Electoral Systems, Ethnic Cleavages, and Experience with Democracy

Recent studies show the effects of electoral systems and ethnic cleavages on the number of parties in emerging democracies differ from those effects observed in more established democracies. Building on recent arguments maintaining the quality of democracy improves with experience, we argue the reason for the differences in the findings between established and emerging democracies is that the effects of these variables on the number of parties differ according to a country’s experience with elections. To test this argument, we analyse party system fragmentation in 89 established and emerging democracies and the conditioning effects experience with elections have on the effects of district magnitude, ethnic cleavages, and variables relating to the presidential party system. The results show the effects of institutional and social cleavage variables differ substantially between emerging and established democracies, but these effects begin to approximate those seen in more established democracies with additional experience with elections.

A belief revision framework for revising epistemic states with partial epistemic states

Belief revision performs belief change on an agent’s beliefs when new evidence (either of the form of a propositional formula or of the form of a total pre-order on a set of interpretations) is received. Jeffrey’s rule is commonly used for revising probabilistic epistemic states when new information is probabilistically uncertain. In this paper, we propose a general epistemic revision framework where new evidence is of the form of a partial epistemic state. Our framework extends Jeffrey’s rule with uncertain inputs and covers well-known existing frameworks such as ordinal conditional function (OCF) or possibility theory. We then define a set of postulates that such revision operators shall satisfy and establish representation theorems to characterize those postulates. We show that these postulates reveal common characteristics of various existing revision strategies and are satisfied by OCF conditionalization, Jeffrey’s rule of conditioning and possibility conditionalization. Furthermore, when reducing to the belief revision situation, our postulates can induce Darwiche and Pearl’s postulates C1 and C2.

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, butmany other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

Finding Merit in Judicial Appointments: NIJAC and the Search for a New Judiciary in Northern Ireland

The post-Agreement constitutional architecture has produced a new legal space in Northern Ireland. While the court structure has largely endured in a recognisable format there are perhaps now new expectations of how it will function in the next stage of Northern Ireland’s transition from a society in conflict. These expectations come into focus around the nature and role of the judiciary that is to oversee this new legal space. At the same time there are other, wider forces pressing upon the judiciary across the United Kingdom and these are being acted out in the various appointment commissions and regimes that have been created to modernise the judiciary. This all contributes to establishing a dynamic context for considering whether and/or how the judiciary in Northern Ireland is changing, and the forces that may be conditioning any change. This chapter looks at some of the expectations that might arise for the judiciary. It focuses both on some ideas about what might be the role of a judge in a transitional context, and the debate about how judges generally should be appointed across the United Kingdom where the idea of “merit” emerges as governing concept. Next consideration is given to how this idea of merit plays out in the Northern Ireland context and, in particular, how it impacts on the appointment of women to senior judicial roles which has emerged as the central concern in the new dispensation. Here the chapter draws on two pieces of research: the first looking at the issues surrounding judicial appointments and attitudes towards seeking such posts in the Northern Ireland context, and a second project where the idea of “merit” as a governing factor in judicial appointment was further explored in focus groups and interviews. Finally the chapter looks ahead at the challenges around judicial appointment that remain and suggests that notion of ‘merit’ has not provided the robust foundation which its proponents imagined it would.

Energy Saving - Another Perspective for Parameter Optimization of P and PI Controllers

Modern control methods like optimal control and model predictive control (MPC) provide a framework for simultaneous regulation of the tracking performance and limiting the control energy, thus have been widely deployed in industrial applications. Yet, due to its simplicity and robustness, the conventional P (Proportional) and PI (Proportional–Integral) control are still the most common methods used in many engineering systems, such as electric power systems, automotive, and Heating, Ventilation and Air Conditioning (HVAC) for buildings, where energy efficiency and energy saving are the critical issues to be addressed. Yet, little has been done so far to explore the effect of its parameter tuning on both the system performance and control energy consumption, and how these two objectives are correlated within the P and PI control framework. In this paper, the P and PI controllers are designed with a simultaneous consideration of these two aspects. Two case studies are investigated in detail, including the control of Voltage Source Converters (VSCs) for transmitting offshore wind power to onshore AC grid through High Voltage DC links, and the control of HVAC systems. Results reveal that there exists a better trade-off between the tracking performance and the control energy through a proper choice of the P and PI controller parameters.

Interhemispheric inhibition of corticospinal projections to forearm muscles

OBJECTIVE: Interhemispheric inhibition (IHI) is typically examined via responses elicited in intrinsic hand muscles. As the cortical representations of proximal and distal muscles in the upper limb are distinguished in terms of their inter-hemispheric projections, we sought to determine whether the IHI parameters established for the hand apply more generally.

METHODS: We investigated IHI at 5 different conditioning stimulus (CS) intensities and a range of short-latency inter-stimulus intervals (ISIs) in healthy participants. Conditioning and test stimuli were delivered over the M1 representation of the right and left flexor carpi radialis respectively.

RESULTS: IHI increased as a function of CS intensity, and was present for ISIs between 7 and 15ms. Inhibition was most pronounced for the 10ms ISI at all CS intensities.

CONCLUSIONS: The range of parameters for which IHI is elicited in projections to the forearm is similar to that reported for the hand. The specific utility lies in delineation of stimulus parameters that permit both potentiation and attenuation of IHI to be assessed.

SIGNIFICANCE: In light of evidence that there is a greater density of callosal projections between cortical areas that represent proximal muscles than between those corresponding to distal limb muscles, and in view of the assumption that variations in functional connectivity to which such differences give rise may have important implications for motor behavior, it is critical to determine whether processes mediating the expression of IHI depend on the effector that is studied. This issue is of further broad significance given the practical utility of movements generated by muscles proximal to the wrist in the context of upper limb rehabilitation.

Hemopoietic chimerism following stem cell transplantation

Hematopoietic chimerism is a measure of the number of donor and recipient cells in the host following stem cell transplantation (SCT). The type of conditioning therapy prior to SCT has a major impact on the chimeric status in the recipient. Different techniques of measurement have varying sensitivities. The use of polymerase chain reaction (PCR) of short tandem repeats (STR) using fluorescent amplification permits quantification using Genescan analysis. When SCT is used for malignant haematological disorders, measurement of chimeric status may indicate early relapse and in aplastic anemia graft rejection. Reduced intensity or T-cell depletion is associated with mixed haemopoietic chimerism. SCT for benign haematological disorders does not require complete donor chimerism for a successful outcome.

Favorable effect on acute and chronic graft-versus-host disease with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anemia

Between August 1989 and November 2003, 33 patients at our center with acquired aplastic anemia underwent bone marrow transplantation (BMT) from HLA-identical sibling donors with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies (MoAb) for conditioning. The median age at BMT was 17 years (range, 4-46 years). Before BMT, 58% were heavily transfused (>50 transfusions), and 42% had previously experienced treatment failure with antithymocyte globulin-based immunosuppressive therapy. Unmanipulated bone marrow was used as the source of stem cells in all patients except 1. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine alone in 19 (58%) patients; 14 received anti-CD52 MoAb in addition to cyclosporine. The conditioning regimen was well tolerated without significant acute toxicity. Graft failure was seen in 8 patients (primary, n = 4; secondary, n = 4). Of those whose grafts failed, 4 survived long-term (complete autologous recovery, n = 2; rescue with previously stored marrow, n = 1; second allograft, n = 1). The cumulative incidence of graft failure and grade II to IV acute and chronic GVHD was 24%, 14%, and 4%, respectively. None developed extensive chronic GVHD. With a median follow-up of 59 months, the 5-year survival was 81% (95% confidence interval, 68%-96%). No unexpected early or late infectious or noninfectious complications were observed. We conclude that the conditioning regimen containing cyclophosphamide and anti-CD52 MoAb is well tolerated and effective for acquired aplastic anemia with HLA-matched sibling donors. The favorable effect on the incidence and severity of GVHD is noteworthy in this study and warrants further investigation.

Marrow aplasia developing 13 years after HLA-identical sibling allogeneic transplantation for chronic myeloid leukaemia:successful treatment with antithymocyte globulin and peripheral blood stem cell infusion from the original donor

Secondary or late graft failure has been defined as the development of inadequate marrow function after initial engraftment has been achieved. We describe a case of profound marrow aplasia occurring 13 years after sibling allogeneic bone marrow transplantation for chronic myeloid leukaemia (CML) in first chronic phase. Although the patient remained a complete donor chimera, thereby suggesting that an unselected infusion of donor peripheral blood stem cells (PBSC) or bone marrow might be indicated, the newly acquired aplasia was thought to be immune in aetiology and some immunosuppression was therefore considered appropriate. Rapid haematological recovery was achieved after the infusion of unselected PBSC from the original donor following conditioning with anti-thymocyte globulin (ATG).

Leukaemic transformation of donor cells in a patient receiving a second allogeneic bone marrow transplant for severe aplastic anaemia

Allogeneic blood or bone marrow transplantation is a successful treatment for leukaemia and severe aplastic anaemia (SAA). Graft rejection following transplantation for leukaemia is a rare event but leukaemic relapse may occur at varying rates, depending upon the stage of leukaemia at which the transplant was undertaken and the type of leukaemia. Relapse is generally assumed to occur in residual host cells, which are refractory to, or escape from the myeloablative conditioning therapy. Rare cases have been described, however, in which the leukaemia recurs in cells of donor origin. Lack of a successful outcome of blood or bone marrow transplantation for severe aplastic anaemia (SAA), however, is due to late graft rejection or graft-versus-host disease. Leukaemia in cells of donor origin has rarely been reported in patients following allogeneic bone marrow transplantation for SAA. This report describes leukaemic transformation in donor cells following a second allogeneic BMT for severe aplastic anaemia. PCR of short tandem repeats in bone marrow aspirates and in colonies derived from BFUE and CFU-GM indicated the donor origin of leukaemia. Donor leukaemia is a rare event following transplantation for severe aplastic anaemia but may represent the persistence or perturbation of a stromal defect in these patients inducing leukaemic change in donor haemopoietic stem cells.

FLAG-idarubicin and allogeneic stem cell transplantation for Ph-positive ALL beyond first remission

We describe a single centre experience of eight consecutive patients with relapsed or refractory Ph+ ALL treated with the FLAG/idarubicin regimen followed by BMT or PBSCT. Following FLAG/idarubicin, one achieved a partial response and seven CR. All patients subsequently received allogeneic transplants: one sibling BMT, three matched unrelated (MUD) BMT and four sibling PBSCT. Two patients received second transplants with PBSC from their original BM donors following FLA/Ida with no further conditioning. Three patients are alive in CR 9, 24 and 32 months after transplant. Seven of eight patients had a cytogenetic response following FLAG/Ida induction and one of seven became bcr-abl negative. All eight patients had a complete cytogenetic response following transplant. Four of five assessable patients became p190 bcr-abl negative after transplant; three of these subsequently relapsed. Both patients with the p210 bcr-abl transcript remained bcr-abl positive in CR after transplant. FLAG/Ida was well tolerated and appears to be effective in inducing remission in relapsed Ph+ ALL. The use of FDR-containing chemotherapy without further conditioning prior to PBSCT deserves further study in heavily pre-treated patients and, in patients with relapsed ALL following BMT, may be a safer option than DLI (donor lymphocyte infusion) by avoiding the associated risk of aplasia.

High frequency of donor chimerism after allogeneic transplantation of CD34+-selected peripheral blood cells

Ex vivo T cell depletion of allogeneic grafts is associated with a high (up to 80%) rate of mixed chimerism (MC) posttransplantation. The number of transplanted progenitor cells is an important factor in achieving complete donor chimerism in the T cell depletion setting. Use of granulocyte colony-stimulating factor (G-CSF) peripheral blood allografts allows the administration of large numbers of CD34+ cells. We studied the chimeric status of 13 patients who received allogeneic CD34+-selected peripheral blood progenitor cell transplants (allo-PBPCTs/CD34+) from HLA-identical sibling donors. Patients were conditioned with cyclophosphamide (120 mg/kg) and total-body irradiation (13 Gy in four fractions). Apheresis products were T cell-depleted by the immunoadsorption avidin-biotin method. The median number of CD34+ and CD3+ cells infused was 2.8x10(6)/kg (range 1.9-8.6x10(6)/kg) and 0.4x10(6)/kg (range 0.3-1x10(6)/kg), respectively. Molecular analysis of the engraftment was performed using polymerase chain reaction (PCR) amplification of highly polymorphic short tandem repeat (PCR-STR) sequences in peripheral blood samples. MC was detected in two (15%) of 13 patients. These two patients relapsed at 8 and 10 months after transplant, respectively. The remaining 11 patients showed complete donor chimerism and were in clinical remission after a maximum follow-up period of 24 months (range 6-24 months). These results were compared with those obtained in 10 patients who were treated with T cell-depleted bone marrow transplantation by means of elutriation and who received the same conditioning treatment and similar amounts of CD3+ cells (median 0.45x10(6)/kg; not significant) but a lower number of CD34+ cells (median 0.8x10(6)/kg; p = 0.001). MC was documented in six of 10 patients (60%), which was significantly higher than in the allo-PBPCT/CD34+ group (p = 0.04). We conclude that a high frequency of complete donor chimerism is achieved in patients receiving allo-PBPCT/CD34+ and that this is most likely due to the high number of progenitor cells administered.

Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.

Polymerase chain reaction based methods for assessing chimerism following allogeneic bone marrow transplantation

It is important to be able to assess the contribution of donor cells to the graft followmg bone marrow transplantation (BMT), as complete engraftment of marrow progenitors that can give rise to long term donor derived hemopoiesis may be important in long-term disease-free survival. The contribution of the donor marrow, both in terms of filling the marrow "space" created by the intense conditioning regimen and in its ability to mediate a graft versus leukemia effect may be assessed by studying the kinetics of the engraftment process. As BMT involves repopulation of the host hemopoietic system with donor cells, recipients of allogeneic marrow are referred to as hemopoietic chimeras. A donor chimera is an individual who exhibits complete donor hemopoiesis and we would imagine that donor chimertsm carries the best long-term prognosis. A patient who has both donor and recipient cells coexistmg in a stable fashion post-BMT without hematological evidence of relapse or graft rejection is referred to as a mixed chimera. Mixed chimerism may be a prelude to graft rejection or leukemic relapse; therefore, it is important to be able to monitor the presence of these cells in a precise manner.

Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer

Despite compelling preclinical data in colorectal cancer (CRC), the efficacy of HDACIs has been disappointing in the clinic. The goal of this study was to evaluate the effectiveness of vorinostat and panobinostat in a dose- and exposure-dependent manner in order to better understand the dynamics of drug action and antitumor efficacy. In a standard 72 h drug exposure MTS assay, notable concentration-dependent antiproliferative effects were observed in the IC50 range of 1.2-2.8 μmol/L for vorinostat and 5.1-17.5 nmol/L for panobinostat. However, shorter clinically relevant exposures of 3 or 6 h failed to elicit any significant growth inhibition and in most cases a >24 h exposure to vorinostat or panobinostat was required to induce a sigmoidal dose-response. Similar results were observed in colony formation assays where ≥ 24 h of exposure was required to effectively reduce colony formation. Induction of acetyl-H3, acetyl-H4 and p21 by vorinostat were transient and rapidly reversed within 12 h of drug removal. In contrast, panobinostat-induced acetyl-H3, acetyl-H4, and p21 persisted for 48 h after an initial 3 h exposure. Treatment of HCT116 xenografts with panobinostat induced significant increases in acetyl-H3 and downregulation of thymidylate synthase after treatment. Although HDACIs exert both potent growth inhibition and cytotoxic effects when CRC cells were exposed to drug for ≥ 24 h, these cells demonstrate an inherent ability to survive HDACI concentrations and exposure times that exceed those clinically achievable. Continued efforts to develop novel HDACIs with improved pharmacokinetics/phamacodynamics, enhanced intratumoral delivery and class/isoform-specificity are needed to improve the therapeutic potential of HDACIs and HDACI-based combination regimens in solid tumors.