Comparative analyses reveal a phenylalanine ammonia lyase dependent and salicylic acid mediated host resistance in Zingiber zerumbet against the necrotrophic soft rot pathogen Pythium myriotylum.

Little is known about the molecular basis of host defense in resistant wild species Zingiber zerumbet (L.) Smith against the soil-borne, necrotrophic oomycete pathogen Pythium myriotylum Drechsler, which causes the devastating soft rot disease in the spice crop ginger (Zingiber officinale Roscoe). We investigated the pattern of host defense between Z. zerumbet and ginger in response to P. myriotylum inoculation. Analysis of gene expression microarray data revealed enrichment of phenylpropanoid biosynthetic genes, particularly lignin biosynthesis genes, in pathogen-inoculated Z. zerumbet compared to ginger. RT-qPCR analysis showed the robust activation of phenylpropanoid biosynthesis genes in Z. zerumbet, including the core genes PAL, C4H, 4CL, and the monolignol biosynthesis and polymerization genes such as CCR, CAD, C3H, CCoAOMT, F5H, COMT, and LAC. Additionally, Z. zerumbet exhibited the accumulation of the phenolic acids including p-coumaric acid, sinapic acid, and ferulic acid that are characteristic of the cell walls of commelinoid monocots like Zingiberaceae and are involved in cell wall strengthening by cross linking with lignin. Z. zerumbet also had higher total lignin and total phenolics content compared to pathogen-inoculated ginger. Phloroglucinol staining revealed the enhanced fortification of cell walls in Z. zerumbet, specifically in xylem vessels and surrounding cells. The trypan blue staining indicated inhibition of pathogen growth in Z. zerumbet at the first leaf whorl, while ginger showed complete colonization of the pith within 36 h post inoculation (hpi). Accumulation of salicylic acid (SA) and induction of SA regulator NPR1 and the signaling marker PR1 were observed in Z. zerumbet. Silencing of PAL in Z. zerumbet through VIGS suppressed downstream genes, leading to reduced phenylpropanoid accumulation and SA level, resulting in the susceptibility of plants to P. myriotylum. These findings highlight the essential role of PAL-dependent mechanisms in resistance against P. myriotylum in Z. zerumbet. Moreover, our results suggest an unconventional role for SA in mediating host resistance against a necrotroph. Targeting the phenylpropanoid pathway could be a promising strategy for the effective management of P. myriotylum in ginger.

Analysis of non-volatile metabolites and quantitation of the anti-arthritic alkaloid sinomenine from blood fruit (Haematocarpus validus (Miers) Bakh.f. ex Forman).

Haematocarpus validus (Miers) Bakh. f. ex Forman, a lesser-known fruit and medicinal plant of high nutraceutical and medicinal value, is used as anti-arthritic, hepatoprotective, and anti-inflammatory agents in ethnomedicine. Metabolome studies in H. validus are a virgin area of research and here we report the spectra of non-volatiles present in the methanolic leaf and fruit extract, using high-resolution liquid chromatography-mass spectrometry. Furthermore, the alkaloid sinomenine was quantified using high-performance thin layer chromatography spectrodensitometric analysis owing to its pharmacological importance as anti-arthritic and anti-inflammatory drug. Electrospray ionization with protonation in positive mode was selected for the analysis and the spectral data was interrogated using MassHunter software. A total of 40 compounds were identified from leaf and fruit samples and the major classes of compounds identified were alkaloids, terpenoids, steroids, tripeptides, vitamins, and related compounds. For separation and quantitation of sinomenine, chloroform:methanol:water (60:30:6.5, v/v) was used as the mobile phase and sinomenine hydrochloride as reference compound. The analysis confirmed the presence of sinomenine in both non-defatted and defatted methanolic leaf extract with quantities 45.73 and 26.02 mg/100 g dry weight, respectively. H. validus is a non-conventional source of sinomenine, the anti-arthritic and anti-inflammatory alkaloid. Sinomenine detected in this study supports the ethnomedicinal uses of H. validus as an anti-arthritic agent. Further study is needed to elucidate the underlying molecular mechanism of its anti-arthritic attributes as well as the corresponding structure-activity relationships.

Response to Nikhil Govind - What is a knowledge system?

The editorial by Nikhil Govind in the Indian Journal of Medical Ethics is disturbing because of its epistemological connotations [1]. In this rejoinder, I will not address the merits or demerits of indigenous traditions in medicine, or homeopathy (which, though not an indigenous tradition is part of what is infelicitously called AYUSH - Ayurveda, Yoga, Unani, Siddha and Homeopathy). What I am concerned with here are the questions of knowledge, the scientific method, and its connotations.

Wild edible fruit crop Haematocarpus validus (Miers) Bakh.f. ex Forman (Khoon phal): a novel source of nutraceuticals.

Bioprospecting of underexplored plants opens up new avenues for developing value added products, ready-to-use herbal formulations and nutraceuticals. This study investigates the volatile metabolome and mineral composition of Haematocarpus validus (Khoon phal), an ethnic fruit crop of tropical Asia. H. validus is used for curing hepatic diseases, anemic and inflammatory conditions in ethnic medicine. Analysis of EI mass spectra on GC-MS platform detected 54 and 48 compounds from fruit and leaf extract respectively. Quinic acid (a hepato-protectant) predominates among volatiles in fruit (29.13%) and unsaturated fatty acids in leaf (61%). Through HP-TLC spectrodensitometric study, quinic acid was quantified as 292.95 mg/100 g dry weight. Five macroelements and 17 microelements were analyzed using ICP-AES and ICP-MS respectively. H. validus fruit has very high K/Na ratio (280.65) and both fruit and leaf are rich in Fe content (57.29 and 38.44 mg/100 g dry weight respectively). High unsaturated fatty acid/ saturated fatty acid ratio and abundance of linoleic acid (55.54% of total fatty acids) in leaf along with relatively high content of conjugated linoleic acid suggest its potential usefulness in pharmaceutical and nutraceutical industry. This is the first report on volatile metabolome of H. validus fruit and leaf. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-04997-7.

Robotics for catheter ablation of cardiac arrhythmias: Current technologies and practical approaches.

Robotic technology has emerged as an important tool to facilitate catheter ablation of arrhythmias. Robotic cardiac electrophysiology technology includes remote magnetic navigation and manual robotic navigation. Robotics can confer advantages with respect to ease of catheter manipulation in anatomically challenging spaces, minimization of fluoroscopic exposure to both patients and operators, and reduction in operator fatigue. This review provides a comprehensive summary of robotic electrophysiology technology, its practical applications and its safety and efficacy for targeting cardiac arrhythmias.

Effects of focal impulse and rotor modulation-guided ablation on atrial arrhythmia termination and inducibility: Impact on outcomes after treatment of persistent atrial fibrillation.

INTRODUCTION: The role of focal impulse and rotor modulation (FIRM)-guided ablation for the treatment of atrial fibrillation (AF) remains unclear. Previous studies on the FIRM-guided ablation outcomes have been limited by a focus on AF termination as an endpoint and by patient population heterogeneity. We sought to determine differences in rates of AF termination, inducibility, and recurrence in patients with persistent AF undergoing first-time ablation with a FIRM-guided approach compared with patients undergoing conventional ablation. METHODS AND RESULTS: Eight-five consecutive patients (38 FIRM, 47 conventional) with persistent AF undergoing first-time ablation were retrospectively analyzed. There were no significant differences in the rates of AF termination in the FIRM group compared to the conventional group (26% vs 15%; P = .15). Rates of inducible AF after ablation were 37% in the FIRM group and 30% in the conventional group (P = .32). Over a median follow-up of 2.4 years, the rates of freedom from AF were similar between the FIRM and conventional groups (1-year freedom from AF 65% vs 50%, respectively; P = .18). Procedural termination of AF with either FIRM ablation or conventional ablation was not associated with any significant reduction in AF recurrence. CONCLUSION: A FIRM-guided approach was not associated with a significant difference in freedom from AF when compared to conventional ablation. Termination of AF with ablation was not associated with increased freedom from AF. While AF termination using substrate-based ablation may have mechanistic implications for understanding AF rotor physiology, its impact on clinical outcomes remains unclear.

Subclinical atrial fibrillation detection with a floating atrial sensing dipole in single lead implantable cardioverter-defibrillator systems: Results of the SENSE trial.

INTRODUCTION: Subclinical atrial fibrillation (AF), in the form of cardiac implantable device-detected atrial high rate episodes (AHREs), has been associated with increased thromboembolism. An implantable cardioverter-defibrillator (ICD) lead with a floating atrial dipole may permit a single lead (DX) ICD system to detect AHREs. We sought to assess the utility of the DX ICD system for subclinical AF detection in patients, with a prospective multicenter, cohort-controlled trial. METHODS AND RESULTS: One hundred fifty patients without prior history of AF (age 59 ± 13 years; 108 [72%] male) were enrolled into the DX cohort and implanted with a Biotronik DX ICD system at eight centers. Age-, sex-, and left ventricular ejection fraction-matched single- and dual-chamber ICD cohorts were derived from a Cornell database and from the IMPACT trial, respectively. The primary endpoint were AHRE detection at 12 months. During median 12 months follow-up, AHREs were detected in 19 (13%) patients in the DX, 8 (5.3%) in the single-chamber, and 19 (13%) in the dual-chamber cohorts. The rate of AHRE detection was significantly higher in the DX cohort compared to the single-chamber cohort (P = .026), but not significantly different compared to the dual-chamber cohort. There were no inappropriate ICD therapies in the DX cohort. At 12 months, only 3.0% of patients in the DX cohort had sensed atrial amplitudes less than 1.0 mV. CONCLUSION: Use of a DX ICD lead allows subclinical AF detection with a single lead DX system that is superior to that of a conventional single-chamber ICD system.

The Prehistoric Indian Ayurvedic Rice Shashtika Is an Extant Early Domesticate With a Distinct Selection History.

Fully domesticated rice is considered to have emerged in India at approximately 2000 B.C., although its origin in India remains a contentious issue. The fast-growing 60-days rice strain described in the Vedic literature (1900-500 B.C.) and termed Shashtika (Sanskrit) or Njavara (Dravidian etymology) in Ayurveda texts including the seminal texts Charaka Samhita and Sushruta Samhita (circa 660-1000 B.C.) is a reliable extant strain among the numerous strains described in the Ayurveda literature. We here report the results of the phylogenetic analysis of Njavara accessions in relation to the cultivars belonging to the known ancestral sub-groups indica, japonica, aromatic, and aus in rice gene pool and the populations of the progenitor species Oryza rufipogon using genetic and gene genealogical methods. Based on neutral microsatellite markers, Njavara produced a major clade, which comprised of minor clades corresponding to the genotypic classes reported in Njavara germplasm, and was distinct from that were produced by the ancestral sub-groups. Further we performed a phylogenetic analysis using the combined sequence of 19 unlinked EST-based sequence tagged site (STS) loci with proven potential in inferring rice phylogeny. In the phylogenetic tree also the Njavara genotypic classes were clearly separated from the ancestral sub-groups. For most loci the genealogical analysis produced a high frequency central haplotype shared among most of the rice samples analyzed in the study including Njavara and a set of O. rufipogon accessions. The haplotypes sharing pattern with the progenitor O. rufipogon suggests a Central India-Southeast Asia origin for Njavara. Results signify that Njavara is genetically distinct in relation to the known ancestral sub-groups in rice. Further, from the phylogenetic features together with the reported morphological characteristics, it is likely that Njavara is an extant early domesticate in Indian rice gene pool, preserved in pure form over millennia by the traditional prudence in on-farm selection using 60-days maturity, because of its medicinal applications.

Comparison of robotic magnetic navigation-guided and manual catheter ablation of ventricular arrhythmias arising from the papillary muscles.

Aims: Due to the complex anatomy of the left ventricular (LV) and right ventricular (RV) papillary muscles (PMs), PM ventricular arrhythmias (VAs) can be challenging to target with ablation. We sought to compare the outcomes of robotic magnetic navigation-guided (RMN) ablation and manual ablation of VAs arising from the LV and RV PMs. Methods and results: We evaluated 35 consecutive patients (mean age 65 ± 12 years, 69% male) who underwent catheter ablation of 38 VAs originating from the LV and RV PMs as confirmed by intracardiac echocardiography. Catheter ablation was initially performed using RMN-guidance in 24 (69%) patients and manual guidance in 11 (31%) patients. Demographic and procedural data were recorded and compared between the two groups. The VA sites of origin were mapped to 20 (53%) anterolateral LV PMs, 14 (37%) posteromedial LV PMs, and 4 (11%) RV PMs Acute successful ablation was achieved for 20 (74%) VAs using RMN-guided ablation and 8 (73%) VAs using manual ablation (P = 1.000). Fluoroscopy times were significantly lower among patients undergoing RMN ablation compared to patients undergoing manual ablation [median 7.3, interquartile range (IQR) 3.9-18 vs. 24 (16-44) min; P = 0.005]. Retrograde transaortic approach was used in 1 (4%) RMN patients and 5 (46%) manual patients (P = 0.005). No procedural complications were seen in study patients. Conclusion: Use of an RMN-guided approach to target PM VAs results in comparable success rates seen with manual ablation but with lower fluoroscopy times and decreased use of transaortic retrograde access.

The National Medical Commission - More of the same.

The Cabinet chaired by the Prime Minister has accepted six amendments to the National Medical Commission Bill suggested by the Department-related Parliamentary Standing Committee (1). These amendments are: the proposed National Licentiate Examination has been replaced by a countrywide final MBBS examination called the National Exit Test (NEXT); the bridge course to train practitioners from AYUSH (Ayurveda, Unani, Siddha and Homeopathy) in modern medicine has been removed, and it has been left to individual states to take a decision about this; the percentage of seats in private medical training institutions under fee regulation has been increased from 40% to 50%; the number of nominees from the states and Union territories who are members of the Commission has been increased from three to six; the penalties for non-compliance with educational norms for colleges has been modified; and the punishment for practising modern medicine without qualification has been made imprisonment up to one year and a fine of Rs 5 lakh.

Left atrial thrombus and dense spontaneous echocardiographic contrast in patients on continuous direct oral anticoagulant therapy undergoing catheter ablation of atrial fibrillation: Comparison of dabigatran, rivaroxaban, and apixaban.

BACKGROUND: Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described. OBJECTIVE: We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs. METHODS: We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on ≥4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient. RESULTS: Despite ≥4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT. CONCLUSION: In this study, ∼3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection.

Measuring physiological responses to the arts in people with a dementia.

The dementias are a group of progressive symptoms that have multiple causes, usually caused by disease or injury of the brain, affecting higher brain functions such as language, perception, memory, reasoning and mood; they can also be associated with changes in personality. Arts interventions and interaction with the arts can create meaningful, positive experiences for people with a dementia, as well as improve quality of life. Qualitative research in particular, has been able to describe the emotional responses the arts can produce, but quantifiable changes have not been well documented. Physiological measurements such as stress hormone levels and galvanic skin response show promise in being able to quantify such responses. When taken together, these can give a picture of the kinds of physiological outcomes that are associated with positive affect and improvements in mental wellbeing in the context of arts interventions. This review provides a critical overview of the studies which measure some form of physiological outcome in response to the arts or an arts intervention in people with dementia, and indicates how future research in this area can help to broaden our understanding of the effects of the arts in dementia research and care.

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies.

BACKGROUND: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. OBJECTIVE: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. PATIENTS AND METHODS: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. RESULTS: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. CONCLUSIONS: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug-drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104.

Utility of Pre-Induction Ventriculoatrial Response to Adenosine in the Diagnosis of Orthodromic Reciprocating Tachycardia.

OBJECTIVES: This study sought to evaluate the utility of ventriculoatrial (VA) conduction patterns in response to adenosine in predicting inducibility of orthodromic reciprocating tachycardia (ORT). BACKGROUND: Adenosine is known to consistently block atrioventricular (AV) nodal conduction. We hypothesized that persistent VA conduction despite administration of adenosine would have a high predictive value for identifying the presence of a retrograde accessory pathway (AP) and associated ORT. METHODS: A total of 168 patients undergoing electrophysiological study for supraventricular tachycardia (SVT) had assessment of VA conduction during ventricular pacing and adenosine administration. Standard pacing maneuvers were then used for induction and diagnosis of the SVT mechanism. RESULTS: Absence of VA block to adenosine (doses up to 24 mg) had 88% sensitivity and 91% specificity for identifying ORT (positive predictive value 76%, negative predictive value 96%). Four patients with adenosine-induced VA block and inducible ORT had decremental APs. Adenosine caused VA block in 6 patients with eccentric VA activation due to atypical AV nodal conduction, and concentric VA conduction persisted in all 12 patients with a septal AP. Adenosine unmasked free-wall APs in 10 patients by blocking AV nodal conduction, shifting VA activation from concentric to eccentric. CONCLUSIONS: The response of VA conduction to adenosine is a highly sensitive and specific method for detecting retrograde AP conduction and inducible ORT. Adenosine-induced VA block rules out inducible ORT due to a nondecremental AP. In cases of VA fusion, adenosine-induced block of AV nodal conduction can delineate the location of the AP atrial insertion site.

Physiological Effects Associated with Quinoa Consumption and Implications for Research Involving Humans: a Review.

Quinoa is a pseudo-grain consumed as a dietary staple in South America. In recent years, consumer demand for quinoa in the developed world has grown steadily. Its perceived health benefits have been cited as a driving force behind this trend, but there are very few human studies investigating the impact of quinoa consumption. The aim of this review was to identify physiological effects of quinoa consumption with potential for human health. A critical evaluation of animal model studies was conducted. The quality of identified studies was assessed using a methodological quality assessment tool and summative conclusions were drawn to guide the direction of future human research. The majority of studies were of fair quality. Purported physiological effects of quinoa consumption included decreased weight gain, improved lipid profile and improved capacity to respond to oxidative stress. These physiological effects were attributed to the presence of saponins, protein and 20-hydroxyecdysone in the quinoa seed. The implications of these findings are that human studies should investigate the impact of quinoa consumption on weight gain and lipid levels. The role of quinoa as an antioxidant is still unclear and requires further elucidation in animal models.

Differentiation of papillary muscle from fascicular and mitral annular ventricular arrhythmias in patients with and without structural heart disease.

BACKGROUND: Idiopathic left ventricular arrhythmias (VAs) and those caused by structural heart disease can originate from the papillary muscles, fascicles, and mitral annulus. Differentiation of these arrhythmias can be challenging because they present with a right bundle branch block morphology by electrocardiography. We sought to identify clinical, electrocardiographic, and electrophysiological features that distinguish these left VAs in patients with and without structural heart disease. METHOD AND RESULTS: Patients undergoing catheter ablation for papillary muscle, fascicular, or mitral annular VAs were studied. Demographic data and electrocardiographic and electrophysiological findings were analyzed. Fifty-two VAs in 51 patients (32 [63%] male; mean age 61±15 years) with papillary muscle (n=18), fascicular (n=15), and mitral annular (n=19) origins were studied. Patients with papillary muscle VAs were older and had higher prevalence of left ventricular dysfunction (67% versus 13% of fascicular VA patients [P=0.009]) and coronary artery disease (78% versus 37% of mitral annular VA patients [P=0.036]). Papillary muscle VAs were distinguished electrocardiographically from fascicular VAs by longer QRS durations and lower prevalence of r

Mechanisms and clinical significance of adenosine-induced dormant accessory pathway conduction after catheter ablation.

BACKGROUND: Adenosine can unmask dormant pulmonary vein conduction after isolation. The role of adenosine in uncovering dormant accessory pathway (AP) conduction after AP ablation is unknown. METHODS AND RESULTS: We evaluated 109 consecutive patients (age, 41 ± 28 years; 62 [57%] men) who were administered adenosine after successful AP ablation. Dormant AP conduction was defined as adenosine-induced recurrent AP conduction, as demonstrated by recurrent preexcitation or change in retrograde ventriculoatrial activation patterns. Dormant AP conduction was identified in 13 (12%) patients. Adenosine led to transient retrograde AP conduction in 6 patients and transient anterograde AP conduction in 8 patients. In all these cases, adenosine-induced AP conduction occurred during the bradycardia phase of adenosine effect and resulted in dormant AP conduction times shorter than atrioventricular nodal conduction times before adenosine administration. On the basis of analysis of timing of occurrence of dormant AP conduction, the mechanism of adenosine-induced AP conduction was determined to be caused by AP excitability recovery in ≥ 12 (92%) cases. The presence of dormant AP conduction was a significant predictor of chronic recurrent AP conduction requiring repeat ablation (odds ratio, 8.54; 95% confidence interval, 1.09-66.9; P=0.041). CONCLUSIONS: Adenosine can unmask dormant AP conduction after catheter ablation. Direct effects of adenosine on the AP, possibly via AP membrane potential hyperpolarization, are the dominant mechanism of adenosine-induced AP conduction after ablation. Dormant AP conduction is associated with higher rates of recurrent AP conduction requiring repeat ablation.