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Adaptor protein-3 (AP-3) is an ubiquitous cytoplasmic complex that shuttles cargo proteins from the trans-Golgi and a tubular-endosomal compartment to endosome-lysosome-related organelles.

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Several conditions have been described to cause osteoporosis, including diabetes mellitus. While the relationship between type 1 diabetes and osteopenia is well documented in the literature, data on the presence of this complication in type 2 diabetes have not been well established. We studied a population composed of 66 post-menopausal women with type 2 diabetes and a control population. We examined bone mineral density with the dual-energy X-ray absorptiometry (DXA) technique at the lumbar and femoral levels and, in a subgroup of patients, we also measured the levels of markers of bone remodelling. We found significantly higher levels of bone mineral density at the femoral (but not lumbar) level in the diabetic subjects compared with the control population in all the examined subregions, except Ward's triangle. Moreover, we found higher levels of some markers of bone resorption (urinary calcium and hydroxyproline, telopeptide) in the patients with diabetes, while urinary crosslinks were higher in the controls. On the basis of these results, we suggest that osteoporosis cannot be considered a complication of type 2 diabetes and that, from a metabolic point of view, bone resorption is greater in diabetic patients than in normal subjects, as suggested by the high levels of most of the markers of osteoclastic activity.

The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide.Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients. IntroductionNeutrophils are essential components of the innate immune system because they constitute the first line of defense against bacterial and fungal pathogens. An efficient response against these microorganisms requires that neutrophils carry a fully operational machinery, including proteases, antimicrobial peptides, and reactive oxygen. 1,2 In contrast, a reduction of neutrophil blood counts or a defect in their antimicrobial apparatus exposes the host to threats from many pathogens as observed in chronic granulomatous disease and in other functional defects of phagocytes. [3][4][5][6] Severe congenital neutropenia (SCN) is an uncommon hematologic disorder characterized by reduction of absolute neutrophil counts (ANCs; usually Ͻ 0.2 ϫ 10 9 cells/L), due to maturation arrest of neutrophil precursors in the bone marrow at the promyelocyte stage. If left untreated, the large majority of children affected by SCN dies in the first years of life from invasive infections. 7,8 However, the empiric use of the polypeptide granulocyte colonystimulating factor (G-CSF) for the treatment of SCN has drastically changed the clinical outcome of this condition by increasing absolute neutrophil count values and reducing the episodes of infection in the vast majority of patients. [7][8][9][10] Nonetheless, SCN patients who are receiving G-CSF are at high risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In particular, a higher risk of MDS/AML is observed in SCN children who display a poor response to the treatment with G-CSF and/or receive large doses of the growth factor (above 8 g/kg per day). In addi...

Over a 10-year period after GK radiosurgery, an increasing percentage of patients achieve cure, or adequate control of the disease on pharmacological therapy, at the expense of increasing novel pituitary deficiencies.