The acid-labile subunit of human ternary insulin-like growth factor-binding protein complex in girls with central precocious puberty before and during gonadotropin-releasing hormone analog therapy

The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty. We studied serum ALS, free IGF-I, total IGF-I, IGFBP-3 levels and IGFBP-3 protease activity in 13 girls, aged 1.6-7.8 yr (mean, 5.9 +/- 2.2), diagnosed as having CPP before and after 6 and 12 months of GnRH analog (GnRHa) therapy. The ALS SD score before treatment was high (1.4 +/- 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 +/- 0.54 (P < 0.01) and -0.4 +/- 0.61 (P < 0.01), respectively]. Serum IGF-I and IGFBP-3 were also increased before treatment, but both of these factors remained elevated after 6 and 12 months of GnRH-A therapy [IGF-I SD score, 3.20 +/- 1.64, 2.92 +/- 1.82, and 3.68 +/- 1.94 (P = NS), respectively; IGFBP-3 SD score, 1.02 +/- 0.53, 0.94 +/- 0.68, and 1.22 +/- 0.87 (P = NS), respectively]. Serum free IGF-I levels and IGFBP-3 proteolytic activity did not vary significantly from their pretreatment values during GnRHa therapy. In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy.     

Identification of α-thalassemia mutations in subjects from Eastern Sicily (Italy) with abnormal hematological indices and normal Hb A2

We analyzed the prevalence of α-thalassemia mutations in 298 subjects from Eastern Sicily (Italy) with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), normal HbA₂ and HbF, and normal serum iron. In 131 subjects (43.9%) we found six different genotypes of α-thalassemia: -α^3.7/αα (36.6%), -α^3.7/-α^3.7 (27.5%), –^MED/αα (10.0%), -α^20.5/αα (9.1%), α^HphIα/αα (8.4%), α^HphIα/α^HphIα (6.1%), and -α^3.7/α^HphIα (2.3%). Our data underline that in Eastern Sicily populations, the molecular screening of α-thalassemia mutations and/or deletions may be useful to better characterize the clinically asymptomatic subjects with a slightly reduced MCV and MCH and normal iron status.     

Role of Bowel Ultrasound in the Diagnosis and Follow-up of Patients with Crohn's Disease

Crohn's disease (CD) is an inflammatory chronic bowel disorder; it can involve the whole gastrointestinal tract, but its localization in the ileum or colon is most common. The reference standard for the diagnosis of CD is ileocolonoscopy with histologic assessment. The reference standard for the detection of any complications is surgery. However, imaging techniques have an important role both in the detection/localization of CD and in the follow-up of CD patients. In the last few years, the technical development of ultrasound equipment, the advent of new technologies such as elastography and mostly the increased expertise of sonographers have boosted the role of bowel ultrasound in assessment of the gastrointestinal tract. In fact, bowel ultrasound is particularly attractive thanks to its widespread availability, non-invasiveness, low cost and good reproducibility, as it can be easily repeated during follow-up. The aim of this article is to provide an extensive overview of the actual role of bowel ultrasound in the detection and follow-up of patients with CD.     

Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction

Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.     

Bilirubin influence on oxidative lung damage and surfactant surface tension properties

To study the hypothesis that hyperbilirubinemia might reduce in vivo oxidative lung damage while also diminishing lung surfactant surface tension properties during acute lung injury, we performed a randomized study in a rabbit model of acute lung injury. Twenty rabbits were randomized to receive bilirubin or saline intravenously. Acute lung injury was induced by lung lavages with saline. Lung tissue oxidation was evaluated by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and protein carbonyls (PC) in bronchial aspirate (BA) samples. Surface surfactant activity was studied in BA samples using a capillary surfactometer. Bilirubin BA concentration increased in bilirubin-treated rabbits, while it remained undetectable in controls. A similar increase in TH, AOPP, and PC bronchial aspirate concentrations was found in both the study and control groups, while surfactant surface activity was lower in the bilirubin than in the control group. We conclude that during hyperbilirubinemia, bilirubin enters the lung tissue, where it can be detected in BA fluid. Bilirubin is not effective as an antioxidant agent and exerts a detrimental effect on lung surfactant surface tension properties. These findings may have relevance to the management of premature neonates suffering from respiratory distress syndrome and hyperbilirubinemia.     

Cost-effectiveness treatment with Rituximab in patients with rheumatoid arthritis in real life

The cost-effectiveness of treatments that have the potential to change the “natural history” of a chronic progressive disease has to be evaluated over the long term. Cost-effectiveness estimates have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. This analysis focused on the use of Rituximab in treating patients with moderate to severe RA for whom at least one anti-TNFα blocking agent had failed. The aim of our study was to evaluate the cost-effectiveness in 32 patients with rheumatoid arthritis in therapy with a single infusion of Rituximab 1,000 mg given on days 1 and 15 of each month for 1 year. After 6 months of treatment, we observed for all 32 patients a total quality-adjusted life year (QALY) gained of 11,840 with an average of 0.37 QALY for a single patient, a treatment cost of €5,610 and a QALY/cost ICER (incremental cost-effectiveness ratio) of €15,114. After 1 year of treatment, we observed data for 28 patients with a total QALY gained of 11,480 with an average of 0.41 QALY for a single patient, a treatment cost of €9,690 and a QALY/cost ICER (incremental cost-effectiveness ratio) of €23,696. The benefit of using Rituximab is cost-effectiveness with a QALY/gained under the acceptable threshold of €50,000 in our observational study. These are important data for discussion from the economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.     

Antiretroviral therapy in prevention of HIV and TB: update on current research efforts

There is considerable scientific evidence supporting the use of antiretroviral therapy (ART) in prevention of human immunodeficiency virus (HIV) and tuberculosis (TB) infections. The complex nature of the HIV and TB prevention responses, resource constraints, remaining questions about cost and feasibility, and the need to use a solid evidence base to make policy decisions, and the implementation challenges to translating trial data to operational settings require a well-organised and coordinated response to research in this area. To this end, we aimed to catalogue the ongoing and planned research activities that evaluate the impact of ART plus other interventions on HIV- and/or TB-related morbidity, mortality, risk behaviour, HIV incidence and transmission. Using a limited search methodology, 50 projects were identified examining ART as prevention, representing 5 regions and 52 countries with a global distribution. There are 24 randomised controlled clinical trials with at least 12 large randomised individual or community cluster trials in resource-constrained settings that are in the planning or early implementation stages. There is considerable heterogeneity between studies in terms of methodology, interventions and geographical location. While the identified studies will undoubtedly advance our understanding of the efficacy and effectiveness of ART for prevention, some key questions may remain unanswered or only partially answered. The large number and wide variety of research projects emphasise the importance of this research issue and clearly demonstrate the potential for synergies, partnerships and coordination across funding agencies.     

Early psoriatic arthritis: the clinical spectrum

OBJECTIVE: To characterize the clinical pattern of early psoriatic arthritis (PsA). METHODS: We studied 47 consecutive patients: 29 had definite PsA and 18 had the "sine psoriasis" subset. Inclusion criteria were articular and/or entheseal involvement of < or =12 weeks' duration and the exclusive use, before enrollment, of nonsteroidal antiinflammatory drugs to control articular symptoms. All patients underwent clinical examination, blood tests, total-body bone scintigraphy, articular ultrasonography, and radiography of clinically involved joints and/or entheses. RESULTS: On the basis of clinical examination, early PsA was an oligo-enthesoarthritis in over 75% of patients studied. In contrast, the number of joints and/or entheses showing increased tracer uptake on bone scintigraphy was 3 times greater, compared to the clinical evidence (p < 0.001). Articular ultrasonography confirmed the inflammatory involvement of synovium and/or entheses in all articular sites active at time of bone scintigraphy, but silent at clinical examination. In addition, 7 patients showed the occurrence of joint and/or entheseal erosions on standard radiography. CONCLUSION: Bone scintigraphy yields a more accurate evaluation of entheso-articular involvement and distribution in patients with early PsA. Our results suggest that clinical oligo-enthesoarthritic presentation of early PsA might represent in most cases a polyarticular condition that is at increased risk for clinical progression. These findings have a significant influence on the clinical decision-making process in patients with early PsA.