Modelling the effects of disopyramide on short QT syndrome variant 1 in the human ventricles

The short QT syndrome (SQTS) is a recently identified genetic disorder associated with ventricular and/or atrial arrhythmias and increased risk of sudden cardiac death. The SQTS variant 1 (SQT1) N588K mutation to the hERG gene causes a gain-of-function to IKr which shortens the ventricular effective refractory period (ERP), as well as reducing the potency of several drugs which block the hERG channel. This study used computational modelling to assess the effects of disopyramide (DISO), a class 1a anti-arrhythmic agent, on human ventricular electro-physiology in SQT1. The O'Hara Rudy dynamic (ORd) model of the human ventricle action potential (AP) was modified to incorporate a Markov chain model of IKr/hERG including formulations for wild type (WT) and SQT1 N588K mutant hERG channels. The blocking effects of DISO on IKr, INa, ICaL, and Ito were modelled using IC50 and Hill coefficient values from the literature. The ability of DISO to prolong the QT interval was evaluated using a 1D model of human ventricular cells with transmural heterogeneities and the corresponding pseudo-ECG. At a clinically-relevant concentration of 10 μM DISO, the action potential duration (APD) at the single cell level was increased significantly through inhibition of mutant SQT1-hERG channels. The corrected QT interval in tissue was prolonged. This study provides further evidence that DISO is a suitable treatment for hERG-mediated SQTS

Modelling the effects of disopyramide on short QT syndrome variant 1 in the human ventricles

The short QT syndrome (SQTS) is a recently identified genetic disorder associated with ventricular and/or atrial arrhythmias and increased risk of sudden cardiac death. The SQTS variant 1 (SQT1) N588K mutation to the hERG gene causes a gain-of-function to IKr which shortens the ventricular effective refractory period (ERP), as well as reducing the potency of several drugs which block the hERG channel. This study used computational modelling to assess the effects of disopyramide (DISO), a class 1a anti-arrhythmic agent, on human ventricular electro-physiology in SQT1. The O'Hara Rudy dynamic (ORd) model of the human ventricle action potential (AP) was modified to incorporate a Markov chain model of IKr/hERG including formulations for wild type (WT) and SQT1 N588K mutant hERG channels. The blocking effects of DISO on IKr, INa, ICaL, and Ito were modelled using IC50 and Hill coefficient values from the literature. The ability of DISO to prolong the QT interval was evaluated using a 1D model of human ventricular cells with transmural heterogeneities and the corresponding pseudo-ECG. At a clinically-relevant concentration of 10 μM DISO, the action potential duration (APD) at the single cell level was increased significantly through inhibition of mutant SQT1-hERG channels. The corrected QT interval in tissue was prolonged. This study provides further evidence that DISO is a suitable treatment for hERG-mediated SQTS

Quantum jumps of light recording the birth and death of a photon in a cavity

A microscopic system under continuous observation exhibits at random times sudden jumps between its states. The detection of this essential quantum feature requires a quantum non-demolition (QND) measurement repeated many times during the system evolution. Quantum jumps of trapped massive particles (electrons, ions or molecules) have been observed, which is not the case of the jumps of light quanta. Usual photodetectors absorb light and are thus unable to detect the same photon twice. They must be replaced by a transparent counter 'seeing' photons without destroying them3. Moreover, the light has to be stored over a duration much longer than the QND detection time. We have fulfilled these challenging conditions and observed photon number quantum jumps. Microwave photons are stored in a superconducting cavity for times in the second range. They are repeatedly probed by a stream of non-absorbing atoms. An atom interferometer measures the atomic dipole phase shift induced by the non-resonant cavity field, so that the final atom state reveals directly the presence of a single photon in the cavity. Sequences of hundreds of atoms highly correlated in the same state, are interrupted by sudden state-switchings. These telegraphic signals record, for the first time, the birth, life and death of individual photons. Applying a similar QND procedure to mesoscopic fields with tens of photons opens new perspectives for the exploration of the quantum to classical boundary

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

Major surgery in an osteosarcoma patient refusing blood transfusion: case report

We describe an unusual case of osteosarcoma in a Jehovah's Witness patient who underwent chemotherapy and major surgery without the need for blood transfusion. This 16-year-old girl presented with osteosarcoma of the right proximal tibia requiring proximal tibia resection, followed by endoprosthesis replacement. She was successfully treated with neoadjuvant chemotherapy and surgery with the support of haematinics, granulocyte colony-stimulating factor, recombinant erythropoietin and intraoperative normovolaemic haemodilution. This case illustrates the importance of maintaining effective, open communication and exploring acceptable therapeutic alternative in the management of these patients, whilst still respecting their beliefs

Solvent effects in permeation assessed in vivo by skin surface biopsy

BACKGROUND: Transdermal drug delivery has become an important means of drug administration. It presents numerous advantages but it is still limited by the small number of drugs with a suitable profile. The use of solvents that affect the skin barrier function is one of the classic strategies of penetration enhancement. Some of these solvents have well characterised actions on the stratum corneum, but the majority are still selected using empirical criteria. The objective of this work was to conduct a systematic study on the ability to affect skin permeation of solvents commonly used in transdermal formulations. An innovative methodology in this area was employed, consisting of the combination of skin surface biopsy with colorimetry. METHODS: The study compared in vivo differences in the permeation of a hydrophilic (methylene blue) and a lipophilic (Sudan III) dye, after treatment of the skin with different vehicles. Consecutive skin surface biopsies of each site were taken and the cumulative amounts of the dyes in the stripped stratum corneum were measured by reflectance colourimetry. RESULTS: Results indicate that the amount of methylene blue present in the stratum corneum varied significantly with different skin pre-treatments. Some solvents provided a 1.5 fold penetration enhancement but others decreased by almost half the permeation of the dye. The permeation of Sudan III was less significantly affected by solvent pre-treatment. CONCLUSIONS: This study has only superficially explored the potential of the combination of skin surface biopsy and colourimetry, but the encouraging results obtained confirm that the methodology can be extended to the study of more complex formulations

Measurement of cortisol in saliva: a comparison of measurement error within and between international academic-research laboratories

Objective: Hundreds of scientific publications are produced annually that involve the measurement of cortisol in saliva. Intra- and inter-laboratory variation in salivary cortisol results has the potential to contribute to cross- study inconsistencies in findings, and the perception that salivary cortisol results are unreliable. This study rigor- ously estimates sources of measurement variability in the assay of salivary cortisol within and between established international academic-based laboratories that specialize in saliva analyses. One hundred young adults (Mean age: 23.10 years; 62 females) donated 2 mL of whole saliva by passive drool. Each sample was split into multiple- 100 µL aliquots and immediately frozen. One aliquot of each of the 100 participants’ saliva was transported to academic laboratories (N = 9) in the United States, Canada, UK, and Germany and assayed for cortisol by the same commercially available immunoassay. Results: 1.76% of the variance in salivary cortisol levels was attributable to differences between duplicate assays of the same sample within laboratories, 7.93% of the variance was associated with differences between laboratories, and 90.31% to differences between samples. In established-qualified laboratories, measurement error of salivary cortisol is minimal, and inter-laboratory differences in measurement are unlikely to have a major influence on the determined values

Evaluation of the color stability of two techniquesfor reproducing artificial irides after microwave polymerization

The use of ocular prostheses for ophthalmic patients aims to rebuild facial aesthetics and provide an artificial substitute to the visual organ. Natural intemperate conditions promote discoloration of artificial irides and many studies have attempted to produce irides with greater chromatic paint durability using different paint materials. OBJECTIVES: The present study evaluated the color stability of artificial irides obtained with two techniques (oil painting and digital image) and submitted to microwave polymerization. MATERIAL AND METHODS: Forty samples were fabricated simulating ocular prostheses. each sample was constituted by one disc of acrylic resin N1 and one disc of colorless acrylic resin with the iris interposed between the discs. The irides in brown and blue color were obtained by oil painting or digital image. The color stability was determined by a reflection spectrophotometer and measurements were taken before and after microwave polymerization. Statistical analysis of the techniques for reproducing artificial irides was performed by applying the normal data distribution test followed by 2-way ANOVA and Tukey HSD test (α=.05). RESULTS: Chromatic alterations occurred in all specimens and statistically significant differences were observed between the oil-painted samples and those obtained by digital imaging. There was no statistical difference between the brown and blue colors. Independently of technique, all samples suffered color alterations after microwave polymerization. CONCLUSION: The digital imaging technique for reproducing irides presented better color stability after microwave polymerization