Multigenic control of skin tumor susceptibility in SENCARA/Pt mice

Skin tumors induced in mice by initiation-promotion (2 microg DMBA-2 microg TPA) protocols were found to be under multigenic control. Eighty- one N2 mice from the cross (BALB/cAnPt x SENCARA/Pt)F1 x SENCARA/Pt that were either solidly resistant (no papillomas) or highly susceptible (> or = 7 papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite markers to check for associations with susceptible and resistant phenotypes. A locus on Chr 5 (Skts4) was found to control the susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to papilloma formation. In addition, higher than expected linkage scores were seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is required to establish whether genes determining papilloma formation are located in these regions of the genome. In general, no evidence was seen for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in 17 microdissected papillomas from (BALB/c x SENCARA)F1 hybrid mice.      

Needlescopic surgery for cryptorchidism: the initial series

PURPOSE: The aim of this study is to report the initial experience with needlescopic surgery (2-mm optics and instrumentation exclusively) for the cryptorchid testicle. METHODS: Ten patients (age 8 months to 37 years) underwent 12 needlescopic procedures: orchiopexy (n = 8), orchiectomy (n = 2), and diagnostic exploration with attempted excision of testicular remnant (n = 2). Two patients underwent bilateral needlescopic orchiopexy. Needlescopic (2 mm) optics and instrumentation were used exclusively in the pediatric patients. RESULTS: All procedures were completed successfully by needlescopic techniques. Mean surgical time was 110 minutes (range, 60 to 180 minutes), and blood loss was 6 mL (range, 0 to 20 mL). There were no intraoperative complications. All procedures were performed on an outpatient basis. In all 8 orchidopexies, the testis was successfully brought to a scrotal position. CONCLUSIONS: Needlescopic techniques allow safe performance of various procedures for a cryptorchid testicle. The cosmetic result is excellent.     

Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers.

Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites.     

Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer.

Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. DNA sequence variations in the vascular endothelial growth factor (VEGF) gene may lead to altered VEGF production and/or activity, thereby causing interindividual differences in the susceptibility to lung cancer via their actions on the pathways of tumor angiogenesis. To test this hypothesis, we investigated the potential association between three VEGF polymorphisms (-460T > C, +405C > G, and 936C > T)/haplotypes and the risk of lung cancer in a Korean population. VEGF genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency matched for age and sex. VEGF haplotypes were predicted using Bayesian algorithm in the phase program. Compared with the combined +405 CC and CG genotype, the +405 GG genotype found associated with a significantly decreased risk of small cell carcinoma [SCC; adjusted odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.17-0.78]. The 936 CT genotype and the combined 936 CT and TT genotype were also associated with a significantly decreased risk of SCC compared with the 936 CC genotype (adjusted OR, 0.47; 95% CI, 0.26-0.85 and adjusted OR, 0.44; 95% CI, 0.24-0.80, respectively). Haplotype CGT was associated with a significantly decreased risk of SCC (adjusted OR, 0.39; 95% CI, 0.18-0.87), whereas haplotype TCC conferred a significantly increased risk of SCC (adjusted OR, 1.63; 95% CI, 1.14-2.33). None of the VEGF polymorphisms studied significantly influenced the susceptibility to lung cancer except SCC. However, haplotypes TCT and TGT were significantly associated with the risk of overall lung cancer, respectively (adjusted OR, 0.38; 95% CI, 0.25-0.60 and adjusted OR, 3.94; 95% CI, 2.00-7.76, respectively). These effects of haplotypes TCT and TGT on lung cancer risk were observed in three major histologic types of lung cancer. These results suggest that the VEGF gene may be contribute to an inherited predisposition to lung cancer.     

Adhesive force of chondrocytes to cartilage. Effects of chondroitinase ABC

Chondrocyte transplantation is a clinical procedure for cartilage repair. Transplanted cells may have difficulty attaching to the surface of chondral lesions because of the anti-adhesive properties of the proteoglycan rich matrix. This study used micromanipulation methods to determine if pretreatment of cartilage with chondroitinase ABC affects chondrocyte adhesion to cartilage and if chondrocytes adhere preferentially to the superficial, middle, or deep layers of cartilage. Bovine chondrocytes were transplanted in vitro on articular cartilage sections cut perpendicular to the articular surface. At various times between 15 and 75 minutes after seeding, a micropipette micromanipulation system was used to measure the adhesion force of individual chondrocytes to cartilage. The chondrocyte adhesion force increased with chondroitinase ABC treatment and seeding time but generally was similar for the different regions of articular cartilage (superficial, middle, deep layer) to which the cells were attached. For normal cartilage, the adhesion force increased from 1.29 +/- 0.24 mdyne after 15 to 30 minutes seeding to 5.29 +/- 0.25 mdyne after 60 to 75 minutes. Treatment with chondroitinase ABC at certain concentrations and durations (1.0 U/mL for 5 minutes or 0.5 or 1 U/mL for 15 minutes) led to an increase in adhesion force, whereas relatively low concentration or treatment time (0.25 U/mL for 15 minutes or 0.5 U/mL for 5 minutes) had little or no detectable effect. The increase in adhesion attributable to chondroitinase ABC treatment appeared most marked (+144% to +292%) for short (15 to 30 minutes) seeding durations but was still significant (+46%) for the longest seeding period (60 to 75 minutes) studied after the 1 U/mL for 15 minute treatment condition. These results provide direct biomechanical evidence that enzymatic treatment of a cartilage surface can enhance chondrocyte adhesion.     

Comparison of the effects of dexmedetomidine and propofol on hypothermia in patients under spinal anesthesia: a prospective,randomized, and controlled trial

Background: Redistribution hypothermia caused by vasodilation during anesthesia is the primary cause of perioperative hypothermia. Propofol exerts a dose-dependent vasodilatory effect, whereas dexmedetomidine induces peripheral vasoconstriction at high plasma concentrations. This study compared the effects of dexmedetomidine and propofol on core temperature in patients undergoing surgery under spinal anesthesia.Methods: This prospective study included 40 patients (aged 19-70 years) with American Society of Anesthesiologists Physical Status class I-III who underwent elective orthopedic lower-limb surgery under spinal anesthesia. Patients were randomly allocated to a dexmedetomidine or propofol group (n = 20 per group). After induction of spinal anesthesia, patients received dexmedetomidine (loading dose: 1 μg/kg over 10 min; maintenance dose: 0.2-0.7 μg/kg/h) or propofol (loading dose: 75 μg/kg over 10 min; maintenance dose: 12.5-75 μg/kg/min). The doses of sedatives were titrated to maintain moderate sedation. During the perioperative period, tympanic temperatures, thermal comfort score, and shivering grade were recorded.Results: Core temperature at the end of surgery did not differ significantly between the groups (36.4 ± 0.4 and 36.1 ± 0.7°C in the dexmedetomidine and propofol groups, respectively; P = 0.118). The lowest perioperative temperature, incidence and severity of perioperative hypothermia, thermal comfort score, and shivering grade did not differ significantly between the groups (all P > 0.05).Conclusions: In patients undergoing spinal anesthesia with moderate sedation, the effect of dexmedetomidine on patients'' core temperature was similar to that of propofol.     

Study of Optimal Perimetric Testing In Children (OPTIC): developing consensus and setting research priorities for perimetry in the management of children with glaucoma

BackgroundPerimetry is important in the management of children with glaucoma, but there is limited evidence-based guidance on its use. We report an expert consensus-based study to update guidance and identify areas requiring further research.MethodsExperts were invited to participate in a modified Delphi consensus process. Panel selection was based on clinical experience of managing children with glaucoma and UK-based training to minimise diversity of view due to healthcare setting. Questionnaires were delivered electronically, and analysed to establish ‘agreement’. Divergence of opinions was investigated and resolved where possible through further iterations.Results7/9 experts invited agreed to participate. Consensus (≥5/7 (71%) in agreement) was achieved for 21/26 (80.8%) items in 2 rounds, generating recommendations to start perimetry from approximately 7 years of age (IQR: 6.75–7.25), and use qualitative methods in conjunction with automated reliability indices to assess test quality. There was a lack of agreement about defining progressive visual field (VF) loss and methods for implementing perimetry longitudinally.Panel members highlighted the importance of informing decisions based upon individual circumstances—from gauging maturity/capability when selecting tests and interpreting outcomes, to accounting for specific clinical features (e.g. poor IOP control and/or suspected progressive VF loss) when making decisions about frequency of testing.ConclusionsThere is commonality of expert views in relation to implementing perimetry and interpreting test quality in the management of children with glaucoma. However, there remains a lack of agreement about defining progressive VF loss, and utilising perimetry over an individuals’ lifetime, highlighting the need for further research.Subject terms: Paediatrics, Glaucoma