Following the licensure of the Oka/Merck varicella vaccine in Italy in January 2003, the Sicilian health authorities launched a universal vaccination programme in all nine Local Health Units. A two-cohort vaccination strategy was adopted to minimise the shift of the mean age of varicella occurrence to older age groups, with the goal of vaccinating with one dose at least 80% of children in their second year of life and 50% of susceptible adolescents in their 12th year of life. Two studies were implemented in parallel to closely monitor vaccination coverage as well as varicella incidence.

The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid)(BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors.Oncogene advance online publication, 8 June 2009; doi:10.1038/onc.2009.125.

To evaluate the usefulness of conventional serological methods with western blot assay (WB) in congenital toxoplasmosis diagnosis, we prospectively enrolled in a clinical and serological follow-up all pregnant women with Toxoplasma gondii infection and their offspring, referred to us from October 2004. Western blot and standard serological test were performed on sera collected from mother during pregnancy and from mother and child at birth, at postpartum month 1-3-6-9 and 12. At this point in time, 22 pregnant women and 14 infants have completed the follow-up. 4 newborns were infected and 2 had specific toxoplasmosis anomalies at the birth. In mothers without seroconversion, the WB performed during pregnancy demonstrates the highest accordance with postnatal follow-up whereas in 1 case the negative result of PCR analysis was not confirmed by postnatal observation. The detection of anti-T gondii IgG against 8 kDa accessory antigenic band and against the accessory band included between 35 and 40 kDa band in immunoblot assay was useful for diagnosis of acute phase but did not improve the evaluation of comparative postnatal profile. Althougth few infants have concluded the postnatal follow-up, the preliminary results showed a greater value of using a IgM and IgA WB test than other standard method for the early diagnosis of toxoplasmosis at birth also in child born to treated mothers. The comparative anti-T gondii IgG immunoblot profile of mother and child permitted us to reduce the time of ruling out infection in newborns born to mothers with probable or possible infection and/or when prenatal diagnosis is negative or not performed.

Various critical issues still surround the management of toxoplasmosis in pregnant women and neonates. Although the study of specific antibodies remains an essential parameter for diagnosing materno-fetal infection and establishing time of infection, the method needs to be carefully and critically reviewed due to the distinctive immunological sensitivity of the neonate. We began a retrospective epidemiological study of the pre-natal management of Toxoplasma gondii (TG) infection to evaluate the incidence of congenital toxoplasmosis in children in a southern Italian area (Sicily). 230 children born between 1999 and 2005 to mothers with TG infection during pregnancy enrolled in the G. Di Cristina Children's Hospital of Palermo. Retrospective analysis of the maternal sample established that 150 (65%) of the 230 infants enrolled in the study were born to a mother with probable infection, while the remaining 80 (35%) were born to a mother with definite infection. To date, the results of the neonatal follow-up programme have confirmed the diagnosis of congenital infection in 16 infants (7%); for 43%, diagnosis was made early due to the presence, at birth or in the first month of life, of specific anti-TG IgM. Sequelae were observed in 8/16 infected infants. Sequelae in infected born to mothers with infection in the third trimester opens up the problematic issue of which therapeutic approach to adopt for these women: even without consensus support, a combined regimen of Pyrimethamine-Sulfadiazine could be advocated, even in the absence of prenatal diagnosis. Currently, the best diagnostic strategy involves the sequential or contemporaneous combination of more than one of the currently available methods, as no method on its own can ensure an appropriate level of accuracy.

The majority of anaplastic large cell lymphomas (ALCLs) express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, which is oncogenic due to its constitutive tyrosine kinase activity. Transformation by NPM-ALK not only increases proliferation, but also modifies cell shape and motility in both lymphoid and fibroblastic cells. We report that the Rac1 GTPase, a known cytoskeletal regulator, is activated by NPM-ALK in ALCL cell lines (Karpas 299 and Cost) and transfected cells (lymphoid Ba/F3 cells, NIH-3T3 fibroblasts). We have identified Vav3 as one of the exchange factors involved in Rac1 activation. Stimulation of Vav3 and Rac1 by NPM-ALK is under the control of Src kinases. It involves formation of a signaling complex between NPM-ALK, pp60(c-src), Lyn and Vav3, in which Vav3 associates with tyrosine 343 of NPM-ALK via its SH2 domain. Moreover, Vav3 is phosphorylated in NPM-ALK positive biopsies from patients suffering from ALCL, demonstrating the pathological relevance of this observation. The use of Vav3-specific shRNA and a dominant negative Rac1 mutant demonstrates the central role of GTPases in NPM-ALK elicited motility and invasion.Oncogene advance online publication, 12 November 2007; doi:10.1038/sj.onc.1210921.

AIM: In order to assess the consequences of different clinical approaches in the prenatal management of congenital toxoplasmosis, we retrospectively reviewed 58 pregnant women with Toxoplasma seroconversion and prospectively enrolled their 59 infants, referred to us from 1999 to 2004. METHODS: Data on clinical, laboratory and demographic characteristics of the pregnant women were collected. Their children were entered into a 48-month follow-up programme in which clinical, instrumental, ophthalmologic and serologic evaluations were carried out at birth, at 1, 3, 6, 9, 15, 18, 24, 36 and at 48 months of life. Paediatric treatment with Spiramycin alone or alternated with Pyrime-thamine-Sulphadiazine was administered according to the different clinical cases. RESULTS: Time of infection was dated in the first trimester for 24 women (41%), in the second trimester for 18 women (31%) and in the third trimester for 16 (28%). In the first trimester of pregnancy 20 of the 24 infected women had undergone amniocentesis, while the test had not been performed on any of the women infected in the third trimester. Serological follow-up revealed that 11 (19%) of the infants had been infected. An alternating regimen with Pyrimethamine-Sulphadoxine was administered to the infected children. All the infants were clinically asymptomatic, and the instrumental follow-up revealed specific toxoplasmosis anomalies in 4/11 infected children. CONCLUSION: Our results highlight issues and problems concerning current prenatal diagnostic tests and the therapeutic approach based on PCR testing of amniotic fluid alone. The incidence of ocular-cerebral lesions observed in children born to women with seroconversion in the third trimester raises questions about the diagnostic and therapeutic approach for these women and their offspring. Paediatric therapeutic protocol, with alternating Pyrime-thamine-Sulphadiazine regimen, applied also to asymptomatic children born to women with inadequate prenatal diagnostic management, could prevent severe sequelae.

Auxological and endocrinological complications frequently occur in children with connatal HIV infection. These complications seem to be related both to the infection itself and the antiretroviral therapy. Many children consequently show height-weight and pubertal retardation without any evidence of hormonal deficit. We studied 10 children with connatal HIV infection who were enrolled in this analysis and followed up for 7 years in order to evaluate their height-weight growth, pubertal maturation, bone age progression and hormonal pattern [basal Growth hormone (GH) and GH after Clonidine or Insulin stimulation, Insulin-like Growth Factor 1 (IGF-1), Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), FSH, LH, ACTH and Cortisol, TSH, fT4, T4, T3, Ab-TGO, Leptin]. Three children showed a height lower than 3rd centile during the first two years of their life and in prepubertal age, with recurring improvement in their growth rate. Weight growth was very compromised in one girl, remaining firmly lower than 3rd centile during the follow-up. Three children presented a weight lower than 3rd centile until they were two years old. However, a height growth rate higher than 10th centile was found in nine children throughout the follow-up, while it was pathological in five children. The blood level of Leptin was higher at the beginning of the study: 0.82 - 11.68 ng/l (M 3.29; SD 4.15) than at its conclusion: 0.2 - 3 ng/l (M 1.65; DS 1.01). There was a statistically significant correlation between leptinemia and the CD4/CD8 count (p: 0.010; r: 0.916) and the CDC classification (p: 0.006; r: 0.937), indicating a strong relationship with the degree of virological and immunological impairment. The authors stress the importance of a careful height-weight growth rate control in HIV-infected children, as it reflects the clinical and virological course of the disease. Adequate control of the infection allows physiological growth in most patients. Moreover, we emphasize the utility of IGFBP-3 and IGF-1 measurements, since they represent growth markers which are more exact and better capable of reproduction than GH.