Permanent His Bundle Pacing: Electrophysiological and Echocardiographic Observations From Long-Term Follow-Up

Background Permanent His bundle pacing (HBP) is a physiological alternative to right ventricular pacing. It is not known whether HBP can cause His-Purkinje conduction (HPC) disease. The aim of our study is to assess His bundle capture and its effect on left ventricular (LV) function in long-term follow-up and to determine HPC at the time of pulse generator change (GC) in patients with chronic HBP. Methods HB electrograms were recorded from the pacing lead at implant and GC. HBP QRS duration (QRSd), His-ventricular (HV) intervals, and HB pacing thresholds at GC were compared with implant measurements. HPC was assessed by pacing at cycle lengths of 700 ms, 600 ms, and 500 ms at GC. LV internal diameters, ejection fraction (EF), and valve dysfunction at baseline were compared with echocardiography during follow-up. Results GC was performed in 20 patients (men 13; age 74 ± 14 years) with HBP at 70 ± 24 months postimplant. HV intervals remained unchanged from initial implant (44 ± 4 ms vs 45 ± 4 ms). During HBP at 700 ms, 600 ms, and 500 ms (n = 17), consistent 1:1 HPC was present. HBP QRSd remained unchanged during follow-up (117 ± 20 ms vs 118 ± 23 ms). HBP threshold at implant and GC was 1.9 ± 1.1 V and 2.5 ± 1.2 V @ 0.5 ms. Despite high pacing burden (77 ± 13%), there was no significant change in LVEF (50 ± 14% at implant) during follow-up (55 ± 6%, P = 0.06). Conclusions HBP does not appear to cause new HPC abnormalities and is associated with stable HBP QRSd during long-term follow-up. Despite high pacing burden, HBP did not result in deterioration of left ventricular systolic function or cause new valve dysfunction

Conservatives and the Constabulary in Great Britain: cross-dressing conundrums

Purpose This chapter is devoted to analysing the historical peculiarity of the contemporary British politics of policing. Methodology/approach Research is based on an analysis of policy statements and debates, news reports, and official statistics, in the light of historical studies of the earlier politics of policing. Findings The Conservative government’s police reform programme severely diminishes the resources, powers, status and independence of the police, reversing the Tory’s traditional unquestioning support of the police. The package is shown to reflect broader changes in political economy and culture under neoliberalism. Originality/value There has been no previous academic analysis bringing together the various aspects of the reform programme, contrasting it with previous historical understanding of the politics of policing, and linking it to broader contemporary change

Predicting flow reversals in chaotic natural convection using data assimilation

A simplified model of natural convection, similar to the Lorenz (1963) system, is compared to computational fluid dynamics simulations in order to test data assimilation methods and better understand the dynamics of convection. The thermosyphon is represented by a long time flow simulation, which serves as a reference "truth". Forecasts are then made using the Lorenz-like model and synchronized to noisy and limited observations of the truth using data assimilation. The resulting analysis is observed to infer dynamics absent from the model when using short assimilation windows. Furthermore, chaotic flow reversal occurrence and residency times in each rotational state are forecast using analysis data. Flow reversals have been successfully forecast in the related Lorenz system, as part of a perfect model experiment, but never in the presence of significant model error or unobserved variables. Finally, we provide new details concerning the fluid dynamical processes present in the thermosyphon during these flow reversals

Update on HER-2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition

During the past decade there has been renewed interest in the use of vaccine immunotherapy for the treatment of cancer. This review focuses on HER2/neu, a tumour-associated antigen that is overexpressed in 10–40% of breast cancers and other carcinomata. Several immunogenic HER2/neu peptides recognized by T lymphocytes have been identified to be included in cancer vaccines. Some of these peptides have been assessed in clinical trials of patients with breast and ovarian cancer. Although it has been possible to detect immunological responses against the peptides in the immunized patients, no clinical responses have so far been described. Immunological tolerance to self-antigens like HER2/neu may limit the functional immune responses against them. It will be of interest to determine whether immune responses against HER2/neu epitopes can be of relevance to cancer treatment

Local governance in the new Police Scotland:Renegotiating power, recognition and responsiveness

A marked, but by no means universal, trend in Europe over the last decade or so has been the centralization or amalgamation of regional police organizations into larger or single units. Scotland is a case in point, its eight regional services becoming one Police Scotland in April 2013. Although the reform process was relatively consensual, the new organization has been the subject of numerous controversies, some of which reflect an actual or perceived loss of the local in Scottish policing. Drawing on a qualitative study of the emerging local governance arrangements, we explore the negotiated character of large-scale organizational reform, demonstrating that it is best understood as a process not an event. We also argue that appeals to localism are not mere expressions of sentiment and resistance to change. They reflect the particular historical development of policing and public service delivery in Scotland at the level of municipal government, but also strong convictions that policing should be subject to democratic deliberation and should recognize and be responsive to those subject to it – what we argue here are necessary functions of police governance in general

The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia

The contributions of fibre atrophy, fibre loss, in situ specific force and voluntary activation to weakness in sarcopenia remain unclear. To investigate, forty older (20 women; age 72±4yrs) and 31 younger adults (15 women, age 22±3yrs) completed measurements. The knee extensor maximal voluntary torque (MVC) was measured as well as voluntary activation, patella tendon moment arm length, muscle volume and fascicle architecture to estimate in situ specific force. Fibre cross-sectional area (FCSA), fibre numbers and connective tissue contents were also estimated from vastus lateralis biopsies. The MVC, quadriceps volume and specific force were 39%, 28% and 17% lower, respectively, in old compared with young, but voluntary activation was not different. The difference in muscle size was due in almost equal proportions to lower type II FCSA and fewer fibres. Five years later (n=23) the MVC, muscle volume and voluntary activation in old decreased an additional 12%, 6% and 4%, respectively, but there was no further change in specific force. Conclusions: in situ specific force declines relatively early in older age and reduced voluntary activation occurs later, but the overall weakness in sarcopenia is mainly related to loss of both type I and II fibres and type II fibre atrophy

Firm-size distribution and price-cost margins in Dutch manufacturing

Industrial economists surmise a relation between the size distribution of firms and performance. Usually, attention is focused on the high end of the size distribution. The widely used 4-firm seller concentration, C4, ignores what happens at the low end of the size distribution. An investigation is presented of the extent to which the level and the growth of small business presence influence price-cost margins in Dutch manufacturing. A large data set of 66 industries for a 13-year period is used. This allows the investigation of both small business influences within a framework in which that of many other market structure variables is also studied. Evidence is shown that price-cost margins are influenced by large firm dominance, growth in small business presence, capital intensity, business cycle, international trade, and buyer concentration

Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds

BACKGROUND: Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. METHODS: Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroids and after PCFT silencing. Inhibitors of lactate dehydrogenase (LDH-A) were tested in vitro and in vivo. LDH-A expression was determined in tissue microarrays of radically resected malignant pleural mesothelioma (MPM, N = 33) and diffuse peritoneal mesothelioma (DMPM, N = 56) patients. RESULTS: Overexpression of hypoxia marker CAIX was associated with low PCFT expression and decreased MPM cell growth inhibition by pemetrexed. Through integration of PCR arrays in hypoxic cells and spheroids and following PCFT silencing, we identified the upregulation of LDH-A, which correlated with shorter survival of MPM and DMPM patients. Novel LDH-A inhibitors enhanced spheroid disintegration and displayed synergistic effects with pemetrexed in MPM and gemcitabine in DMPM cells. Studies with bioluminescent hypoxic orthotopic and subcutaneous DMPM athymic-mice models revealed the marked antitumour activity of the LDH-A inhibitor NHI-Glc-2, alone or combined with gemcitabine. CONCLUSIONS: This study provides novel insights into hypoxia/PCFT-dependent chemoresistance, unravelling the potential prognostic value of LDH-A, and demonstrating the preclinical activity of LDH-A inhibitors