An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy.

OBJECTIVES: Non-melanoma skin cancers are the most frequently occurring type of cancer worldwide. They can be effectively treated using topical dermatological photodynamic therapy (PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease remains superficial. Novel iron chelating agents are being investigated to enhance the effectiveness and extend the applications of this treatment modality, as limiting free iron increases the accumulation of PpIX available for light activation and thus cell kill. METHODS: Human lung fibroblasts (MRC-5) and epithelial squamous carcinoma (A431) cells were treated with PpIX precursors (aminolaevulinic acid [ALA] or methyl-aminolevulinate [MAL]) with or without the separate hydroxypyridinone iron chelating agent (CP94) or alternatively, the new combined iron chelator and PpIX producing agent, AP2-18. PpIX fluorescence was monitored hourly for 6 hours prior to irradiation. PDT effectiveness was then assessed the following day using the lactate dehydrogenase and neutral red assays. RESULTS: Generally, iron chelation achieved via CP94 or AP2-18 administration significantly increased PpIX fluorescence. ALA was more effective as a PpIX-prodrug than MAL in A431 cells, corresponding with the lower PpIX accumulation observed with the latter congener in this cell type. Addition of either iron chelating agent consistently increased PpIX accumulation but did not always convey an extra beneficial effect on PpIX-PDT cell kill when using the already highly effective higher dose of ALA. However, these adjuvants were highly beneficial in the skin cancer cells when compared with MAL administration alone. AP2-18 was also at least as effective as CP94 + ALA/MAL co-administration throughout and significantly better than CP94 supplementation at increasing PpIX fluorescence in MRC5 cells as well as at lower doses where PpIX accumulation was observed to be more limited. CONCLUSIONS: PpIX fluorescence levels, as well as PDT cell kill effects on irradiation can be significantly increased by pyridinone iron chelation, either via the addition of CP94 to the administration of a PpIX precursor or alternatively via the newly synthesized combined PpIX prodrug and siderophore, AP2-18. The effect of the latter compound appears to be at least equivalent to, if not better than, the separate administration of its constituent parts, particularly when employing MAL to destroy skin cancer cells. AP2-18 therefore warrants further detailed analysis, as it may have the potential to improve dermatological PDT outcomes in applications currently requiring enhancement. Lasers Surg. Med. 50:552-565, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Potential Benefits of an Integrated Electric-Acoustic Sound Processor with Children: A Preliminary Report.

BACKGROUND: A number of published studies have demonstrated the benefits of electric-acoustic stimulation (EAS) over conventional electric stimulation for adults with functional low-frequency acoustic hearing and severe-to-profound high-frequency hearing loss. These benefits potentially include better speech recognition in quiet and in noise, better localization, improvements in sound quality, better music appreciation and aptitude, and better pitch recognition. There is, however, a paucity of published reports describing the potential benefits and limitations of EAS for children with functional low-frequency acoustic hearing and severe-to-profound high-frequency hearing loss. PURPOSE: The objective of this study was to explore the potential benefits of EAS for children. RESEARCH DESIGN: A repeated measures design was used to evaluate performance differences obtained with EAS stimulation versus acoustic- and electric-only stimulation. STUDY SAMPLE: Seven users of Cochlear Nucleus Hybrid, Nucleus 24 Freedom, CI512, and CI422 implants were included in the study. DATA COLLECTION AND ANALYSIS: Sentence recognition (assayed using the pediatric version of the AzBio sentence recognition test) was evaluated in quiet and at three fixed signal-to-noise ratios (SNR) (0, +5, and +10 dB). Functional hearing performance was also evaluated with the use of questionnaires, including the comparative version of the Speech, Spatial, and Qualities, the Listening Inventory for Education Revised, and the Children's Home Inventory for Listening Difficulties. RESULTS: Speech recognition in noise was typically better with EAS compared to participants' performance with acoustic- and electric-only stimulation, particularly when evaluated at the less favorable SNR. Additionally, in real-world situations, children generally preferred to use EAS compared to electric-only stimulation. Also, the participants' classroom teachers observed better hearing performance in the classroom with the use of EAS. CONCLUSIONS: Use of EAS provided better speech recognition in quiet and in noise when compared to performance obtained with use of acoustic- and electric-only stimulation, and children responded favorably to the use of EAS implemented in an integrated sound processor for real-world use.

Is Beta Radiation Better than 5 Flurouracil as an Adjunct for Trabeculectomy Surgery When Combined with Cataract Surgery? A Randomised Controlled Trial.

INTRODUCTION: In an African setting surgery is generally accepted as the treatment of first choice for glaucoma. A problem with trabeculectomy surgery for the glaucomas is the frequent co-existence and exacerbation of cataract. We report a randomized controlled trial to compare the use of beta radiation with 5FU in combined cataract and glaucoma surgery. PARTICIPANTS AND METHODS: Consenting adults aged >40 years with glaucoma, an IOP>21mmHG and cataract were enrolled and randomised to receive either 1000cG ß radiation application or sub-conjunctival 5fluorouracil (5FU) at the time of combined trabeculectomy and phaco-emulsification with lens implant surgery. RESULTS: 385 individuals were eligible for inclusion of whom 301 consented to inclusion in the study (one eye per patient). 150 were randomised to the 5FU arm and 151 received ß radiation. In the 12 months following surgery there were 40 failures (IOP>21mmHg) in the 5FU arm and 34 failures in the beta arm. The hazard ratio for the beta radiation arm compared to the 5FU arm, adjusted for IOP at baseline, was 0.83 (95% c.i. 0.54 to 1.28; P = 0.40). The improvement from mean presenting visual acuities of 0.91 and 0.86 logMAR to 0.62 and 0.54 in the 5FU and beta arms respectively was comparable between groups (P = 0.4 adjusting for baseline VA). Incidence of complications did not differ between the two groups. DISCUSSION: This study highlights several important issues in the quest for a therapeutic strategy for the glaucomas in an African context. Firstly, there is no evidence of an important difference between the use of 5FU and beta radiation as an anti-metabolite in phacotrabeculectomy. Secondly phacotrabeculectomy is a successful operation that improves visual acuity as well as controlling IOP in a majority of patients. Although the success of trabeculectomy in lowering IOP is reduced when combined with phacoemulsification compared with trabeculectomy alone, this finding has to be set against the possible need for subsequent cataract surgery following trabeculectomy alone, which represents a second trip and expense for the patient and results in 10-61% failure of the trabeculectomy at one year post-cataract surgery. TRIAL REGISTRATION: ISRCTN Registry ISRCTN36436933.

AP39, A Mitochondrially Targeted Hydrogen Sulfide Donor, Exerts Protective Effects in Renal Epithelial Cells Subjected to Oxidative Stress in Vitro and in Acute Renal Injury in Vivo.

This study evaluated the effects of AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl) phenoxy)decyl) triphenyl phosphonium bromide], a mitochondrially targeted donor of hydrogen sulfide (H2S) in an in vitro model of hypoxia/oxidative stress injury in NRK-49F rat kidney epithelial cells (NRK cells) and in a rat model of renal ischemia-reperfusion injury. Renal oxidative stress was induced by the addition of glucose oxidase, which generates hydrogen peroxide in the culture medium at a constant rate. Glucose oxidase (GOx)-induced oxidative stress led to mitochondrial dysfunction, decreased intracellular ATP content, and, at higher concentrations, increased intracellular oxidant formation (estimated by the fluorescent probe 2, 7-dichlorofluorescein, DCF) and promoted necrosis (estimated by the measurement of lactate dehydrogenase release into the medium) of the NRK cells in vitro. Pretreatment with AP39 (30-300 nM) exerted a concentration-dependent protective effect against all of the above effects of GOx. Most of the effects of AP39 followed a bell-shaped concentration-response curve; at the highest concentration of GOx tested, AP39 was no longer able to afford cytoprotective effects. Rats subjected to renal ischemia/reperfusion responded with a marked increase (over four-fold over sham control baseline) blood urea nitrogen and creatinine levels in blood, indicative of significant renal damage. This was associated with increased neutrophil infiltration into the kidneys (assessed by the myeloperoxidase assay in kidney homogenates), increased oxidative stress (assessed by the malondialdehyde assay in kidney homogenates), and an increase in plasma levels of IL-12. Pretreatment with AP39 (0.1, 0.2, and 0.3 mg/kg) provided a dose-dependent protection against these pathophysiological alterations; the most pronounced protective effect was observed at the 0.3 mg/kg dose of the H2S donor; nevertheless, AP39 failed to achieve a complete normalization of any of the injury markers measured. The partial protective effects of AP39 correlated with a partial improvement of kidney histological scores and reduced TUNEL staining (an indicator of DNA damage and apoptosis). In summary, the mitochondria-targeted H2S donor AP39 exerted dose-dependent protective effects against renal epithelial cell injury in vitro and renal ischemia-reperfusion injury in vivo. We hypothesize that the beneficial actions of AP39 are related to the reduction of cellular oxidative stress, and subsequent attenuation of various positive feed-forward cycles of inflammatory and oxidative processes.

AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.

The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. Addition of AP39 (30-300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage.

The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.

The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1ß, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.

Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint?

Hydrogen sulfide (H(2)S) has recently been proposed as an endogenous mediator of inflammation and is present in human synovial fluid. This study determined whether primary human articular chondrocytes (HACs) and mesenchymal progenitor cells (MPCs) could synthesize H(2)S in response to pro-inflammatory cytokines relevant to human arthropathies, and to determine the cellular responses to endogenous and pharmacological H(2)S. HACs and MPCs were exposed to IL-1ß, IL-6, TNF-α and lipopolysaccharide (LPS). The expression and enzymatic activity of the H(2)S synthesizing enzymes cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) were determined by Western blot and zinc-trap spectrophotometry, respectively. Cellular oxidative stress was induced by H(2)O(2), the peroxynitrite donor SIN-1 and 4-hydroxynonenal (4-HNE). Cell death was assessed by 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (DCm) was determined in situ by flow cytometry. Endogenous H(2) S synthesis was inhibited by siRNA-mediated knockdown of CSE and CBS and pharmacological inhibitors D,L-propargylglycine and aminoxyacetate, respectively. Exogenous H(2)S was generated using GYY4137. Under basal conditions HACs and MPCs expressed CBS and CSE and synthesized H(2)S in a CBS-dependent manner, whereas CSE expression and activity was induced by treatment of cells with IL-1ß, TNF-α, IL-6 or LPS. Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H(2)S synthesis or by CBS/CSE-siRNA treatment. These data suggest CSE is an inducible source of H(2)S in cultured HACs and MPCs. H(2)S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention.

Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study.

BACKGROUND: The development of a totally subcutaneous implantable defibrillator (S-ICD) system requires a new approach for arrhythmia detection. To evaluate arrhythmia discrimination of one such system, the Subcutaneous versus Transvenous Arrhythmia Recognition Testing (START) study was designed as a prospective, multicenter trial comparing simulated sensing performances of the S-ICD system with single- (SC-TV) and dual-chamber transvenous (DC-TV) implantable cardioverter-defibrillator (ICD) systems. METHODS: At ICD implantation, induced ventricular and atrial arrhythmias were recorded simultaneously in transvenous (right ventricular [RV] → superior vena cava [SVC]+ Coil) and cutaneous electrode configurations. Recorded signals of ventricular (n = 46) and atrial arrhythmias (n = 50) with ventricular rates >170 bpm from 64 patients were used to compare detection performance of the S-ICD system with TV-ICD systems from 3 manufacturers. Appropriate detection of ventricular tachyarrhythmias was assessed with devices programmed in single-zone (rate ≥ 170 bpm) and dual-zone configurations (ventricular fibrillation ≥ 240 bpm; ventricular tachycardia ≥ 170 bpm). S-ICD specificity performance for supraventricular arrhythmias was compared to single- and dual-chamber devices in a dual-zone configuration. RESULTS: Appropriate detection of ventricular tachyarrhythmias for subcutaneous and TV devices in single- and dual-zone configurations was 100% and >99%, respectively. Specificity for supraventricular arrhythmias was significantly better for the S-ICD system compared to 2 of 3 TV systems, as well as the composite of TV devices (98.0%[S-ICD] vs 76.7%[SC-TV range: 64.0-92.0%] vs 68.0%[DC-TV range: 32.7-89.8%; P < 0.001]). CONCLUSION: Appropriate ventricular arrhythmia detection is excellent for all ICD systems evaluated; however, specificity of supraventricular arrhythmia discrimination by the S-ICD system is better than discrimination by 2 of 3 TV systems.

Tumor-stromal cell interactions and opportunities for therapeutic intervention.

Tumor tissue is composed of both cancer cells and stromal cells recruited from normal tissue. These cells include fibroblastic cells, endothelial cells, and cells of hematopoietic origin. The host-derived stromal cells play a critical role in all aspects of cancer biology including transformation, progression, tumor growth, and drug resistance. The interactions between stromal cells and cancer cells are of intense interest, and their complex interactions are beginning to be identified. Therapies that target components of the tumor microenvironment are showing efficacy in the clinic, particularly when used in combination with other therapeutic agents. In general these agents have been well tolerated, and targeting the stromal components may be a strategy for circumventing the problem of drug resistance. In this review, we highlight major stromal components, their interactions with tumor cells, and therapeutic approaches that disrupt host-tumor cell interactions. Advances in understanding host stromal components with respect to origin, subsets, and their signaling networks will reveal novel targets. Synergistic approaches that disrupt multiple host-tumor cell signaling pathways will lead to more effective therapies for cancer.

Long-term fish oil supplementation induces cardiac electrical remodeling by changing channel protein expression in the rabbit model.

Clinical trials and epidemiological studies have suggested that dietary fish oil (FO) supplementation can provide an anti-arrhythmic benefit in some patient populations. The underlying mechanisms are not entirely clear. We wanted to understand how FO supplementation (for 4 weeks) affected the action potential configuration/duration of ventricular myocytes, and the ionic mechanism(s)/molecular basis for these effects. The experiments were conducted on adult rabbits, a widely used animal model for cardiac electrophysiology and pathophysiology. We used gas chromatography-mass spectroscopy to confirm that FO feeding produced a marked increase in the content of n-3 polyunsaturated fatty acids in the phospholipids of rabbit hearts. Left ventricular myocytes were used in current and voltage clamp experiments to monitor action potentials and ionic currents, respectively. Action potentials of myocytes from FO-fed rabbits exhibited much more positive plateau voltages and prolonged durations. These changes could be explained by an increase in the L-type Ca current (I(CaL)) and a decrease in the transient outward current (I(to)) in these myocytes. FO feeding did not change the delayed rectifier or inward rectifier current. Immunoblot experiments showed that the FO-feeding induced changes in I(CaL) and I(to) were associated with corresponding changes in the protein levels of major pore-forming subunits of these channels: increase in Cav1.2 and decrease in Kv4.2 and Kv1.4. There was no change in other channel subunits (Cav1.1, Kv4.3, KChIP2, and ERG1). We conclude that long-term fish oil supplementation can impact on cardiac electrical activity at least partially by changing channel subunit expression in cardiac myocytes.

Measuring mindfulness and examining its relationship with alcohol use and negative consequences.

Mindfulness has been proposed as a useful adjunct to alcohol abuse treatment. However, very little research has examined the basic relationship between alcohol use and mindfulness. Inconsistency in definition and measurement of mindfulness across studies makes such research difficult to interpret and conduct. Therefore, the current research sought to validate an emerging mindfulness measure, the Five Facet Mindfulness Questionnaire (FFMQ), and examine its relationship with alcohol use and alcohol-related negative consequences among a sample of 316 college-aged adults. The purported factor structure of the FFMQ was examined using confirmatory factor analysis. Structural equation modeling was used to examine relations among mindfulness, alcohol use, and alcohol-related negative consequences. Consistent with past research, results supported the five-factor structure of the FFMQ. Structural equation modeling analyses revealed that two awareness-based factors of mindfulness were negatively related to alcohol use. After controlling for alcohol use, one acceptance-based factor (nonjudging of thoughts and feelings) was negatively related to alcohol-related consequences, and one awareness-based factor was positively related to consequences (all ps < .05). Effect sizes were small-medium. The results reported here inform the burgeoning development of mindfulness-based addiction treatment and provide additional psychometric validation of the FFMQ.

Efficacy of a cooled bipolar epicardial radiofrequency ablation probe for creating transmural myocardial lesions.

OBJECTIVE: Creation of transmural myocardial lesions with epicardial surgical devices to treat atrial fibrillation is difficult. A new cooled bipolar radiofrequency ablation probe was used to create transmural myocardial lesions under controlled conditions. METHODS: The Coolrail (AtriCure, Inc, West Chester, Ohio) is a handheld probe with 2 parallel 30-mm long radiofrequency conductors. Conductors are cooled by water irrigation. Lesions were delivered to epicardial surface of isolated bovine myocardium sliced 3- to 8-mm thick, with blood flow beneath tissue at 0 or 0.4 m/s. Contact pressure between probe and tissue was either 450 g or 900 g. Tissue temperatures were measured. Tissue was sectioned every 5 mm along lesion long axis to determine lesion dimensions. RESULTS: For 80 experiments with 450-g contact pressure, epicardial lesion length was 31.3 mm (interquartile range, 30.1-32.8 mm); endocardial lesion length was 14.1 mm (interquartile range, 0.0-22.6 mm). Average lesion depth was 4.2 +/- 0.74 mm. Temperature at probe interface was 81 degrees C +/- 21 degrees C; that at blood pool interface was 53 degrees C +/- 12 degrees C. Lesions were always transmural when tissue thickness was 4.0 mm or less. Endocardial blood flow did not influence lesion depth. With 900-g contact pressure, increased depth was always transmural at 4.8-mm tissue thickness or less. CONCLUSIONS: This irrigated bipolar radiofrequency probe consistently produced transmural lesions in tissue 4 mm or thinner under controlled conditions in vitro. Lesion depth was increased by greater pressure on probe and not affected by blood flow. Endocardial lesions were smaller than epicardial dimensions.

A totally implantable hearing system--design and function characterization in 3D computational model and temporal bones.

Implantable middle ear hearing devices are emerging as an effective technology for patients with mild to moderately severe sensorineural hearing loss. Several devices with electromagnetic or piezoelectric transducers have been investigated or developed in the US and Europe since 1990. This paper reports a totally implantable hearing system (TIHS) currently under investigation in Oklahoma. The TIHS consists of implant transducer (magnet), implantable coil and microphone, DSP-audio signal processor, rechargeable battery, and remote control unit. The design of TIHS is based on a 3D finite element model of the human ear and the analysis of electromagnetic coupling of the transducer. Function of the TIHS is characterized over the auditory frequency range in three aspects: (1) mass loading effect on residual hearing with a passive implant, (2) efficiency of electromagnetic coupling between the implanted coil and magnet, and (3) functional gain of whole unit in response to acoustic input across the human skin. This paper focuses on mass loading effect and the efficiency of electromagnetic coupling of TIHS determined from the FE model of the human ear and the cadaver ears or temporal bones. Some preliminary data of whole unit function are also presented in the paper.

The anatomic location of the soul from the heart, through the brain, to the whole body, and beyond: a journey through Western history, science, and philosophy.

OBJECTIVE: To describe representative Western philosophical, theological, and scientific ideas regarding the nature and location of the soul from the Egyptians to the contemporary period; and to determine the principal themes that have structured the history of the development of the concept of the soul and the implications of the concept of the soul for medical theory and practice. METHODS: We surveyed the ancient Egyptian, Greek, and Roman periods, the early, Medieval, and late Christian eras, as well as the Renaissance, Enlightenment, and Modern periods to determine the most salient ideas regarding the nature and location of the soul. RESULTS: In the history of Western theological, philosophical, and scientific/medical thought, there exist 2 dominant and, in many respects, incompatible concepts of the soul: one that understands the soul to be spiritual and immortal, and another that understands the soul to be material and mortal. In both cases, the soul has been described as being located in a specific organ or anatomic structure or as pan-corporeal, pervading the entire body, and, in some instances, trans-human and even pan-cosmological. Moreover, efforts to discern the nature and location of the soul have, throughout Western history, stimulated physiological exploration as well as theoretical understanding of human anatomy. The search for the soul has, in other words, led to a deepening of our scientific knowledge regarding the physiological and, in particular, cardiovascular and neurological nature of human beings. In addition, in virtually every period, the concept of the soul has shaped how societies thought about, evaluated, and understood the moral legitimacy of scientific and medical procedures: from performing abortions and autopsies to engaging in stem cell research and genetic engineering. CONCLUSION: Our work enriches our shared understanding of the soul by describing some of the key formulations regarding the nature and location of the soul by philosophers, theologians, and physicians. In doing so, we are better able to appreciate the significant role that the concept of the soul has played in the development of Western scientific, medical, and spiritual life. Although ideas about the soul have changed significantly throughout Western history, the idea of the soul as being real and essential to one's personhood has been, and remains, pervasive throughout every period of Western history.

Fixation and detachment of superior and anterior malleolar ligaments in human middle ear: experiment and modeling.

The aim of this study is to investigate the function of the superior malleolar ligament (SML) and the anterior malleolar ligament (AML) in human middle ear for sound transmission through simulations of fixation and detachment of these ligaments in human temporal bones and a finite element (FE) ear model. Two laser vibrometers were used to measure the vibrations of the tympanic membrane (TM) and stapes footplate. A 3-D FE ear model was used to predict the transfer function of the middle ear with ligament fixation and detachment. The results demonstrate that fixations and detachments of the SML and AML had different effects on TM and stapes footplate movements. Fixation of the SML resulted in a reduction of displacement of the TM (umbo) and the footplate at low frequencies (f<1000 Hz), but also caused a shift of displacement peak to higher frequencies. Fixation of both SML and AML caused a reduction of 15 dB at umbo or stapes at low frequencies. Detachment of the SML had almost no effect on TM and footplate mobility, but AML detachment had a minor effect on TM and footplate movement. The FE model was able to predict the effects of SML and AML fixation and detachment.

Atrial arrhythmias following ostial or circumferential pulmonary vein ablation.

AIMS: The incidence, clinical significance and optimum treatment of AF ablation-induced proarrhythmia is not entirely known. This report describes the incidence and management of atrial arrhythmias occurring after various techniques for the ablative therapy of atrial fibrillation (AF). METHODS: Five hundred and forty-four patients with paroxysmal atrial fibrillation were subjected to ostial pulmonary vein (PV) (n = 204), antral (n = 300), or circumferential (n = 40) ablation around the PV ostia. RESULTS: Atrial tachycardia or flutter during the first 6 months after AF ablation was detected in 14 patients and was more common among patients subjected to circumferential or circumferential and linear ablation (18% and 22%, respectively) than to other techniques (p < 0.001). The risk of atrial tachycardia or flutter among patients who underwent ostial, ostial with lines and antral ablation was 1%, 8% and 1%, respectively. No difference was observed in the risk of atrial arrhythmia between patients who underwent ablation with or without additional lines, either ostial (p = 0.17) or circumferential (p = 0.99). Re-ablation was performed in patients with sustained atrial arrhythmia (11 out of 14 patients). At 6 months, no recurrence was seen in 10 of these patients as well as in 3 patients with non-sustained atrial tachycardia or flutter. CONCLUSIONS: The incidence of atrial tachycardia or flutter following AF ablation is lower for ostial than circumferential ablation. The addition of lines along the mitral isthmus and between the superior PVs does not significantly affect the risk of ablation-induced arrhythmia. Non-sustained atrial tachycardia or flutter following AF ablation procedures does not always require additional ablation.

Dual-chamber versus single-chamber detection enhancements for implantable defibrillator rhythm diagnosis: the detect supraventricular tachycardia study.

BACKGROUND: Delivery of inappropriate shocks caused by misdetection of supraventricular tachycardia (SVT) remains a substantial complication of implanted cardioverter/defibrillator (ICD) therapy. Whether use of optimally programmed dual-chamber ICDs lowers this risk compared with that in single-chamber ICDs is not clear. METHODS AND RESULTS: Subjects with a clinical indication for ICD (n=400) at 27 participating centers received dual-chamber ICDs and were randomly assigned to strictly defined optimal single- or dual-chamber detection in a single-blind manner. Programming minimized ventricular pacing. The primary end point was the proportion of SVT episodes inappropriately detected from the time of programming until crossover or end of study. On a per-episode basis, 42% of the episodes in the single-chamber arm and 69% of the episodes in the dual-chamber arm were due to SVT. Mortality (3.5% in both groups) and early study withdrawal (14% single-chamber, 11% dual-chamber) were similar in both groups. The rate of inappropriate detection of SVT was 39.5% in the single-chamber detection arm compared with 30.9% in the dual-chamber arm. The odds of inappropriate detection were decreased by almost half with the use of the dual-chamber detection enhancements (odds ratio, 0.53; 95% confidence interval, 0.30 to 0.94; P=0.03). CONCLUSIONS: Dual-chamber ICDs, programmed to optimize detection enhancements and to minimize ventricular pacing, significantly decrease inappropriate detection.