IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.     

Fatal meconium aspiration in spite of appropriate perinatal airway management: pulmonary and placental evidence of prenatal disease

The cytoskeletal components of hamster oocytes, zygotes, and spontaneously activated parthogenotes were examined after immunocytochemical labeling. Microtubules were found only in the anastral, tangentially arranged second meiotic spindle of unfertilized oocytes. Taxol treatment of unfertilized oocytes greatly augmented astral microtubules in both the metaphase II spindle and the cortex. Disruption of the meiotic spindle microtubules with nocodazole resulted in cortical chromosomal scattering. During hamster sperm incorporation and pronuclear formation, no sperm aster was detected in association with the male DNA. Instead, a large overlapping array of microtubules assembled in the cortex. By mitosis, this interphase array disassembled and an anastral metaphase spindle formed. Microtubule and chromatin configurations were also imaged in hamster oocytes injected with human sperm. Astral microtubules were absent from the sperm centrosome. The implications of these results are discussed in relation to the hamster oocyte penetration assay, a test commonly used by in vitro fertilization clinics to demonstrate the fertilizing ability of human sperm. We conclude that since hamsters and humans follow different methods of centrosome inheritance, maternal and paternal, respectively, the hamster may be an inappropriate model for exploring microtubule and centrosomal defects in humans or for assaying postinsemination forms of human male fertility defects.     

Effectiveness of participatory ergonomic interventions on health outcomes: a systematic review

The objective of this study was to conduct a systematic review of the literature on the effectiveness of participatory ergonomic (PE) interventions for improving workers' health. The search strategy targeted six electronic databases and identified 442 potential articles. Each article was examined by pairs of reviewers for relevance (assessed a participative ergonomic workplace intervention, with at least one health outcome, published in English in peer reviewed literature). Twenty-three articles met relevance criteria and were then appraised for methodological strength. Using a best evidence synthesis approach, 12 studies that were rated as 'medium' or higher provided partial to moderate evidence that PE interventions have a positive impact on: musculoskeletal symptoms, reducing injuries and workers' compensation claims, and a reduction in lost days from work or sickness absence. However, the magnitude of the effect requires more precise definition.     

Revealing 180° domains in ferroelectric crystals by photorefractive beam coupling

We describe a simple, optical technique for mapping 180° domains hidden inside photorefractive crystals. We intersect two coherent light beams in the crystal. Photorefractive coupling between the two beams causes one beam to emerge with a map of all the crystal's 180° domains imprinted upon it. We tested many BaTiO(3) crystals and found that they all contained 180° domains, with the relative volume of these domains varying from 25% to 0.1%.     

Mathematical models of the transitions between endocrine therapy responsive and resistant states in breast cancer

Endocrine therapy, targeting the oestrogen receptor pathway, is the most common treatment for oestrogen receptor-positive breast cancers. Unfortunately, these tumours frequently develop resistance to endocrine therapies. Among the strategies to treat resistant tumours are sequential treatment (in which second-line drugs are used to gain additional responses) and intermittent treatment (in which a ‘drug holiday’ is imposed between treatments). To gain a more rigorous understanding of the mechanisms underlying these strategies, we present a mathematical model that captures the transitions among three different, experimentally observed, oestrogen-sensitivity phenotypes in breast cancer (sensitive, hypersensitive and independent). To provide a global view of the transitions between these phenotypes, we compute the potential landscape associated with the model. We show how this oestrogen response landscape can be reshaped by population selection, which is a crucial force in promoting acquired resistance. Techniques from statistical physics are used to create a population-level state-transition model from the cellular-level model. We then illustrate how this population-level model can be used to analyse and optimize sequential and intermittent oestrogen-deprivation protocols for breast cancer. The approach used in this study is general and can also be applied to investigate treatment strategies for other types of cancer.     

Isomeric Carborane Neuromuscular Blocking Agents

We synthesized a family of neuromuscular blocking agents (NMB) based on decamethonium, but containing a carborane cluster in the methylene chain between the two quaternary ammonium groups. The carborane cluster isomers o-NMB, m-NMB, and p-NMB were tested in animals for neuromuscular block and compared with agents used clinically: rocuronium and decamethonium. All three isomers caused reversible muscle weakness in mice as determined by grip strength and inverted screen tests, with a potency rank of p-NMB > rocuronium > decamethonium > m-NMB > o-NMB. The mechanism of action of the compounds was determined by using the in vitro rat phrenic nerve hemi-diaphragm preparation and electrophysiologic measurements in cells. Neostigmine reversed hemi-diaphragm weakness caused by the three isomers and rocuronium, but not succinylcholine. In electrophysiologic recordings of currents through acetylcholine receptor channels, the carborane compounds did not activate channel activity but did inhibit channel activation by acetylcholine. These results demonstrate that the carborane neuromuscular blocking agents are non-depolarizers in contrast to the depolarizing action of the parent compound.     

Drivers of microbial community composition in mesophilic and thermophilic temperature-phased anaerobic digestion pre-treatment reactors

Temperature-phased anaerobic digestion (TPAD) is an emerging technology that facilitates improved performance and pathogen destruction in anaerobic sewage sludge digestion by optimising conditions for 1) hydrolytic and acidogenic organisms in a first-stage/pre-treatment reactor and then 2) methogenic populations in a second stage reactor. Pre-treatment reactors are typically operated at 55–65 °C and as such select for thermophilic bacterial communities. However, details of key microbial populations in hydrolytic communities and links to functionality are very limited. In this study, experimental thermophilic pre-treatment (TP) and control mesophilic pre-treatment (MP) reactors were operated as first-stages of TPAD systems treating activated sludge for 340 days. The TP system was operated sequentially at 50, 60 and 65 °C, while the MP rector was held at 35 °C for the entire period. The composition of microbial communities associated with the MP and TP pre-treatment reactors was characterised weekly using terminal-restriction fragment length polymorphism (T-RFLP) supported by clone library sequencing of 16S rRNA gene amplicons. The outcomes of this approach were confirmed using 454 pyrosequencing of gene amplicons and fluorescence in-situ hybridisation (FISH). TP associated bacterial communities were dominated by populations affiliated to the Firmicutes, Thermotogae, Proteobacteria and Chloroflexi. In particular there was a progression from Thermotogae to Lutispora and Coprothermobacter and diversity decreased as temperature and hydrolysis performance increased. While change in the composition of TP associated bacterial communities was attributable to temperature, that of MP associated bacterial communities was related to the composition of the incoming feed. This study determined processes driving the dynamics of key microbial populations that are correlated with an enhanced hydrolytic functionality of the TPAD system.