Fibrolamellar Carcinoma of Liver: A Primary Malignant Oncocytic Carcinoid?

Immunohistochemical and ultrastructural findings in two cases of fibrolamellar carcinoma of the liver and two cases of hepatocellular carcinoma of the common histologic type are described. Ultrastructural examination of both cases of fibrolamellar carcinoma revealed the presence of neurosecretory (NS) granules which were sparse in some cells and abundant in others. Many of the tumor cells had a distinct oncocytic appearance with abundant mitochondria. A portion of the glutaraldehyde-fixed neoplasm was processed for the uranaffin reaction (an ultrastructural cytochemical stain specific for the NS granules of neuroendocrine tissue). Abundant uranaffin-positive granules were found in the neoplastic cells of both cases of fibrolamellar carcinoma, whereas no uranaffin-positive granules were found in hepatocellular carcinoma of the common histologic type. There was no statistical difference in the mean diameter of the uranaffin-positive granules measured from both cases. Immunohisto-chemistry revealed the presence of neuron-specific enolase (NSE) and serotonin in one of the two cases of fibrolamellar carcinoma and no NSE staining in two cases of hepatocellular carcinoma of the common histologic type. These findings suggest that some liver tumors presenting histologically as fibrolamellar carcinoma may be neuroendocrine in nature.     

Binding and antimineralocorticoid activities of spirolactones in toad bladder

The role of the soluble pool (cytoplasmic or cytosolic) of [3H]-aldosterone binding sites in the toad bladder was assessed by the use of two spirolactones, prorenone and spironolactone as a reference drug. Prorenone fulfills all the criteria for a specific competitive antagonist of aldosterone for its effect on Na+ transport. Compared with spironolactone (Ki approximately equal to 1 microM), prorenone was about eightfold less potent (Ki approximately equal to 8 microM). Competition for [3H]aldosterone binding sites by spironolactone and prorenone revealed an order of potency (spironolactone greater than prorenone) that corresponded to their antagonist activities in the Na+ transport assay. There was a linear correlation between the effects of the two spirolactones on the aldosterone-stimulated Na+ transport and their ability to displace [3H]aldosterone from its binding sites in the soluble pool. Finally [3H]prorenone binding sites were detected in the soluble pool but an insignificant number of antagonist-receptor complexes were found associated with the nuclear pool. Our study indicates that the aldosterone binding sites of the soluble pool are indeed mineralocorticoid receptors, which are probably the first intracellular mediators leading to an increased Na+ reabsorption.     

Three highly polymorphic microsatellites at the human myelin oligodendrocyte glycoprotein locus, 100 kb telomeric to HLA-F : Characterization and relation to HLA haplotypes

The MOG locus, located on chromosomal bands 6p21.3-p22 and mapped about 100 kb telomeric to HLA-F, was isolated from cosmid ICRFcl09A2434 and shown to contain three microsatellites. These CA-repeat polymorphic markers were characterized in a sample of 173 healthy unrelated individuals and 84 DNAs from the HLA Workshop reference panel, by a method combining fluorescence labeling of PCR products and use of an automated DNA sequencer. For the three markers, frequencies of heterozygotes are well predicted from allele frequencies by the Hardy—Weinberg rule, which suggests that problems of allele nonamplification are unlikely. Typing of cell lines homozygous in the HLA region allowed unambiguous definition of 81 HLA-MOG haplotypes and showed that several HLA ancestral haplotypes extended to the MOG region. The high degree of polymorphism (59%, 51%, and 81% at the three loci, respectively, and 87% at the haplotype level) makes these new markers informative for association or linkage studies with diseases such as hemochromatosis or multiple sclerosis, and for studies aimed at precisely delineating the site of crossover in chromosomes in which recombination occurred in the distal part of the HLA class I region.     

Taste and olfaction: Independence vs interaction

Twenty persons sipped and judged overall perceived magnitude, odor magnitude, and taste magnitude of various concentrations of the odorant citral, the tastants sodium chloride and sucrose, and odorant-tastant combinations. In a second experiment, the same twenty persons sniffed and judged perceived odor magnitude for the same set of stimuli. The investigation probed two primary questions: Does the apparent harmony of an olfactory-taste mixture dictate the degree of additivity in that mixture? Does harmony of the components influence the production of any taste-smell confusion? The data from both the harmonious mixture (citral and sucrose) and the dissonant mixture (citral and NaCl) imply absence of sensory inhibition or facilitation between taste and olfaction. Nevertheless, both types of mixtures led to substantial taste-smell confusion whereby olfactory stimulation evoked sensations of taste.     

ASC:SIL ratio following implementation of the 2001 Bethesda System

The 2001 Bethesda system (TBS 2001) eliminated the "satisfactory but limited by" category, benign cellular changes (BCC), and the designations "favor benign" (ASC-B) and "favor low grade" (ASC-L) for atypical squamous cells. We compared the unsatisfactory rate and atypical squamous cells:squamous intraepithelial lesions (ASC:SIL) ratio pre- and postimplementation of TBS 2001 to see if there was an increase in unsatisfactory specimens, ASC rate, and altered ASC:SIL ratio. Pap Tests (569,726) reviewed at the Cytopathology Laboratory of Women and Infants Hospital from 1998-2002 were included. TBS 1991 terminology was used through December 31, 2001. Conversion to TBS 2001 took place on January 1, 2002. The average ASC:SIL ratios pre- and postimplementation of TBS 2001 were 1.52:1 and 1.42:1, respectively. The rates of unsatisfactory specimens and ASC remained unchanged. Conversion to TBS 2001 did not adversely affect the ASC:SIL ratio or the detection rates of abnormalities of Pap tests.     

Intralesion transplantation of serotonergic precursors enhances locomotor recovery but has no effect on development of chronic central pain following hemisection injury in rats

The effects of intralesion grafts of serotonergic precursors on locomotor recovery and development of chronic pain were assessed after chronic spinal cord hemisection injury (SCI) in rats. Serotonin- and brain-derived neurotrophic factor-secreting (RN46A-B14) and RN46A-vector-only cells were transplanted into the site of T13 lateral hemisection 10 days following injury in immunosuppressed animals, and locomotor and pain related behaviors were assessed weekly for 28 days. There were significant improvements in the degree of spontaneous locomotor recovery, but no significant difference was found in the magnitude of development of mechanical allodynia or thermal hyperalgesia in any transplant group. From these results, we conclude that intraparenchymal engraftment of RN46A-B14 cells is largely ineffective in influencing somatosensory outcomes after SCI, in contrast with the efficacy of dorsal intrathecal placement.     

Signalling during hypoxia in human T lymphocytes – critical role of the src protein tyrosine kinase p56Lck in the O2 sensitivity of Kv1.3 channels

T lymphocytes encounter hypoxia when they migrate to pathological sites such as tumours and wounds. The inability of T cells to provide an efficient defence at these sites can in part be explained by the hypoxic environment. Kv1.3 channels, important components of the T cell activation process are inhibited by hypoxia and their inhibition accounts for a hypoxia-induced decrease in T cell proliferation. Although Kv1.3 channels play a key role in T cell O₂ sensing, the signalling mechanisms mediating their response to hypoxia are still not understood. In this study, we show that the src-protein tyrosine kinase p56Lck (Lck) is required for Kv1.3 channel response to hypoxia. Pre-exposure to the src inhibitor PP2 abolished the hypoxia-induced inhibition of Kv1.3 channels in primary human T lymphocytes. Moreover, Kv1.3 channel sensitivity to hypoxia was lost in Lck-deficient Jurkat T cells. Further studies with recombinant Kv1.3 channels showed that Kv1.3 channels lack intrinsic O₂ sensitivity, but delivery of Lck into the cells and transfection of a constitutively active Lck (Y505FLck) restored their sensitivity to hypoxia. Although Lck is necessary for the Kv1.3 channel response to hypoxia, it does not directly inhibit Kv1.3 channels. Indeed, under normal oxygen tension, delivery of active Lck into L929 cells and overexpression of Y505FLck did not decrease recombinant Kv1.3 currents. On the contrary, activation of endogenous src kinases increased wild-type Kv1.3 currents in T lymphocytes. Our findings indicate that Lck is required for the acute response to hypoxia of human T lymphocytes as it is necessary to confer O₂ sensitivity on Kv1.3 channels.