Cervical cancer and human papillomavirus: epidemiological evidence and perspectives for prevention

The ts1 Moloney murine leukemia virus causes a degenerative neurologic disease in mice characterized by the development of noninflammatory spongiform encephalomyelopathy. To determine whether gag and pol gene products and viral replication are necessary for the ts1-env gene product to cause neurodegeneration, we generated transgenic mice harboring only ts1-env. Neuropathological lesions were observed in mice expressing the transgene in the central nervous system. This implies that gag and pol gene products and viral replication are not necessary for ts1-env to cause a mild form of neurodegeneration in mice.     

Intracavernous invagination of pituitary macro-adenomas

Depending on authors, intra-cavernous invasion by a pituitary adenoma is found in 9% to 40% of cases. In the light of our own experience, we think that such an invasion is probably much less frequent than usually evoked on CT-scan and MRI. In our study, it was confirmed in only one case over 125 (0.80%), though radiological data suspected an intra-cavernous invasion 17 times. An anatomical study on 20 cadavers showed that 30% of normal pituitary glands present with a lateral expansion into one or both cavernous sinuses (CS). These natural invaginations were already evoked by Harris and Rhoton in 1976. They can resemble an intra-cavernous extension or invasion on MRI views, moreover when an adenoma increases the volume of this expansion, and in the absence of any rupture of the medial wall of the CS. The medial wall of the CS is, in fact, constituted by a dural pouch which close-fits the pituitary gland and its expansions; it invaginates more or less in the CS, depending on the importance of the pituitary lateral expansion. In case of a large adenoma, the finger-glove lateral distension of the pouch disappears progressively during the tumoral removal. Finally the dura returns to its normal place back, at the end of the procedure. This concept of invagination of the CS medial wall, as opposed to that of invasion and therefore of rupture of the dural plane, explains the wide range of figures concerning the frequency of intracavernous invasion by pituitary adenomas, in the literature. These figures are all the more variable as there is no absolute criteria of intra-cavernous invasion on CT-scan nor MRI views. In the same way, no clinical criteria can be retained to assume the existence of such an invasion. So, an ophthalmoplegia seems to be usually linked to a compression of occulomotors nerves; it recovers in a large majority of cases, after the adenoma is removed. In conclusion we emphasize the necessity of interpreting with great care radiological imaging when it evokes' a possible intra-cavernous invasion of a pituitary adenoma. The indication of an eventual radiotherapy should be retained with as much care as possible, since complete removal of an adenoma and its lateral expansion(s) is almost always feasible through a trans-sphenoidal route.     

Expression of P-cadherin identifies prostate-specific-antigen-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas. Implications for prostate cancer biology

PURPOSE: To evaluate the efficacy of dynamic computed tomography (CT) for differentiating benign from malignant solitary pulmonary nodules (SPNs). MATERIALS AND METHODS: Sixty-five patients with noncalcified SPNs (diameter, < or = 30 mm; 42 malignant, 16 benign, seven inflammatory) underwent single-location dynamic contrast material-enhanced (100 mL, 4 mL/sec) serial CT. Peak height of time-attenuation curves and ratio of peak height of the SPN to that of the aorta were measured. Precontrast attenuation and enhancement pattern were recorded. Perfusion was calculated from the maximum gradient of the time-attenuation curve and the peak height of the aorta. RESULTS: Peak heights of malignant (41.9 HU +/- 2.8) and inflammatory (43.6 HU +/- 7.7) SPNs were significantly higher than that (13.4 HU +/- 2.2) of benign SPNs (P < .001; P < .01). SPN-to-aorta ratios in malignant and inflammatory SPNs were significantly higher than that in benign SPNs (P < .001, P < .05). No statistically significant differences in the peak height and SPN-to-aorta ratio were found between malignant and inflammatory SPNs. Precontrast attenuation of inflammatory SPNs was lower than that of malignant SPNs (P < .05). Perfusion values in malignant and inflammatory SPNs were significantly higher than that of the benign SPNs (P < .01). CONCLUSION: Dynamic CT provides quantitative information about blood flow patterns of SPNs and is an applicable diagnostic method for differentiating SPNs.     

Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum

BACKGROUND/AIMS: Prediction of response to interferon therapy is important in the management of chronic hepatitis C. Pre-therapy data are valuable but they may be inaccurate in some cases. Our aim was to investigate whether the biochemical and virological events that occur early during interferon therapy in chronic hepatitis C may predict the final result of the treatment. METHODS: ALT and serum HCV-RNA were serially measured in 53 HCV-RNA-positive patients who received a standard 6-month course of interferon therapy. Eleven patients with a sustained response, 23 who responded but subsequently relapsed and 19 who did not respond were studied. HCV-RNA was measured with a commercial kit (Amplicor HCV). RESULTS: After 4 weeks of treatment, HCV-RNA became negative in 73% of sustained responders, in 26% of transient responders (p = 0.02) and in none of the non-responders. Corresponding figures after 8 weeks of therapy were 82% in sustained responders, 61% in transient responders and 9% in non-responders. The difference between sustained and transient responders at this time was not significant. After 4 weeks of therapy, 82% of sustained responders, 52% of transient responders and none of the non-responders presented normalization of alanine transferase. The difference between sustained and transient responders was not significant. Corresponding figures for normalization of alanine transferase at 8 weeks were 82%, 96% and 0% respectively. At the end of treatment, all sustained responders, 70% of transient responders and none of the non-responders had cleared HCV-RNA from serum. CONCLUSIONS: A rapid normalization of alanine transferase induced by interferon therapy is associated with response, but does not differentiate between transient and permanent response. In contrast, clearance of HCV-RNA after 4 weeks of treatment, but not after 8 weeks, is significatively associated with sustained response. Testing for HCV-RNA early during interferon administration may be valuable for further decisions concerning therapy in patients with chronic hepatitis C.     

Alternate amino terminal processing of surfactant protein A results in cysteinyl isoforms required for multimer formation

The biological functions of rat surfactant protein A (SP-A), an oligomer composed of 18 polypeptide subunits derived from a single gene, are dependent on intact disulfide bonds. Reducible and collagenase-reversible covalent linkages of as many as six or more subunits in the molecule indicate the presence of at least two NH2-terminal interchain disulfide bonds. However, the reported primary structure of rat SP-A predicts that only Cys6 in this region is available for interchain disulfide formation. Direct evidence for a second disulfide bridge was obtained by analyses of a set of three mutant SP-As with telescoping deletions from the reported NH2-terminus. Two of the truncated recombinant proteins formed reducible dimers despite deletion of the domain containing Cys6. Edman degradation revealed that each mutant protein was a mixture of two isoforms with and without an isoleucine-lysine-cysteine (IKC) extension at the NH2-terminus, which was derived from the COOH-terminal end of the reported signal peptide. Large variations in the abundance of the IKC isoforms between truncated SP-As suggested that the amino acid sequences located downstream from the signal peptide modulated alternate-site cleavage by signal peptidase. Elution of the newly identified cysteine in the position of DiPTH-Cys indicated participation in disulfide linkage, which was interchain based on the direct correlation between prevalence of the IKC variant and the extent of dimerization for each truncated protein. Sequencing of both native rat SP-A and human SP-A also revealed isoforms with disulfide-forming NH2-terminal extensions. The extended rat SP-A isoforms were enriched in the more fully glycosylated and multimeric SP-A species separated on SDS-PAGE gels. Thus, a novel post translational modification results in naturally occurring cysteinyl isoforms of rat SP-A, which are essential for multimer formation.     

Characterisation of circulating chromogranin A in human cancer patients

The structure of circulating chromogranin A (CgA) of phaeochromocytoma patients was characterised and compared with that of CgA extracted from tumours. Size exclusion chromatography experiments provided evidence that CgA is present in the blood of different patients, as well as in tumour extracts, as multiple forms having different hydrodynamic sizes of 600 kDa (CgA-I), 100 kDa (CgA-II) and 55 kDA (CgA-III). The amount of each CgA form as a proportion of the total antigenic material was different in different patients. Western blot analysis of chromatographic fractions indicated that these forms are made up by polypeptides of similar molecular weight (about 60-70 kDa). All CgA forms express the epitopes recognised by two monoclonal antibodies (A11 and B4E11), directed against residues 68-70 and 81-90 of human CgA. However, their relative immunoreactivity was markedly different. No evidence for the presence of multimeric complexes in the CgA-I fraction was obtained by various immunological and biochemical methods. These results suggest that circulating CgA in phaeochromocytoma patients consists of at least three forms that appear to be made up by polypeptides with similar molecular weight and different hydrodynamic properties and immunoreactivity. We hypothesise that different conformations and shapes contribute to the heterogeneity of circulating CgA.     

A two-stage half-sib design for mapping quantitative trait loci in food animals

Daughter and granddaughter half-sib designs for mapping quantitative trait loci were modified to increase experimental power. This new design includes a two-stage procedure, in contrast to conventional one-step half-sib designs. In stage 1, a few progeny of each sire are genotyped for marker loci. Based on the analyses of stage 1 data, some sires are chosen to continue genotyping more progeny for stage 2. When multiple chromosomes are under investigation, chromosomes and sires for stage 2 are selected based on the analysis of stage 1 data. Sire selection results in increased frequency of heterozygous genotypes of interest in stage 2 if the markers are linked to those genes. Chromosome selection can increase the proportion of chromosomes with segregating quantitative trait loci in stage 2 if not all of the chromosomes evaluated in stage 1 have segregating quantitative trait loci. Numerical results indicated that two-stage half-sib designs are generally more powerful than conventional designs when 1) the noncentrality parameter is moderate or larger, 2) larger quantitative trait loci are mapped using tightly linked markers in larger families, and 3) variation is large in numbers and sizes of segregating quantitative trait loci among the chromosomes evaluated in stage 1.     

Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDs, PCDFs and PCBs

On Nov. 20-22, 1995, a World Health Organization working group consisting of 12 scientific representatives from 6 different countries met to reassess the health risks to infants associated with perinatal exposure to polyhalogenated aromatic hydrocarbons (PHAHs). Following a review of previous WHO/EURO consultations, as part of their comprehensive programme on PCDDs, PCDFs and PCBs, current exposure information and recent experimental and epidemiologic data were discussed. Exposure assessments within the past decade have revealed that in the case of breast milk samples concentrations of PCDDs/DFs and PCBs have shown a continual decline, in certain countries by up to 50%. New experimental data has revealed that a variety of structural, functional and behaviourial alterations can be induced in rodent species following exposure to PHAHs while a Dutch collaborative PCB/dioxin study has illustrated subtle clinical, endocrine and mental/psychomotor development effects can occur in breast fed infants. The provisional conclusions of the working group were: 1) current evidence does not warrant altering the previous WHO recommendation for promotion/support of breast feeding and 2) based on new clinical data which supports the biological plausibility of certain observed experimental observations, continued and enhanced effort should be directed towards identifying and controlling sources of environmental input for these contaminants.