Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: matched case-control study, pathological analysis, and pathogenetic hypothesis

Large cell change (LCC), characterized by cellular enlargement, nuclear pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain uncertain. Therefore, we assessed the prognostic value of LCC as a marker of subsequent hepatocellular carcinoma (HCC) through a case-control study that compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant recipients with HCC to specimens from a control group of recipients without HCC, matched for sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in 16 (43%) of the study and 7 (19%) of the control group biopsy specimens. By matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a morphological transition or a histogenetic association between the two lesions. LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a greater degree of apoptosis than normal hepatocytes (labeling indices of 1.9 and 0.23; P = .03) To reconcile these findings, we propose that LCC derives from derangements in the hepatocyte's normal process of polyploidization. Such derangements, possibly caused by chronic inflammation-induced DNA damage, could yield a population of enlarged liver cells with nuclear atypia and pleomorphism, frequent binuclearity, and minimal proliferation. According to this hypothesis, LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC but would not represent a direct malignant precursor.     

Interpersonal conflict and physical violence during the childbearing year

Reducing physical abuse directed at women by male partners is one of the nation's Year 2000 health objectives. An important target group for achieving this health objective is pregnant women. The present study examines the frequency, severity, perpetrators and psychosocial correlates of violence during the childbearing year. A panel of 275 women were interviewed 3 times during pregnancy and at 6 months postpartum. Moderate or severe violence was somewhat more common during the postpartum period than during the prenatal period--19% of women reported experiencing moderate or severe violence prenatally, compared to 25% in the postpartum period. For partner-perpetrated violence, being better educated was associated with increased risk of violence as was having had a sex partner who ever shot drugs; being older, having a confidant and having social support from friends were significant protective factors. For violence perpetrated by someone other than a male partner, having a confidant was a significant protective factor. Obstetric care providers who routinely come in contact with pregnant women, as well as emergency department staff, need to be systematically screening for violence against women. Efforts to enhance women's social support networks should be included in primary and secondary prevention programs.     

Investigation of specimen mislabelling in paraffin-embedded tissue using a rapid, allele-specific, PCR-based HLA class II typing method

Topical application of 5-aminolevulinic acid (5-ALA), with subsequent synthesis of protoporphyrin IX (PPIX), is a novel outstanding procedure for photodynamic treatment. So far, clinical experience has been reported with creams containing 5-ALA for the therapy of skin cancer, oral application for the treatment of gastrointestinal disease and intravesical instillation of 5-ALA solutions for fluorescence detection of superficial bladder cancer. Inhalation of 5-ALA for the staining of bronchial malignancies is a preferred method in clinical pulmonology. Since no adverse reaction was observed in lung function in a canine following inhalation of 5-ALA in increasing concentrations, clinical applications were performed. Seven patients with positive or suspicious sputum cytology, but negative white light bronchoscopy, received 5-10 wt.% 5-ALA in NaCl solution by means of a medical nebulizer. No side effects were observed during and after 5-ALA inhalation. After a period of 3 h, patients underwent fluorescence bronchoscopy using violet light for fluorescence excitation and an optical multichannel analyzer for fluorescence detection in situ. The results showed fluorescence spectra which could be related to PPIX induced by 5-ALA in the bronchial mucosa. The fluorescence intensity was sufficiently high for video imaging using a target integrating color CCD camera adapted to the flexible bronchoscope. Carcinoma in situ, as well as dysplasias, showed a clear positive fluorescence. A correlation of fluorescence contrast with histology on 30 biopsies revealed a high sensitivity, but a specificity below 50%. Improvements in light and drug dosimetry will form the basis for further clinical trials.     

Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

BACKGROUND: The efficacy of highly active antiretroviral treatment (HAART) in HIV-1 disease may vary between nucleoside-naive and experienced patients as well as between patients with different viral phenotypes and in different stages of disease. OBJECTIVE: To investigate variables of importance for successful long-term viral suppression by analysing virological, clinical and immunological characteristics at initiation of protease inhibitor treatment on suppression of HIV RNA over 1 year. DESIGN: An open, non-randomized, observational clinical study. SETTING: Venh?lsan, Department of Dermatovenereology, S?der Hospital, Stockholm, Sweden. PATIENTS: A total of 147 unselected advanced patients with known HIV-1 infection for a mean of 7 years, of whom 37% had AIDS and who started treatment with a protease inhibitor during 1996. INTERVENTIONS: All patients received HAART with at least two nucleoside analogues in combination with either indinavir (81%) or ritonavir (19%). The majority (77%) had been previously treated with nucleoside analogues for a mean of 39 months. MEASUREMENTS: CD4+ lymphocyte count, plasma HIV-1 RNA, viral phenotype and HIV-1 coreceptor CCR-5 genotype at baseline. Viral load and CD4+ lymphocyte count were determined every 3 months. RESULTS: Patients were analysed on an intention-to-treat basis. The mean CD4+ lymphocyte count at baseline was 170 x 10(6)/l and the median viral load was 68 600 copies/ml. Heterozygosity for the delta32 deletion of the CCR-5 gene (delta32/wt) was found in 27%. MT-2 positive virus (syncytium-inducing) was isolated in 46%. Logistic regression revealed that nucleoside analogue experience and baseline log10 HIV-1 RNA were the only factors independently related to plasma HIV-1 RNA levels below 500 copies/ml after 1 year of treatment, which was found in 69%. CONCLUSION: The virological outcome after 1 year of HAART was strongly correlated to prior treatment history and baseline viral load, whereas CD4+ lymphocyte count, CCR-5 genotype and viral biological phenotype had less influence. The long-term antiviral efficacy of HAART was lowest in individuals with previous nucleoside analogue treatment and a high baseline viral load. In these individuals an even more aggressive treatment should be considered.     

Detection of point mutations by solid-phase methods

Several techniques exist that permit the efficient distinction among characterized DNA sequence variants. In this review we discuss a number of such analytic procedures. These techniques all take advantage of a variety solid supports to prepare and analyze reaction products. The described diagnostic principles are now being applied for the development of miniaturized assay formats, suitable for automated detection of large sets of sequences in clinical samples.     

Soluble tumour necrosis factor receptor release after anti-CD3 monoclonal antibody treatment in mice is independent of tumour necrosis factor-alpha release

The involvement of TNF-alpha in the release of soluble TNF receptors was assessed in mice, treated with anti-CD3 monoclonal antibodies. After treatment with three different anti-CD3 mAb, we simultaneously studied serum levels of TNF-alpha, soluble TNF receptor P55 and P75. All three anti-CD3 mAb triggered the release of both of the soluble TNF receptors, whereas only one of the anti-CD3 mAb triggered TNF-alpha release. These data demonstrate that in our model soluble TNF receptor release is independent of TNF-alpha release.     

Neurobehavioral effects from exposure to dental amalgam Hg(o): new distinctions between recent exposure and Hg body burden

Potential toxicity from exposure to mercury vapor (Hg(o)) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central nervous system (CNS) toxicity associated with handling Hg-containing amalgam materials among dental personnel with very low levels of Hg(o) exposure (i.e., urinary Hg <4 microg/l), applying a neurobehavioral test battery to evaluate CNS functions in relation to both recent exposure and Hg body burden. New distinctions between subtle preclinical effects on symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 microg/l, presents convincing new evidence of adverse behavioral effects associated with low Hg(o) exposures within the range of that received by the general population.     

Craf-1 protein kinase is essential for mouse development

The complete cDNA of the mouse integral membrane protein 2B gene (Itm2b) was determined by sequence analysis of expressed sequence tag (EST) clone L26775 and a clone isolated from a cDNA library of the osteogenic stromal cell line MN7 (Mathieu et al., 1992. Calcif. Tissue Int. 50, 362-371) and by 5' rapid amplification of cDNA ends (RACE). Alignment of different mouse ESTs confirmed the entire sequence. Northern blot analysis of different neonatal and adult mouse tissues showed that Itm2b is ubiquitously expressed. There are three mRNAs with different lengths in neonatal as well as in adult tissues, originating from alternative polyadenylation by usage of one consensus and two additional variant polyadenylation signals. The cDNA sequence of the human Itm2b homolog (ITM2B) was assembled using data from available human ESTs. Both the mouse and the human gene code for a protein of 266 amino acids (aa) that is homologous to a previously described integral membrane protein, Itm2A, of which the expression is restricted to osteo- and chondrogenic tissues. Itm2A and Itm2B belong to a family of type II integral membrane proteins, which contains a third member, Itm2C (Deleersnijder et al., 1996. J. Biol. Chem. 271, 19475-19482). The human ITM2B and mouse Itm2b genes were previously mapped as unknown ESTs to conserved syntenic regions Homo sapiens 13q12-13 and Mus musculus 14.