How strong is the edge effect in the adsorption of anticancer drugs on a graphene cluster?

The adsorption of nucleobase-analog anticancer drugs (fluorouracil, thioguanine, and mercaptopurine) on a graphene flake (C₅₄H₁₈) was investigated by shifting the site at which adsorption occurs from one end of the sheet to the other end. The counterpoise-corrected M06-2X/cc-pVDZ binding energies revealed that the binding stability decreases in the sequence thioguanine?>?mercaptopurine?>?fluorouracil. We found that adsorption near the middle of the sheet is more favorable than adsorption near the edge due to the edge effect. This edge effect is stronger for the adsorption of thioguanine or mercaptopurine than for fluorouracil adsorption. However, the edge effect reduces the binding energy of the drug to the flake by only a small amount, <5 kcal/mol, depending on the adsorption site and the alignment of the drug at this site.     

Association between Human Prothrombin Variant (T165M) and Kidney Stone Disease

We previously reported the association between prothrombin (F2), encoding a stone inhibitor protein - urinary prothrombin fragment 1 (UPTF1), and the risk of kidney stone disease in Northeastern Thai patients. To identify specific F2 variation responsible for the kidney stone risk, we conducted sequencing analysis of this gene in a group of the patients with kidney stone disease. Five intronic SNPs (rs2070850, rs2070852, rs1799867, rs2282687, and rs3136516) and one exonic non-synonymous single nucleotide polymorphism (nsSNP; rs5896) were found. The five intronic SNPs have no functional change as predicted by computer programs while the nsSNP rs5896 (c.494 C>T) located in exon 6 results in a substitution of threonine (T) by methionine (M) at the position 165 (T165M). The nsSNP rs5896 was subsequently genotyped in 209 patients and 216 control subjects. Genotypic and allelic frequencies of this nsSNP were analyzed for their association with kidney stone disease. The frequency of CC genotype of rs5896 was significantly lower in the patient group (13.4%) than that in the control group (22.2%) (P = 0.017, OR 0.54, 95% CI 0.32–0.90), and the frequency of C allele was significantly lower in the patient group (36.1%) than that in the control group (45.6%) (P = 0.005, OR 0.68, 95% CI 0.51–0.89). The significant differences of genotype and allele frequencies were maintained only in the female group (P = 0.033 and 0.003, respectively). The effect of amino-acid change on UPTF1 structure was also examined by homologous modeling and in silico mutagenesis. T165 is conserved and T165M substitution will affect hydrogen bond formation with E180. In conclusion, our results indicate that prothrombin variant (T165M) is associated with kidney stone risk in the Northeastern Thai female patients.     

Ocular fixation with quadriceps tendon allograft

Management of difficult strabismus, such as strabismus fixus and paralytic strabismus, in order to maintain the alignment is complicated. There are many surgical approaches described in the current literature, together with notes on the materials used to stabilize these deformities. We present a new surgical approach using quadriceps tendon allograft for the correction of difficult strabismus such as strabismus fixus and paralytic strabismus. Our idea for using deep frozen quadriceps tendons developed from the fact that this is the most stable and strongest tendon in the whole body. Six patients with strabismus fixus (n = 1), paralytic strabismus secondary to extraocular muscle damage (n = 1) and combined cranial nerve palsy (n = 4) were operated on using a strip of deep frozen quadriceps tendon allograft suturedonto both the globe and the periosteum. The mean age of the patients was 44.33years. (range 17–71 years) All the patients were followed up for six months. The mean preoperative deviation in the six cases was 60 prism diopters(PD) (range 30–123 PD) The mean change in horizontal alignment at 1 month, 3 months and 6 months postoperatively was 54PD, 53 PD and 49.16 PD respectively. We had only one case of under correction. This may possible be due to the remaining function of the antagonist and/or the fact that we had used the distal end of the quadriceps tendon. When the patient (patient No. 5) who had 2 operations was excluded, the mean change in horizontal alignment was 48.6 PD,47.4PD and 43.6 PD. Post-operatively there was no infection or any other complications. According to our study of existing literature, these cases of deep frozen quadriceps tendon allograft application for the indications mentioned above are the first reported cases of its type. We conclude that ocular fixation with quadriceps tendon to the periosteum is a safe and effective option for the management of difficult strabismus. Further research on a larger cohort of patients and longer follow-up time are needed. This revised version was published online in July 2006 with corrections to the Cover Date.     

A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. In this study we report a novel missense mutation, G609R, causing dominant dRTA in affected members of a large Caucasian pedigree who all exhibited metabolic acidosis with alkaline urine, prominent nephrocalcinosis, and progressive renal impairment. To investigate the potential disease mechanism, the consequent effects of this mutation were determined. We first assessed anion transport function of G609R by expression in Xenopus oocytes. Western blotting and immunofluorescence demonstrated that the mutant protein was expressed at the oocyte cell surface. Measuring chloride and bicarbonate fluxes revealed normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-inhibitable anion exchange, suggesting that loss-of-function of kAE1 cannot explain the severe disease phenotype in this kindred. We next expressed epitope-tagged wild-type or mutant kAE1 in Madin-Darby canine kidney cells. In monolayers grown to polarity, mutant kAE1 was detected subapically and at the apical membrane, as well as at the basolateral membrane, in contrast to the normal basolateral appearance of wild-type kAE1. These findings suggest that the seventh transmembrane domain that contains Gly-609 plays an important role in targeting kAE1 to the correct cell surface compartment. They confirm that dominant dRTA is associated with non-polarized trafficking of the protein, with no significant effect on anion transport function in vitro, which remains an unusual mechanism of human disease.