Targeted disruption of the pregnancy-associated plasma protein-A gene is associated with diminished smooth muscle cell response to insulin-like growth factor-I and resistance to neointimal hyperplasia after vascular injury

IGF-I is an important determinant of the vascular response to injury in large part through its ability to stimulate migration and proliferation of smooth muscle cells (SMCs). In this study, we used mice with targeted disruption of the pregnancy-associated plasma protein-A gene (PAPP-A-/-) and wild-type (WT) littermates to test the hypotheses that PAPP-A, a metalloproteinase that cleaves inhibitory IGF binding protein (IGFBP)-4, regulates vascular SMC responses to IGF-I in vitro and is critical for the development of vascular neointima after injury in vivo. Vascular SMCs from PAPP-A-/- mice lacked IGFBP-4 protease activity and failed to respond to treatment with IGF-I in the presence of IGFBP-4, whereas SMCs from WT mice with robust IGFBP-4 protease activity showed significant migratory and proliferative responses to IGF-I/IGFBP-4. For in vivo testing, PAPP-A-/- and WT mice underwent unilateral carotid ligation, a model of injury-induced neointimal hyperplasia. In WT mice, PAPP-A mRNA expression was markedly elevated 7 and 14 d after carotid ligation, associated with a progressive increase in neointimal hyperplasia and, in many cases, with complete occlusion of the vessel at 28 d. In contrast, PAPP-A-/- mice showed little evidence of progression resulting in a 75% reduction in neointimal area when compared with WT at 28 d. Cells staining for proliferating cell nuclear antigen were plentiful in the SMC-rich medial and neointimal areas of the injured WT vessel in stark contrast to the relatively few proliferating cells in the same areas of the PAPP-A-/- vessel. Expression of IGF-I and IGFBP-4 was similarly elevated in injured carotids from WT and PAPP-A-/- mice with no change in IGF-I receptor expression. IGFBP-5, an IGF-responsive gene, was increased 2-fold in WT but not in PAPP-A-/- carotids, suggesting reduced IGF activity in the absence of PAPP-A. Thus, PAPP-A-deficient mice are resistant to neointimal formation after injury, which may be explained in part by the ability of PAPP-A to enhance local IGF-I stimulation of vascular SMCs through proteolysis of IGFBP-4.     

Severe respiratory syncytial virus (RSV) infection in infants with neuromuscular diseases and immune deficiency syndromes

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in infants and children. There is growing evidence of severe RSV disease in infants with neuromuscular diseases and immune deficiency syndromes. Factors predisposing to a more severe course of RSV disease in neuromuscular diseases include the impaired ability to clear secretions from the airways due to ineffective cough, respiratory muscle weakness, high prevalence of gastro-oesophageal reflux and swallowing dysfunction which leads to aspiration. Similarly, pulmonary disease is a common presenting feature and complication of T-cell immunodeficiency. Infants with severe congenital and acquired immune deficiency syndromes may demonstrate prolonged viral shedding in RSV LRTI and are reported to have increased morbidity and mortality associated with RSV infection. Although not indicated in most guideline statements, palivizumab prophylaxis for these uncommon underlying conditions is under consideration by clinicians. Prospective studies are needed to determine the burden of RSV disease in these children.     

Prenatal stress and infant affective reactivity at five months of age

Background

Prospective studies concerning prenatal stress and its outcome on children's emotional development postulated a potential influence of prenatal hormonal levels or emotional stressors on child development [1-3]. In a retrospective study, an influence of maternal emotional stress on infant affective reactivity was found [4].

Aims

This study was conducted in order to confirm these findings in a prospective study design.

Study design

A prospective longitudinal study design was conducted with three study waves during pregnancy and one time point five months postnatally.

Subjects

The final sample consisted of n = 104 mother-infant dyads.

Outcome measures

Maternal baseline cortisol levels and emotional stress were assessed in each trimester of pregnancy. Children were examined with the infant reactivity battery according to Kagan & Snidman [5] at the age of five months.

Results

Mothers of children with high affective reactivity (cry score ≥ 7) were significantly less depressed (p < .10) and perceived less stress (p < .05) in mid-pregnancy and were confronted with less external stress factors (p < .10) at the end of pregnancy. Cortisol levels did not differ in both groups in any pregnancy trimenon (p > .05).

Conclusions

These data add a new specific aspect to the ‘fetal programming hypothesis’ and are the first to confirm the speculative data from retrospective studies. Baseline cortisol does not seem to be the ‘hormonal mediator’ of this association. Therefore, cortisol stress reactivity or other neuroendocrine mechanisms should be assessed in future studies.     

Improvement of Statin Utilization in Veterans With Diabetes Through Pharmacy Interventions

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an effort aimed at increasing the use of statins among veterans with diabetes at a Veterans Affairs medical center in New Mexico.     

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant

Background

Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers.

Aims

To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia.

Study design

Retrospective single centre case-control study.

Subjects

Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls.

Outcome measures

Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations.

Results

Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p = .022 and .024, respectively). Lowest PaCO₂ values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p = .033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome.

Conclusion

We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.     

High risk for RSV bronchiolitis in late preterms and selected infants affected by rare disorders: a dilemma of specific prevention

Respiratory syncytial virus (RSV) is the most frequent aetiologic agent that causes bronchiolitis and lower respiratory tract infection in infants. These infections may be severe and even life-threatening in selected high-risk populations. Traditional, well-established, high-risk populations are preterm infants with or without chronic lung disease and children with congenital heart disease. For these children, RSV prophylaxis using palivizumab, a monoclonal anti-RSV humanised antibody against the F-protein of RSV, has proven safe and efficacious in preventing RSV-related hospitalisation. Recently, a number of rare medical conditions have been associated with the risk of severe RSV infections. Evidence of safety and efficacy of RSV prophylaxis in these populations is lacking. Given the low incidence of these conditions, randomised trials are not feasible. A practical, opinion-based approach to this dilemma is offered in this paper. It is proposed that these rare disorders may qualify for RSV prophylaxis if the association between a specific condition and the risk of severe RSV infection is confirmed in at least 3 independent publications, of which at least 1 includes a prospective cohort study. To facilitate pharmaco-economic analyses, at least one of the three studies must also report on the absolute risk of severe RSV infection in the specified illness. The authors believe that qualification criteria will enable caregivers to target RSV prophylaxis more effectively in children with rare conditions and the proposed approach provides direction for future epidemiological studies on the risk of severe RSV infection in children with these uncommon, medical illnesses.     

Injection of IL-12- and IL-18-encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms

IL-12 and IL-18 are mediators involved in the onset and progression of the autoimmune disease developing in MRL/Mp-Tnfrsf6(lpr) (lpr) mice, which display symptoms similar to the human systemic lupus erythematosus (SLE). The pathology is characterized by progressive lymphadenopathy and auto-antibody-mediated multiple organ failure, e.g. glomerulonephritis, or pneumonitis and a concomitant increase in serum levels for IFNgamma and tumor necrosis factor-alpha (TNFalpha). In this study, we intramuscularly injected lpr mice with plasmids encoding IL-12 and IL-18, either alone or in combination, in order to affect the development of the autoimmune disease. Five biweekly injections of the combined plasmids starting at 4-5 weeks of age diminished serum levels of TNFalpha and reduced the ability of lymphocytes from treated mice to produce IFNgamma in vitro. Injection of both plasmids synergistically attenuated the development of autoimmune syndromes, lymphoproliferation in secondary lymphoid organs, proteinuria and kidney damage, and pneumonitis. We conclude that IL-12 and IL-18 synergistically affect the pathogenesis of the T(h)1-dependent autoimmune syndrome of lpr mice and that approaches that target both IL-12 and IL-18 may be a therapeutic option in the treatment of autoimmune SLE.     

Does blood rheology revert to normal after myocardial infarction?

After myocardial infarction there is an acute deterioration of the flow properties of blood. The present study was designed to test whether the abnormality persists. Blood and plasma viscosity, red cell aggregation and deformability, haematocrit, erythrocyte sedimentation rate, white cell count, cholesterol, and triglycerides were measured in 51 patients who had had a myocardial infarction 5.4 (mean) years before. Results in patients and controls were compared and matched pairs with identical cardiovascular risk factors were also selected. Blood viscosity and red cell aggregation were increased and red cell deformability was decreased in the 51 patients. The abnormalities were independent of the interval since infarction and persisted for years. The rheological abnormalities present after myocardial infarction are at least partly independent of the acute event and acute phase reactions. They contribute to the reduced perfusion of the microcirculation of the heart.     

Effectiveness of a brief psychotherapeutic intervention compared with treatment as usual for adolescent nonsuicidal self-injury: a single-centre,randomised controlled trial

Although nonsuicidal self-injury (NSSI) is a clinically significant behavior, evidence-based, specific, time-, and cost-effective treatment approaches are lacking. The aim of this study was to compare the efficacies of a brief cognitive-behavioral psychotherapy manual, the Cutting Down Programme (CDP), and treatment as usual (TAU) in the treatment of adolescent NSSI. We conducted a single-centre randomised controlled trial (RCT). Eligible participants were aged 12–17 years engaging in repetitive NSSI (at least 5 times within the past 6 months). We randomly allocated 74 participants to CDP (n?=?37) or TAU (n?=?37; in a 1:1 ratio). Outcome measures were administered before treatment (T0), directly after CDP or 4 months after baseline evaluation in the TAU group (T1), and another 6 months later (T2; primary endpoint). Primary outcome was a 50% reduction in NSSI frequency within the past 6 months at 10-month follow-up (T2). Regarding the primary outcome, there were no significant differences between the CDP (n?=?26; 70.3%) and TAU group [n?=?27; 73.0%; χ²(1)?=?0.07; p?=?0.797]; NSSI frequency within the past 6 months was significantly reduced at T2 [χ²(1)?=?12.45; p?<?0.001] with no between-group difference [χ²(1)?=?0.14; p?=?0.704]. However, we found a significant group x point of measurement interaction [χ²(2)?=?7.78; p?=?0.021] regarding NSSI within the last month indicating at T1. CDP was equally effective and achieved faster recovery compared to a significantly more intensive TAU in treating adolescent NSSI. The CDP could provide a brief and pragmatic first treatment within a stepped-care model for NSSI in routine clinical care.

Clinical Trial Registration The trial was prospectively registered in the German Registry of Clinical Trials (https://www.drks.de; DRKS00003605) and is now complete.