The clinical and economic costs associated with regional disparities in varicella vaccine coverage in Italy over 50 years (2020-2070).

Italy implemented two-dose universal varicella vaccination (UVV) regionally from 2003 to 2013 and nationally from 2017 onwards. Our objective was to analyze regional disparities in varicella outcomes resulting from disparities in vaccine coverage rates (VCRs) projected over a 50-year time-horizon (2020-2070). A previously published dynamic transmission model was updated to quantify the potential public health impact of the UVV program in Italy at the national and regional levels. Four 2-dose vaccine strategies utilizing monovalent (V) and quadrivalent (MMRV) vaccines were evaluated for each region: (A) MMRV-MSD/MMRV-MSD, (B) MMRV-GSK/MMRV-GSK, (C) V-MSD/MMRV-MSD, and (D) V-GSK/MMRV-GSK. Costs were reported in 2022 Euros. Costs and quality-adjusted life-years (QALYs) were discounted 3% annually. Under strategy A, the three regions with the lowest first-dose VCR reported increased varicella cases (+ 34.3%), hospitalizations (+ 20.0%), QALYs lost (+ 5.9%), payer costs (+ 22.2%), and societal costs (+ 14.6%) over the 50-year time-horizon compared to the three regions with highest first-dose VCR. Regions with low first-dose VCR were more sensitive to changes in VCR than high first-dose VCR regions. Results with respect to second-dose VCR were qualitatively similar, although smaller in magnitude. Results were similar across all vaccine strategies.

Validation of a molecular diagnostic assay for CALR exon 9 indels in myeloproliferative neoplasms: identification of coexisting JAK2 and CALR mutations and a novel 9 bp deletion in CALR.

INTRODUCTION: The 2008 WHO criteria for the diagnosis and classification of myeloproliferative neoplasms (MPN) rely in part upon the assessment of mutations in JAK2 and MPL genes. Recently, mutations in calreticulin (CALR) have been identified in MPN lacking JAK2 and MPL mutations. We have validated a sensitive fragment analysis assay to detect CALR mutations. METHODS: Genomic DNA from peripheral blood, bone marrow, and FFPE bone marrow clot preparations from 52 MPN specimens with known JAK2 and MPL mutation status and 29 non-MPN specimens was analyzed. CALR mutation testing was performed by fragment length analysis, and the results were confirmed by sequencing. Accuracy, precision, sensitivity, specificity, and robustness of the assay were determined. RESULTS: Forty specimens (32 JAK2+, 2 JAK2-/MPL+, and 6 JAK2-/MPL-) were negative for CALR mutations. Twelve specimens had CALR mutations including 52 bp deletion (5), 5 bp insertion (6), and a novel 9 bp deletion (1). This 9 bp inframe deletion occurring at an allelic burden of 50% would delete three amino acids. One specimen with a 52 bp deletion also had JAK2 V617F mutation. All 29 non-MPN specimens were negative for CALR mutations. The assay accurately identified the mutation status of all 52 MPN specimens and had a coefficient of variation <3% for the fragment size and mutant peaks with a sensitivity of 5% for indels. CONCLUSIONS: Fragment analysis is an accurate and sensitive method for the detection of CALR indels. The novel 9 bp deletion is likely a germline variant. Consequence of coexisting JAK2 V617F and CALR mutations requires careful interpretation.

Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor ß (TGFß) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFß pathway. While TGFß antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFß signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma.

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.

Multiple repeat caesarean section in the UK: incidence and consequences to mother and child. A national, prospective, cohort study.

OBJECTIVE: To estimate the incidence of multiple repeat caesarean section (MRCS) (five or more) in the UK and to describe the outcomes for women and their babies relative to women having fewer repeat caesarean sections. DESIGN: A national population-based prospective cohort study using the UK Obstetric Surveillance System (UKOSS). SETTING: All UK hospitals with consultant-led maternity units. POPULATION: Ninety-four women having their fifth or greater MRCS between January 2009 and December 2009, and 175 comparison women having their second to fourth caesarean section. METHODS: Prospective cohort and comparison identification through the UKOSS monthly mailing system. MAIN OUTCOME MEASURES: Incidence, maternal and neonatal complications. Relative risk, unadjusted (OR) and adjusted (aOR) odds ratio estimates. RESULTS: The estimated UK incidence of MRCS was 1.20 per 10 000 maternities [95% confidence interval (CI), 0.97-1.47]. Women with MRCS had significantly more major obstetric haemorrhages (>1500 ml) (aOR, 18.6; 95% CI, 3.89-88.8), visceral damage (aOR, 17.6; 95% CI, 1.85-167.1) and critical care admissions (aOR, 15.5; 95% CI, 3.16-76.0), than women with lower order repeat caesarean sections. These risks were greatest in the 18% of women with MRCS who also had placenta praevia or accreta. Neonates of mothers having MRCS were significantly more likely to be born prior to 37 weeks of gestation (OR, 6.15; 95% CI, 2.56-15.78) and therefore had higher rates of complications and admissions. CONCLUSIONS: MRCS is associated with greater maternal and neonatal morbidity than fewer caesarean sections. The associated maternal morbidity is largely secondary to placenta praevia and accreta, whereas higher rates of preterm delivery are most likely a response to antepartum haemorrhage.

Oncogenically active MYD88 mutations in human lymphoma.

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-ß. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.

Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

Prognostic value of regulatory T cells, lymphoma-associated macrophages, and MUM-1 expression in follicular lymphoma treated before and after the introduction of monoclonal antibody therapy: a Southwest Oncology Group Study.

BACKGROUND: The purpose was to examine the prognostic impact of features of tumor cells and immune microenvironment in patients with follicular lymphoma treated with and without anti-CD20 monoclonal antibody therapy. PATIENTS AND METHODS: Tissue microarrays were constructed from archived tissue obtained from patients on three sequential Southwest Oncology Group (SWOG) trials for FL. All three trials included anthracycline-based chemotherapy. Anti-CD20 monoclonal antibodies were included for patients in the latter two trials. Immunohistochemistry was used to study the number and distribution of cells staining for forkhead box protein P3 (FOXP3) and lymphoma-associated macrophages (LAMs) and the number of lymphoma cells staining for myeloma-associated antigen-1 (MUM-1). Cox proportional hazards regression was used to evaluate the association between marker expression and overall survival (OS). RESULTS: The number or pattern of infiltrating FOXP3 cells and LAMs did not correlate with OS in sequential SWOG studies for FL. The presence of MUM-1 correlated with lower OS for patients who received monoclonal antibody but not for those treated with chemotherapy alone. CONCLUSIONS: Immune cell composition of lymph nodes did not correlate with OS in this analysis of trials in FL. The mechanism of the observed correlation between MUM-1 expression and adverse prognosis in patients receiving monoclonal antibody therapy requires confirmation.

Cost-effectiveness of raltegravir in antiretroviral treatment-experienced HIV-1-infected patients in Switzerland.

OBJECTIVES: Raltegravir, a novel integrase inhibitor, has shown great efficacy in reducing HIV viral load among treatment-experienced patients. A cohort state-transition model was used to assess the long-term effect of raltegravir treatment on costs and quality-adjusted life expectancy from a Swiss perspective. METHODS: Patients were stratified into health states according to opportunistic infection status, HIV RNA level, and CD4 count, with each group assigned a treatment cost and utility (quality of life) score. Model inputs came from published studies, clinical trials, and database analyses. Results were used to calculate incremental cost-effectiveness ratio (ICER) of raltegravir use, expressed in Swiss francs (CHF) as incremental cost/quality-adjusted life-year (QALY) gained. Future costs and QALYs were discounted at 3% per year. RESULTS: Five years of raltegravir treatment increased discounted quality-adjusted life expectancy by 3.73 years over placebo, with additional discounted cost of CHF 170,347, resulting in an ICER of CHF 45,687/QALY. ICERs ranged from CHF 42,751 to 53,478/QALY for treatment duration of 3 and 10 years, respectively. Results were most sensitive to changes in raltegravir treatment duration, source of estimated quality of life weights, and raltegravir price. CONCLUSIONS: Adding raltegravir to optimized background therapy was a cost-effective strategy for treatment-experienced patients in Switzerland.

Stromal gene signatures in large-B-cell lymphomas.

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Work design and analysis for space-based manufacturing: a case analysis of initial design issues.

The purpose of the present research was to investigate the nature of potential manufacturing tasks humans may execute in a space environment. The success of space-based manufacturing (SBM) is suggested to be a precursor to permanent human presence in space. A working hypothesis for this study was that human work in the SBM environment would be substantially different from terrestrial manufacturing work. To investigate this hypothesis, a case analysis approach was developed that employed a function allocation and task analysis of a representative SBM process: the production of tailored industrial crystals. This research approach was chosen as the current state of engineering design for SBM is in the conceptual and early flow sheeting phases of a system life cycle. Results of the task analysis and function allocation process suggest response to corrective maintenance functions and to abnormal system conditions should be allocated to humans as opposed to automation. These results are discussed in relation to human factors engineering challenges associated with long-duration human presence in an SBM environment.

hTid-1, a human DnaJ protein, modulates the interferon signaling pathway.

The Jak family of protein-tyrosine kinases are crucial for the signaling of a large number of different polypeptide ligands, including the interferons, many cytokines, erythropoietin, and growth factors. Through their interaction with receptors, the Jaks initiate a signaling cascade resulting in the activation of gene transcription and ultimately a cellular response to various ligands. In addition to their role in cellular signaling, alteration of Jak activity has been implicated in several disease states. In identifying Jak2-interacting proteins with the yeast two-hybrid system, we cloned the human homologue of the Drosophila melanogaster tumor suppressor gene lethal () tumorous imaginal discs, which encodes the protein Tid56. Drosophila Tid56 and its human homologue hTid-1 represent members of the DnaJ family of molecular chaperones. The TID1 gene encodes two splice variants hTid-1(S) and hTid-1(L). We confirmed the interaction between Jak2 and hTid-1(S) or hTid-1(L) by immunoprecipitation from COS-1 cells expressing these proteins. The interaction between endogenous hTid-1 and Jak2 was shown in HEp2 cells. We further showed that hTid-1 interacts with the human interferon-gamma (Hu-IFN-gamma) receptor subunit IFN-gamma R2. In addition, using a chimeric construct where the extracellular domain of IFN-gamma R2 was fused to the kinase domain of Jak2, we showed that hTid-1 binds more efficiently to the chimera with an active kinase domain than to a similar construct with an inactive kinase domain. Additionally, the data demonstrate that hTid-1 isoforms as well as Jak2 interact with Hsp70/Hsc70 in vivo, and the interaction between Hsp70/Hsc70 and hTid-1 is reduced after IFN-gamma treatment. Furthermore, both hTid-1(S) and hTid-1(L) can modulate IFN-gamma-mediated transcriptional activity.

The effect of alendronate on fracture-related healthcare utilization and costs: the fracture intervention trial.

The Vertebral Fracture Arm (VFA) of the Fracture Intervention Trial (FIT) study demonstrated that alendronate reduced the incidence of spine, forearm and hip fractures in women with low bone mass and existing vertebral fractures by about 50%. The objective of the present study was to determine the effects of alendronate therapy versus placebo on fracture-related healthcare utilization and costs. Participants were randomly assigned to double-masked treatment with alendronate (5 mg/day for 2 years and then 10 mg/day for 1 year) or placebo for 3 years. For each patient experiencing a clinical fracture, we determined whether treatment in an emergency room, hospital, nursing home and/or rehabilitation hospital was a consequence of the fracture. The VFA of the FIT Study enrolled 2027 women aged 55-81 years with low bone mass and pre-existing vertebral fractures from population-based listings in 11 metropolitan areas of the United States. We measured (1) the proportion of patients who had any fracture-related healthcare event and (2) the estimated cost of fracture-related healthcare services. Alendronate significantly reduced the proportion of patients utilizing fracture-related healthcare (emergency room, hospital, rehabilitation hospital or nursing home) by 25% (p = 0.038). Alendronate significantly reduced the costs associated with hip-fracture-related care by 58%, or $181 per patient randomized (p = 0.036). The reduction in fracture-related total costs was 35% ($190 per patient randomized) in the alendronate group relative to the placebo group (p = 0.114). Alendronate thus not only reduces the incidence of clinical fractures and associated morbidity, but reduces the proportion of patients utilizing the associated healthcare resources.

Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study.

Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm with a variable histologic appearance that may mimic other spindle cell processes, particularly nodular fasciitis, desmoid tumor, and in intra-abdominal locations, gastrointestinal stromal tumor. Recently, gene fusions involving ALK at chromosome 2p23 have been described in IMTs. The resultant ALK protein overexpression in the myofibroblastic component of these tumors is detectable by immunohistochemistry. We examined 73 IMTs, 20 cases of nodular fasciitis, 15 desmoid fibromatoses, and 15 gastrointestinal stromal tumors by immunohistochemistry using ALK-11, a rabbit polyclonal antibody that recognizes the C-terminus of the protein. ALK positivity was detected in 44 of 73 (60%) IMTs. All cases of nodular fasciitis, desmoid fibromatosis, and gastrointestinal stromal tumors were ALK negative (p < 0.001). These findings demonstrate that ALK positivity is common in IMTs, and immunohistochemistry using anti-ALK antibodies can be helpful in the differential diagnosis of these neoplasms. In addition, anti-ALK staining seems to correlate with those IMTs that have the typical tri-patterned histologic appearance and clinical presentation, providing additional support to the premise that IMT is a distinctive clinicopathologic entity within the broad category of inflammatory pseudotumors.

Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined TIMI 10B-TIMI 14 experience).

Earlier studies have suggested that immediate percutaneous coronary intervention (PCI) following thrombolytic therapy for acute myocardial infarction (AMI) is associated with an increase in adverse events and that routine PCI in this setting has offered no advantage over a conservative strategy. To reassess this issue in a more recent era, we evaluated 1,938 patients from the Thrombolysis in Myocardial Infarction (TIMI) 10B and 14 trials of AMI. Patients in TIMI 10B were randomized to receive tissue plasminogen activator or TNK tissue plasminogen activator, whereas patients in TIMI 14B trial were randomized to receive thrombolytic therapy with or without abciximab. All patients underwent angiography 90 minutes after receiving pharmacologic therapy. Patients who underwent PCI were classified as having undergone a rescue procedure (TIMI 0 or 1 flow at 90 minutes), an adjunctive procedure (TIMI 2 or 3 flow at 90 minutes), or a delayed procedure (performed >150 minutes after symptom onset, median of 2.75 days). Among patients with TIMI 0 or 1 flow, there was a trend for lower 30-day mortality among patients who underwent rescue PCI than among those who did not (6% vs 17%, p = 0.01, adjusted p = 0.28). Patients who underwent adjunctive PCI had similar 30-day mortality and/or reinfarction as those who underwent delayed PCI. In a multivariate model both had lower 30-day mortality and/or reinfarction than patients with "successful thrombolysis" (i.e., TIMI 3 flow at 90 minutes) who did not undergo revascularization (p = 0.02). Thus, early PCI following AMI is associated with excellent outcomes. Randomized trials of an early invasive strategy following thrombolysis are warranted.

Long-term outcome following coronary stent embolization or misdeployment.

Twenty-three patients were identified as having either coronary stent embolization or misdeployment at our center over a 4-year period. They were matched to an equal number of controls who underwent a stenting procedure but in whom embolization or misdeployment did not occur. Baseline demographic characteristics were similar between the 2 groups. The embolization group required higher mean predilation pressure than the control group and more of the embolization group required a predilation pressure >10 atm before attempted stent placement (7 vs 1, p = 0.02). Total procedure and fluoroscopy time as well as dye volume were dramatically higher in the embolization group compared with the control group. Lesion angulation >45 degrees was predictive of stent embolization and 6 of 23 (23%) stents embolized during passage through a previously deployed stent. Sixteen cases of stent embolization and/or misdeployment occurred within the coronary circulation, 8 of which were retrieved, and 7 stents embolized to the central and/or peripheral circulation. A total of 23 major adverse coronary events occurred in the case group versus 7 events in the control group (p = 0.04) over a mean follow-up of 36 +/- 13 months. Fifteen of the events (65%) in the case group occurred in those 8 patients in whom the stent remained in the coronary circulation, including 3 bypass surgeries, 2 myocardial infarctions, 5 repeat percutaneous interventions, and 1 death after hospital discharge. Only 1 patient in whom the stent embolized outside the coronary circulation demonstrated possible evidence for peripheral vascular insufficiency. Intracoronary stent embolization in which the stent remains misdeployed in the coronary circulation is associated with poor long-term outcomes. Extracoronary stent embolization is associated with minimal long-term sequelae.

Effectiveness of bi-atrial pacing for reducing atrial fibrillation after coronary artery bypass graft surgery.

Atrial fibrillation (AF) is common after cardiac surgery and adds significant cost and morbidity. The use of prophylactic pacing strategies to prevent post-operative AF has been controversial. We previously performed a pilot study which suggested that the combination of beta-blockers and bi-atrial pacing (BAP) may reduce AF after cardiac surgery. We prospectively randomized 118 patients to continuous BAP for up to 96 hours post-operatively versus standard therapy. All patients were treated with beta-blockers as tolerated. Patients were paced in the AAI mode at a rate of 100 pulses per minute. The primary endpoint of the study was the occurrence of sustained AF (>10 minutes). There was a significant reduction in the incidence of AF in the BAP group among patients undergoing coronary artery bypass graft surgery with or without aortic valve replacement (35 % vs. 19 % AF; OR=0.38, 95 % CI 0.15, 0.93; p <0.05). Including patients undergoing isolated aortic valve surgery (n=7), there remained a strong trend toward a reduction of AF with pacing (no atrial pacing [NAP] vs. BAP; 35 % vs. 21 % AF; OR=0.48, 95 % CI 0.21, 1.11; p=0.08). Patients age 70 or greater benefited most from pacing (NAP vs. BAP; 55 vs. 25 % AF; p<0.05), while those less than 70 years of age did not (17 vs. 18 % p=NS). There was a significant reduction in the amount of time spent in the intensive care unit among patients receiving BAP (50+/-40 vs. 37+/-25 h; p<0.05).BAP together with beta-blockade after coronary artery bypass graft surgery reduces the incidence of post-operative atrial AF. Elderly patients (age 70 or greater) appear to benefit most, and may be a group to whom this therapy should be targeted.

Induction of the ubiquitin-proteasome pathway during the keratocyte transition to the repair fibroblast phenotype.

PURPOSE: To examine dynamics and function of the ubiquitin (Ub)-proteasome pathway (UPP) during corneal stromal cell acquisition of the repair fibroblast phenotype. METHODS: An established cell culture model was used in which freshly isolated rabbit corneal stromal cells acquire a repair fibroblast phenotype, thereby mimicking injury-induced stromal cell activation. RESULTS: Transition to the repair fibroblast phenotype during the 72 hours after initial plating was coincident with progressive UPP induction. Levels of Ub, Ub-conjugated proteins, ubiquitinylating enzymes E1 and E2-25K, and 26 S proteasome increased two- to fivefold in activated stromal cells. These increases were associated with enhanced (>10-fold) capacity for Ub-dependent proteolysis of (125)I-labeled H2A and with progressive (>6-fold) increases in the UPP substrate, inhibitor of kappaBalpha (IkappaBalpha). Because IkappaBalpha expression is induced by nuclear factor (NF)-kappaB, this finding suggests that rates of constitutive NF-kappaB activation, and thus IkappaBalpha degradation, are elevated in activated stromal cells. Both freshly isolated and activated stromal cells degraded IkappaBalpha in response to IL-1alpha; yet, only activated stromal cells maintained autocrine IL-1alpha expression after 24 hours. UPP induction was coincident with a more than 90% loss of tissue transketolase (TKT) and aldehyde dehydrogenase (ALDH) class 1. TKT was stabilized during the repair phenotype transition by proteasome inhibition and was degraded (>30%/h) by the UPP in cell-free assays. CONCLUSIONS: Coordinate induction of the UPP during stromal cell activation alters levels of IkappaBalpha and TKT, two UPP substrates that are implicated in the loss of tissue stasis and corneal clarity after injury.