Quality of life measures in Italian children with atopic dermatitis and their families

The use of unlicensed and "off-label" medicines in children is widespread. Between 50-80% of the medicines currently administered to children have neither been tested nor authorized for their use in the paediatric population which represents approximately 25% of the whole European population. On 26 January 2007, entered into force the European Regulation of Paediatric Medicines. It aims at the quality of research into medicines for children but without subjecting the paediatric population to unnecessary clinical trial. This article addresses ethical and legal issues arising from the regulation and makes recommendations for the framework conditions facilitating the development of clinical research with children.     

A case of progression from type II cryoglobulinaemia to Waldenstrom’s macroglobulinaemia in a patient with chronic hepatitis C

In recent years, much interest has been generated over the potential of human embryonic stem cells in transplantation medicine. The ground-breaking study of Fraidenraich and colleagues conclusively demonstrated that rescue of lethal cardiac defects in Id knockout mutant mouse embryos was not due to transplanted embryonic stem cells giving rise to functional new tissues within the defective embryonic heart. Instead, there is indirect evidence that the observed therapeutic effect was due to various secreted factors emanating from the transplanted cells. This therefore introduces the exciting prospect of utilizing human embryonic stem cells as "catalysts" to promote biological repair and regeneration in transplantation therapy. Nevertheless, the immunological barrier against allogenic transplantation, as well as the teratogenic potential of human embryonic stem cells poses major technical challenges. A possible strategy to overcome the immunological barrier may be to impose a temporary regimen of immunosuppressive drugs followed by their gradual withdrawal, once adequate tissue regeneration has been achieved. Other more novel alternatives include the use of microencapsulation to block interaction with the transplant recipient's immune system, and co-transplantation with bone marrow-derived mesenchymal stem cells, which have been demonstrated to possess immuno-suppressive properties. The teratogenic potential of human embryonic stem cells could possibly be alleviated by directing the differentiation of these cells to specific lineages prior to transplantation, or through mitotic inactivation. Co-transplantation with autologous adult stem cells may represent a novel strategy to further enhance the "catalytic" effects of human embryonic stem cells. The various factors secreted by human embryonic stem cells could then have a concentrated localized effect on relatively large numbers of co-transplanted autologous adult stem cells, which may in turn lead to enhanced repair and regeneration of the damaged tissue or organ. This new therapeutic strategy needs to rigorously investigated, in view of its potentially important clinical applications.     

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome

A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --> p16.1::8p23 --> pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --> q32::4p15.3 --> qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --> 4p16.3::8p23 --> 8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.     

Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I

Recently, a spinal muscular atrophy (SMA) determining gene, termed survival motor neuron (SMN) gene, has been isolated from the 5q13 region and found deleted in most patients. A highly homologous copy of this gene has also been isolated and located in a centromeric position. We have analyzed 158 patients (SMA types I-IV) and found deletions of SMN exon 7 in 96.8%. Mutations other than gross deletions seem to be extremely rare. In one of the undeleted SMA type I patients, a newborn who survived for only 42 days, we detected a maternally inherited 5 bp microdeletion in exon 3, resulting in a premature stop codon. By RT-PCR and long range PCR amplification we were able to show that the deletion belongs to the SMN gene, rather than to the centromeric copy, and that the proposita had no paternal SMN gene. Analysis of the neuronal apoptosis inhibitor protein (NAIP) gene, which maps close to SMN and has been proposed as a SMA modifying gene, suggests the presence of at least one full-length copy. Haplotype analysis of closely linked polymorphic markers suggests that the proposita also lacks the maternally derived copy of the centromeric homologue of SMN supporting the hypothesis that the severity of the phenotype might depend on the reduced number of centromeric genes in addition to the frameshift mutation.      

Economic analysis of two structured treatment and teaching programs on asthma

The aims of the present study were as follows:

• 1). to evaluate the medical outcomes of two treatment and educational asthma programs
• 2). to determine by cost-analysis both cost and economic outcome of the programs
• 3). to perform a cost-benefit analysis (determining the net cost-benefit) and a cost-effectiveness analysis (determining the cost per unit of effect and the incremental cost-effectiveness ratio) from the perspective of health program policy makers (HPP; indirect costs, i.e., loss of productivity, excluded) and of society as a whole (Saw; all costs included).

Patients were randomly assigned to a complete (CP; n = 32) or reduced (RP; n = 33) program: the RP group received a reduced education (self-reading of an educational booklet on asthma), while the CP group attended an “asthma school”, consisting of six lessons based on the same booklet and including educational videotapes. Both programs included peak-flow monitoring and treatment according to international guidelines, and follow-up. The outcome variables (asthma attacks, urgent medical examinations, admission days, working days lost) did not differ significantly between CP and RP. Morbidity savings were $1894.70 (CP) and $1697.80 (RP) according to Saw, and $1349.50 and $1301.80, respectively, according to HPP. The net cost-benefit was $1181.50 for CP and $1028.00 for RP, and the cost-benefit ratio per dollar spent was 1:2.6 for CP and 1:2.5 for RP, according to Saw. One day of admission prevented had a cost of $110.20 (CP) and $94.10 (RP). CP gave slightly better results and was slightly more cost-effective than RP in improving patients' welfare. It cannot be excluded that the retrospective analysis used to determine baseline costs might have inflated differences for both groups. Sensitivity analysis was slightly in favor of RP when the outcome variables were tested at their upper and lower 95% CI.     

Efficacy of human recombinant erythropoietin plus IFN-alpha in patients affected by chronic hepatitis C.

Determination of serum iron levels in patients affected by chronic hepatitis C is considered fundamental for studying the response to interferon-alpha (IFN-alpha) treatment. IFN could induce anemia, which is promptly corrected by exogenous administration of recombinant human erythropoietin (rHuEPO). The aim of our study was to verify the possible beneficial effect of rHuEPO in patients affected by chronic hepatitis C and treated with IFN. Seventy consecutive patients (42 males and 28 females, mean age 46.4+/-5.2 years) affected by chronic hepatitis C were enrolled. In all patients, chronic hepatitis C was diagnosed on the basis of clinical and biological findings (alanine aminotransferase [ALT] serum levels at least 2-fold higher than normal values for at least 12 months and the presence of anti-HCV antibodies). All patients were negative for hepatitis B virus (HBV) infection, hepatitis D virus (HDV infection, and HIV infection. Statistical analysis was carried out using the Wilcoxon nonparametric sum rank test, the Spearman correlation rank test, and the Friedman ANOVA and Kendall coefficient of concordance. At the end of the treatment, our study series showed significant differences in serum levels of AST (p < 0.001), iron (p < 0.001), and ferritin (p < 0.001). At the end of the follow-up period, significant differences were seen in ALT, aspartate (AST), and iron ferritin and transferrin levels. All differences favored patients who received IFN-alpha and rHuEPO. We think that the depletion of circulating iron may improve the immune response impaired by iron accumulation in the liver. Our study confirms the important role played by iron in the response to IFN treatment, suggesting that the use of rHuEPO induces a better response to IFN in patients with chronic hepatitis C by activation of erythropoiesis.