Clinical studies with In-111 BLEDTA, a tumor-imaging conjugate of bleomycin with a bifunctional chelating agent

Indium-111 BLEDTA, a bleomycin analog containing an EDTA group, was used for tumor imaging in 110 patients with cancer. Scans with In-111 BLEDTA agreed with biopsy results in 75 of 95 patients (79% accuracy). A positive scan was obtained in 71 of 88 patients with a positive biopsy (81% sensitivity). In 21 of 95 patients (22%), the scan revealed tumor sites that had not been detected. The main limitation of visualization was the size of the tumor (1.5--2.0 cm diameter was the smallest size seen). Background radioactivity in the liver, spleen, and bone marrow also made tumor detection in these areas more difficult. The cause of this background, and of false-positive uptake in sites of inflammation, is correlated with specific radiolabeling of polymorphonuclear leukocytes by In-111 BLEDTA. Means of eliminating this background are discussed.     

Complications of home parenteral nutrition in a large pediatric series

When adequate nutrition cannot be provided by enteral route as a consequence of failure of intestinal functions, parenteral nutrition (PN) become the only way to maintain adequate nutrition; however, prolonged periods of PN can lead to severe complications. Furthermore, long hospital admissions for this form of nutrition can be detrimental for the child and the family. In the past 20 years, home parenteral nutrition (HPN) programs have been developed. The aim of our study was to retrospectively evaluate the kind and the frequency of complications in a HPN pediatric case series. We had 61 patients on HPN. Total duration of the program was 27,740 days (76 total years, mean 1.2 years per patient). We observed a total of 58 complications; mean 0.79 per patient per year with a prevalence of central venous catheter-related complications (mechanical, 52%; infective, 26%). We had a very low incidence of metabolic complications (3%) and a low incidence of PN-related hepatic complications (19%). None of the complications described was the cause of death. Half of our patients have been able to stop the program. We had a low incidence (0.20 per patient per year) of septic episodes, lower than we had in patients on hospital PN in the same period (0.38 per patient per year). We had to replace 20 catheters, 18 of them for mechanical problems. Our study shows that HPN still can be a valid alternative to small intestinal transplantation in patients affected by intestinal failure and that only patients with PN-related liver disease must be considered early candidates for combined liver-small bowel transplant.     

B cells in SLE: different biological drugs for different pathogenic mechanisms

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a complex multi-factorial pathogenesis and a great clinical polymorphism. SLE is considered to be a B cell disease in which autoantibodies are the major players. Recently, the central role of B cells has been confirmed and it has been shown that that the relative frequency of B cells subsets is altered in SLE patients. Conventional immunosuppressive therapies such as azathioprine, cyclophosphamide or methotrexate, reduce disease activity and improves the patient's general health conditions. These treatments have possible side effects; in fact they could compromise liver function, fertility and innate and adaptive immune responses. Moreover, for unknown reasons a small group of SLE patients is refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The progress in therapeutic antibody technology has led to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In contrast to general immuno-suppression, the availability of drugs interfering with specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease in each patient.     

Congenital brucellosis: a rare cause of respiratory distress in neonates

Brucellosis represents a rare cause of neonatal infection. In this article we report a very unusual case of congenital infection due to BRUCELLA MELITENSIS in a term neonate presenting after birth with severe respiratory distress and radiological manifestations (lobar consolidation and diffuse interstitial infiltrations) compatible with pulmonary involvement. The neonate was successfully treated with trimethoprim-sulfamethoxazole, rifampicin, and gentamicin.     

Prenatal management and postnatal separation of omphalopagus and craniopagus conjoined twins

Two cases of prenatally diagnosed conjoined twins are presented: a set of omphalopagus twins sharing a common liver, and a set of craniopagus with involvement limited to the skull. In both cases, prenatal diagnosis allowed accurate planning of pre- and postnatal management. Prenatal management involved serial imaging and counseling with participation of different specialists according to imaging findings. In the rare case of conjoined twins, an interdisciplinary approach is required, with feto-maternal specialists playing a pivotal role in co-ordinating teamwork and planning successive stages of management.     

Increased expression of the oligopeptidase THOP1 is a neuroprotective response to Abeta toxicity

In a comprehensive proteomics study aiming at the identification of proteins associated with amyloid-beta (Abeta)-mediated toxicity in cultured cortical neurons, we have identified Thimet oligopeptidase (THOP1). Functional modulation of THOP1 levels in primary cortical neurons demonstrated that its overexpression was neuroprotective against Abeta toxicity, while RNAi knockdown made neurons more vulnerable to amyloid peptide. In the TgCRND8 transgenic mouse model of amyloid plaque deposition, an age-dependent increase of THOP1 expression was found in brain tissue, where it co-localized with Abeta plaques. In accordance with these findings, THOP1 expression was significantly increased in human AD brain tissue as compared to non-demented controls. These results provide compelling evidence for a neuroprotective role of THOP1 against toxic effects of Abeta in the early stages of AD pathology, and suggest that the observed increase in THOP1 expression might be part of a compensatory defense mechanism of the brain against an increased Abeta load.     

TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases

NF-κB activation depends on the IKK complex consisting of the catalytically active IKK1 and 2 subunits and the scaffold protein NEMO. Hitherto, IKK2 activation has always been associated with IκBα degradation, NF-κB activation, and cytokine production. In contrast, we found that in SCF-stimulated primary bone marrow-derived mast cells (BMMCs), IKK2 is alternatively activated. Mechanistically, activated TAK1 mediates the association between c-Kit and IKK2 and therefore facilitates the Lyn-dependent IKK2 activation which suffices to mediate mitogenic signaling but, surprisingly, does not result in NF-κB activation. Moreover, the c-Kit-mediated and Lyn-dependent IKK2 activation is targeted by MyD88-dependent pathways leading to enhanced IKK2 activation and therefore to potentiated effector functions. In neoplastic cells, expressing constitutively active c-Kit mutants, activated TAK1 and IKKs do also not induce NF-κB activation but mediate uncontrolled proliferation, resistance to apoptosis and enables IL-33 to mediate c-Kit-dependent signaling. Together, we identified the formation of the c-Kit-Lyn-TAK1 signalosome which mediates IKK2 activation. Unexpectedly, this IKK activation is uncoupled from the NF-κB-machinery but is critical to modulate functional cell responses in primary-, and mediates uncontrolled proliferation and survival of tumor-mast cells. Therefore, targeting TAK1 and IKKs might be a novel approach to treat c-Kit-driven diseases.