Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation

BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. METHODS: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. RESULTS: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis). CONCLUSIONS: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.     

Sporadic cases of acute autochthonous hepatitis E in Spain

BACKGROUND/AIMS: In industrialized countries hepatitis E virus (HEV) infection is rare and its diagnosis is difficult because the utility of available tests is not well established. METHODS: We studied the presence of acute HEV infection markers in a cluster of 11 cases of acute hepatitis with IgG anti-HEV antibodies. RESULTS: Three cases were confirmed as acute hepatitis E and 8 as presumptive hepatitis E, two as a past HEV infection and one could not be determined. Three different HEV strains were identified in serum from 3 patients. Two strains belonged to genotype 3, the predominant genotype found in local urban sewage and the other strain belonged to genotype 1 and was considered an imported strain. CONCLUSIONS: Our findings demonstrate the presence of some autochthonous, sporadic acute hepatitis E cases as well as an imported case in our area and the transitory nature of virological and serological markers for HEV.     

Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.     

Spatial distribution of axon collaterals of single inferior olive neurons

The aim of this study was to define the overall distribution pattern of the axon collaterals of single inferior olive (IO) neurons in relation to the multiple somatotopic maps defined by the climbing fiber (CF) input through the cerebellar cortex. In a previous study (Rosina and Provini: Brain Res. 289:45-63, '83), it was shown that the IO neurons supply interlobar collaterals to pairs of somatotopically related areas in the intermediate part of the anterior lobe (PIAL), in the paramedian lobule (PML), in crus II, and in the simple lobule, within strips C1 to D2. The residual branches then could either distribute within single folia or to adjacent folia within each somatotopically defined cerebellar area or both. We studied whether or not the IO axons branch over neighboring folia of the face-forelimb (FL) areas of PIAL and PML and how this interfolial branching relates to the interlobar collateralization by using the multiple fluorescent retrograde tracing technique. The main results of the study were as follows: the axons from neurons in IO subdivisions that are related to strips C1-C3 give off two interfolial branches in the FL area of PIAL and practically no interfolial collaterals are given in the FL area of PML; and the neurons that give off interfolial collaterals also give interlobar branches. From these data we have inferred the general branching pattern of the IO neurons that convey FL information to PIAL and PML. Each neuron gives off two interlobar collaterals: the branch directed to PIAL splits again into two interfolial collaterals, while each of these three collaterals should give off about three branches within each target folium to account for the ten collaterals estimated to be present in the cat. The distribution pattern of IO axon collaterals proposed here suggests that the same CF-relayed information may interact, at the Purkinje cell level, with different sets of mossy fiber inputs. The effect of this interaction would be to modulate the motor commands forwarded to specific muscle groups in relation to the different conditions under which a given movement is executed.     

Prolactin-releasing effect of zetidoline, a new neuroleptic agent, in the rat

The effect of a new neuroleptic agent, zetidoline, 1-(3-chlorophenyl)-3-[2-(3,3-dimethyl-l-azetidinyl)ethyl]imidaz olidin-2-one (ZET), on prolactin release was studied in both male and female rats and compared to that of the classic antipsychotic drugs chlorpromazine and haloperidol. Time-course and dose-effect studies showed that ZET induces a rapid and short lasting increase in plasma prolactin levels, with a significant increase after a dose as low as 0.33 mg/kg, i.p.. The overall patterns of prolactin release appeared to be similar in both sexes but the response was markedly greater in females than in males. The prolactin-releasing effect of ZET was counteracted by apomorphine and L-dopa, which indicates that blockade of dopamine receptors is the basis of its neuroendocrine action. As a prolactin-releaser, ZET was found to be about 5 times as potent as chlorpromazine and about one-ninth as potent as haloperidol.     

Mutation rate of the hepadnavirus genome

An essential factor for charting the evolution of hepadnaviruses is an estimation of the mutation rate of the virus genome during replication in the host. In order to determine the mutation rate of the hepadnavirus genome under defined experimental conditions, we transfected 10 neonatal woodchucks with an infectious molecular clone of woodchuck hepatitis virus (WHV). By 4 months post-transfection, all 10 animals showed serological evidence for WHV infection. Subsequently, 1 animal became chronically infected and was used for further study. At 16 months post-transfection WHV DNA from serum virions was cloned and the nucleotide sequence of three independent progeny genomes compared directly with that of the input recombinant DNA. Although the consensus nucleotide sequence remained unchanged, we found three differences in individual progeny genomes when compared to the parental genome sequence. Thus, we estimate the mutation rate of the WHV genome to be less than or equal to 2 X 10(-4) base substitutions/site/year. This figure is one to two orders of magnitude lower than the mutation rates previously calculated for the positive- and negative-strand RNA viruses, but is similar to the mutation rate of the gag gene which is the most slowly evolving gene of retroviruses. Therefore, we find that the hepadnavirus genome is relatively stable during replication in host tissues when compared to other viruses that lack polymerase-associated proofreading functions.     

Pontocerebellar system linking the two hemispheres by intracerebellar branching

Origin and percentage of bilaterally projecting pontocerebellar neurons whose axons branch within the cerebellum and link the two cerebellar hemispheres were studied in cats using double retrograde fluorescent tracing and lesion techniques. These pontocerebellar neurons, which can be viewed as a separate component of the pontocerebellar system, account for 5-10% of the pontine neurons projecting to the lateral hemisphere. The system is mainly composed of neurons the axons of which recross within the cerebellum. The pontocerebellar interhemispheric system described here is likely to be the basis for the previously described intracerebellar commissural system. The bilateral distribution of these fibers may provide an important substrate for the coordination of bilaterally performed movements.