Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high-density mapping

OBJECTIVES This study sought to evaluate the relationship between fibrosis imaged by delayed-enhancement (DE) magnetic resonance imaging (MRI) and atrial electrograms (Egms) in persistent atrial fibrillation (AF). BACKGROUND Atrial fractionated Egms are strongly related to slow anisotropic conduction. Their relationship to atrial fibrosis has not yet been investigated. METHODS Atrial high-resolution MRI of 18 patients with persistent AF (11 long-lasting persistent AF) was registered with mapping geometry (NavX electro-anatomical system (version 8.0, St. Jude Medical, St. Paul, Minnesota)). DE areas were categorized as dense or patchy, depending on their DE content. Left atrial Egms during AF were acquired using a high-density, 20-pole catheter (514 ± 77 sites/map). Fractionation, organization/regularity, local mean cycle length (CL), and voltage were analyzed with regard to DE. RESULTS Patients with long-lasting persistent versus persistent AF had larger left atrial (LA) surface area (134 ± 38 cm(2) vs. 98 ± 9 cm(2), p = 0.02), a higher amount of atrial DE (70 ± 16 cm(2) vs. 49 ± 10 cm(2), p = 0.01), more complex fractionated atrial Egm (CFAE) extent (54 ± 16 cm(2) vs. 28 ± 15 cm(2), p = 0.02), and a shorter baseline AF CL (147 ± 10 ms vs. 182 ± 14 ms, p = 0.01). Continuous CFAE (CFEmean [NavX algorithm that quantifies Egm fractionation] <80 ms) occupied 38 ± 19% of total LA surface area. Dense DE was detected at the left posterior left atrium. In contrast, the right posterior left atrium contained predominantly patchy DE. Most CFAE (48 ± 14%) occurred at non-DE LA sites, followed by 41 ± 12% CFAE at patchy DE and 11 ± 6% at dense DE regions (p = 0.005 and p = 0.008, respectively); 19 ± 6% CFAE sites occurred at border zones of dense DE. Egms were less fractionated, with longer CL and lower voltage at dense DE versus non-DE regions: CFEmean: 97 ms versus 76 ms, p < 0.0001; local CL: 153 ms versus 143 ms, p < 0.0001; mean voltage: 0.63 mV versus 0.86 mV, p < 0.0001. CONCLUSIONS Atrial fibrosis as defined by DE MRI is associated with slower and more organized electrical activity but with lower voltage than healthy atrial areas. Ninety percent of continuous CFAE sites occur at non-DE and patchy DE LA sites. These findings are important when choosing the ablation strategy in persistent AF.

Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats

Inefficient alveolar wound repair contributes to the development of pulmonary fibrosis. Hepatocyte growth factor (HGF) is a potent growth factor for alveolar type II epithelial cells (AECII) and may improve repair and reduce fibrosis. We studied whether targeted gene transfer of HGF specifically to AECII improves lung fibrosis in bleomycin-induced lung fibrosis. A plasmid encoding human HGF expressed from the human surfactant protein C promoter (pSpC-hHGF) was designed, and extracorporeal electroporation-mediated gene transfer of HGF specifically to AECII was performed 7 days after bleomycin-induced lung injury in the rat. Animals were killed 7 days after hHGF gene transfer. Electroporation-mediated HGF gene transfer resulted in HGF expression specifically in AECII at biologically relevant levels. HGF gene transfer reduced pulmonary fibrosis as assessed by histology, hydroxyproline determination, and design-based stereology compared with controls. Our results indicate that the antifibrotic effect of HGF is due in part to a reduction of transforming growth factor-β(1), modulation of the epithelial-mesenchymal transition, and reduction of extravascular fibrin deposition. We conclude that targeted HGF gene transfer specifically to AECII decreases bleomycin-induced lung fibrosis and may therefore represent a novel cell-specific gene transfer technology to treat pulmonary fibrosis.

Reduced olfactory bulb volume in adults with a history of childhood maltreatment

The human olfactory bulb (OB) is the first relay station of the olfactory pathway and may have the potential for postnatal neurogenesis in early childhood. In animals, chronic stress affects the OB and olfactory functioning. For humans, it has been shown that major depressive disorder is accompanied by reduced OB volume and reduced olfactory function. However, it is not clear if major stress in childhood development also affects olfactory functioning and OB volume in humans. OB volume was measured and olfactory function was tested in 17 depressive patients with and 10 without a history of severe childhood maltreatment (CM). CM patients exhibited a significantly reduced olfactory threshold and identification ability. The OB volume of the CM patients was significantly reduced to 80% of the non-CM patients. In conclusion, postnatal neurogenesis might be by reduced in CM, which may affect olfactory function of the brain in later life. Alternatively, a reduced OB volume may enhance psychological vulnerability in the presence of adverse childhood conditions although other areas not analyzed in this study may also be involved.

Attenuation of fibrosis in vitro and in vivo with SPARC siRNA.

INTRODUCTION: SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs. METHODS: In in vitro studies, skin fibroblasts obtained from a Tgfbr1 knock-in mouse (TBR1CA; Cre-ER) were transfected with SPARC siRNA. Gene and protein expressions of the Col1a2 and the Ctgf were examined by real-time RT-PCR and Western blotting, respectively. In in vivo studies, C57BL/6 mice were induced for skin and lung fibrosis by bleomycin and followed by SPARC siRNA treatment through subcutaneous injection and intratracheal instillation, respectively. The pathological changes of skin and lungs were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression changes of collagen in the tissues were assessed by real-time RT-PCR and non-crosslinked fibrillar collagen content assays. RESULTS: SPARC siRNA significantly reduced gene and protein expression of collagen type 1 in fibroblasts obtained from the TBR1CA; Cre-ER mouse that was induced for constitutively active TGF-beta receptor I. Skin and lung fibrosis induced by bleomycin was markedly reduced by treatment with SPARC siRNA. The anti-fibrotic effect of SPARC siRNA in vivo was accompanied by an inhibition of Ctgf expression in these same tissues. CONCLUSIONS: Specific inhibition of SPARC effectively reduced fibrotic changes in vitro and in vivo. SPARC inhibition may represent a potential therapeutic approach to fibrotic diseases.

Life-threatening adverse events following therapeutic opioid administration in adults: Is pharmacogenetic analysis useful?

BACKGROUND Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses.

Correlation of serum and urinary matrix metalloproteases/tissue inhibitors of metalloproteases with subclinical allograft fibrosis in renal transplantation

Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodeling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n=15), IF/TA 1 (n=15) and IF/TA 2-3 (n=10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2-3 (p=0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA≥1 compared to a previous biopsy obtained three months before; n=11) and stable grade of IF/TA (i.e. delta IF/TA=0; n=20). Next, we investigated whether urinary/serum MMP/TIMP levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6months post-transplant (n=25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMP/TIMP levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p≤0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6months post-transplant. This could be explained by the dynamic process of extracellular matrix remodeling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA.

Essentials of forensic post-mortem MR imaging in adults

Post-mortem MR (PMMR) imaging is a powerful diagnostic tool with a wide scope in forensic radiology. In the past 20 years, PMMR has been used as both an adjunct and an alternative to autopsy. The role of PMMR in forensic death investigations largely depends on the rules and habits of local jurisdictions, availability of experts, financial resources, and individual case circumstances. PMMR images are affected by post-mortem changes, including position-dependent sedimentation, variable body temperature and decomposition. Investigators must be familiar with the appearance of normal findings on PMMR to distinguish them from disease or injury. Coronal whole-body images provide a comprehensive overview. Notably, short tau inversion–recovery (STIR) images enable investigators to screen for pathological fluid accumulation, to which we refer as “forensic sentinel sign”. If scan time is short, subsequent PMMR imaging may be focussed on regions with a positive forensic sentinel sign. PMMR offers excellent anatomical detail and is especially useful to visualize pathologies of the brain, heart, subcutaneous fat tissue and abdominal organs. PMMR may also be used to document skeletal injury. Cardiovascular imaging is a core area of PMMR imaging and growing evidence indicates that PMMR is able to detect ischaemic injury at an earlier stage than traditional autopsy and routine histology. The aim of this review is to present an overview of normal findings on forensic PMMR, provide general advice on the application of PMMR and summarise the current literature on PMMR imaging of the head and neck, cardiovascular system, abdomen and musculoskeletal system.

Feeling present in arousing virtual reality worlds: prefrontal brain regions differentially orchestrate presence experience in adults and children

Virtual reality (VR) is a powerful tool for simulating aspects of the real world. The success of VR is thought to depend on its ability to evoke a sense of "being there", that is, the feeling of "Presence". In view of the rapid progress in the development of increasingly more sophisticated virtual environments (VE), the importance of understanding the neural underpinnings of presence is growing. To date however, the neural correlates of this phenomenon have received very scant attention. An fMRI-based study with 52 adults and 25 children was therefore conducted using a highly immersive VE. The experience of presence in adult subjects was found to be modulated by two major strategies involving two homologous prefrontal brain structures. Whereas the right DLPFC controlled the sense of presence by down-regulating the activation in the egocentric dorsal visual processing stream, the left DLPFC up-regulated widespread areas of the medial prefrontal cortex known to be involved in self-reflective and stimulus-independent thoughts. In contrast, there was no evidence of these two strategies in children. In fact, anatomical analyses showed that these two prefrontal areas have not yet reached full maturity in children. Taken together, this study presents the first findings that show activation of a highly specific neural network orchestrating the experience of presence in adult subjects, and that the absence of activity in this neural network might contribute to the generally increased susceptibility of children for the experience of presence in VEs.

Virtual reality and the role of the prefrontal cortex in adults and children

In this review, the neural underpinnings of the experience of presence are outlined. Firstly, it is shown that presence is associated with activation of a distributed network, which includes the dorsal and ventral visual stream, the parietal cortex, the premotor cortex, mesial temporal areas, the brainstem and the thalamus. Secondly, the dorsolateral prefrontal cortex (DLPFC) is identified as a key node of the network as it modulates the activity of the network and the associated experience of presence. Thirdly, children lack the strong modulatory influence of the DLPFC on the network due to their unmatured frontal cortex. Fourthly, it is shown that presence-related measures are influenced by manipulating the activation in the DLPFC using transcranial direct current stimulation (tDCS) while participants are exposed to the virtual roller coaster ride. Finally, the findings are discussed in the context of current models explaining the experience of presence, the rubber hand illusion, and out-of-body experiences.

Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 (PKHD1) Gene

Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD.

Clinical and haematological predictors of antibiotic prescribing for acute cough in adults in Swiss practices - an observational study.

BackgroundAcute cough is a common problem in general practice and is often caused by a self-limiting, viral infection. Nonetheless, antibiotics are often prescribed in this situation, which may lead to unnecessary side effects and, even worse, the development of antibiotic resistant microorganisms worldwide. This study assessed the role of point-of-care C-reactive protein (CRP) testing and other predictors of antibiotic prescription in patients who present with acute cough in general practice.MethodsPatient characteristics, symptoms, signs, and laboratory and X-ray findings from 348 patients presenting to 39 general practitioners with acute cough, as well as the GPs themselves, were recorded by fourth-year medical students during their three-week clerkships in general practice. Patient and clinician characteristics of those prescribed and not-prescribed antibiotics were compared using a mixed-effects model.ResultsOf 315 patients included in the study, 22% were prescribed antibiotics. The two groups of patients, those prescribed antibiotics and those treated symptomatically, differed significantly in age, demand for antibiotics, days of cough, rhinitis, lung auscultation, haemoglobin level, white blood cell count, CRP level and the GP¿s license to self-dispense antibiotics. After regression analysis, only the CRP level, the white blood cell count and the duration of the symptoms were statistically significant predictors of antibiotic prescription.ConclusionsThe antibiotic prescription rate of 22% in adult patients with acute cough in the Swiss primary care setting is low compared to other countries. GPs appear to use point-of-care CRP testing in addition to the duration of clinical symptoms to help them decide whether or not to prescribe antibiotics.

The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor.

INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic lung disease, resulting in respiratory insufficiency and reduced survival. Pulmonary fibrosis is a result of repeated alveolar epithelial microinjuries, followed by abnormal regeneration and repair processes in the lung. Recently, stem cells and their secretome have been investigated as a novel therapeutic approach in pulmonary fibrosis. We evaluated the potential of induced pluripotent stem cells (iPSC) conditioned media (iPSC-cm) to regenerate and repair the alveolar epithelium in vitro and improve bleomycin induced lung injury in vivo. METHODS IPSC-cm was collected from cultured iPSC derived from human foreskin fibroblasts and its biological effects on alveolar epithelial wound repair was studied in an alveolar wound healing assay in vitro. Furthermore, iPSC-cm was intratracheally instilled 7 days after bleomycin induced injury in the rat lungs and histologically and biochemically assessed 7 days after instillation. RESULTS iPSC-cm increased alveolar epithelial wound repair in vitro compared with medium control. Intratracheal instillation of iPSC-cm in bleomycin-injured lungs reduced the collagen content and improved lung fibrosis in the rat lung in vivo. Profibrotic TGFbeta1 and alpha-smooth muscle actin (alpha-sma) expression were markedly reduced in the iPSC-cm treated group compared with control. Antifibrotic hepatocyte growth factor (HGF) was detected in iPSC-cm in biologically relevant levels, and specific inhibition of HGF in iPSC-cm attenuated the antifibrotic effect of iPSC-cm, indicating a central role of HGF in iPSC-cm. CONCLUSION iPSC-cm increased alveolar epithelial wound repair in vitro and attenuated bleomycin induced fibrosis in vivo, partially due to the presence of HGF and may represent a promising novel, cell free therapeutic option against lung injury and fibrosis.