Effect of Cardiac Resynchronization Therapy on Inflammation in Congestive Heart Failure: A Review.

Congestive heart failure is associated with increased levels of several inflammatory mediators, and animal studies have shown that infusion of a number of cytokines can induce heart failure. However, several drugs with proven efficacy in heart failure have failed to affect inflammatory mediators, and anti-inflammatory therapy in heart failure patients has thus far been disappointing. Hence, to what extent heart failure is caused by or responsible for the increased inflammatory burden in the patient is still unclear. Over the past couple of decades, resynchronization therapy with a biventricular pacemaker has emerged as an effective treatment in a subset of heart failure patients, reducing both morbidity and mortality. Such treatment has also been shown to affect the inflammation associated with heart failure. In this study, we review recent data on the association between heart failure and inflammation, and in particular how resynchronization therapy can affect the inflammatory process.

Atrial fibrillation: inflammation in disguise?

Atrial fibrillation is highly prevalent, and affected patients are at an increased risk of a number of complications, including heart failure and thrombo-embolism. Over the past years, there has been increasing interest in the role of inflammatory processes in atrial fibrillation, from the first occurrence of the arrhythmia to dreaded complications such as strokes or peripheral emboli. As the standard drug combination which aims at rate control and anticoagulation only offers partial protection against complications, newer agents are needed to optimize treatment. In this paper, we review recent knowledge regarding the impact of inflammation on the occurrence, recurrence, perpetuation and complications of the arrhythmia, as well as the role of anti-inflammatory therapies in the treatment for the disease.

Physical exercise augmented cognitive behaviour therapy for older adults with generalised anxiety disorder (PEXACOG): a feasibility study for a randomized controlled trial.

BACKGROUND: Generalised anxiety disorder (GAD) is a frequent and severe disorder among older adults. For older adults with GAD the effect of the recommended treatment, cognitive behaviour therapy (CBT), is reduced. Physical exercise (PE) may enhance the effect of CBT by improving cognitive function and increasing levels of brain-derived neurotrophic factor (BDNF), a predictor of the effect of CBT in patients with anxiety. The aim of the study was to assess the feasibility of a randomized controlled trial (RCT) investigating treatment effect of the combination of CBT and PE for GAD in a sample of older adults, including procedures for assessment and treatment. METHODS: Four participants aged 62-70 years (M = 65.5, SD = 3.2) with a primary diagnosis of GAD were included. Participants received 15 weeks of PE in combination with 10 weeks of CBT. Participants completed self-report measures, and clinical, biological, physiological and neuropsychological tests at pre-, interim- and post-treatment. RESULTS: Procedures, protocols, and results are presented. One participant dropped out during treatment. For the three participants completing, the total adherence to PE and CBT was 80% and 100%, respectively. An independent assessor concluded that the completers no longer fulfilled the criteria for GAD after treatment. Changes in self-report measures suggest symptom reduction related to anxiety and worry. The sample is considered representative for the target population. CONCLUSIONS: The results indicate that combining CBT and PE for older adults with GAD is feasible, and that the procedures and tests are suitable and manageable for the current sample. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02690441. Registered on 24 February 2016, https://clinicaltrials.gov/ct2/show/NCT02690441 .

LDL apheresis and inflammation--implications for atherosclerosis.

Low-density lipoprotein (LDL) apheresis is an extracorporeal treatment modality used in high-risk patients when LDL cholesterol levels cannot be reduced adequately with medication. The treatment is highly effective, but could be affected by potential unwanted effects on pro- and anti-inflammatory biomarkers. In this paper, we review the literature regarding the effect of LDL apheresis on pro- and anti-inflammatory biomarkers important in atherosclerosis, also as patients in LDL apheresis have high risk for atherosclerotic complications. We discuss the effect of LDL apheresis on complement, cytokines and finally a group of other selected pro- and anti-inflammatory biomarkers. The complement system is affected by LDL apheresis, and there are differences between different LDL apheresis systems. The plasma separation columns seem to trigger the formation of proinflammatory complement factors including C3a and C5a, while the same anaphylatoxins are adsorbed by the LDL apheresis columns, however, to varying degree. Proinflammatory cytokines are to some extent adsorbed by the LDL apheresis columns, while some of the anti-inflammatory cytokines increase during treatment. Finally, we discuss the effect of apheresis on different biomarkers including C-reactive protein, fibrinogen, adhesion molecules, myeloperoxidase and HDL cholesterol. In conclusion, even if there are differences between pro- and anti-inflammatory biomarkers during LDL apheresis, the consequences for the patients are largely unknown and larger studies need to be performed. Preferably, they should be comparing the effect of different LDL apheresis columns on the total inflammatory profile, and this should be related to clinical endpoints.

Local Mapping of Polar Ionospheric Electrodynamics.

An accurate description of the state of the ionosphere is crucial for understanding the physics of Earth's coupling to space, including many potentially hazardous space weather phenomena. To support this effort, ground networks of magnetometer stations, optical instruments, and radars have been deployed. However, the spatial coverage of such networks is naturally restricted by the distribution of land mass and access to necessary infrastructure. We present a new technique for local mapping of polar ionospheric electrodynamics, for use in regions with high data density, such as Fennoscandia and North America. The technique is based on spherical elementary current systems (SECS), which were originally developed to map ionospheric currents. We expand their use by linking magnetic field perturbations in space and on ground, convection measurements from space and ground, and conductance measurements, via the ionospheric Ohm's law. The result is a technique that is similar to the Assimilative Mapping of Ionospheric Electrodynamics (AMIE) technique, but tailored for regional analyses of arbitrary spatial extent and resolution. We demonstrate our technique on synthetic data, and with real data from three different regions. We also discuss limitations of the technique and potential areas for improvement.

Efficacy of intergrating vestibular rehabilitation and cognitive behaviour therapy in persons with persistent dizziness in primary care- a study protocol for a randomised controlled trial.

BACKGROUND: Dizziness is a common complaint, and the symptom often persists, together with additional complaints. A treatment combining Vestibular Rehabilitation (VR) and Cognitive Behaviour Therapy (CBT) is suggested. However, further research is necessary to evaluate the efficacy of such an intervention. The objective of this paper is to present the design of a randomised controlled trial aiming at evaluating the efficacy of an integrated treatment of VR and CBT on dizziness, physical function, psychological complaints and quality of life in persons with persistent dizziness. METHODS/DESIGN: The randomised controlled trial is an assessor-blinded, block-randomised, parallel-group design, with a 6- and 12-month follow-up. The study includes 125 participants from Bergen (Norway) and surrounding areas. Included participants present with persistent dizziness lasting for at least 3 months, triggered or exacerbated by movement. All participants receive a one-session treatment (Brief Intervention Vestibular Rehabilitation; BI-VR) with VR before being randomised into a control group or an intervention group. The intervention group will further be offered an eight-session treatment integrating VR and CBT. The primary outcomes in the study are the Dizziness Handicap Inventory and preferred gait velocity. DISCUSSION: Previous studies combining these treatments have been of varying methodological quality, with small samples, and long-term effects have not been maintained. In addition, only the CBT has been administered in supervised sessions, with VR offered as home exercises. The current study focusses on the integrated treatment, a sufficiently powered sample size, and a standardised treatment programme evaluated by validated outcomes using a standardised assessment protocol. TRIAL REGISTRATION: www.clinicaltrials.gov, ID: NCT02655575 . Registered on 14 January 2016.

Feasibility of integrating vestibular rehabilitation and cognitive behaviour therapy for people with persistent dizziness.

PURPOSE: To evaluate the feasibility of integrating vestibular rehabilitation and cognitive behaviour therapy (VR-CBT) for people with persistent dizziness in primary care. DESIGN: Prospective single-group pre- and post-test study. PARTICIPANTS: Adults (aged 18-70) with acute onset of dizziness and symptoms lasting a minimum 3 months, recruited from Bergen municipality. METHODS: Participants attended eight weekly group sessions of VR-CBT intervention. Feasibility outcomes consisted of recruitment and testing procedures, intervention adherence, and participant feedback, besides change in primary outcomes. The primary outcomes were Dizziness Handicap Inventory (DHI) and preferred gait velocity. RESULTS: Seven participants were recruited for the study. All participants completed the pre-treatment tests, five participants completed the intervention and answered post-treatment questionnaires, and three completed post-treatment testing. Of the five participants, three attended at least 75% of the VR-CBT sessions, and two 50% of the sessions. Participants reported that the VR-CBT was relevant and led to improvement in function. DHI scores improved beyond minimal important change in two out of five participants, and preferred gait velocity increased beyond minimal important change in two out of three participants. CONCLUSION: The current tests and VR-CBT treatment protocols were feasible. Some changes are suggested to optimise the protocols, before conducting a randomised controlled trial. TRIAL REGISTRATION: NCT02655575. Registered 14 January 2016-retrospectively registered.

Massive pulmonary embolism with cardiac arrest treated with continuous thrombolysis and concomitant hypothermia.

This case report describes the clinical course in a 49-year-old man with repeated cardiac arrests due to massive pulmonary embolism. He was successfully treated with intravenous tenecteplase followed by catheter-based alteplase infusion during external cooling. The case illustrates that vitally important bolus thrombolytic therapy may be continued as catheter-based treatment along with hypothermia without significant bleeding complications.

A young man with acute dilated cardiomyopathy associated with methylphenidate.

An 18-year-old obese man with a body mass index of 40, diagnosed with attention-deficit hyperactivity disorder and treated with methylphenidate (Concerta) was acutely admitted to hospital with hypoxia and dyspnoea. On investigation signs of liver-, renal-, and heart-failure were found. Noradrenalin infusion was started. Echocardiography showed dilated left ventricle and an ejection fraction (EF) of 25%. Liver function improved, noradrenalin and dobutamine were tapered, but three days after admission a new echocardiography showed an EF of 10%. The patient was transferred to the National Hospital (Rikshospitalet, Oslo), where intensified treatment including intra aortic balloon pump (IABP) was instituted. Cardiac function improved, and 3 weeks later the IABP was disconnected. EF at this point was 15%. The patient was denied heart transplantation due to various cofactors. The investigation concluded with a probable relationship between his cardiomyopathy and the use of methylphenidate (Concerta).

Treatment of acute myocardial infarction in the sub-arctic region of Norway. Do we offer an equal quality of care?

Patients, relatives, healthcare workers and administrators are concerned about the quality of care offered. We aimed to explore the treatment of acute myocatrdial infarction (AMI) in Northern Norway, compare it with the national figures, and document whether there is an equal quality of care or not. The retrospective study included data on patients' treatment for AMI. The following sources were employed. The Norwegian Patient Registry, National Quality of Care Database, Norwegian Myocardial Infarction Registry and data from the National Air Ambulance Services of Norway. The period 2012-2014/15 was studied and the variables were: incidence of AMI, gender and age adjusted rates of AMI and revascularization (PCI, CABG) based on patient's place of living (according to hospital catchment area) and 30-day survival rate. The annual incidence of AMI was 9% higher in the northern region. Significant incidence variations (2.7-5.9 AMI/1000 inhabitants) between the hospitals' catchment areas were revealed. The 30-day survival rate varied between 85.1-92.1% between hospitals. The variation in revascularization/AMI rate was 0.72-1.54. Air amublance services' availability varied through the day. In conclusion, significant variations in the AMI rate and an unequal service within the region was revealed.

A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform.

Human progesterone target tissues contain two progesterone receptors: B-receptors (hPRB), which are 933 amino acids in length, and A-receptors (hPRA), which lack the N-terminal 164 amino acids. The two isoforms differ functionally when they are occupied by agonists or antagonists. We postulated that the unique 164-amino acid, B-upstream segment (BUS) is in part responsible for the functional differences between the two isoforms and have constructed a series of hPR expression vectors encoding BUS fused to isolated down-stream functional domains of the receptors. These include the two transactivation domains: activation function-1 (AF1), located in a 90-amino acid segment just up-stream of the DNA-binding domain (DBD) and nuclear localization signal (NLS), and AF2, located in the hormone-binding domain. BUS is a highly phosphorylated domain, and contains the serine residues responsible for the hPRB triplet protein structure. The construct containing BUS-DBD-NLS binds tightly to DNA when aided by accessory nuclear factors. In HeLa cells, BUS-DBD-NLS strongly and autonomously activates transcription of chloramphenicol acetyltransferase (CAT) from a promoter containing two progesterone response elements (PRE2-TATAtk-CAT). Transcription levels with BUS-DBD-NLS are equivalent to those seen with full-length hPRB, and are higher than those seen with hPRA. BUS specifically requires an intact hPR DBD to be transcriptionally active. DBD mutants that cannot bind DNA or whose DNA binding specificity has been switched to an estrogen response element cannot cooperate in BUS transcriptional activity. The function of BUS-DBD-NLS is promoter and cell specific. It does not transactivate a CAT reporter driven by the mouse mammary tumor virus promoter in HeLa cells and poorly transactivates PRE2-TATAtk-CAT in PR-negative T47D breast cancer cells. However, in the breast cancer cells, BUS-DBD-NLS transactivation of PRE2-TATAtk-CAT can be reconstituted by either elevating cellular levels of cAMP or linking BUS and DBD to AF1 or AF2 of hPR, each of which alone is also inactive in these cells. We conclude that hPRB contains a unique third activation function (AF3) located within BUS and requiring the functional DBD of hPR. Depending on the promoter or cell tested, AF3 can activate transcription autonomously, or it can functionally synergize with AF1 or AF2. Autonomous AF3 function may explain the unexpected transactivating actions of antiprogestin-occupied hPRB, an issue of importance in hormone-resistant breast cancers and in tissue-specific agonist-like effects of hormone antagonists.

Use of short-lived green fluorescent protein for the detection of proteasome inhibition.

Human embryonic kidney (HEK293) cells were stably transduced with a retroviral vector containing an expression cassette for a short-lived green fluorescent protein (d2EGFP) and the neomycin resistance gene (Neor). When Neor HEK293 clones were treated with proteasome inhibitors, lactacystin or MG132, an increase in the constitutive levels of d2EGFP expression was observed. Based on flow cytometry, proteasome inhibitors induced a 5- to 10-fold increase in the fluorescent intensity of d2EGFP in HEK293 cell clones. However, in the presence of proteasome inhibitors, HEK293 clones showed a 4- to 6.5-fold increase in d2EGFP concentration as determined by western blot analysis. Our data suggest that d2EGFP is a useful indicator of proteasome inhibition. Therefore, stable expression of d2EGFP in mammalian cells is potentially useful for high-throughput screening of cDNAs or pharmaceutical drugs that repress proteasome functions in vivo.

Cyclosporin A regulates the levels of cyclophilin A in neuroblastoma cells in culture.

Cyclophilin A (CyP-A), a member of a highly conserved family of proteins, immunophilins, is the major intracellular receptor for the immunosuppressive drug, cyclosporin A (CsA). CyP-A is widely expressed in many tissues, but is found in the highest concentration in brain tissues and may perform critical neuronal functions. CsA is a known neurotoxin. Therefore, understanding the regulation of CyP-A levels in nerve cells, particularly by CsA, is important. We have utilized murine neuroblastoma (NB) cells as an experimental model to investigate this issue. Our results show that CsA alone was sufficient to induce morphological differentiation in undifferentiated NB cells and to increase CyP-A levels as determined by immunostaining. However, inducing terminal differentiation by elevating adenosine 3',5'-cyclic monophosphate (cAMP) levels using either 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724), an inhibitor of cyclic nucleotide phosphodiesterase, or prostaglandin E1 (PGE1), a stimulator of adenylate cyclase, was not sufficient to increase CyP-A levels. CsA was required to increase CyP-A levels in both RO20-1724- and PGE1-induced differentiated NB cells. Increases in CyP-A levels, however, occurred without any change in the expression of the CyP-A gene as determined by reverse-transcriptase polymerase-chain reaction analysis using (CyP-A)-specific primers. These results suggest that CsA regulates the level of its own binding protein, CyP-A, in both undifferentiated and cAMP-induced differentiated NB cells in culture.

Differentiation genes: are they primary targets for human carcinogenesis?

In spite of extensive research in molecular carcinogenesis, genes that can be considered primary targets in human carcinogenesis remain to be identified. Mutated oncogenes or cellular growth regulatory genes, when incorporated into normal human epithelial cells, failed to immortalize or transform these cells. Therefore, they may be secondary events in human carcinogenesis. Based on some experimental studies we have proposed that downregulation of a differentiation gene may be the primary event in human carcinogenesis. Such a gene could be referred to as a tumor-initiating gene. Downregulation of a differentiation gene can be accomplished by a mutation in the differentiation gene, by activation of differentiation suppressor genes, and by inactivation of tumor suppressor genes. Downregulation of a differentiation gene can lead to immortalization of normal cells. Mutations in cellular proto-oncogenes, growth regulatory genes, and tumor suppressor genes in immortalized cells can lead to transformation. Such genes could be called tumor-promoting genes. This hypothesis can be documented by experiments published on differentiation of neuroblastoma (NB) cells in culture. The fact that terminal differentiation can be induced in NB cells by adenosine 3',5'-cyclic monophosphate (cAMP) suggests that the differentiation gene in these cells is not mutated, and thus can be activated by an appropriate agent. The fact that cAMP-resistant cells exist in NB cell populations suggests that a differentiation gene is mutated in these cancer cells, or that differentiation regulatory genes have become unresponsive to cAMP. In addition to cAMP, several other differentiating agents have been identified. Our proposed hypothesis of carcinogenesis can also be applied to other human tumors such as melanoma, pheochromocytoma, medulloblastoma, glioma, sarcoma, and colon cancer.

Multiple antioxidants in the prevention and treatment of Alzheimer disease: analysis of biologic rationale.

The etiology of Alzheimer disease (AD) is not well understood; therefore, neither prevention strategies nor long-term effective treatment modalities are available for this disease. Based on laboratory and clinical studies, it appears that reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are generated extracellularly and intracellularly by various mechanisms are among the major intermediary risk factors that initiate and promote neurodegeneration in idiopathic AD. Therefore, multiple antioxidant supplements could be useful in the prevention of AD, and as an adjunct to standard therapy in the treatment of AD. The products of inflammatory reactions such as prostaglandins (PGs; PGE1 and PGA1), free radicals, cytokines, and complement proteins are neurotoxic. Nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit the synthesis of PGs, reduce the rate of deterioration of cognitive functions in patients with advanced AD. Cholinergic drugs are routinely used in the treatment of AD to improve cognitive functions. Therefore, we propose that a combination of multiple antioxidants and NSAIDs may be more beneficial in the prevention of AD, and that this combination taken together with cholinergic drugs may be more effective in the treatment of AD than the individual agents alone. We also hypothesize that, in idiopathic AD, epigenetic components of neurons such as mitochondria, membranes, other membranous structures, and protein modifications--rather than the genes of neurons--are the primary targets for the action of neurotoxins including free radicals. In some familial AD, mutations in amyloid precursor protein and presenilins are associated with the risk of early onset of this disease; however, their mechanisms of action are not fully understood.

Relative sensitivity of undifferentiated and cyclic adenosine 3',5'-monophosphate-induced differentiated neuroblastoma cells to cyclosporin A: potential role of beta-amyloid and ubiquitin in neurotoxicity.

Cyclosporin A is routinely used in transplant therapy following allogeneic or xenogeneic tissue transplantation to prevent rejection. This immunosuppressive drug is also neurotoxic; however, its mechanisms of action for neurotoxicity are poorly understood. Undifferentiated and cyclic adenosine 3',5'-monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells were used as an experimental model to study the toxicity of cyclosporin A. Results showed that cyclosporin A promoted the outgrowth of neurites and inhibited the growth of undifferentiated NB cells. When cyclosporin A was added simultaneously with RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, or with prostaglandin E1, a stimulator of adenylate cyclase, it markedly enhanced the growth inhibitory and differentiation effects of these cAMP-stimulating agents. In addition, cyclosporin A added to cAMP-induced differentiated NB cells caused dose-dependent degeneration of these cells as evidenced by the vacuolization of cytoplasm and the fragmentation of nuclear and cytoplasmic materials; however, neurites remained intact. Cyclosporin A alone did not alter the intensity of cell immunostaining for ubiquitin or beta-amyloid peptide (amino acids 1-14) (Abeta1-14); however, it enhanced the intensity of staining for both ubiquitin and Abeta in cells that were treated with cAMP-stimulating agents. The intensity of staining of amyloid precursor protein (amino acids 44-63) (APP44-66) did not change in any treated group, suggesting that the increase in Abeta staining is due to increased processing of APP to Abeta. We propose that one of the mechanisms of cyclosporin A-induced neurotoxicity involves increased levels of Abeta and ubiquitin.

[Check list for the use of thrombolytics and other drugs in acute myocardial infarction]. / Sjekkliste ved behandling av akutt hjerteinfarkt med trombolytika og andre medikamenter.

MATERIALS AND METHODS: Data on all patients with acute myocardial infarction who were treated in Nordland County Hospital in a six-month period in 1996 were analyzed retrospectively (137 patients). After the introduction of checklists for the treatment of such patients, we did a prospective six-month registration in 1997 (111 patients) in order to find out whether treatment and delay times had improved. RESULTS: The proportion of patients who received thrombolytic treatment did not change (28% in 1996 as compared to 25% in 1997). The in-hospital delay time before treatment did not differ before and after the introduction of a check-list (approximately 40 minutes in both periods). There was an increase in the use of intravenous beta blockers and aspirin. INTERPRETATION: The percentage of patients with acute myocardial infarction receiving thrombolytics in our hospital does not differ substantially from that of other hospitals in Norway.

An infant with thanatophoric dwarfism surviving 169 days.

A female infant with thanatophoric dwarfism surviving 169 days is described. The genetics of the entity are briefly discussed.