Tremor Suppression by Rhythmic Transcranial Current Stimulation

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Highlights? Phase-cancelling cortical stimulation attenuates Parkinsonian tremor ? Prolonged stimulation may invoke adaptive mechanisms ? Phase cancellation may provide a generic treatment approach to oscillopathies ? TACS provides a convenient probe of cortical circuit dynamics in humans     

Electron paramagnetic resonance analysis of the vimentin tail domain reveals points of order in a largely disordered region and conformational adaptation upon filament assembly

Very little data have been reported that describe the structure of the tail domain of any cytoplasmic intermediate filament (IF) protein. We report here the results of studies using site directed spin labeling and electron paramagnetic resonance (SDSL‐EPR) to explore the structure and dynamics of the tail domain of human vimentin in tetramers (protofilaments) and filaments. The data demonstrate that in contrast to the vimentin head and rod domains, the tail domains are not closely apposed in protofilaments. However, upon assembly into intact IFs, several sites, including positions 445, 446, 451, and 452, the conserved “beta‐site,” become closely apposed, indicating dynamic changes in tail domain structure that accompany filament elongation. No evidence is seen for coiled‐coil structure within the region studied, in either protofilaments or assembled filaments. EPR analysis also establishes that more than half of the tail domain is very flexible in both the assembly intermediate and the intact IF. However, by positioning the spin label at distinct sites, EPR is able to identify both the rod proximal region and sites flanking the beta‐site motif as rigid locations within the tail. The rod proximal region is well assembled at the tetramer stage with only slight changes occurring during filament elongation. In contrast, at the beta site, the polypeptide backbone transitions from flexible in the assembly intermediate to much more rigid in the intact IF. These data support a model in which the distal tail domain structure undergoes significant conformational change during filament elongation and final assembly.     

Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: Comparison with TPEN and PAC-1

The lipophilic, cell-penetrating zinc chelator N,N,N′,N′,-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (K_d), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2′-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN > ZnA-Pyr > ZnA-DPA > PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO₄, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO₄ reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and ROS production.     

The Impact of Telehealthcare on the Quality and Safety of Care: A Systematic Overview

Background

Telehealthcare involves the use of information and communication technologies to deliver healthcare at a distance and to support patient self-management through remote monitoring and personalised feedback. It is timely to scrutinise the evidence regarding the benefits, risks and costs of telehealthcare.

Methods and Findings

Two reviewers searched for relevant systematic reviews published from January 1997 to November 2011 in: The Cochrane Library, MEDLINE, EMBASE, LILACS, IndMed and PakMed. Reviewers undertook independent quality assessment of studies using the Critical Appraisal Skills Programme (CASP) tool for systematic reviews. 1,782 review articles were identified, from which 80 systematic reviews were selected for inclusion. These covered a range of telehealthcare models involving both synchronous (live) and asynchronous (store-and-forward) interactions between provider and patients. Many studies showed no differences in outcomes between telehealthcare and usual care. Several reviews highlighted the large number of short-term (<12 months) feasibility studies with under 20 participants. Effects of telehealthcare on health service indicators were reported in several reviews, particularly reduced hospitalisations. The reported clinical effectiveness of telehealthcare interventions for patients with long-term conditions appeared to be greatest in those with more severe disease at high-risk of hospitalisation and death. The failure of many studies to adequately describe the intervention makes it difficult to disentangle the contributions of technological and human/organisational factors on the outcomes reported. Evidence on the cost-effectiveness of telehealthcare remains sparse. Patient safety considerations were absent from the evaluative telehealthcare literature.

Conclusions

Policymakers and planners need to be aware that investment in telehealthcare will not inevitably yield clinical or economic benefits. It is likely that the greatest gains will be achieved for patients at highest risk of serious outcomes. There is a need for longer-term studies in order to determine whether the benefits demonstrated in time limited trials are sustained.     

Qualitative Analysis of Round-Table Discussions on the Business Case and Procurement Challenges for Hospital Electronic Prescribing Systems

Objectives

There is a pressing need to understand the challenges surrounding procurement of and business case development for hospital electronic prescribing systems, and to identify possible strategies to enhance the efficiency of these processes in order to assist strategic decision making.

Materials and Methods

We organized eight multi-disciplinary round-table discussions in the United Kingdom. Participants included policy makers, representatives from hospitals, system developers, academics, and patients. Each discussion was digitally audio-recorded, transcribed verbatim and, together with accompanying field notes, analyzed thematically with NVivo9.

Results

We drew on data from 17 participants (approximately eight per roundtable), six hours of discussion, and 15 pages of field notes. Key challenges included silo planning with systems not being considered as part of an integrated organizational information technology strategy, lack of opportunity for interactions between customers and potential suppliers, lack of support for hospitals in choosing appropriate systems, difficulty of balancing structured planning with flexibility, and the on-going challenge of distinguishing “wants” and aspirations from organizational “needs”.

Discussion and conclusions

Development of business cases for major investments in information technology does not take place in an organizational vacuum. Building on previously identified potentially transferable dimensions to the development and execution of business cases surrounding measurements of costs/benefits and risk management, we have identified additional components relevant to ePrescribing systems. These include: considerations surrounding strategic context, case for change and objectives, future service requirements and options appraisal, capital and revenue implications, timescale and deliverability, and risk analysis and management.     

Purification and characterization of two thermostable protease fractions from Bacillus megaterium

Protease enzyme from Bacillus megaterium was successively purified by ammonium sulfate precipitation, ion exchange chromatography on DEAE-cellulose and gel filtration chromatography on Sephadex G-200. The purification steps of protease resulted in the production of two protease fractions namely protease P1 and P2 with specific activities of 561.27 and 317.23 U mg^?1 of protein, respectively. The molecular weights of B. megaterium P1 and P2 were 28 and 25 KDa, respectively. The purified fractions P1 and P2 were rich in aspartic acid and serine. Relatively higher amounts of alanine, leucine, glycine, valine, thereonine valine and glutamic acid were also present. The maximum protease activities for both enzyme fractions were attained at 50 °C, pH 7.5, 1% of gelatine concentration and 0.5 enzyme concentrations. P1 and P2 fractions were more stable over pH 7.0–8.5 and able to prolong their thermal stability up to 80 °C. The effect of different inhibitors on the protease activity of both enzyme fractions was also studied. The enzyme was found to be serine active as it had been affected by lower concentrations of phenylmethylsulfonyl fluoride (PMSF). Complete dehairing of the enzyme-treated skin was achieved in 12 h, at room temperature.     

The functional −94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer

Objective: To investigate the allele and genotype frequencies of NFKB1 ?94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population. Methods: Genomic DNA was extracted from the peripheral blood samples of 474 study subjects, which consisted of 237 histopathologically confirmed CRC patients and an equal number of cancer-free controls. The NFKB1 ?94 ins/del ATTG (rs28720239) polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Results: The frequencies of wildtype (del/del), heterozygous (del/ins) and variant (ins/ins) genotypes in CRC patients were 31.7%, 53.6% and 14.8%, respectively, while those in cancer-free controls were 35.0%, 58.2% and 6.8%, respectively. The frequency of the variant genotype was significantly higher in cases compared to controls (P < 0.01). Evaluation of the risk association of the polymorphic genotypes revealed that the variant genotype could contribute to a significantly increased risk of CRC (OR = 2.42, 95% CI = 1.24–4.73, P < 0.01). Conclusions: The variant allele of NFKB1 ?94 ins/del ATTG (rs28362491) polymorphism is associated with higher risk of sporadic CRC in Malaysian population.     

A Novel Homozygous p.R1105X Mutation of the AP4E1 Gene in Twins with Hereditary Spastic Paraplegia and Mycobacterial Disease

We report identical twins with intellectual disability, progressive spastic paraplegia and short stature, born to a consanguineous family. Intriguingly, both children presented with lymphadenitis caused by the live Bacillus Calmette-Guérin (BCG) vaccine. Two syndromes – hereditary spastic paraplegia (HSP) and mycobacterial disease – thus occurred simultaneously. Whole-exome sequencing (WES) revealed a homozygous nonsense mutation (p.R1105X) of the AP4E1 gene, which was confirmed by Sanger sequencing. The p.R1105X mutation has no effect on AP4E1 mRNA levels, but results in lower levels of AP-4ε protein and of the other components of the AP-4 complex, as shown by western blotting, immunoprecipitation and immunofluorescence. Thus, the C-terminal part of the AP-4ε subunit plays an important role in maintaining the integrity of the AP-4 complex. No abnormalities of the IL-12/IFN-γ axis or oxidative burst pathways were identified. In conclusion, we identified twins with autosomal recessive AP-4 deficiency associated with HSP and mycobacterial disease, suggesting that AP-4 may play important role in the neurological and immunological systems.