Low Doses of Allyphenyline and Cyclomethyline,Effective against Morphine Dependence,Elicit an Antidepressant-like Effect

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Quantitative analysis of nucleolar margination in diagnostic cytopathology

Summary The diagnostic value of nucleolar margination, defined as the percentage of nucleoli touching the nuclear membrane, was investigated in 359 cytological preparations of benign and malignant lesions of the thyroid, breast, prostate and central nervous system. Premalignant lesions of the uterine cervix and non-invasive papillary carcinomas of the bladder were also examined. It was observed that the percentages in benign lesions were, in general, lower than in the malignant and that the values increased progressively with increasing grade in the cervix and bladder. When the overlap index was calculated, this gave exact information on the usefulness of nucleolar margination in distinguishing benign from malignant lesions, particularly in the prostate and thyroid and, to a lesser extent, in the breast and central nervous system. As for lesions of different grades, the calculation of the index allowed the identification of two subgroups, one corresponding to low grades (mild cervical dysplasia or urothelial papillary carcinoma of grade 1), the other subgroup to high grades (severe cervical dysplasia and carcinoma in situ, or papillary carcinoma of grade 3). Moderate dysplasia cases and grade 2 papillary carcinomas do not appear as separate intermediate categories but rather show values falling into the range of either the higher or lower grades. The margination values obtained from the cytological preparations corresponded well to those in the histological slides obtained from the resected specimens. In conclusion, nucleolar margination appears to be a feature which is easy to evaluate in a reproducible way and useful in cytological diagnosis.     

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.     

Serum and urine acute kidney injury biomarkers in asphyxiated neonates

Background

We evaluated serum (s) cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) and urine (u) CysC, NGAL and kidney injury molecule-1 (KIM-1) as markers of acute kidney injury (AKI) in asphyxiated neonates.

Methods

AKI biomarkers were measured in 13 asphyxiated neonates born at ≥36?weeks gestational age (eight with AKI and five without AKI) and 22 controls. AKI was defined as serum creatinine ≥1.5?mg/dl for >24?h or rising values >0.3?mg/dl from day of life (DOL) 1. Biomarkers were measured on DOL 1, 3, and 10.

Results

Asphyxiated neonates had significantly higher sCysC on DOL 1 as well as sNGAL and uCysC and uNGAL (standardized to urine creatinine and absolute values) than controls at all time points. Compared to controls, significantly higher sNGAL, uCysC, and uNGAL values were observed in the asphyxia-AKI and asphyxia–no AKI subgroups. Regarding uKIM-1, only the absolute values were significantly higher in asphyxiated neonates (DOL 10). sNGAL, uCyst, and uNGAL had a significant diagnostic performance as predictors AKI on DOL 1.

Conclusions

sNGAL, uCysC, and uNGAL are sensitive, early AKI biomarkers, increasing significantly in asphyxiated neonates even in those not fulfilling AKI criteria. Their measurement on DOL 1 is predictive of post-asphyxia-AKI.     

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.