maternal offending had a less prominent effect on child developmental difficulties.

Conclusion

Parental offending is a strong risk factor for early and pervasive behavioural and emotional problems in offspring, and may be a key indicator of high risk for later antisocial behaviour.