Arrhythmic Risk Profile and Outcomes of Patients Undergoing Cardiac Sympathetic Denervation for Recurrent Monomorphic Ventricular Tachycardia After Ablation.

Background Cardiac sympathetic denervation (CSD) has been used as a bailout strategy for refractory ventricular tachycardia (VT). Risk of VT recurrence in patients with scar-related monomorphic VT referred for CSD and the extent to which CSD can modify this risk is unknown. We aimed to quantify arrhythmia recurrence risk and impact of CSD in this population. Methods and Results Adjusted competing risk time to event models were developed to adjust for risk of VT recurrence and sustained VT/implantable cardioverter-defibrillator shocks after VT ablation based on patient comorbidities at the time of VT ablation. Adjusted VT and implantable cardioverter-defibrillator shock recurrence rates were estimated for the subgroup who subsequently required CSD after ablation. The expected adjusted recurrence rates were then compared with the observed rates after CSD. Data from 381 patients with scar-mediated monomorphic VT who underwent VT ablation were analyzed, excluding patients with polymorphic VT. Sixty eight patients underwent CSD for recurrent VT. CSD reduced the expected adjusted VT recurrence rate by 36% (expected rate of 5.61 versus observed rate of 3.58 per 100 person-months, P=0.01) and the sustained VT/implantable cardioverter-defibrillator shock rates by 34% (expected rate of 4.34 versus observed 2.85 per 100 person-months, P=0.03). The median number of sustained VT/implantable cardioverter-defibrillator shocks in the year before versus the year after CSD was reduced by 90% (10 versus 1, P<0.0001). Conclusions Patients referred for CSD for refractory scar-mediated monomorphic VT are at a higher risk of VT recurrence after ablation as compared with those not requiring CSD, mostly because of their cardiac comorbidities. CSD significantly reduced both the expected risk of recurrences and VT burden.

[Pediatric medulloblastoma: Retrospective series of 52 patients]. / Médulloblastomes de l'enfant: étude rétrospective portant sur 52 patients.

PURPOSE: Retrospective analysis of the results of 52 children irradiated for a medulloblastoma. PATIENTS AND METHODS: Between 1974 and 2012, 52 children with an average age of 6 years and a half (11 months-17 years and a half) were treated with surgery then with radiotherapy at the Comprehensive Cancer Centre of Strasbourg (France). For 44 children, the treatment consisted of a chemotherapy. RESULTS: After a mean follow-up of 106.6 months (7-446 months), 13 relapses and 24 deaths were observed. Overall survival at 5 years and 10 years were 62% and 57%, respectively. Disease-free survival at 5 years and 10 years were 80% and 63%, respectively. Univariate analysis found the following adverse prognostic factors: the existence of a postoperative residue, the positivity of the cerebrospinal fluid, the metastatic status and medulloblastoma of high-risk. Positivity of the cerebrospinal fluid remains a negative factor in multivariate analysis. CONCLUSION: These results confirm the survival rate obtained by a conventional approach (surgery then irradiation). Insufficiency of results and rarity of medulloblastoma require the establishment of international protocols.

[Adult medulloblastoma: Retrospective series of 21 patients]. / Médulloblastomes de l'adulte: étude rétrospective portant sur 21 patients.

PURPOSE: Retrospective analysis of the results of 21 adults treated for medulloblastoma. PATIENTS AND METHODS: Between 1978 and 2011, 21 adults with an average age of 31 years (18.3-50) were treated with surgery then with radiotherapy (n=20) at the Comprehensive Cancer Center of Strasbourg. For some (n=12), treatment consisted of chemotherapy. RESULTS: After a mean follow-up of 122 months (19-423), six relapses and seven deaths were observed. Overall survival at 5 years and 10 years was 89.4 ± 7.1% for both. Disease-free survival at 5 years and 10 years was 79.6 ± 9.2% and 85.7 ± 7.6% and 60.6 ± 17.7%, respectively. CONCLUSION: The rarity of medulloblastoma, especially in adults and these results confirm the necessity of international protocols.

Relationship between sinus rhythm late activation zones and critical sites for scar-related ventricular tachycardia: systematic analysis of isochronal late activation mapping.

BACKGROUND: It is not known whether the most delayed late potentials are functionally most specific for scar-related ventricular tachycardia (VT) circuits. METHODS AND RESULTS: Isochronal late activation maps were constructed to display ventricular activation during sinus rhythm over 8 isochrones. Analysis was performed at successful VT termination sites and prospectively tested. Thirty-three patients with 47 scar-related VTs where a critical site was demonstrated by termination of VT during ablation were retrospectively analyzed. In those who underwent mapping of multiple surfaces, 90% of critical sites were on the surface that contained the latest late potential. However, only 11% of critical sites were localized to the latest isochrone (87.5%-100%) of ventricular activation. The median percentage of latest activation at critical sites was 78% at a distance from the latest isochrone of 18 mm. Sites critical to reentry were harbored in regions with slow conduction velocity, where 3 isochrones were present within a 1-cm radius. Ten consecutive patients underwent ablation prospectively guided by isochronal late activation maps, targeting concentric isochrones outside of the latest isochrone. Elimination of the targeted VT was achieved in 90%. Termination of VT was achieved in 6 patients at a mean ventricular activation percentage of 78%, with only 1 requiring ablation in the latest isochrone. CONCLUSIONS: Late potentials identified in the latest isochrone of activation during sinus rhythm are infrequently correlated with successful ablation sites for VT. The targeting of slow conduction regions propagating into the latest zone of activation may be a novel and promising strategy for substrate modification.

Peripheral α-defensins 1 and 2 are elevated in Alzheimer's disease.

Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-ß (Aß) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aß was fragile and prone to degradation in the AIBL samples, even when stored at -80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aß levels are required to supplement their prognostic power.

The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120.

GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.

An emulsion restores the skin barrier by decreasing the skin pH and inflammation in a canine experimental model.

The aim of this study was to investigate the effect of Douxo(®) Calm Mousse (Sogeval, Laval, France) on restoration of the skin barrier in a canine model of barrier disruption. Tape strips were performed, daily for 6 days, on the lateral thorax of five healthy beagle dogs. Douxo(®) Calm Mousse was applied daily for 5 days to one side of the thorax and the opposite side was left untreated. The effects of treatment were evaluated by measurement of transepidermal water loss (TEWL) and pH and by histological assessment of disrupted skin at various times during barrier repair. Although no effect on TEWL was observed, Douxo(®) Calm Mousse maintained an acidic pH after three applications and reduced skin inflammation, which was most pronounced after five applications. The results of the study suggest that Douxo(®) Calm Mousse exerts a beneficial effect on barrier restoration and on markers of inflammation.

Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts.

BACKGROUND: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed. OBJECTIVE: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment. METHODS: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function. RESULTS: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04). CONCLUSIONS: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.

[Radio-induced breast morphoea: an unrecognized complication]. / Morphée du sein radio-induite : une complication méconnue.

Morphoea is a localized scleroderma. Since the 1990s, it is described as a complication after irradiation for breast cancer. This complication is unrecognized and underdiagnosed. Irradiation seems to be a factor inducing an autoimmune process. Clinicians should be aware in case of an erythema in a treated area, appearing on average one year after the end of the irradiation. Histology alone can prove the diagnosis and rule out differential diagnoses: principally mastitis (carcinomatous, infectious), chronic radiodermatitis or radiation recall. Treatment of this rare complication is not consensual; it is most often topical steroids. The evolution is marked by a gradual decrease from the initial inflammation. Sclerosis persists, more or less substantially.

Increased risk of cognitive impairment in patients with diabetes is associated with metformin.

OBJECTIVE: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS: Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22). RESULTS: Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92]). CONCLUSIONS: Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Is there a therapeutic role for selenium in alpha-1 antitrypsin deficiency?

Selenium is an essential trace mineral of fundamental importance to human health. Much of its beneficial influence is attributed to its presence within selenoproteins, a group of proteins containing the rare amino acid selenocysteine. There are 25 known human selenoproteins including glutathione peroxidases, thioredoxin reductases and selenoproteins. Selenoprotein S (SEPS1) is an endoplasmic reticulum (ER) resident selenoprotein involved in the removal of misfolded proteins from the ER. SEPS1 expression can be induced by ER stress, an event that is associated with conformational disorders and occurs due to accumulation of misfolded proteins within the ER. Alpha-1 antitrypsin (AAT) deficiency, also known as genetic emphysema, is a conformational disorder in which the roles of ER stress, SEPS1 and selenium have been investigated. SEPS1 can relieve ER stress in an in vitro model of AAT deficiency by reducing levels of active ATF6 and inhibiting grp78 promoter- and NFκB activity; some of these effects are enhanced in the presence of selenium supplementation. Other studies examining the molecular mechanisms by which selenium mediates its anti-inflammatory effects have identified a role for prostaglandin 15d-PGJ2 in targeting NFκB and PPARγ. Together these ER stress-relieving and anti-inflammatory properties suggest a therapeutic potential for selenium supplementation in genetic emphysema.

Vitamin D as a clinical biomarker in multiple sclerosis.

INTRODUCTION: Vitamin D has attracted a lot of attention in relation to multiple sclerosis (MS) and many other disorders; however, the evidence for a major role(s) for vitamin D in MS is compelling and multifactorial involving results from epidemiology, immunology, genetics, biochemistry and translational medicine. AREAS COVERED: Multiple studies that illustrate that insufficient levels of vitamin D not only contribute to the risk of getting MS but may also worsen disease progression for MS patients are discussed. Genetic evidence also implicates vitamin D as being important in MS since individuals are at greater risk of getting MS if they harbor a mutation in a gene responsible for vitamin D synthesis (25-hydroxylase). Other modifiers of MS disease appear to interact with the vitamin D receptor. The Epstein-Barr virus (EBV) is a risk factor for MS and may in part worsen disease through the interactions between one of its gene products (EBNA-3) and the vitamin D receptor to attenuate vitamin D-regulated genes. Retrospective studies have shown that higher vitamin D levels are associated with a significant improvement of clinical and magnetic resonance imaging outcomes. Increasing clinical observations are also indicating adverse effects of low vitamin D in MS. EXPERT OPINION: Mounting evidence from epidemiology, genetic, retrospective clinical studies and emerging basic science studies support a strong rationale for how vitamin D could be an important modifier of MS disease. Well-designed clinical trials are now ongoing and will provide further insight on how vitamin D supplementation may impact MS.

Tissue voltage discordance during tachycardia versus sinus rhythm: implications for catheter ablation.

BACKGROUND: Electroanatomic mapping systems are an important tool to identify cardiac chamber voltage and assess channels of slow conduction. OBJECTIVE: To assess the correlation between electroanatomic mapping voltage maps obtained during macroreentrant tachycardia compared to sinus rhythm (SR) with a contact mapping system. METHODS: We retrospectively evaluated patients with atrial flutter (AFL) referred for radiofrequency ablation with electroanatomic voltage maps obtained during AFL and SR. The atrium was divided into predetermined segments. Overall atrial and segmental peak-to-peak bipolar voltages in AFL and SR were assessed. To directly compare a region within the same patient, tissue voltage differences during AFL and SR were assessed on the basis of mean voltage difference. RESULTS: Sixteen patients (87% men) had available voltage maps. Eighty-one percent had typical cavotricuspid isthmus-dependent right AFL. A mean of 441.7±153.9 vs 398.1±125.4 total points (P = .22) were sampled during AFL and SR, with a mean of 99.5±58.9 vs 91.2±60.4 points (P = .45) sampled per region. Overall right atrial mean voltage was significantly higher during AFL than SR (0.554±0.092mV vs 0.473±0.079mV; P≤.001), with the lateral wall (0.707±0.120mV vs 0.573±0.097mV; P = .0004) and the cavotricuspid isthmus (0.559±0.100mV vs 0.356±0.066mV; P<.0001) also showing higher mean voltage during AFL. When compared within an individual patient, 19% (14 of 75) of the patient regions had a>0.5mV mean voltage difference and 40% (30 of 75) had a>0.25mV mean voltage difference. CONCLUSIONS: These data suggest that voltage maps performed during macroreentrant atrial arrhythmias often vary significantly from maps obtained during SR.

The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis.

RATIONALE: Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear. OBJECTIVES: To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation. METHODS: The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis. MEASUREMENTS AND MAIN RESULTS: We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is the main causative agent. Gt overcame the positive effect of 1,25-OH vitamin D(3) on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomography mosaic pattern consistent with sustained pulmonary function. CONCLUSIONS: This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.

Catheter ablation of typical atrial flutter in severe pulmonary hypertension.

BACKGROUND: Radiofrequency ablation is first-line therapy for atrial flutter (AFL). There are no studies of ablation in patients with severe pulmonary arterial hypertension (PAH). METHODS: Consecutive patients with severe PAH (systolic pulmonary artery pressure >60 mmHg) and AFL referred for ablation were evaluated. Patients with complex congenital heart disease were excluded. RESULTS: A total of 14 AFL ablation procedures were undertaken in 12 patients. A total of 75% of patients were female; mean age 49 ± 12 years. SPAP prior to ablation was 99 ± 35 mmHg. Baseline 6-minute walk distance was 295 ± 118 m. ECG demonstrated a typical AFL pattern in only 42% of cases. Baseline AFL cycle length was longer in PAH patients compared to controls (295 ± 53 ms vs 252 ± 35 ms, P = 0.006). Cavotricuspid isthmus dependence was verified in 86% of cases. Acute success was obtained in 86% of procedures. SPAP decreased from 114 ± 44 mmHg to 82 ± 38 mmHg after ablation (P = 0.004). BNP levels were lower postablation (787 ± 832 pg/mL vs 522 ± 745 pg/mL, P = 0.02). Complications were seen in 14%. A total of 80% (8/10) of patients were free of AFL at 3 months; 75% (6/8) at 1 year. CONCLUSION: Ablation of AFL in severe PAH patients is feasible, with good short- and intermediate-term success rates. The ECG pattern is not a reliable marker of isthmus dependence. The SPAP and BNP levels may decrease postablation. AFL may be a marker of poor outcomes in patients with PAH with a 1-year mortality rate of 42% in this study. This rate is higher than expected in the general PAH population.

Characterization of myocardial scars: electrophysiological imaging correlates in a porcine infarct model.

BACKGROUND: Definition of myocardial scars as identified by electroanatomic mapping is integral to catheter ablation of ventricular tachycardia (VT). Myocardial imaging can also identify scars prior to ablation. However, the relationship between imaging and voltage mapping is not well characterized. OBJECTIVE: The purpose of this study was to verify the anatomic location and heterogeneity of scars as obtained by electroanatomic mapping with contrast-enhanced MRI (CeMRI) and histopathology, and to characterize the distribution of late potentials in a chronic porcine infarct model. METHODS: In vivo 3-dimensional cardiac CeMRI was performed in 5 infarcted porcine hearts. High-density electroanatomic mapping was used to generate epicardial and endocardial voltage maps. Scar surface area and position on CeMRI were then correlated with voltage maps. Locations of late potentials were subsequently identified. These were classified according to their duration and fractionation. All hearts underwent histopathological examination after mapping. RESULTS: The total dense scar surface area and location on CeMRI correlated to the total epicardial and endocardial surface scar on electroanatomic maps. Electroanatomic mapping (average of 1,532 ± 480 points per infarcted heart) showed that fractionated late potentials were more common in dense scars (<0.50 mV) as compared with border zone regions (0.51 to 1.5 mV), and were more commonly observed on the epicardium. CONCLUSION: In vivo, CeMRI can identify areas of transmural and nontransmural dense scars. Fractionated late diastolic potentials are more common on the epicardium than the endocardium in dense scar. These findings have implications for catheter ablation of VT and for targeting the delivery of future therapies to scarred regions.

Distribution of late potentials within infarct scars assessed by ultra high-density mapping.

BACKGROUND: Late potential (LP) electrograms represent areas of slow conduction and are often sites critical to reentrant tachycardia circuits. The distribution of LPs within infarct scar is not known. OBJECTIVE: The purpose of this study was to delineate infarct heterogeneity using ultra high-density mapping and to determine the location of LPs with respect to scar architecture. METHODS: Detailed endocardial (n = 21) and epicardial (n = 8) ultra high-density mapping was performed to delineate the substrate for ventricular tachycardia (VT) in 21 patients with ischemic cardiomyopathy. LP was defined as a low-voltage electrogram (< 1.5 mV) with distinct onset after the QRS. Very late potentials (vLPs) were classified as LPs with onset > 100 ms after the QRS. RESULTS: A mean of 787 ± 391 and 810 ± 375 points in the LV endocardium and epicardium were sampled. Multipolar mapping identified heterogeneous islets (HIs) with relatively preserved electrogram amplitudes (≥ 0.51 mv) within dense scar (8.5 ± 4.9/4.5 ± 2.6 HIs per endocardium/epicardium) in all patients. In maps on which putative VT isthmuses were identified (25/29), 57% of vLP were recorded in or adjacent to HI. An LP-targeted ablation strategy combined with pace mapping achieved acute success in all patients (complete success in 52% and partial success in 48%). After 15 ± 7 months, 65% of patients remained free of VT episodes. CONCLUSION: Ultra high-density mapping with a multipolar catheter facilitates the delineation of heterogeneous scar architecture at higher resolution. Electrograms within and adjacent to HIs have a higher incidence of vLP, and these sites are frequently critical to reentry. These findings have important implications for substrate-based ablation strategies.

Nonpharmacologic management of atrial fibrillation: role of the pulmonary veins and posterior left atrium.

Nonpharmacologic approaches for the management of atrial fibrillation are rapidly emerging as the mainstay for definitive management of this arrhythmia. Over the past several years, numerous studies reported in the literature have highlighted various aspects of the pathophysiologic mechanisms underlying atrial fibrillation. The purpose of this review is to place the current approaches being used for arrhythmia management in the context of the current knowledge of about arrhythmia mechanisms.

Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

Silencing onion lachrymatory factor synthase causes a significant change in the sulfur secondary metabolite profile.

Through a single genetic transformation in onion (Allium cepa), a crop recalcitrant to genetic transformation, we suppressed the lachrymatory factor synthase gene using RNA interference silencing in six plants. This reduced lachrymatory synthase activity by up to 1,544-fold, so that when wounded the onions produced significantly reduced levels of tear-inducing lachrymatory factor. We then confirmed, through a novel colorimetric assay, that this silencing had shifted the trans-S-1-propenyl-l-cysteine sulfoxide breakdown pathway so that more 1-propenyl sulfenic acid was converted into di-1-propenyl thiosulfinate. A consequence of this raised thiosulfinate level was a marked increase in the downstream production of a nonenzymatically produced zwiebelane isomer and other volatile sulfur compounds, di-1-propenyl disulfide and 2-mercapto-3,4-dimethyl-2,3-dihydrothiophene, which had previously been reported in trace amounts or had not been detected in onion. The consequences of this dramatic simultaneous down- and up-regulation of secondary sulfur products on the health and flavor attributes of the onion are discussed.