Association of multiple liver cell adenomas with spontaneous intrahepatic portohepatic shunt

The association of multiple liver cell adenomas containing foci of focal nodular hyperplasia with a spontaneous intrahepatic portohepatic venous shunt is reported in a 13-year-old male patient. At least eight nodules less than 10 cm in diameter were recognized and proved by means of surgical resection or surgical biopsies. These lesions were heterogeneous and hypodense on precontrast computed tomographic (CT) scans, and were slightly enhanced after injection of contrast medium. At magnetic resonance (MR) imaging, the signal intensity of these nodules varied. It was either hyperintense or hypointense on T1-weighted SE images. Sonography and angiography demonstrated a portohepatic venous shunt and hepatic arterialization was observed. These findings emphasize the hypothesis that hepatic arterialization may cause the development of liver cell adenomas. Moreover, it is suggested that liver cell adenoma and focal nodular hyperplasia have a common pathogenesis.     

Obesity and non-alcoholic steatohepatitis

Obesity is the most important risk factor associated with non-alcoholic steatohepatitis, which is caused by to impaired insulin activity, overflow of portal triglycerides, and production of inflammatory cytokines; all of these are deleterious to hepatocytes. These phenomena facilitate disruptions in hepatic physiology, as observed in alcoholic hepatitis; however, consumption of this substance is absent. Non-alcoholic steatohepatitis has had a great impact due to the fact that previously, main cases of cryptogenic cirrhosis actually were attributed to this disease. Despite advances in understanding the pathophysiologic process of the disease, there is no better treatment than weight reduction (a combination of diet and exercise). In this issue, we describe the most important topics with regard to non-alcoholic steatohepatitis and the obesity-related process.     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Chromosome breakage syndromes and cancer

There exist numerous genetic disorders, marked by chromosome instability, that are strikingly associated with various cancers. Both the chromosomal instabilities and neoplastic outcomes are related to abnormalities of DNA metabolism, DNA repair, cell-cycle governance, or control of apoptosis. Among these diseases are ataxia telangectasia and Nijmegen breakage syndrome, with increased incidences of lymphomas. Bloom syndrome, Werner syndrome, and Rothmund-Thompson syndrome, each characterized by a DNA helicase defect, are associated with early incidences of different cancers. Other diseases combining the phenotype of chromosomal instabilities and neoplastic development are Fanconi anemia and breast cancers associated with mutant BRCA1 and BRCA2 genes. The cloning of the encoding genes and the characterization of their products have resulted in partial understanding of the pathways of cellular DNA surveillance and maintenance of genomic rectitude. The exact pathways fully linking the genetic defect mechanisms to the eventual development of various neoplasias remain to be elucidated, but progress in defining the molecular genetics of these entities suggests that many of them are disorders of DNA recombination. Each defect involves a separate protein in these complex pathways.     

Monitoring and assessment indicators in 2001 of "Roll Back Malaria" initiative in Benin

Within the context of WHO/CDS/RBM/2000, a survey was conducted in 2001 by the National Malaria Control Program of Benin. Following a well-thought-out choice, the survey took place simultaneously in health areas corresponding to epidemiological regions. Morbidity due to malaria is very high among children under five years admitted in external clinic (44.3% of cases) and (46.5%) for hospitalization. The crude rate of mortality is 129%. The use of non-impregnated bednet is usually met in three health areas, where 47.4% of the household have at least one non-impregnated bednet versus 5.4% of household with impregnated bednets. Percentage of pregnant women sleeping under an impregnated bednet and following chemoprophylaxis is respectively 43.3% and 3.8%. Results obtained at the end of this database survey in 2001 have facilitated the definition of indicators of the process, results and impact which remain very useful for the implementation of the monitoring and assessment system of "Roll Back Malaria" in Benin.     

The "Will Rogers effect" on stage grading

Will Rogers phenomenon affects survival statistics applied to clinical research and could determine a misreading of results. Stage migration due to new methods of diagnostic imaging and staging invasive procedures could improve actuarial survival in each stage. TNM System is impaired when survival rates come from different inhomogeneous countries, regions and eras. Randomized trials suffer this fallacious phenomenon when staging depends on the different treatments which are to be evaluated.     

Is the alpha-beta ratio of prostate cancer really low? A prospective, non-randomized trial comparing standard and hyperfractionated conformal radiation therapy.

BACKGROUND AND PURPOSE: The objectives of the current study were to compare genito-urinary (GU) and gastro-intestinal (GI) toxicities as well as biochemical control (bRFS) in prostate cancer, utilizing conventional (2.0 Gy daily) (STD) or hyperfractionated (HFX) conformal irradiation (CRT). HFX (1.2 Gy BID) was chosen as a radiobiological method to try to reduce long term sequelae without compromising local control. PATIENTS AND METHODS: Three-hundred-and-seventy consecutive patients (pts) entered this prospective, non-randomized trial in the period January 1993-January 2003; 209 were treated with STD and 161 with HFX CRT. All were evaluable for acute toxicity analysis, 179 (STD) and 151 pts (HFX) being evaluable for late sequelae and bRFS analyses. Pt characteristics were not statistically different in the two groups. CRT consisted of a 4-field technique for prostate and/or pelvic nodes and a 5-field boost with rectal shielding. Median doses were 74 and 79.2 Gy for STD and HFX patients respectively, the latter dose being isoeffective for tumour control assuming alpha/beta=10 (EQD(2)=73.9 Gy). Median follow-up was 29.4 months (25.2 mos for STD; 37.7 mos for HFX; P<0.01). The two regimens were compared in terms of acute and late GU and GI toxicities and 5-year bRFS by univariate and multivariate analyses. RESULTS: Acute grade> or =2 GU toxicity was higher in the STD group (48.6% versus 37.3% in HFX, P=0.03), while no significant difference was found for acute GI toxicity. Late grade> or =2 GU and GI toxicities were lower in the HFX group (5-year actuarial rate: GU: 10.1% versus 20.3%, P=0.05; GI: 6.0% versus 10.6%, P=0.18). Five-year bRFS were 70% (+/-13.8%, 95% CI) and 82.6% (+/-7.2%) for STD and HFX, respectively (P=0.44); a trend favouring HFX was found in the subgroup of pts who did not receive hormonal therapy (5-year bRFS: 85.9%+/-12.4% versus 63.9%+/-23.8%, P=0.15). Multivariate analysis revealed only risk groups and age statistically related to bRFS but not fractionation regimen. Using the Nahum-Chapman TLCP model and prostate parameter set, which includes hypoxia, the TLCPs are approximately equal for the two regimens, whereas assuming alpha/beta=1.5 and no hypoxia we obtain 73% for the STD group but only 36% for the HFX group. CONCLUSIONS: As expected from radiobiological considerations, HFX reduces GI and GU late toxicities. Concerning early bRFS, our clinical findings suggest that HFX is no less effective than STD when delivering an isoeffective (alpha/beta=10) dose. Despite the relatively short follow-up, this result appears to be inconsistent with a low alpha/beta ratio for prostate cancer.     

Role of smooth muscle cells in the initiation and early progression of atherosclerosis

The initiation of atherosclerosis results from complex interactions of circulating factors and various cell types in the vessel wall, including endothelial cells, lymphocytes, monocytes, and smooth muscle cells (SMCs). Recent reviews highlight the role of activated endothelium and inflammatory cell recruitment in the initiation of and progression of early atherosclerosis. Yet, human autopsy studies, in vitro mechanistic studies, and in vivo correlative data suggest an important role for SMCs in the initiation of atherosclerosis. SMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli can modify the type of matrix proteins produced. In turn, the type of matrix present can affect the lipid content of the developing plaque and the proliferative index of the cells that are adherent to it. SMCs are also capable of functions typically attributed to other cell types. Like macrophages, SMCs can express a variety of receptors for lipid uptake and can form foam-like cells, thereby participating in the early accumulation of plaque lipid. Like endothelial cells, SMCs can also express a variety of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 to which monocytes and lymphocytes can adhere and migrate into the vessel wall. In addition, through these adhesion molecules, SMCs can also stabilize these cells against apoptosis, thus contributing to the early cellularity of the lesion. Like many cells within the developing plaque, SMCs also produce many cytokines such as PDGF, transforming growth factor-beta, IFNgamma, and MCP-1, all of which contribute to the initiation and propagation of the inflammatory response to lipid. Recent advances in SMC-specific gene modulation have enhanced our ability to determine the role of SMCs in early atherogenesis.