Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study.

Background: Several lines of research suggest that prefrontal cortex dysfunctions observed in obsessive compulsive disorder (OCD) and schizophrenia (SKZ) are linked to two partially independent neuroanatomic systems: the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex, with different neuroanatomic connections, including the striatum. The primary aim of this study was to test this hypothesis using a double dissociation study of neuropsychological tasks performance of the dorsolateral prefrontal cortex and ventromedial prefrontal cortex.

Methods: We administered the Wisconsin Card Sorting Test, the Gambling Task, and the four-disk version of the Tower of Hanoi to 110 SKZ and 67 OCD patients and 56 control subjects.

Islet allotransplantation in type 1 diabetic patients.

Islet transplantation was proposed more than 10 years ago as treatment for normalising glucose homeostasis in type 1 diabetic patients. Since the beginning it has aroused great interest among diabetic patients being an easy procedure, burdened by minor complications: islet transplantation in fact consists on a transhepatic percutaneous injection under local anaesthesia. The initial clinical outcomes not came up to expectations, being low the insulin independence rate and the long term graft function in recipients.

ADP-ribosylation factor 6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth.

The mechanisms coordinating adhesion, actin organization, and membrane traffic during growth cone migration are poorly understood. Neuritogenesis and branching from retinal neurons are regulated by the Rac1B/Rac3 GTPase. We have identified a functional connection between ADP-ribosylation factor (Arf) 6 and p95-APP1 during the regulation of Rac1B-mediated neuritogenesis.

Validity of hepatic resection for cancer in the elderly.

This retrospective review assessed the safety and validity of elective hepatic resection for cancer in patients > or = 65 years of age. Fifty-two patients (31M; 21F; mean age: 70 +/- 5 years; range: 65-82) > or = 65 years of age underwent hepatic resection for cancer between January 1992 and May 1999). The overall preoperative mortality rate was 8%.

Localization of focal adhesion kinase isoforms in cells of the central nervous system.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which in non-neuronal cells is localized to focal adhesions, where it participates to adhesion-dependent intracellular signalling. FAK is highly expressed in the central nervous system both during development and in the adult. FAK(+), a splice isoform of FAK selectively enriched in neurons, contains a three-amino acid insertion in the carboxy-terminal sequence responsible for the localization of FAK to focal adhesions.

Rapamycin impairs antigen uptake of human dendritic cells.

Background: Rapamycin is a recently introduced immunosuppressive agent. Its effect on lymphocytes has been extensively studied. Whether it can also modulate dendritic cell (DC) function is unknown.

Clonal anergy is maintained independently of T cell proliferation.

Ag encounter in the absence of proliferation results in the establishment of T cell unresponsiveness, also known as T cell clonal anergy. Anergic T cells fail to proliferate upon restimulation because of the inability to produce IL-2 and to properly regulate the G(1) cell cycle checkpoint. Because optimal TCR and CD28 engagement can elicit IL-2-independent cell cycle progression, we investigated whether CD3/CD28-mediated activation of anergic T cells could overcome G(1) cell cycle block, drive T cell proliferation, and thus reverse clonal anergy.

Binding of Sp1 to the proximal promoter links constitutive expression of the human uPA gene and invasive potential of PC3 cells.

Activated transcription of the urokinase-type plasminogen activator (uPA) gene depends on the enhancer, located approximately 2 kb from the start of transcription. The proximal promoter, driving basal transcription, contains a GC-/GA-rich sequence immediately upstream of the TATA box. We have investigated the role played by this element in the transcription of the uPA gene in HeLa and PC3 cells, which do not express or constitutively express the gene, respectively.

Non-viral approach toward gene therapy of cystic fibrosis lung disease.

Since Cystic Fibrosis (CF) is an autosomal recessive disorder due to mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, studies towards a gene therapy approach to its treatment followed immediately upon the cloning of the gene. It was demonstrated that the insertion of a single copy of the wild-type gene restored the normal phenotype in CF cells in vitro. Encouraging results were obtained in many in vivo model systems (CF transgenic mice) involving viral as well as non-viral vectors, which demonstrated the recovery of CFTR function in the airways.

Fluorescence resonance energy transfer detection of synaptophysin I and vesicle-associated membrane protein 2 interactions during exocytosis from single live synapses.

To investigate the molecular interactions of synaptophysin I and vesicle-associated membrane protein 2 (VAMP2)/synaptobrevin II during exocytosis, we have used time-lapse videomicroscopy to measure fluorescence resonance energy transfer in live neurons. For this purpose, fluorescent protein variants fused to synaptophysin I or VAMP2 were expressed in rat hippocampal neurons. We show that synaptophysin I and VAMP2 form both homo- and hetero-oligomers on the synaptic vesicle membrane.

Spatial and temporal regulation of Ca2+/calmodulin-dependent protein kinase II activity in developing neurons.

We have studied Ca2+/calmodulin-dependent protein kinase II (CaMKII) isoform distribution and activity in embryonic hippocampal neurons developing in culture. We have found a strong correlation between the expression of the alpha subunit of the enzyme and the ability to undergo depolarization-dependent phosphorylation, which in young neurons is limited to the somatodendritic pool of the kinase. The lack of responsiveness of the axons of young alphaCaMKII-positive neurons is not caused by a lower Ca2+ influx but rather by a differential balance between kinase and phosphatase activities in this compartment.

Analysis of the subcellular distribution of avian p95-APP2, an ARF-GAP orthologous to mammalian paxillin kinase linker.

We describe here the identification and characterization of avian p95-APP2, a multi-domain protein of a recently identified family of ADP-ribosylation factor (ARF)-GTPase-activating proteins (GAPs) including mammalian G protein-coupled receptor kinases (GRK)-interactor 1 (GIT1), paxillin kinase linker (PKL), and GIT2, as well as avian p95-APP1. The p95-APP2 is eluted from Rac-GTP-gamma-S, but not from Rac-GDP-beta-S columns. As other members of the family, p95-APP2 has binding regions for the focal adhesion protein paxillin, and for the Rac exchanging factor PIX.

Constitutive TrkA activity in receptor-overexpressing PC12 clones.

We have studied ligand-independent signaling by the nerve growth factor receptor TrkA in PC12 clones, under conditions of receptor overexpression. Our results indicate that TrkA-overexpressing PC12 clones display constitutive receptor activation, involving both the mature, 140-kDa form and the immature, intracellular 110-kDa form of the receptor. Phosphorylation of Tyr 674/675, located in the activation loop domain and reflecting TrkA kinase activity, appears particularly prominent in the immature form of the receptor.

Successful [correction of Succesful] transplantation of human islets in recipients bearing a kidney graft.

Aims/hypothesis: Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable.

Methods: Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy.

Re-evaluation of primary structure, topology, and localization of Scamper, a putative intracellular Ca2+ channel activated by sphingosylphosphocholine.

Naturally occurring sphingoid molecules control vital functions of the cell through their interaction with specific receptors. Proliferation, differentiation and programmed death result in fact from a fine balance of signals, among which sphingosine and structurally related molecules play fundamental roles, acting as either first or second messengers. The corresponding receptors need to be identified in order that the role of sphingoid molecules can be established.

Optic neuritis: differential diagnosis.

Optic neuritis can be mimicked by other optic neuropathies and by anterior segment, choroidal or retinal diseases. Retinal diseases may cause central visual loss when they involve the macular or peripapillary area. Central serous retinopathy, hereditary retinal diseases, white dots syndromes and autoimmune retinopathies may present a clinical picture similar to that of optic neuritis.

Molecular mechanisms regulating the subcellular localization of p95-APP1 between the endosomal recycling compartment and sites of actin organization at the cell surface.

Cell migration requires coordination between adhesion, actin organization and membrane traffic. Rac and ARF6 have been shown to cooperate for the organization of actin at the cell surface. Recently, the GIT family of ARF-GAPs has been identified, which includes proteins that can functionally interact with both ARF and Rac GTPases.

Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation.

We investigated the capacity of human islets to produce monocyte chemoattractant protein-1 (MCP-1). Primary cultures of pancreatic islets expressed and secreted MCP-1, as determined by Northern blot, immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. The produced MCP-1 was biologically active as it attracted monocytes in chemotaxis assay, and chemotactic activity was almost abrogated by a neutralizing anti-MCP-1 monoclonal antibody.

Nestin is a neuroepithelial target gene of thyroid transcription factor-1, a homeoprotein required for forebrain organogenesis.

Thyroid transcription factor-1 (TTF-1, also known as NKX2.1 and T/EBP), a transcription factor belonging to the NKX-2 family of homeodomain-containing genes, plays an essential role in the organogenesis of the thyroid gland, lung, and ventral forebrain. Nestin is an intermediate filament protein strongly expressed in multipotential neuroepithelial stem cells and rapidly down-regulated during postnatal life.

Control of astrocyte Ca(2+) oscillations and waves by oscillating translocation and activation of protein kinase C.

Background: Glutamate-induced Ca2+ oscillations and waves coordinate astrocyte signaling responses, which in turn regulate neuronal excitability. Recent studies have suggested that the generation of these Ca2+ oscillations requires a negative feedback that involves the activation of conventional protein kinase C (cPKC). Here, we use total internal reflection fluorescence (TIRF) microscopy to investigate if and how periodic plasma membrane translocation of cPKC is used to generate Ca2+ oscillations and waves.

High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI.

Aims/hypothesis: The aim of this study was to assess the prevalence of glucokinase gene mutations in Italian children with MODY and to investigate genotype/phenotype correlations of the mutants.

Methods: Screening for sequence variants in the glucokinase gene was performed by denaturing gradient gel electrophoresis and direct sequencing in 132 children with maturity onset diabetes of the young (MODY) and in 9 children with chronic fasting hyperglycaemia but without laboratory evidence for Type I (insulin-dependent) diabetes mellitus and with normoglycaemic parents ("non-classical" MODY).

Results: Altogether 54 mutations were identified in the MODY group (54/132 or 41%) and 3 among the "non-classical" MODY individuals (3/9 or 33%).

Surgical outcomes for colorectal cancer patients including the elderly.

Background/aims: The aim of this study was to compare the short- and long-term outcome of older and younger colorectal cancer patients resected for cure.

Methodology: Three hundred and forty-six consecutive colorectal cancer patients who underwent some form of surgery were analyzed. One hundred and forty-four patients were < 65 years old (group 1), 151 patients were 65-79 years old (group 2), and 51 patients were 80 years or more (group 3).

Prognostic value of the modified TNM (Izumi) classification of hepatocellular carcinoma in 53 cirrhotic patients undergoing resection.

Background/aims: Few studies have assessed the significance of prognostic factors in cirrhotic patients undergoing resection for hepatocellular carcinoma.

Methodology: Overall survival and disease-free survival were evaluated in 53 cirrhotic patients undergoing hepatic resection for supervening hepatocellular carcinoma. The value of the UICC TNM classification, and the Izumi modified staging system on prognosis were analyzed.

Role of integrins in the peripheral nervous system.

Integrins, a subgroup of adhesion receptors, are transmembrane glycoproteins that mediate interactions between cytoplasm and the extracellular environment. These interactions influence, among others, events such as cell migration, proliferation, and differentiation. Differential expression of integrins is developmentally regulated in the peripheral nervous system (PNS) and is associated with crucial events in both physiological and pathological processes.

Bacterial infections and inflammation in the lungs of cystic fibrosis patients.

The aim of this review is to describe the role of respiratory epithelial cells in processes that contribute to the pathogenesis of lung disease in patients with cystic fibrosis.