Predicting time to serologic diagnosis of AQP4+ NMOSD based on clinical factors and social determinants of health.

BACKGROUND: Early serologic diagnosis and initiation of targeted therapy are associated with better outcomes in aquaporin-4 IgG positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To determine predictors of time to serologic diagnosis of AQP4+ NMOSD. METHODS: In CANOPTICS, a multi-centre, Canadian cohort study of NMOSD, we retrospectively evaluated time from the first clinical attack to first positive AQP4-IgG serology. We used a multivariable negative binomial regression model to evaluate possible predictors of time to diagnosis. RESULTS: We identified 129 participants with AQP4+ NMOSD from 7 centres. Diagnostic delay of >1 month was observed in 82 (63.6 %). Asian compared to European (White) ethnicity (IRR:0.40, 95 % CI:0.21-0.78), female sex (IRR:0.56, 95 % CI:0.32-0.99), later calendar year (IRR:0.84, 95 % CI:0.81-0.86), and hospitalization for the first attack (IRR:0.35, 95 % CI:0.20-0.62) were associated with shorter times to serologic diagnosis. We did not observe any overall effect of Afro-Caribbean ethnicity, but in exploratory analyses, Afro-Caribbean individuals with low income had longer times to diagnosis. CONCLUSION: More than 60 % of patients with NMOSD experienced delays to AQP4-IgG serologic diagnosis in this cohort. Given evidence of more adverse long-term outcomes in Afro-Caribbean individuals with NMOSD, intersectional effects of ethnicity and social determinants of health merit further study.

A Canadian case control study investigating demographic and environmental factors associated with MOGAD.

BACKGROUND: Little is known about demographic and environmental factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). OBJECTIVE: To investigate factors associated with MOGAD using a case-control design and validated questionnaire from the Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS). METHODS: We enrolled patients with positive MOG antibody serology and diagnosis of MOGAD at six Canadian centres. MOGAD participants completed the EnvIMS questionnaire, and were compared to unaffected controls from the Canadian arm of EnvIMS. We calculated crude and adjusted odds ratios (OR) using logistic regression models and Firth's procedure for rare events. RESULTS: We enrolled 39 MOGAD participants with mean (SD) age 45.0 (14.4) years, 28 (71.8 %) women, 25 (64.1 %) White, 26 (66.7 %) residents of Ontario, and mean BMI 28.6 (7.1). They were compared to 956 controls. Using multivariable logistic regression, larger body size at age 10 years (OR: 3.57, 95 % CI:1.23 - 10.33) and non-White ethnicity (OR:3.81, 95 % CI:1.93-7.54) were associated with higher odds of MOGAD. Among Ontario residents, current BMI ≥30 was associated with higher odds of MOGAD (OR:2.79, 95 % CI:1.03-7.53). CONCLUSION: Our findings are hypothesis-generating due to the sample size, but suggest that obesity and ethnicity should be explored as potential risk factors for MOGAD in other settings.

A national case-control study investigating demographic and environmental factors associated with NMOSD.

BACKGROUND: Risk factors for aquaporin-4 (AQP4+) antibody neuromyelitis optica spectrum disorder (NMOSD) are not well-established. OBJECTIVE: To investigate demographic and environmental factors associated with NMOSD using a validated questionnaire and case-control design. METHODS: We enrolled patients with AQP4 + NMOSD through six Canadian Multiple Sclerosis Clinics. Participants completed the validated Environmental Risk Factors in Multiple Sclerosis Study (EnvIMS) questionnaire. Their responses were compared to those of 956 unaffected controls from the Canadian arm of EnvIMS. We calculated odds ratios (ORs) for the association between each variable and NMOSD using logistic regression and Firth's procedure for rare events. RESULTS: In 122 participants (87.7% female) with NMOSD, odds of NMOSD in East Asian and Black participants were ⩾8 times that observed in White participants. Birthplace outside Canada was associated with an increased risk of NMOSD (OR = 5.5, 95% confidence interval (CI) = 3.6-8.3) as were concomitant autoimmune diseases (OR = 2.7, 95% CI = 1.4-5.0). No association was observed with reproductive history or age at menarche. CONCLUSION: In this case-control study, risk of NMOSD in East Asian and Black versus White individuals was greater than that observed in many previous studies. Despite the preponderance of affected women, we did not observe any association with hormonal factors such as reproductive history or age at menarche.

A Systematic Scoping Review on Migrant Health Coverage in Thailand.

(1) Background: Thailand is a major migrant receiving country and pioneer of migrant health policy in the ASEAN region. However, on the ground, coverage of migrants is faced with multiple barriers. (2) Objectives: We aim to scope and analyse the types of available evidence on migrant health coverage in Thailand and identify knowledge gaps. Specifically, we characterise the literature along year of publication, migrant subpopulation, health domain, scope of coverage, methods, study design, objectives and results. (3) Methods: We searched PubMed, Web of Science, Google Scholar, Cochrane Database, Worldwide Science and the Asian Citation Index for peer-reviewed and grey literature in October 2021 for studies analysing original data on health coverage of migrants in Thailand. To conceptualise health coverage, we used the three dimensions availability, accessibility and acceptability. (4) Results: 101 articles were included in the final analysis. Sixty-three were published after 2016, 39 focused on migrant workers and 18 on migrants in general. Forty-two concentrated on health in broader terms, followed by reproductive and maternal health (n = 31). Thirty-eight assessed coverage of specific services and 36 health coverage in general. Migrants themselves and key informants were the main data sources in 80 and 43 of the articles, respectively. Forty publications were qualitative, while 38 applied quantitative methods (22% descriptive; 7% analytical). Among the health coverage components, 79 articles included aspects of accessibility, followed by acceptability (n = 59) and availability (n = 30). (5) Conclusions: While there is a high number and broad range of studies on migrant health coverage in Thailand, we found that research on migrant subgroups, such as victims of trafficking and migrant children, as well as on the health domains, non-communicable diseases and occupational and mental health is neglected.

Designed to Be Green, Economic, and Efficient: A Ketone-Ester-Alcohol-Alkane Blend for Future Spark-Ignition Engines.

Model-based fuel design can tailor fuels to advanced engine concepts while minimizing environmental impact and production costs. A rationally designed ketone-ester-alcohol-alkane (KEAA) blend for high efficiency spark-ignition engines was assessed in a multi-disciplinary manner, from production cost to ignition characteristics, engine performance, ecotoxicity, microbial storage stability, and carbon footprint. The comparison included RON 95 E10, ethanol, and two previously designed fuels. KEAA showed high indicated efficiencies in a single-cylinder research engine. Ignition delay time measurements confirmed KEAA's high auto-ignition resistance. KEAA exhibits a moderate toxicity and is not prone to microbial infestation. A well-to-wheel analysis showed the potential to lower the carbon footprint by 95 percent compared to RON 95 E10. The findings motivate further investigations on KEAA and demonstrate advancements in model-based fuel design.

[Attitudes to publication of quality testing reports in nursing homes]. / Einstellungen zur Veröffentlichung von Qualitätsberichten in Pflegeeinrichtungen.

BACKGROUND: The Nursing and Living Quality Act (PfleWoqG) regulates the implementation of legally regulated quality inspections and publication of statutory quality inspection reports for residential nursing homes in Bavaria. In the currently valid version, the quality records have to be published but a decision of the higher administrative court (VGH) repealed this rule and it is no longer in force. OBJECTIVE AND METHODS: Within the framework of a project for the Bavarian State Ministry for Health and Nursing concerning the revision of the publication of legally regulated quality testing reports, appraisals by the institutional management in nursing homes were collated. The E­survey reached 24% (n = 529) of all residential care homes for elderly people and residential care homes for handicapped people in Bavaria. RESULTS AND CONCLUSION: Approximately two thirds of the persons questioned attested that the inspections and the resulting reports reflected an appropriate picture of the quality of nursing carried out in the institutions. Nevertheless, the vast majority did not approve of the obligatory publication of the quality testing records. While the inspections were seen as a valuable basis to reflect on the quality of care in the institutions, it was simultaneously argued that the inspections are only snapshots, which could be misinterpreted by the public. It was criticized that the quality testing records were not comprehensible for users. Furthermore, it was commented that the ratings of the responsible authorities were influenced by the competence of the inspectors and their subjective point of view and there was therefore a risk that invalid results would be made public.

Impaired Subcortical Detection of Auditory Changes in Schizophrenia but Not in Major Depression.

The mismatch negativity is a cortical response to auditory changes and its reduction is a consistent finding in schizophrenia. Recent evidence revealed that the human brain detects auditory changes already at subcortical stages of the auditory pathway. This finding, however, raises the question where in the auditory hierarchy the schizophrenic deficit first evolves and whether the well-known cortical deficit may be a consequence of dysfunction at lower hierarchical levels. Finally, it should be resolved whether mismatch profiles differ between schizophrenia and affective disorders which exhibit auditory processing deficits as well. We used functional magnetic resonance imaging to assess auditory mismatch processing in 29 patients with schizophrenia, 27 patients with major depression, and 31 healthy control subjects. Analysis included whole-brain activation, region of interest, path and connectivity analysis. In schizophrenia, mismatch deficits emerged at all stages of the auditory pathway including the inferior colliculus, thalamus, auditory, and prefrontal cortex. In depression, deficits were observed in the prefrontal cortex only. Path analysis revealed that activation deficits propagated from subcortical to cortical nodes in a feed-forward mechanism. Finally, both patient groups exhibited reduced connectivity along this processing stream. Auditory mismatch impairments in schizophrenia already manifest at the subcortical level. Moreover, subcortical deficits contribute to the well-known cortical deficits and show specificity for schizophrenia. In contrast, depression is associated with cortical dysfunction only. Hence, schizophrenia and major depression exhibit different neural profiles of sensory processing deficits. Our findings add to a converging body of evidence for brainstem and thalamic dysfunction as a hallmark of schizophrenia.

Fronto-parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing.

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty-five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed-based connectivity analyses investigated depression-specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto-parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed-to voxel analysis on the whole-brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto-parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.

Assessing the coherence of narratives of traumatic events with latent semantic analysis.

OBJECTIVE: Memories of traumatic events are thought to be less coherent than memories for nontraumatic events, and expressive writing about traumatic events may help create more organized, coherent memories. Investigations of traumatic memories have been hampered by limitations in conceptualizing and measuring memory organization and coherence. The objective of this investigation was to compare the coherence of written narratives of trauma and neutral memories and examine changes in coherence of trauma narratives as a function of repeated expressive writing about the trauma using an atheoretical, computational method for assessing the coherence of text. METHOD: Participants (N = 246) wrote 3 times about either their daily activities (neutral condition) or the most traumatic event of their lives. Latent semantic analysis, a method of calculating meaning from text based on semantic association between words, was used to assess narrative coherence as the average semantic association between contiguous sentences. RESULTS: Neutral narratives were more coherent than trauma narratives overall, but neutral narratives decreased whereas trauma narratives increased in coherence from the first to the final session. CONCLUSIONS: These findings provide evidence that memories for trauma experiences are less coherent than neutral memories and suggest that writing helps to create a more coherent representation of a traumatic event, highlighting a potential mechanism for expressive writing's effects. Results demonstrate the utility of latent semantic analysis for examining coherence of memories of traumatic events. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Correction: Conceptual design and analysis of ITM oxy-combustion power cycles.

Correction for 'Conceptual design and analysis of ITM oxy-combustion power cycles' by N. D. Mancini et al., Phys. Chem. Chem. Phys., 2011, 13, 21351-21361.

Effect of expressive and neutral writing on respiratory sinus arrhythmia response over time.

BACKGROUND AND OBJECTIVES: Parasympathetic activity, as indexed by respiratory sinus arrhythmia (RSA), underlies key aspects of emotional and cognitive self-regulation. Examining time-varying RSA response during expressive writing about trauma may help inform theory about mechanisms of this intervention. The present study investigated changes in RSA during expressive writing. METHODS: Participants (N = 246, Mage = 21.5 years, 72% female) were randomly assigned to expressive or neutral writing conditions and wrote for three 20-min sessions. RSA was measured continuously during the first and third writing session. RESULTS: Linear mixed model analyses of RSA changes within and across sessions by writing groups found that neutral writers, but not expressive writers, exhibited change in RSA. The overall RSA changes during expressive and neutral writing are consistent with theory about the relationship between cognitive and emotional processing mechanisms and vagal activation. LIMITATIONS: As the present study was not a clinical sample selected on trauma exposure, findings should be considered preliminary. Additionally, engagement of affective and cognitive processes was only hypothesized, as manipulation checks were not performed. CONCLUSIONS: The present study illustrates the benefits of examining changes in RSA over time. Future work with clinical samples should include additional measures and tasks to better define these mechanisms and rule out alternative hypotheses.

"Nine Dimensions": A multidisciplinary approach for community engagement in a complex postwar border region as part of the targeted malaria elimination in Karen/Kayin State, Myanmar.

Background: In light of growing antimalarial drug resistance in Southeast Asia, control programmes have become increasingly focused on malaria elimination, composed of mass drug administration coupled with prompt diagnosis and treatment of symptomatic cases. The key to a successful elimination programme centres on high participation rates in targeted communities, often enhanced by community engagement (CE) efforts. Social science research was conducted to develop a conceptual framework used for CE activities in the Targeted Malaria Elimination programme, as a cross-border operation in Karen/Kayin State, Myanmar. Methods: Data was collected from three main sources: (1) participant observation and semi-structured interviews of CE team members; (2) participant observation and semi-structured interviews with villagers; and (3) records of CE workshops with CE workers conducted as part of the TME programme. Results: Interviews were conducted with 17 CE team members, with 10 participant observations and interviews conducted with villagers and a total of 3 workshops conducted over the course of this pilot programme in 4 villages (November 2013 to October 2014). Thematic analysis was used to construct the nine dimensions for CE in this complex, post-war region: i) history of the people; ii) space; iii) work; iv) knowledge about the world; v) intriguing obstacle (rumour); vi) relationship with the health care system; vii) migration; viii) logic of capitalism influencing openness; and ix) power relations. Conclusions: Conducting CE for the Targeted Malaria Elimination programme was immensely complicated in Karen/Kayin State because of three key realities: heterogeneous terrains, a post-war atmosphere and cross-border operations. These three key realities constituted the nine dimensions, which proved integral to health worker success in conducting CE. Summary of this approach can aid in infectious disease control programmes, such as those using mass drug administration, to engender high rates of community participation.

Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia.

Major theories on the neural basis of schizophrenic core symptoms highlight aberrant salience network activity (insula and anterior cingulate cortex), prefrontal hypoactivation, sensory processing deficits as well as an impaired connectivity between temporal and prefrontal cortices. The mismatch negativity is a potential biomarker of schizophrenia and its reduction might be a consequence of each of these mechanisms. In contrast to the previous electroencephalographic studies, functional magnetic resonance imaging may disentangle the involved brain networks at high spatial resolution and determine contributions from localized brain responses and functional connectivity to the schizophrenic impairments. Twenty-four patients and 24 matched control subjects underwent functional magnetic resonance imaging during an optimized auditory mismatch task. Haemodynamic responses and functional connectivity were compared between groups. These data sets further entered a diagnostic classification analysis to assess impairments on the individual patient level. In the control group, mismatch responses were detected in the auditory cortex, prefrontal cortex and the salience network (insula and anterior cingulate cortex). Furthermore, mismatch processing was associated with a deactivation of the visual system and the dorsal attention network indicating a shift of resources from the visual to the auditory domain. The patients exhibited reduced activation in all of the respective systems (right auditory cortex, prefrontal cortex, and the salience network) as well as reduced deactivation of the visual system and the dorsal attention network. Group differences were most prominent in the anterior cingulate cortex and adjacent prefrontal areas. The latter regions also exhibited a reduced functional connectivity with the auditory cortex in the patients. In the classification analysis, haemodynamic responses yielded a maximal accuracy of 83% based on four features; functional connectivity data performed similarly or worse for up to about 10 features. However, connectivity data yielded a better performance when including more than 10 features yielding up to 90% accuracy. Among others, the most discriminating features represented functional connections between the auditory cortex and the anterior cingulate cortex as well as adjacent prefrontal areas. Auditory mismatch impairments incorporate major neural dysfunctions in schizophrenia. Our data suggest synergistic effects of sensory processing deficits, aberrant salience attribution, prefrontal hypoactivation as well as a disrupted connectivity between temporal and prefrontal cortices. These deficits are associated with subsequent disturbances in modality-specific resource allocation. Capturing different schizophrenic core dysfunctions, functional magnetic resonance imaging during this optimized mismatch paradigm reveals processing impairments on the individual patient level, rendering it a potential biomarker of schizophrenia.

Enhancing the benefits of written emotional disclosure through response training.

Writing about a personal stressful event has been found to have psychological and physical health benefits, especially when physiological response increases during writing. Response training was developed to amplify appropriate physiological reactivity in imagery exposure. The present study examined whether response training enhances the benefits of written emotional disclosure. Participants were assigned to either a written emotional disclosure condition (n=113) or a neutral writing condition (n=133). Participants in each condition wrote for 20 minutes on 3 occasions and received response training (n=79), stimulus training (n=84) or no training (n=83). Heart rate and skin conductance were recorded throughout a 10-minute baseline, 20-minute writing, and a 10-minute recovery period. Self-reported emotion was assessed in each session. One month after completing the sessions, participants completed follow-up assessments of psychological and physical health outcomes. Emotional disclosure elicited greater physiological reactivity and self-reported emotion than neutral writing. Response training amplified physiological reactivity to emotional disclosure. Greater heart rate during emotional disclosure was associated with the greatest reductions in event-related distress, depression, and physical illness symptoms at follow-up, especially among response trained participants. Results support an exposure explanation of emotional disclosure effects and are the first to demonstrate that response training facilitates emotional processing and may be a beneficial adjunct to written emotional disclosure.

In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome.

The T-box transcription factor BRACHYURY (T) is a key regulator of mesoderm formation during early development. Complete loss of T has been shown to lead to embryonic lethality around E10.0. Here we characterize an inducible miRNA-based in vivo knockdown mouse model of T, termed KD3-T, which exhibits a hypomorphic phenotype. KD3-T embryos display axial skeletal defects caused by apoptosis of paraxial mesoderm, which is accompanied by urorectal malformations resembling the murine uro-recto-caudal syndrome and human caudal regression syndrome phenotypes. We show that there is a reduction of T in the notochord of KD3-T embryos which results in impaired notochord differentiation and its subsequent loss, whereas levels of T in the tailbud are sufficient for axis extension and patterning. Furthermore, the notochord in KD3-T embryos adopts a neural character and loses its ability to act as a signaling center. Since KD3-T animals survive until birth, they are useful for examining later roles for T in the development of urorectal tissues.

Matrix metalloproteinase inhibition attenuates atrial remodeling and vulnerability to atrial fibrillation in a canine model of heart failure.

BACKGROUND: Atrial structural remodeling occurs in evolving heart failure (HF) and is an important substrate for the development of atrial fibrillation (AF). The matrix metalloproteinases (MMPs) play a role in extracellular remodeling, and recent studies have demonstrated increased atrial MMP activity in HF. Whether increased MMP activity directly contributes to atrial remodeling and AF in the setting of HF remains unclear. The current study examined the effects of MMP inhibition on atrial structural remodeling and AF vulnerability during HF progression. METHODS AND RESULTS: Three groups of dogs (n = 5 each)--control normal dogs (controls) and 10 dogs subjected to simultaneous atrioventricular pacing (SAVP) for 2 weeks to induce HF and randomly assigned to treatment with placebo (SAVP-placebo) or a MMP inhibitor PGE-7113313, a MMP-1-sparing MMP inhibitor, 6 mg/kg orally twice daily (SAVP-MMPi)--were studied. SAVP-MMPi dogs had less AF inducibility (percent of burst attempts leading to AF episodes: 1.7 +/- 2.9 seconds vs. 23+/-19 seconds, mean +/- SD, P < .05) and maintenance (AF duration: 253 [105 to 326] vs. 1932 [1296 to 2724] seconds, median [25th-75th quartile], P < .05) than SAVP-placebo dogs. The SAVP-MMPi dogs had significantly smaller increases in atrial myocyte cross sectional area, collagen area fraction, and MMP-9 activity relative to controls than SAVP-placebo. There were, however, no significant differences in the changes in chamber dimension and function in the left atrium. CONCLUSIONS: This unique finding of an attenuation of the vulnerability to AF in conjunction with reduced myocyte hypertrophy and fibrosis after MMP inhibition suggests that heightened MMP activity in the atria contributes to atrial structural remodeling and AF promotion during evolving HF.

Selective type 1 angiotensin II receptor blockade attenuates oxidative stress and regulates angiotensin II receptors in the canine failing heart.

BACKGROUND AND OBJECTIVE: Angiotensin II type 1 receptor (AT(1)R) blockade reduces vascular oxidative stress but whether myocardial oxidative stress represents a mechanism for the beneficial effect of AT(1)R blockade in heart failure is unclear. Furthermore, the impact of AT(1)R blockade on the expression of angiotensin II receptors in heart failure has not been well documented. Accordingly, we examined the impact of the AT(1)R blocker candesartan on hemodynamics, left ventricular (LV) remodeling (echocardiography), oxidative stress, and tissue expression of AT(1)Rs and angiotensin II type 2 receptors (AT(2)Rs) in a canine model of pacing-induced heart failure. METHODS AND RESULTS: Animals were randomized to rapid right ventricular-pacing (250 beats/min for 3 weeks) to severe heart failure and treated with candesartan (10 mg/kg daily, n = 8) or placebo (n = 8) from day 3 onwards, or no pacing (sham, n = 7). Candesartan significantly reduced mean pulmonary arterial and LV diastolic pressure, LV end-diastolic and end-systolic volume and ascites, increased cardiac output, dP/dt, and ejection fraction, while reversing the marked increase in aldehydes, a marker of oxidative stress, observed in the placebo group. Although candesartan did not alter LV AT(1)R protein expression compared to placebo or sham, it reversed the decrease in AT(2)R protein observed in the placebo group. CONCLUSION: Our results indicate that in the pacing model of heart failure, chronic AT(1)R blockade attenuates hemodynamic deterioration and limits LV remodeling and dysfunction, in part by reversing oxidative stress and AT(2)R downregulation.

Simultaneous right atrioventricular pacing: a novel model to study atrial remodeling and fibrillation in the setting of heart failure.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia which contributes to morbidity and mortality in patients with heart failure (HF). Atrial remodeling is a key substrate for the development of AF in HF. However, experimental models that study AF in the setting of HF have important limitations. We evaluated a new dog model of atrial remodeling and AF. METHODS AND RESULTS: Twenty-two mongrel dogs were randomized into 2 groups: 14 dogs with simultaneous atrioventricular pacing (SAVP) for 2 weeks (220 beats/min, no AV delay) and 8 control dogs with no pacing. SAVP for 2 weeks induced marked changes in atrial mechanical function and conduction. Left atrial area fractional shortening decreased 61 +/- 17%, whereas left ventricular area fractional shortening decreased by 38 +/- 18% from baseline (both P < .05). Conduction slowed and conduction heterogeneity increased. AF was induced in 83% of SAVP dogs, lasting a median of 1600 seconds, versus no dogs with induced AF in the controls. SAVP significantly increased nonfibrillar collagen in the mid-myocardium of both atrial appendages and matrix metalloproteinase-9 activity. CONCLUSIONS: SAVP in dogs induces structural and electrical remodelling that form the substrate for reproducibly inducible AF. This novel model may be useful for studies of the pathophysiology and treatment of AF in heart failure.

Experimental studies of atrial fibrillation: a comparison of two pacing models.

Rapid ventricular pacing (RVP) is a well-established animal model of atrial fibrillation (AF). However, this model is limited by a high mortality rate and severe heart failure. The purpose of our study was to assess a new canine model of inducible AF. We performed acute, short-term, simultaneous atrioventricular pacing (SAVP) and RVP (in random order) in 14 dogs for 30 s. SAVP produced more echocardiographic pulmonary venous flow reversal, a greater increase in mean pulmonary capillary wedge pressure, and a significantly greater decrease in left atrial emptying function (-84.4 +/- 38.6% vs. -23.7 +/- 27.1%, P < 0.05) than RVP. Thirty dogs were randomized to three, longer-term, study groups: eight dogs in the control group (no pacing), eight dogs in the RVP group (2 wk at 240 beats/min followed by 3 wk at 220 beats/min), and fourteen dogs in the SAVP group (2 wk at 220 beats/min). SAVP induced less left ventricular dysfunction but more left atrial dysfunction than RVP. SAVP dogs had similar atrial effective refractory periods as RVP dogs but more heterogeneity in conduction and more AF inducibility (83% vs. 40%, P < 0.05) and maintenance (median 1,660 vs. 710 s, P < 0.05) than RVP dogs. SAVP induced more collagen turnover and was associated with a significantly greater increase in type III collagen in the atria compared with RVP dogs (6.9 +/- 1.5 vs. 4.8 +/- 1.6, respectively, P < 0.05 vs. 1.1 +/- 0.7 in unpaced control dogs). In conclusion, the SAVP model induced profound mechanical and substrate atrial remodeling and reproducible sustained AF. This new model is clinically relevant and may be useful for testing AF interventions.

Profiling humoral autoimmune repertoire of dilated cardiomyopathy (DCM) patients and development of a disease-associated protein chip.

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by progressive depression of myocardial contractile function and ventricular dilatation. Thirty percent of DCM patients belong to the inherited genetic form; the rest may be idiopathic, viral, autoimmune, or immune-mediated associated with a viral infection. Disturbances in humoral and cellular immunity have been described in cases of myocarditis and DCM. A number of autoantibodies against cardiac cell proteins have been identified in DCM. In this study, we have profiled the autoantibody repertoire of plasma from DCM patients against a human protein array consisting of 37,200 redundant, recombinant human proteins and performed qualitative and quantitative validation of these putative autoantigens on protein microarrays to identify novel putative DCM specific autoantigens. In addition to analyzing the whole IgG autoantibody repertoire, we have also analyzed the IgG3 antibody repertoire in the plasma samples to study the characteristics of IgG3 subclass antibodies. By combining screening of a protein expression library with protein microarray technology, we have detected 26 proteins identified by the IgG antibody repertoire and 6 proteins bound by the IgG3 subclass. Several of these autoantibodies found in plasma of DCM patients, such as the autoantibody against the Kv channel-interacting protein, are associated with heart failure.