Risk of cancer among patients with cutaneous basal cell carcinoma

A population-based cohort of 37,674 patients diagnosed during the period 1978-1991 and registered in the Danish Cancer Registry with basal cell carcinoma of the skin (BCC) were followed for the occurrence of new malignancies. BCC patients experienced significantly increased cancer incidence rates compared with the general Danish population. The elevated cancer risk was not restricted to new cutaneous malignancies. Cancers at various sites, including lip, salivary glands, larynx, lung, breast, kidney and non-Hodgkin lymphoma occurred in significant excess. Patients diagnosed with BCC before the age of 60 years were at higher risk of developing new malignancies than patients diagnosed with BCC at an older age. This age association pertained particularly to breast cancer, testicular cancer and non-Hodgkin lymphoma.     

Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy

BACKGROUND: Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS: In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS: Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.     

MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily

The DNA glycosylase MutY, which is a member of the Helix-hairpin-Helix (HhH) DNA glycosylase superfamily, excises adenine from mispairs with 8-oxoguanine and guanine. High-resolution crystal structures of the MutY catalytic core (cMutY), the complex with bound adenine, and designed mutants reveal the basis for adenine specificity and glycosyl bond cleavage chemistry. The two cMutY helical domains form a positively-charged groove with the adenine-specific pocket at their interface. The Watson-Crick hydrogen bond partners of the bound adenine are substituted by protein atoms, confirming a nucleotide flipping mechanism, and supporting a specific DNA binding orientation by MutY and structurally related DNA glycosylases.     

Hybrid myocardial revascularization after previous left pneumonectomy

Previous intrapericardial left pneumonectomy and irradiation necessitated an unorthodox, staged approach to myocardial revascularization in a patient with unstable angina pectoris, left main artery, and three-vessel coronary artery disease. A saphenous vein bypass graft was constructed from the descending thoracic aorta to the left anterior descending coronary artery via left thoracotomy, without cardiopulmonary bypass. Two days later the patient underwent stenting of the left main and circumflex coronary arteries. Recovery was uneventful.     

Schistosoma mansoni-related morbidity on Ukerewe Island, Tanzania: clinical, ultrasonographical and biochemical parameters

The osmotic responses of isolated human islets were evaluated using a perfusion cryomicroscope device. Individual islet volumes were measured following equilibration with a series of solutions of graded solute concentration. The osmotically inactive volume for human islets was determined to be 25% from a Boyle-van't Hoff plot of these data. A network thermodynamic model was developed via the bond graph method to describe the transport of water and cryoprotective agent in pancreatic islets. The model was curve fit to transient volumetric data for the response of islets to a stepwise exposure to 1 Me2SO at temperatures of 24.0, 3.0, or -3.5 degrees C. Standard membrane transport parameters (Lp, omega, sigma) and interstitial diffusion transport properties (kappa w, kappa p) were calculated from the fitting procedure. The temperature coefficients for membrane transport properties were expressed in terms of activation energies for water (ELp) and Me2SO (E omega). Osmotic challenge experiments conducted with fresh and cryopreserved human islets indicate that frozen/thawed islets exhibit a a slight increase in transport properties.     

Characterization of the equine glycoprotein hormone alpha-subunit gene reveals divergence in the mechanism of pituitary and placental expression

The equine glycoprotein hormone alpha-subunit gene is expressed in both pituitary and placenta, unlike that of all other nonprimate mammals studied, in which expression is limited to pituitary. Previous studies of the 5'-flanking region of the equine alpha-subunit promoter have revealed unique characteristics as well as similarities with the human alpha-subunit promoter, which demonstrates a similar pattern of tissue-specific expression. We have cloned and sequenced the equine alpha-subunit gene and have used tissue culture systems and transgenic mice to characterize its expression. Unlike the human promoter, the cloned equine alpha-subunit promoter failed to direct trophoblast-specific expression in either tissue culture or transgenic mouse models, suggesting an entirely different mechanism for expression. In contrast, the equine alpha-subunit promoter was able to direct gonadotroph expression in both tissue culture and transgenic mouse models. In alphaT3-1 cells, 550 base pair (bp) was sufficient for expression. This expression involves promoter elements identified in other species as playing a role in gonadotroph expression, but mutation of these elements reveals differences in their relative contributions to promoter activity. In mice, 2800 bp of 5'-flanking sequence allowed specific expression in gonadotrophs but not in thyrotrophs or placenta. The pattern of estrogen regulation observed in transgenic mice matched neither the repression that has been observed with human and bovine alpha-subunit promoters in transgenic mice nor the stimulation in mRNA levels reported in mares, suggesting a unique mechanism that is not recapitulated in the transgenic model. Thus the equine alpha-subunit promoter uses a combination of conserved and unique features of gene regulation to direct its pattern of tissue-specific expression.     

Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase

3-methyladenine (3MeA) DNA glycosylases remove 3MeAs from alkylated DNA to initiate the base excision repair pathway. Here we report the generation of mice deficient in the 3MeA DNA glycosylase encoded by the Aag (Mpg) gene. Alkyladenine DNA glycosylase turns out to be the major DNA glycosylase not only for the cytotoxic 3MeA DNA lesion, but also for the mutagenic 1,N6-ethenoadenine (epsilonA) and hypoxanthine lesions. Aag appears to be the only 3MeA and hypoxanthine DNA glycosylase in liver, testes, kidney, and lung, and the only epsilonA DNA glycosylase in liver, testes, and kidney; another epsilonA DNA glycosylase may be expressed in lung. Although alkyladenine DNA glycosylase has the capacity to remove 8-oxoguanine DNA lesions, it does not appear to be the major glycosylase for 8-oxoguanine repair. Fibroblasts derived from Aag -/- mice are alkylation sensitive, indicating that Aag -/- mice may be similarly sensitive.     

Hepatitis C virus E2 protein purified from mammalian cells is frequently recognized by E2-specific antibodies in patient sera

The envelope protein of hepatitis C virus (HCV) is composed of two membrane-associated glycoproteins, E1 and E2. To obtain HCV E2 protein as a secretory form at a high level, we constructed a recombinant chinese hamster ovary (CHO) cell line expressing a C-terminal truncated E2 (E2t) fused to human growth hormone (hGH), CHO/hGHE2t. The hGHE2t fusion protein was purified from the culture supernatant using anti-hGH mAb affinity chromatography at approximately 80% purity. The purified hGHE2t protein appeared to be assembled into oligomers linked by intermolecular disulfide bond(s) when density gradient centrifugation and SDS-polyacrylamide gel electrophoresis were employed. When the purified fusion protein was used for testing its ability to bind to antibodies specific for HCV by enzyme-linked immunosorbent assay, the protein was recognized by antibodies in sera from 90% of HCV-positive patients. Treatment of hGHE2t protein by beta-mercaptoethanol, but not by heat and SDS, significantly reduced its reactivity to the antibodies of patient sera, suggesting that intermolecular and/or intramolecular disulfide bonds are important for its ability to recognize its specific antibody and that the E2 protein contains discontinuous antigenic epitope(s).     

Surgical treatment of acute type B aortic dissection using an endoprosthesis (elephant trunk)

BACKGROUND: The surgical treatment of acute complicated type B aortic dissection continues to be a challenge and is still associated with high morbidity and mortality rates. METHODS: Seventy consecutive patients with an acute type B aortic dissection underwent an elephant trunk procedure through a median sternotomy during deep hypothermic circulatory arrest. An endoprosthesis that was 22 to 24 mm in diameter was inserted through an incision in the arch and held in place with only proximal sutures. RESULTS: The mean arrest time was 31.4 +/- 8.7 minutes, and it was possible to adequately position the endoluminal graft in every patient. The procedure was done in association with other procedures in 13 patients. There were six in-hospital deaths not related to the endoprosthesis, and four late deaths. Late reoperation was necessary in 6 patients to manage leakage at the proximal suture line. CONCLUSIONS: The insertion of an endoprosthesis through the arch for the management of a complicated acute type B dissection has several advantages over the conventional thoracotomy approach. The hospital mortality rate in this series of 70 patients was 20%, and the actuarial 5-year survival rate was 62.5%. We consider the elephant trunk procedure the treatment of choice in patients with type B acute dissections, regardless of whether the dissection is complicated or not.