Spinal cord regeneration: a phenomenon unique to urodeles?

To study the triggering mechanism(s) of the induction of apoptosis following exposure to u.v. light, we used a genetic approach involving cell strains derived from patients with inherited deficiencies in nucleotide excision repair. It was found that cells from patients with Cockayne's syndrome, which are deficient in the processing of u.v.-induced pyrimidine dimers from the transcribed DNA strand, are induced to undergo apoptosis at much lower doses of u.v. light than cells with proficient strand-specific repair. The induction of apoptosis correlated to the induction of p53 and to the inhibition of total RNA and poly(A) mRNA synthesis. We also show that active p53 proteins accumulate following u.v.-irradiation without any apparent requirement for DNA strand breaks or excision repair intermediates. We propose that the blockage of RNA polymerases at DNA lesions in the transcribed strand triggers the induction of a pathway leading to apoptosis. These findings may help explain a long standing enigma of why, despite the DNA repair deficiency, patients with Cockayne's syndrome do not experience an elevated risk for skin cancer since potentially pre-mutagenic cells are eliminated by an easily triggered apoptotic pathway.     

Responsiveness of self-reported and objective measures of disease severity in carpal tunnel syndrome

Responsiveness, the ability to detect meaningful clinical change, is a critical attribute of instruments used to evaluate outcomes of treatments. The authors hypothesized that self-administered symptom severity and functional status questionnaires are more responsive to clinical improvement after carpal tunnel release than traditional physical examination measures of strength and sensibility. Data were obtained from a randomized clinical trial of endoscopic versus open carpal tunnel release conducted in four university medical centers. Patients were evaluated before surgery and 3 months after surgery. Seventy-four patients indicating that they were more than 80% satisfied with the results of surgery were assumed to have clinically meaningful improvement and were the focus of the analysis. Evaluations included questionnaires assessing symptom severity, functional status, and activities of daily living as well as measurement of grip, pinch, and abductor pollicus brevis strength, and 2-point discrimination and Semmes-Weinstein pressure sensibility. Responsiveness was calculated with the standardized response mean (mean change/standard deviation of change) as well as the effect size (mean change/standard deviation of baseline values). The symptom severity scale was four times as responsive, and the functional status and activities of daily living scales were twice as responsive, as the measures of strength and sensibility. Self-administered symptom severity and functional status scales are much more responsive to clinical improvement than measures of neuromuscular impairment and should severe as primary outcomes in clinical studies of therapy for carpal tunnel syndrome.     

Tripe palms: a cutaneous paraneoplastic syndrome

Tripe palms is a cutaneous paraneoplastic syndrome. We report a case of tripe palms in a 71-year-old man with non-small cell lung cancer. Approximately 90% of patients with tripe palms have an associated cancer, most commonly involving the lung or the stomach. Any patient with tripe palms must have a complete cancer workup, especially for lung and stomach cancer.     

Electron transfer by domain movement in cytochrome bc1

The cytochrome bc1 is one of the three major respiratory enzyme complexes residing in the inner mitochondrial membrane. Cytochrome bc1 transfers electrons from ubiquinol to cytochrome c and uses the energy thus released to form an electrochemical gradient across the inner membrane. Our X-ray crystal structures of the complex from chicken, cow and rabbit in both the presence and absence of inhibitors of quinone oxidation, reveal two different locations for the extrinsic domain of one component of the enzyme, an iron-sulphur protein. One location is close enough to the supposed quinol oxidation site to allow reduction of the Fe-S protein by ubiquinol. The other site is close enough to cytochrome c1 to allow oxidation of the Fe-S protein by the cytochrome. As neither location will allow both reactions to proceed at a suitable rate, the reaction mechanism must involve movement of the extrinsic domain of the Fe-S component in order to shuttle electrons from ubiquinol to cytochrome c1. Such a mechanism has not previously been observed in redox protein complexes.     

A 6-year clinical assessment of electronic facial thermography

The authors briefly report their experience regarding the opportunities offered by the use of current ultrasound methods in carotid surgery. They describe: a system for the quantification of athcromasic plaque used to monitor non-operated patients over time; ultrasound methods used to analyse the carotid wall to establish whether it can be utilised as an index of vascular aggression in hypertension, diabetes and atherosclerosis; the use of transcranial Doppler; criteria for the definition of high risk plaque; the applications of eco-color Doppler. The paper also illustrates a new pathology identified by the authors, defined as primary intimal fibrous hyperplasia, and the evolution of the carotid wall after endarterectomy. The structural characteristics of primary hyperplasia can only be shown using ultrasound given that arteriography cannot distinguish it from atheromatic stenosis. After endarterectomy the carotid wall is subject to hematic and hemodynamic stimuli which determine the type of evolution of the wall itself. The authors therefore examine the myointimal reaction, myointimal hyperplasia, early restenosis and late restenosis as different facets of the same phenomenon.     

Immune recognition of viral antigens

The response exhibited by the immune system to viral and other foreign antigens consists of antibody-mediated and T cell-mediated immunity. Structural and molecular biological studies have shown that the antibody response is tailored to provide exquisite specificity by generating binding pockets that are complementary in shape as well as in charge to the antigen. On the other hand, the cellular response uses T-cell receptors (TCRs) and the major histocompatibility complex (MHC) antigens. Structural information on the TCRs is not yet available, but the crystal structures of several MHC class I molecules have shown how one MHC molecule can bind many different peptide sequences that share only the common anchor residue positions that determine allele specificity. MHC class I interactions with the peptide backbone at the N and C termini explain the high specificity of the binding groove for peptide ligands and suggest a universal mode of recognition for peptides to MHC class I molecules. Peptide-MHC class II interactions are less well understood, although recent structural work has shown important differences in the binding clefts of MHC class I and II that lead to longer peptides being bound to class II molecules. Detailed analysis at the molecular level has indicated that conformational changes in both antibodies and MHC molecules occur upon antigen binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aminopeptidases in cells of non-Hodgkin's lymphoma of varying degrees of malignancy and in lymphogranulomatosis

26 cases of lymphoproliferative diseases were studied: 8 cases of reactive follicular hyperplasia (RFH), 11 cases of non-Hodgkin's malignant lymphomas (NML), 7 cases of lymphogranulomatosis (LGM). Only gamma-glutamyl transpeptidase (GGT) was found in lymphoid cells of B- and T-dependent areas of lymph nodes with reactive changes as well as in tumor cells of NML and LGM. GGT activity was more pronounced in NML of high-grade malignancy (centroblast and immunoblast) as compared to lymphomas of lower grade of malignancy (lymphocytic, centroblast-centrocytic and in Lennert lymphoma). GGT activity in cells of Hodgkin and Berezovsky-Sterberg in some cases of LGM was high, in others low. Significant differences in GGT activity between RFH and follicular centroblast-centrocytic lymphoma were not found. Activity of aminopeptidase M was observed in histiocytes, fibroblasts, vessels and areas of connective tissue growth. Aminopeptidase A activity was observed in vessels only. Activity of dipeptidyl(amino)peptidase IV was observed in some lymphoid cells in RFH, NML and LGM. Thus, GGT activity may be considered as a differential-diagnostic marker in separating NML of high and low degree of malignancy and this may presume a different sensitivity to the therapy.     

Synthesis, estrogen receptor binding, and tissue distribution of a new iodovinylestradiol derivative (17alpha,20E)-21-[123I]Iodo-11beta-nitrato-19-norp regna-1,3,5 (10),20-tetraene-3,17-diol (E-[123I]NIVE)

We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).     

Restoration of X-ray and etoposide resistance, Ku-end binding activity and V(D) J recombination to the Chinese hamster sxi-3 mutant by a hamster Ku86 cDNA

Ku is a heterodimeric protein composed of 86 and 70 kDa subunits that binds preferentially to the double-stranded ends of DNA. Recent molecular characterization of ionizing-radiation sensitive (IRs) mutants belonging to the XRCC5 complementation group demonstrated the involvement of Ku in DNA double-strand break (DSB) repair and lymphoid V(D)J recombination. Here, we describe the isolation of a full-length hamster cDNA encoding the large subunit of the Ku heterodimer and demonstrate that the stable expression of this cDNA can functionally restore IR, Ku DNA end-binding activity and V(D)J recombination proficiency in the Chinese hamster IRs sxi-3 mutant. Moreover, we also demonstrate that sxi-3 cells are hypersensitive to etoposide, a DNA topoisomerase II inhibitor, and that resistance to this drug was restored by the Ku86 cDNA. These experiments suggest that a defect in the large subunit of the heterodimeric Ku protein is the sole factor responsible for the known defects of sxi-3 cells and our data of further support the role of Ku in DNA DSB repair and V(D)J recombination.