Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson's Disease: A Single-Center, Randomized, Placebo-Controlled Trial.

A six-month double-blind, placebo-controlled randomized study was conducted to ascertain whether low-dose daily niacin supplementation would improve motor symptoms in Parkinson's disease (PD) patients. A total of 47 PD patients were assigned to receive low-dose niacin or a placebo. At the end of the double-blind phase, all participants received open-label niacin for the next six months. All patients were evaluated at baseline, after six months, and after one year of treatment. The primary outcome measure was the Unified Parkinson's Disease Rating Scale III (UPDRS III) scores. Secondary outcome measures were depression, sleep quality, mental flexibility and cognition, and physical fatigue. Niacin treatment was well-tolerated by forty-five subjects. The mean [95% CI] change in UPDRS III scores at six months of placebo was -0.05 [95% CI, -2.4 to 2.32], and niacin was -1.06 [95% CI, -3.68 to 1.57]. From six to twelve months when both groups received open-label niacin supplementation, the average UPDRS III scores significantly decreased for the placebo group by 4.58 [95% CI, -0.85 to 8.30] and the niacin group by 4.63 [95% CI, 1.42 to 7.83] points. Low-dose niacin supplementation is a well-tolerated adjunct therapy and may improve motor function in PD when taken over a longer period.

A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome whose potential to become one of the most grievous challenges of the healthcare system evidenced by the COVID-19 pandemic. Considering the lack of target-specific treatment for ARDS, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve quality of life and outcomes for ARDS patients. ARDS is a systemic inflammatory disease starting with the pulmonary system and involves all other organs in a morbid bidirectional fashion. Mounting evidence including our findings supporting the notion that cannabinoids have potential to be targeted as regulatory therapeutic modalities in the treatment of inflammatory diseases. Therefore, it is plausible to test their capabilities as alternative therapies in the treatment of ARDS. In this study, we investigated the potential protective effects of cannabichromene (CBC) in an experimental model of ARDS. METHODS: We used, for the first time, an inhalant CBC treatment as a potential therapeutic target in a murine model of ARDS-like symptoms. ARDS was induced by intranasal administration of Poly(I:C), a synthetic mismatched double-stranded RNA, into the C57BL/6 mice (6-10 male mice/group, including sham, placebo, and CBC treated), three once-daily doses followed by a daily dose of inhalant CBC or placebo for the period of 8 days starting the first dose 2 h after the second Poly(I:C) treatment. We employed histologic, immunohistochemistry, and flow cytometry methods to assess the findings. Statistical analysis was performed by using one way analysis of variance (ANOVA) followed by Newman-Keuls post hoc test to determine the differences among the means of all experimental groups and to establish significance (p < 0.05) among all groups. RESULTS: Our data showed that CBC was able to reverse the hypoxia (increasing blood O2 saturation by 8%), ameliorate the symptoms of ARDS (reducing the pro-inflammatory cytokines by 50% in lung and blood), and protect the lung tissues from further destruction. Further analysis showed that CBC may wield its protective effects through transient receptor potential (TRP) cation channels, TRPA1 and TRPV1, increasing their expression by 5-folds in lung tissues compared to sham and untreated mice, re-establishing the homeostasis and immune balance. CONCLUSION: Our findings suggest that inhalant CBC may be an effective alternative therapeutic target in the treatment of ARDS. In addition, Increased expression of TRPs cation channels after CBC treatment proposes a novel role for TRPs (TRPA1 and TRPV2) as new potential mechanism to interpret the beneficial effects of CBC as well as other cannabinoids in the treatment of ARDS as well as other inflammatory diseases. Importantly, delivering CBC through an inhaler device is a translational model supporting the feasibility of trial with human subjects, authorizing further research.

Intranasal infusion of GD3 and GM1 gangliosides downregulates alpha-synuclein and controls tyrosine hydroxylase gene in a PD model mouse.

Parkinson's disease (PD) is characterized by Lewy bodies (composed predominantly of alpha-synuclein [aSyn]) and loss of pigmented midbrain dopaminergic neurons comprising the nigrostriatal pathway. Most PD patients show significant deficiency of gangliosides, including GM1, in the brain, and GM1 ganglioside appears to keep dopaminergic neurons functioning properly. Thus, supplementation of GM1 could potentially provide some rescuing effects. In this study, we demonstrate that intranasal infusion of GD3 and GM1 gangliosides reduces intracellular aSyn levels. GM1 also significantly enhances expression of tyrosine hydroxylase (TH) in the substantia nigra pars compacta of the A53T aSyn overexpressing mouse, following restored nuclear expression of nuclear receptor related 1 (Nurr1, also known as NR4A2), an essential transcription factor for differentiation, maturation, and maintenance of midbrain dopaminergic neurons. GM1 induces epigenetic activation of the TH gene, including augmentation of acetylated histones and recruitment of Nurr1 to the TH promoter region. Our data indicate that intranasal administration of gangliosides could reduce neurotoxic proteins and restore functional neurons via modulating chromatin status by nuclear gangliosides.

Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

Niacin modulates macrophage polarization in Parkinson's disease.

Neuroinflammation remains a central piece in Parkinson's disease (PD) pathophysiology. However, mechanisms by which PD links to the neuroinflammation remain elusive. Here, for the first time, we report that lower dose of niacin in PD patients may affect macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) profile through the niacin receptor GPR109A. Skew in the peripheral macrophages were accompanied by improved quality of life assessments in patients. Low dose niacin supplementation may be beneficial in PD, boosting anti-inflammatory processes and suppressing inflammation. Varied niacin dosages for longer durations may further reveal the potential role of anti-inflammatory interventions in PD progression.

Interprofessional education increases knowledge, promotes team building, and changes practice in the care of Parkinson's disease.

OBJECTIVE: Examine outcomes for the National Parkinson Foundation (NPF) Allied Team Training for Parkinson (ATTP), an interprofessional education (IPE) program in Parkinson's disease (PD) and team-based care for medicine, nursing, occupational, physical and music therapies, physician assistant, social work and speech-language pathology disciplines. BACKGROUND: Healthcare professionals need education in evidence-based PD practices and working effectively in teams. Few evidence-based models of IPE in PD exist. METHODS: Knowledge about PD, team-based care, the role of other disciplines and attitudes towards healthcare teams were measured before and after a protocol-driven training program. Knowledge, attitudes and practice changes were again measured at 6-month post-training. Trainee results were compared to results of controls. RESULTS: Twenty-six NPF-ATTP trainings were held across the U.S. (2003-2013). Compared to control participants (n = 100), trainees (n = 1468) showed statistically significant posttest improvement in all major outcomes, including self-perceived (p < 0.001) and objective knowledge (p < 0.001), Understanding Role of Other Disciplines (p < 0.001), Attitudes Toward Health Care Teams Scale (p < 0.001), and the Attitudes Toward Value of Teams (p < 0.001) subscale. Despite some decline, significant improvements were largely sustained at six-month post-training. Qualitative analyses confirmed post-training practice changes. CONCLUSIONS: The NPF-ATTP model IPE program showed sustained positive gains in knowledge of PD, team strategies and role of other disciplines, team attitudes, and important practice improvements. Further research should examine longer-term outcomes, objectively measure practice changes and mediators, and determine impact on patient outcomes.

Low-dose niacin supplementation modulates GPR109A, niacin index and ameliorates Parkinson's disease symptoms without side effects.

A 65-year-old male, Parkinson's disease patient, was evaluated for GPR109A expression, niacin index, UPDRS scale, handwriting test, and quality of sleep with and without niacin treatment. The evaluation was repeated 3 months after niacin was stopped. Niacin modulated the abovementioned parameters and showed the overall improvement without side effects.

The transesophageal echo probe may contribute to esophageal injury after catheter ablation for paroxysmal atrial fibrillation under general anesthesia: a preliminary observation.

INTRODUCTION: The transesophageal echo probe (TEE) is commonly used before and during atrial fibrillation (AF) ablation under general anesthesia (GA). We sought to determine the potential contribution of the TEE probe to esophageal injury after pulmonary vein isolation (PVI) alone for paroxysmal AF. METHODS AND RESULTS: Seventy-six patients undergoing PVI with TEE, PVI/TEE, 16 undergoing PVI without TEE (PVI/No TEE), and 27 undergoing TEE without any left atrial ablation (TEE/No LA ablation) under GA were included. Posterior wall ablation was power (20-25 W) and time limited (electrogram attenuation or ≤30 s). Esophageal capsule endoscopy (n = 206) was performed pre- and post-procedure and at 2 weeks. Esophageal lesions were seen in 30% of PVI/TEE, 0% of patients in the PVI/No TEE (P = 0.009), and 22% of TEE/No LA ablation groups (P = 0.47 vs. PVI/TEE). There were no instances of esophageal bleeding, perforation, or need for gastrointestinal intervention. Self-resolving dysphagia was the only reported symptom (5%). All lesions healed within 2 weeks. There was no significant difference in the location or morphological appearance of esophageal lesions seen in the PVI/TEE versus TEE/No LA ablation groups. CONCLUSIONS: Esophageal lesions were seen in 30% of patients undergoing PVI alone under GA with use of TEE and in a similar proportion (22%) of patients undergoing TEE in the absence of left atrial ablation. This study makes the preliminary observation that one must be cognizant of the TEE probe as a potential contributor to esophageal injury after AF ablation. Larger studies are needed to confirm these findings.

Upregulation of GPR109A in Parkinson's disease.

BACKGROUND: Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD. METHODS AND FINDINGS: GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-ß, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep. CONCLUSIONS: The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted.

Ten session body image therapy: efficacy of a manualised body image therapy.

OBJECTIVE: To determine the efficacy of 10 session body image therapy (BAT-10) in the treatment of anorexia nervosa with adherence to the methodological guidance for complex interventions. METHOD: Fifty-five adult inpatients with anorexia nervosa at two national centres received the group-based manualised body-image therapy (BAT-10). BAT-10 was refined, developed and manualised over two decades, by using the mindfulness-based cognitive behavioural therapy, including mirror exposure. Outcomes were evaluated using Body Checking Questionnaire, Body Image Avoidance Questionnaire, Physical Appearance State and Trait Anxiety Scale, Eating Disorders Examination Questionnaire and Quality of Life in Eating Disorders. Participant experience was evaluated qualitatively by an interpretative phenomenological analysis. RESULTS: Ten session body image therapy achieved highly statistically significant changes in body checking, body avoidance and anxiety, as well as shape-concern and weight-concern, without the between-therapist effects. The quality of life improved globally but not in relation to the psychological subcategory. DISCUSSION: Ten session body image therapy delivers behavioural and cognitive improvements in body image in the short-term, suggesting an effective, feasible and acceptable manual-based therapy.

Nintendo Wii rehabilitation ("Wii-hab") provides benefits in Parkinson's disease.

Parkinson's disease (PD) impairs both activities of daily living (ADLs) and motor function and has adverse effects on mood in many patients. While dopaminergic medications are quite helpful for motor and ADLs impairments in PD, complementary therapies are also important in helping patients achieve maximum benefits and quality of life. We hypothesized that the Nintendo Wii (Wii) is a useful tool in improving motor and non-motor aspects in patients with PD, given its ability to drive functional movements and interactive nature. We enrolled twenty subjects with early to mid-stage PD in an open-label within-subjects study design where each subject was evaluated at baseline and then re-evaluated after playing the Wii three times per week for four weeks. Subjects were then re-evaluated one month later after not playing the Wii for a month to see if effects carried over. Subjects demonstrated significant improvements in the primary outcome measure (Nottingham Extended Activities of Daily Living Test (NEADL)), quality of life (PDQ-39) and motor function (UPDRS), and a trend toward improved mood (HAM-D) after four weeks of Wii therapy. Follow-up assessments one month later showed continued improvement for quality of life and UPDRS scores. The results demonstrate that Wii therapy provides short-term motor, non-motor, and quality of life benefits in PD. Further studies are needed to determine if there are long-term benefits of Wii therapy in PD.

Geospatial approaches to characterizing agriculture in the Chincoteague Bay subbasin.

Most agricultural information is reported by government sources on a state or county basis. The purpose of this study was to demonstrate use of geospatial data, the 2002 Agricultural Cropland Data Layer (CDL) for the mid-Atlantic region, to characterize agricultural, environmental, and other scientific parameters for the Chincoteague Bay subbasin using geographic information systems. This study demonstrated that agriculture can be characterized accurately on subbasin and subwatershed bases, thus complimenting various assessment technologies. Approximately 28% of the dry land of the subbasin was cropland. Field corn was the largest crop. Soybeans, either singly or double-cropped with wheat, were the second most predominant crop. Although the subbasin is relatively small, cropping practices in the northern part were different from those in the southern portion. Other crops, such as fresh vegetables and vegetables grown for processing, were less than 10% of the total cropland. A conservative approximation of the total pesticide usage in the subbasin in 2002 was over 277,000 lbs of active ingredients. Herbicides represented the most frequently used pesticides in the subbasin, both in number (17) and in total active ingredients (over 261,000 lbs). Ten insecticides predominated in the watershed, while only small quantities of three fungicides were used. Total pesticide usage and intensity were estimated using the CDL. Nutrient inputs to cropland from animal manure, chemical fertilizer, and atmospheric deposition were modeled at over 30 million pounds of nitrogen and over 7 million pounds of phosphorous. Crops under conservation tillage had the largest input of both nutrients.

Long-term omega-3 polyunsaturated fatty acid supplementation reduces the recurrence of persistent atrial fibrillation after electrical cardioversion.

BACKGROUND: Persistent atrial fibrillation (AF) is associated with a high risk of recurrence after electrical cardioversion. OBJECTIVE: We examined if long-term supplementation with omega-3 polyunsaturated fatty acids in fish oils commenced >1 month prior to electrical cardioversion and continued thereafter reduces recurrence of persistent AF. METHODS: This was an open-label, randomized study of 178 patients with persistent AF >1-month duration. Participants were assigned to control group (n = 87) or omega-3 group (6 g/d fish oil; n = 91) and underwent cardioversion 1 month later. Concurrent antiarrhythmic use of sotalol or amiodarone was permitted. Fish oil was continued till return of persistent AF or a maximum of 1 year. Intention-to-treat analysis was performed for the primary end point defined as the recurrence of persistent AF. RESULTS: Mean duration of fish oil intake was 56 days precardioversion and a total of 242 days in follow-up. Eicosapentaenoic acid and docosahexaenoic acid, the active components of fish oils, were 1.8-fold and 2.1-fold higher, respectively, in the omega-3 group compared with controls at the time of cardioversion (P <.001). At 90 days, 38.5% of the patients receiving omega-3 fatty acid supplement had AF recurrence compared with 77.5% of the controls (hazard ratio [omega-3 vs control] 0.38; 95% confidence interval 0.27-0.56; P <.001). Omega-3 intake was associated with a significant reduction in AF recurrence with or without concurrent antiarrhythmic drugs. CONCLUSIONS: Omega-3 polyunsaturated fatty acid supplementation commenced >1 month prior to electrical cardioversion and continued thereafter reduces the recurrence of persistent AF. Randomized controlled trials on long-term fish oil supplementation are needed to confirm these findings.

Effects of chronic omega-3 polyunsaturated fatty acid supplementation on human atrial mechanical function after reversion of atrial arrhythmias to sinus rhythm: reversal of tachycardia-mediated atrial cardiomyopathy with fish oils.

BACKGROUND: Atrial mechanical stunning is a form of tachycardia-mediated atrial cardiomyopathy that manifests after reversion of persistent atrial arrhythmias to sinus rhythm. OBJECTIVES: This study sought to examine whether chronic omega-3 polyunsaturated fatty acid supplementation with fish oils can reverse atrial mechanical stunning. METHODS: Patients undergoing reversion of persistent atrial fibrillation (AF) or atrial flutter (AFL) to sinus rhythm were randomized to a control group (n = 26) or an omega-3 group (n = 23). The latter were prescribed 6 g/day of fish oil for ≥1 month prior to the procedure. Parameters of left atrial appendage function were compared immediately before and immediately after reversion. RESULTS: After fish oil intake for a mean of 70 days, the following were noted favoring the omega-3 group among both AF and AFL patients: (1) 2-fold higher serum omega-3 levels (P < .001), (2) less mean decrease in emptying velocity (e.g., AF: 8% vs. 32%, P = .02), (3) less mean decrease in appendage emptying fraction (e.g., AFL: 7% vs. 60%, P = .002), (4) lower incidence of new or increased spontaneous echocardiographic contrast (e.g., AF: 11% vs. 62.5%, P = .003), and (5) lower incidence of atrial mechanical stunning (e.g., AFL: 20% vs. 100%, P = .001). Omega-3 intake conferred protection against stunning in a multivariable analysis (odds ratio 0.18, P = .02). CONCLUSION: Chronic fish oil ingestion in humans attenuates atrial mechanical stunning after reversion of atrial arrhythmias to sinus rhythm. This suggests that fish oils may target or even reverse underlying cellular and/or structural remodeling that occurs in response to persistent atrial arrhythmias.

Targeted left ventricular endocardial pacing using a steerable introducing guide catheter and active fixation pacing lead.

AIMS: Cardiac resynchronization therapy via the coronary sinus (CS) is not always possible. Left ventricular (LV) endocardial lead placement is a potential alternative. The purpose of this study was to assess the feasibility of endocardial LV pacing using a steerable lead introducer and active fixation polyurethane lead. METHODS AND RESULTS: Endocardial LV lead placement was attempted in nine patients (seven males, age 48-77 years) in whom transvenous CS lead placement had failed. Trans-septal puncture and septal dilatation were performed via the femoral route. A steerable introducer catheter was advanced across the septal puncture site from the right or left subclavian vein into the LV. An active fixation polyurethane lead was then implanted into the high postero-lateral aspect of the LV endocardial wall. All patients were anticoagulated following implant. Successful LV lead placement was achieved in eight patients. There were no acute complications and no embolic events during follow-up (1-32 months). All implanted patients responded well with either improvement in New York Heart Association class or maintenance of symptomatic improvement that had previously been conferred by LV epicardial pacing. CONCLUSION: Targeted LV endocardial pacing is a potential alternative to CS pacing and warrants a trial to characterize long-term benefits and risks.

Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.

Results of well-controlled prospective clinical trials showed the efficacy of lipid-lowering therapies in the reduction of cardiovascular (CV) events in western populations, but they were not reported with a Chinese population. This multicenter study was conducted to determine the effects of Xuezhikang (XZK), a partially purified extract of red yeast rice, on lipoprotein and CV end points in Chinese patients who experienced a previous myocardial infarction. Nearly 5,000 of these patients with average low-density lipoprotein cholesterol levels at baseline were randomly assigned either to placebo or to XZK daily for an average of 4.5 years. The primary end point was a major coronary event that included nonfatal myocardial infarction and death from coronary heart disease. Frequencies of the primary end point were 10.4% in the placebo group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and 45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by 30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels. In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and was safe and well tolerated.

Spirituality and clinical care in eating disorders: a qualitative study.

OBJECTIVE: Historical and contemporary research has posited links between eating disorders and religious asceticism. This study aimed to examine relationships between eating disorders, religion, and treatment. METHOD: Qualitative study using purposeful sampling, applying audiotaped and transcribed depth interview, subjected to interpretative phenomenological analysis. RESULTS: Participants were 10 adult Christian women receiving inpatient treatment for anorexia or bulimia nervosa. Five dominant categories emerged: locus of control, sacrifice, self-image, salvation, maturation. Appetitive control held moral connotations. Negative self-image was common, based more on sin than body-image. Medical treatment could be seen as salvation, with religious conversion manifesting a quest for healing, but treatment failure threatened faith. Beliefs matured during treatment, with prayer, providing a healing relationship. CONCLUSION: Religious beliefs impact on attitudes and motivation in eating disorders. Clinicians' sensitivity determines how beliefs influence clinical outcome. Treatment modifies beliefs such that theological constructs of illness cannot be ignored.

Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae.

Flavonoids are valuable natural products derived from the phenylpropanoid pathway. The objective of this study was to create a host for the biosynthesis of naringenin, the central precursor of many flavonoids. This was accomplished by introducing the phenylpropanoid pathway with the genes for phenylalanine ammonia lyase (PAL) from Rhodosporidium toruloides, 4-coumarate:coenzyme A (CoA) ligase (4CL) from Arabidopsis thaliana, and chalcone synthase (CHS) from Hypericum androsaemum into two Saccharomyces cerevisiae strains, namely, AH22 and a pad1 knockout mutant. Each gene was cloned and inserted into an expression vector under the control of a separate individual GAL10 promoter. Besides its PAL activity, the recombinant PAL enzyme showed tyrosine ammonia lyase activity, which enabled the biosynthesis of naringenin without introducing cinnamate 4-hydroxylase (C4H). 4CL catalyzed the conversion of both trans-cinnamic acid and p-coumaric acid to their corresponding CoA products, which were further converted to pinocembrin chalcone and naringenin chalcone by CHS. These chalcones were cyclized to pinocembrin and naringenin. The yeast AH22 strain coexpressing PAL, 4CL, and CHS produced approximately 7 mg liter(-1) of naringenin and 0.8 mg liter(-1) of pinocembrin. Several by-products, such as 2',4',6'-trihydroxydihydrochalcone and phloretin, were also identified. Precursor feeding studies indicated that metabolic flux to the engineered flavonoid pathway was limited by the flux to the precursor l-tyrosine.

Implantable loop recorders detect tachyarrhythmias in symptomatic patients with negative electrophysiological studies.

BACKGROUND: Implantable loop recorders (ILR) are a valuable tool in the investigation of syncope and compare favourably with non-invasive and intracardiac electrophysiological assessment of bradycardia. They are known to detect tachyarrhythmias but have not been shown to add to the diagnostic yield of electrophysiological testing in symptomatic patients. METHODS: We prospectively studied the first 41 patients (aged 48+/-19 years) in whom ILR were used at our institution after negative electrophysiological studies (EPS). All patients were symptomatic with palpitations (11), syncope (22) or both (8). Nine patients had known structural heart disease (two ischaemic, four cardiomyopathy, two valvular and one congenital). Patients were assessed according to demographic factors, symptoms and investigations. Loop recordings were analysed and assessed according to conventional criteria. RESULTS: Among 41 patients in whom electrophysiological studies had failed to demonstrate arrhythmias, six were found to have clinically significant tachyarrhythmias (four ventricular and two supraventricular). CONCLUSION: ILR diagnose prognostically significant tachyarrhythmias in symptomatic patients with negative electrophysiological studies.

Determination of human ventricular repolarization by noncontact mapping: validation with monophasic action potential recordings.

BACKGROUND: Noncontact mapping (NCM) has not been validated as a clinical technique to measure ventricular repolarization. We used NCM to determine repolarization characteristics by analysis of reconstructed unipolar electrograms (UEs) at the same sites as monophasic action potential (MAP) recordings in the human ventricle. METHODS AND RESULTS: MAPs were recorded from a total of 355 beats at 46 sites in the left or right ventricle of 9 patients undergoing ablation of ventricular tachycardia guided by NCM (EnSite system). Measurements were made during sinus rhythm, constant right ventricular pacing, and ventricular extrastimuli during restitution-curve construction. The EnGuide locator signal was used to document MAP catheter locations on the endocardial geometry. UE-determined activation-recovery interval (ARI) measured at the maximum derivative of the T wave (Wyatt method) and the minimum derivative of the positive T wave (alternative method) was correlated with MAP measured at 90% repolarization (MAP90%) at the same sites. ARI correlated with MAP90% during steady state by the Wyatt method (r=0.83, P<0.001) and the alternative method (r=0.94, P<0.001). Restitution curves constructed from MAP and UE data exhibited the same characteristics, with a mean correlation coefficient of 0.95 (range, 0.90 to 0.99, P<0.001). The error between ARI and MAP90% was greater over a shorter diastolic coupling interval but was not influenced by distance of the sampling site from the multielectrode array. CONCLUSIONS: NCM accurately determines steady-state and dynamic endocardial repolarization in humans. Global, high-density, NCM data could be used to characterize abnormalities of human ventricular repolarization.