A new era in electroencephalographic monitoring? Subscalp devices for ultra-long-term recordings.

Inaccurate subjective seizure counting poses treatment and diagnostic challenges and thus suboptimal quality in epilepsy management. The limitations of existing hospital- and home-based monitoring solutions are motivating the development of minimally invasive, subscalp, implantable electroencephalography (EEG) systems with accompanying cloud-based software. This new generation of ultra-long-term brain monitoring systems is setting expectations for a sea change in the field of clinical epilepsy. From definitive diagnoses and reliable seizure logs to treatment optimization and presurgical seizure foci localization, the clinical need for continuous monitoring of brain electrophysiological activity in epilepsy patients is evident. This paper presents the converging solutions developed independently by researchers and organizations working at the forefront of next generation EEG monitoring. The immediate value of these devices is discussed as well as the potential drivers and hurdles to adoption. Additionally, this paper discusses what the expected value of ultra-long-term EEG data might be in the future with respect to alarms for especially focal seizures, seizure forecasting, and treatment personalization.

Gamma Entrainment in a Large Retrospective Cohort: Implications for Photic Stimulation Therapy for Alzheimer's Disease.

BACKGROUND: Studies on mice models of Alzheimer's disease (AD) have suggested potential therapeutic benefits of intermittent photic stimulation at 40 Hz. OBJECTIVE: We examined the physiological response of 40 Hz intermittent photic stimulation (IPS) on routine EEG in a large retrospective cohort to investigate the effects of age on induced gamma oscillations by intermittent photic stimulation. Since most AD patients are elderly, it is important for future research to know if age affects photic stimulation. METHODS: Retrospective data from 1,464 subjects aged 0- 91. We performed frequency analysis and automatic peak detection and used regression analysis to investigate the effects of age and sex on peak frequencies and amplitude changes. To investigate the spread of the induced gamma oscillations, we assessed averaged topographies of 40 Hz band power. RESULTS: There was a statistically significant but very minor effect of age on amplitude change (- 0.002 normalized power per year, p < 0.0001) but not for sex (p = 0.728). Detection probability of induced peaks was significantly predicted by both age (OR = 0.988, CI 95 % [0.984, 0.993], p < 0.00001) and sex (OR = 0.625, CI 95 % [0.496, 0.787>], p < 0.0001). The induced 40 Hz gamma entrainment is spatially confined to the occipital area. CONCLUSION: There is a significant effect of age on induced gamma activity, but advanced age does not fundamentally change the behavior of the response in either magnitude or spatial distribution. This fact is important regarding future research into the possible therapeutic effects of photic stimulation in patients with AD.

Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University.

PURPOSE: To determine whether a hypofractionated proton therapy regimen will control early-stage disease and maintain low rates of side effects similar to results obtained using standard-fraction proton therapy at our institution. MATERIALS AND METHODS: A cohort of 146 patients with low-risk prostate cancer according to National Comprehensive Cancer Network guidelines (Gleason score <7, prostate-specific antigen [PSA] <10, tumor stage of T1-T2a) received 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks, a dose biologically equivalent to standard fractionation (44-45 fractions of 1.8 Gy to a total of 79.2 to 81 Gy in 0 weeks). Patients were evaluated at least weekly during treatment, at which time documentation of treatment tolerance and acute reactions was obtained. Follow-up visits were conducted every 3 months for the first 1 years, every 6 months for the next 3 years, then annually. Follow-up visits consisted of history and physical examination, PSA measurements, and evaluation of toxicity. RESULTS: The median follow-up time was 42 months (range, 3-96 months). Acute grade 2 urinary toxicity occurred in 16% (20/120) of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7% (2/120). At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). The median time to PSA nadir was 30 months. CONCLUSION: Hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer.

Growth and production of volatile compounds of yarrow (Achillea millefolium L.) under different irrigation depths.

Yarrow (Achillea millefolium L., Asteraceae) is an important medicinal plant used worldwide for its medicinal properties such as the analgesic, antioxidant and anti-inflammatory ones. The aim of this study was to evaluate the growth and production of photosynthetic pigments and of volatile constituents of Achillea millefolium L. under different irrigation depths. The treatments were the application of 55, 110, 220, 440 and 880 mm of water for a period of 110 days. Data were submitted to polynomial regression analysis at 5% probability, while the volatile constituents were analyzed by standard deviation. Different irrigation depths provided quadratic growth responses being the highest dry matter production at the depth of 440 mm. The contents of chlorophyll a, b, total and carotenoids were higher at the lower depth tested (55 mm). The major volatile compounds identified were sabinene, 1,8-cineol, borneol and ß-caryophyllene. Increased water availability reduced the complexity of the volatile fraction of essential oil. Thus, it is recommended that the species be cultivated at 440 mm irrigation depth to have a higher production of dry matter and lower variation in the volatile profile of the essential oil.

Pharmacodynamics and proteomic analysis of acalabrutinib therapy: similarity of on-target effects to ibrutinib and rationale for combination therapy.

Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens. Peripheral blood samples from 21 patients with relapsed/refractory CLL in acalabrutinib phase I (100-400 mg/day) and II (100 mg BID) clinical trials were collected prior to and on days 8 and 28 after treatment initiation and evaluated for plasma chemokines, reverse phase protein array, immunoblotting and pseudoemperipolesis. The on-target pharmacodynamic profile of acalabrutinib in CLL lymphocytes was comparable to ibrutinib in measures of acalabrutinib-mediated changes in CCL3/CCL4 chemokine production, migration assays and changes in B-cell receptor signaling pathway proteins and other downstream survival proteins. Among several CLL-targeted agents, venetoclax, when combined with acalabrutinib, showed optimal complementary activity in vitro, ex vivo and in vivo in TCL-1 adoptive transfer mouse model system of CLL. These findings support selective targeting and combinatorial potential of acalabrutinib.

Green design of a paper test card for urinary iodine analysis.

When young children do not receive adequate amounts of the micronutrient iodine in their diet, their growth and cognitive development can be impaired. Nearly every country in the world has programs in place to track iodine intake and provide supplemental iodine if needed, usually in the form of fortified salt. The iodine nutrition status of a population can be tracked by monitoring iodine levels in urine samples to see if the median value falls in the range of 100-300 micrograms of iodine per liter of urine (µg I/L), which indicates adequate or more than adequate iodine nutrition. Many low and middle-income countries (LMIC) do not have a laboratory capable of carrying out this challenging assay, so samples must be sent out for assay in external labs, which is expensive and time-consuming. In most LMIC, population iodine surveys are carried out every 5-10 years, which limits the utility of the data for program monitoring and evaluation. To solve this problem, we developed a field-friendly paper test card that uses the Sandell-Kolthoff reaction to measure urinary iodine levels. A blind internal validation study showed that 93% of samples (n = 60) of iodide in an artificial urine matrix were categorized correctly by visual analysis as deficient, adequate, or excessive for levels set forth by the World Health Organization. Quantitative measurements based on computer image analysis had an error of 40 ± 20 µg I/L (n = 35 for samples in the calibration range) and these results categorized 88% of the samples (n = 60) correctly. We employed lifecycle analysis principles to address the known toxicity of arsenic, which is an obligatory reagent in the Sandell-Kolthoff reaction. Disposal of the cards in a landfill (their most likely destination after use) could let arsenic leach into groundwater; toxicity characteristic leaching procedure (TCLP) tests showed that the level of arsenic leached from the cards was 28.78 ppm, which is above the United States Environmental Protection Agency's limit of 5 parts per million for solid waste. We integrated a remediation module into the card. This module contains oxone, to oxidize As(III) to As(V) oxyacids, and the iron oxide goethite. TCLP testing showed that the leachable amount of arsenic was reduced by at least 97.6%-from 28.8 ppm to lower than 0.7 ± 0.7 ppm (n = 20). This upstream intervention rendered the test card suitable for landfilling while retaining its functionality to perform a critical public health evaluation.

Growth, photosynthetic pigments and production of essential oil of long-pepper under different light conditions

ABSTRACT Piper hispidinervum C. DC. is popularly known as long-pepper and it owns a commercial value due to the essential oil it produces. Long-pepper oil is rich in safrole and eugenoln components that have insecticidal, fungicidal and bactericidal activity. It has been establish that to medicinal plants light influences not only growth but also essential oil production. The growth, the content of photosynthetic pigments and the essential oil production of Piper hispidinervum at greenhouses with different light conditions was evaluated. The treatments were characterized by cultivation of plants for 180 days under different light conditions, produced by shading greenhouses with 50% and 30% of natural incident irradiance, two colored shading nets red (RN) and blue (BN) both blocking 50% of the incident radiation and one treatment at full-sun (0% of shade). The results showed that the treatments of 50% shade and RN and BN were the ones which stimulated the greater growth. Blue and red light also had the best production of photosynthetic pigments. Essential oil yielded more under full sun therefore this is the most indicated condition to produce seedlings for the chemical and pharmaceutical industry.

Growth, photosynthetic pigments and production of essential oil of long-pepper under different light conditions.

Piper hispidinervum C. DC. is popularly known as long-pepper and it owns a commercial value due to the essential oil it produces. Long-pepper oil is rich in safrole and eugenoln components that have insecticidal, fungicidal and bactericidal activity. It has been establish that to medicinal plants light influences not only growth but also essential oil production. The growth, the content of photosynthetic pigments and the essential oil production of Piper hispidinervum at greenhouses with different light conditions was evaluated. The treatments were characterized by cultivation of plants for 180 days under different light conditions, produced by shading greenhouses with 50% and 30% of natural incident irradiance, two colored shading nets red (RN) and blue (BN) both blocking 50% of the incident radiation and one treatment at full-sun (0% of shade). The results showed that the treatments of 50% shade and RN and BN were the ones which stimulated the greater growth. Blue and red light also had the best production of photosynthetic pigments. Essential oil yielded more under full sun therefore this is the most indicated condition to produce seedlings for the chemical and pharmaceutical industry.

Association of Rapid Care Process Implementation on Reperfusion Times Across Multiple ST-Segment-Elevation Myocardial Infarction Networks.

BACKGROUND: The Mission: Lifeline STEMI Systems Accelerator program, implemented in 16 US metropolitan regions, resulted in more patients receiving timely reperfusion. We assessed whether implementing key care processes was associated with system performance improvement. METHODS AND RESULTS: Hospitals (n=167 with 23 498 ST-segment-elevation myocardial infarction patients) were surveyed before (March 2012) and after (July 2014) program intervention. Data were merged with patient-level clinical data over the same period. For reperfusion, hospitals were grouped by whether a specific process of care was implemented, preexisting, or never implemented. Uptake of 4 key care processes increased after intervention: prehospital catheterization laboratory activation (62%-91%; P<0.001), single call transfer protocol from an outside facility (45%-70%; P<0.001), and emergency department bypass for emergency medical services direct presenters (48%-59%; P=0.002) and transfers (56%-79%; P=0.001). There were significant differences in median first medical contact-to-device times among groups implementing prehospital activation (88 minutes implementers versus 89 minutes preexisting versus 98 minutes nonimplementers; P<0.001 for comparisons). Similarly, patients treated at hospitals implementing single call transfer protocols had shorter median first medical contact-to-device times (112 versus 128 versus 152 minutes; P<0.001). Emergency department bypass was also associated with shorter median first medical contact-to-device times for emergency medical services direct presenters (84 versus 88 versus 94 minutes; P<0.001) and transfers (123 versus 127 versus 167 minutes; P<0.001). CONCLUSIONS: The Accelerator program increased uptake of key care processes, which were associated with improved system performance. These findings support efforts to implement regional ST-segment-elevation myocardial infarction networks focused on prehospital catheterization laboratory activation, single call transfer protocols, and emergency department bypass.

Informing models through empirical relationships between foliar phosphorus, nitrogen and photosynthesis across diverse woody species in tropical forests of Panama.

Our objective was to analyze and summarize data describing photosynthetic parameters and foliar nutrient concentrations from tropical forests in Panama to inform model representation of phosphorus (P) limitation of tropical forest productivity. Gas exchange and nutrient content data were collected from 144 observations of upper canopy leaves from at least 65 species at two forest sites in Panama, differing in species composition, rainfall and soil fertility. Photosynthetic parameters were derived from analysis of assimilation rate vs internal CO2 concentration curves (A/Ci ), and relationships with foliar nitrogen (N) and P content were developed. The relationships between area-based photosynthetic parameters and nutrients were of similar strength for N and P and robust across diverse species and site conditions. The strongest relationship expressed maximum electron transport rate (Jmax ) as a multivariate function of both N and P, and this relationship was improved with the inclusion of independent data on wood density. Models that estimate photosynthesis from foliar N would be improved only modestly by including additional data on foliar P, but doing so may increase the capability of models to predict future conditions in P-limited tropical forests, especially when combined with data on edaphic conditions and other environmental drivers.

Introduction: energy and the subsurface.

This theme issue covers topics at the forefront of scientific research on energy and the subsurface, ranging from carbon dioxide (CO2) sequestration to the recovery of unconventional shale oil and gas resources through hydraulic fracturing. As such, the goal of this theme issue is to have an impact on the scientific community, broadly, by providing a self-contained collection of articles contributing to and reviewing the state-of-the-art of the field. This collection of articles could be used, for example, to set the next generation of research directions, while also being useful as a self-study guide for those interested in entering the field. Review articles are included on the topics of hydraulic fracturing as a multiscale problem, numerical modelling of hydraulic fracture propagation, the role of computational sciences in the upstream oil and gas industry and chemohydrodynamic patterns in porous media. Complementing the reviews is a set of original research papers covering growth models for branched hydraulic crack systems, fluid-driven crack propagation in elastic matrices, elastic and inelastic deformation of fluid-saturated rock, reaction front propagation in fracture matrices, the effects of rock mineralogy and pore structure on stress-dependent permeability of shales, topographic viscous fingering and plume dynamics in porous media convection.This article is part of the themed issue 'Energy and the subsurface'.

Zinc and the prooxidant heart failure phenotype.

Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn and Ca dyshomeostasis, in which consequent hypozincemia compromises Zn homeostasis and Zn-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn]i as antioxidant and [Ca]i as prooxidant can be uncoupled in favor of Zn-based antioxidant defenses. Increased [Zn]i acts as a multifaceted antioxidant by: (1) inhibiting Ca entry through L-type channels and hence cardioprotectant from the Ca-driven mitochondriocentric signal-transducer effector pathway to nonischemic necrosis, (2) serving as catalytic regulator of Cu/Zn-superoxide dismutase, and (3) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously using a ß3-receptor agonist (eg, nebivolol) that enhances NO generation to release inactive cytosolic Zn bound to metallothionein. By recognizing the pathophysiologic relevance of Zn dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling.

Utilização da vitamina D3 e seus metabólitos na alimentação de frangos de corte sobre parâmetros imunológicos e morfometria intestinal / Use of vitamin D3 and its metabolites in broiler feed on immunological parameters and intestinal morphometry

Os efeitos da suplementação da vitamina D3 e de seus diferentes metabólitos foram avaliados na resposta imune e na morfometria intestinal de frangos de corte. Foram utilizados 952 frangos de corte de um dia de idade, distribuídos em um delineamento inteiramente casualizado, com quatro tratamentos, sete repetições e 34 aves por unidade experimental. Os tratamentos foram constituídos por quatros diferentes fontes de vitamina D3: colecalciferol (D3), 25-hidroxicolecalciferol (25(OH)D3),1,25dihidroxicolecalciferol (1,25(OH)2D3) e 1α-hidroxicolecalciferol (1α(OH)D3). As diferentes fontes foram incluídas na dieta, fornecendo 2000 e 1600 UI de vitamina D, nas fases pré-inicial, inicial e de crescimento, respectivamente. O peso relativo do intestino delgado diferiu entre os tratamentos aos 7, 21 e 42 dias e o peso relativo do fígado somente aos 42 dias de idade. Os demais órgãos e parâmetros imunológicos avaliados (peso dos órgãos linfóides, reação de hipersensibilidade cutânea basofílica, avaliação da atividade de macrófagos, dosagem de nitrito e perfil heterofilo: linfócito foram similares entre os animais alimentados com os diferentes metabólitos. Houve efeito (P<0,05) dos diferentes metabólitos da vitamina D3 sobre o comprimento dos vilos de jejuno e íleo aos sete dias, diferindo entre os animais alimentados com 1,25(OH)2D3 e 1α(OH)D3 para jejuno e 1,25(OH)2D3 e vitamina D3 para íleo (P<0,05). Para as demais fases não foi observado influência (P>0,05) dos tratamentos. Os parâmetros imunológicos não foram afetados pelos diferentes metabólitos de vitamina D. Os diferentes metabólitos de vitamina D afetaram positivamente a morfometria intestinal na altura de vilo na fase inicial, sendo os melhores resultados obtido pelos animais alimentados com 1,25(OH)2D3, contudo os parâmetros imunológicos foram similares entre os metabólitos estudados.

The aim of this experiment was to evaluate the effect of different vitamin D metabolites on immune response and intestine morphometry of broiler chickens. We used 952 1-day-old chicks, male Cobb, distributed into a completely randomized design with four treatments, seven replications and 34 birds each. There were evaluated four different metabolites of vitamin D: D3, 25(OH)D3, 1,25(OH)2D3 and 1α(OH)D3, providing 2000 and 1600 IU/kg feed of vitamin D in initial and growth period, respectively. The different metabolites of vitamin D did not affect the relative weight of the organs except for the weight of the intestine and liver at 21 and 42 days. There was a significant effect (P<0.05) of the different metabolites of D3 vitamin on the villi length of jejunum and ileum at 7 days, between animals fed with 1,25(OH)2D3 and 1α(OH)D3 to the jejunum and 1,25(OH)2D3 and vitamin D3 to the ileum (P<0.05). There were no differences (P>0.05) for weight of lymphoid organs, cutaneous basophil hypersensitivity reaction, macrophage activity assessment, measurement of nitric oxide and heterophil profile: lymphocyte. The different sources of vitamin D affect the intestine morphometrics on the villi length in the initial phase, but the effect was not observed in other phases. The immunological parameters were not affected by metabolites of vitamin D.

Amiodarone reduces the amount of ablation during catheter ablation for persistent atrial fibrillation.

AIMS: The step-wise approach to catheter ablation for persistent atrial fibrillation (AF) requires considerable substrate modification targeting at complex fractionated atrial electrograms (CFAEs) in addition to pulmonary vein (PV) isolation. An alternative strategy that minimizes the amount of ablation would be desirable. The aim of this study was to investigate whether the use of pre-procedural amiodarone affects: (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes. METHODS AND RESULTS: We studied 121 consecutive patients with persistent AF who underwent catheter ablation. The patients were divided into two groups: Group 1, amiodarone (n = 31); Group 2, other antiarrhythmic drugs or rate control (n = 90). All the patients underwent a step-wise ablation procedure beginning with PV isolation, then proceeding with ablation of the CFAEs and linear lesions until sinus rhythm was achieved. Mean left atrial cycle length of AF (AFCL) was recorded at each step. The number of CFAE ablation sites was recorded. The number of CFAE sites in Group 1 was significantly less than that in Group 2 (P = 0.0121). The AFCLs after each step in Group 1 were significantly longer than those in Group 2. The procedure time and the radiofrequency time of CFAE ablation in Group 1 were significantly shorter than that in Group 2 (P = 0.0276 and P = 0.0458, respectively). There was no significant difference between the two groups in early and long-term outcomes. CONCLUSION: Use of pre-procedural amiodarone prolongs AFCL during catheter ablation and reduces the number of CFAE sites requiring ablation to achieve procedural success while maintaining equivalent long-term results.

Suicide and drought in New South Wales, Australia, 1970-2007.

There is concern in Australia that droughts substantially increase the incidence of suicide in rural populations, particularly among male farmers and their families. We investigated this possibility for the state of New South Wales (NSW), Australia between 1970 and 2007, analyzing data on suicides with a previously established climatic drought index. Using a generalized additive model that controlled for season, region, and long-term suicide trends, we found an increased relative risk of suicide of 15% (95% confidence interval, 8%-22%) for rural males aged 30-49 y when the drought index rose from the first quartile to the third quartile. In contrast, the risk of suicide for rural females aged >30 y declined with increased values of the drought index. We also observed an increased risk of suicide in spring and early summer. In addition there was a smaller association during unusually warm months at any time of year. The spring suicide increase is well documented in nontropical locations, although its cause is unknown. The possible increased risk of suicide during drought in rural Australia warrants public health focus and concern, as does the annual, predictable increase seen each spring and early summer. Suicide is a complex phenomenon with many interacting social, environmental, and biological causal factors. The relationship between drought and suicide is best understood using a holistic framework. Climate change projections suggest increased frequency and severity of droughts in NSW, accompanied and exacerbated by rising temperatures. Elucidating the relationships between drought and mental health will help facilitate adaptation to climate change.

Systems of care for ST-segment-elevation myocardial infarction: a report From the American Heart Association's Mission: Lifeline.

BACKGROUND: National guidelines call for participation in systems to rapidly diagnose and treat ST-segment-elevation myocardial infarction (STEMI). In order to characterize currently implemented STEMI reperfusion systems and identify practices common to system organization, the American Heart Association surveyed existing systems throughout the United States. METHODS AND RESULTS: A STEMI system was defined as an integrated group of separate entities focused on reperfusion therapy for STEMI within a geographic region that included at least 1 hospital that performs percutaneous coronary intervention and at least 1 emergency medical service agency. Systems meeting this definition were invited to participate in a survey of 42 questions based on expert panel opinion and knowledge of existing systems. Data were collected through the American Heart Association Mission: Lifeline website. Between April 2008 and January 2010, 381 unique systems involving 899 percutaneous coronary intervention hospitals in 47 states responded to the survey, of which 255 systems (67%) involved urban regions. The predominant funding sources for STEMI systems were percutaneous coronary intervention hospitals (n = 320, 84%) and /or cardiology practices (n = 88, 23%). Predominant system characteristics identified by the survey included: STEMI patient acceptance at percutaneous coronary intervention hospital regardless of bed availability (N = 346, 97%); single phone call activation of catheterization laboratory (N = 335, 92%); emergency department physician activation of laboratory without cardiology consultation (N = 318, 87%); data registry participation (N = 311, 84%); and prehospital activation of the laboratory through emergency department notification without cardiology notification (N = 297, 78%). The most common barriers to system implementation were hospital (n = 139, 37%) and cardiology group competition (n = 81, 21%) and emergency medical services transport and finances (n = 99, 26%). CONCLUSIONS: This survey broadly describes the organizational characteristics of collaborative efforts by hospitals and emergency medical services to provide timely reperfusion in the United States. These findings serve as a benchmark for existing systems and should help guide healthcare teams in the process of organizing care for patients with STEMI.

Cellular and molecular pathways to myocardial necrosis and replacement fibrosis.

Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signal-transducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca2+ overloading and subsequent induction of oxidative stress, predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca2+ - Zn2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.

Fibrosis in hypertensive heart disease: molecular pathways and cardioprotective strategies.

Fibrosis is a fundamental component of the adverse structural remodelling of myocardium found in hypertensive heart disease (HHD). A replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium. Such scarring has adverse functional consequences. The extensive distribution of fibrosis involving the right and left heart suggests cardiomyocyte necrosis is widespread. Together, the loss of these contractile elements and fibrous tissue deposition in the form of stiff in-series and in-parallel elastic elements contribute to the progressive failure of this normally efficient muscular pump. Pathogenic mechanisms modulating fibrous tissue formation at sites of repair include auto/paracrine properties of locally generated angiotensin II and endothelin-1. This study focuses on the signal-transducer-effector pathway involved in cardiomyocyte necrosis and the crucial pathogenic role of intracellular calcium overloading, and the subsequent induction of oxidative stress originating within its mitochondria that dictates the opening of the mitochondrial permeability transition pore. The ensuing osmotic destruction of these organelles is followed by necrotic cell death. It is now further recognized that calcium overloading of cardiac myocytes and mitochondria functioning as pro-oxidant is pathophysiologically counterbalanced by an intrinsically coupled zinc entry, which serves as an antioxidant. The prospect of raising intracellular zinc by adjuvant nutriceutical supplementation can, therefore, be preferentially exploited to uncouple this intrinsically coupled calcium-zinc dyshomeostasis in favour of endogenous antioxidant defences. Novel cardioprotective strategies may thus be at hand and deserve to be explored further in the overall management of patients with HHD.

Uncoupling the coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria seen in aldosteronism.

Intracellular [Ca2+]i overloading in cardiomyocytes is a fundamental pathogenic event associated with chronic aldosterone/salt treatment (ALDOST) and accounts for an induction of oxidative stress that leads to necrotic cell death and consequent myocardial scarring. This prooxidant response to Ca2+ overloading in cardiac myocytes and mitochondria is intrinsically coupled to simultaneous increased Zn2+ entry serving as an antioxidant. Herein, we investigated whether Ca2+ and Zn2+ dyshomeostasis and prooxidant to antioxidant dysequilibrium seen at 4 weeks, the pathologic stage of ALDOST, could be uncoupled in favor of antioxidants, using cotreatment with a ZnSO4 supplement; pyrrolidine dithiocarbamate (PDTC), a Zn2+ ionophore; or ZnSO4 in combination with amlodipine (Amlod), a Ca2+ channel blocker. We monitored and compared responses in cardiomyocyte free [Ca2+]i and [Zn2+]i together with biomarkers of oxidative stress in cardiac myocytes and mitochondria. At week 4 of ALDOST and compared with controls, we found (1) an elevation in [Ca2+]i coupled with [Zn2+]i and (2) increased mitochondrial H2O2 production and increased mitochondrial and cardiac 8-isoprostane levels. Cotreatment with the ZnSO4 supplement alone, PDTC, or ZnSO4+Amlod augmented the rise in cardiomyocyte [Zn2+]i beyond that seen with ALDOST alone, whereas attenuating the rise in [Ca2+]i, which together served to reduce oxidative stress. Thus, a coupled dyshomeostasis of intracellular Ca2+ and Zn2+ was demonstrated in cardiac myocytes and mitochondria during 4-week ALDOST, where prooxidants overwhelm antioxidant defenses. This intrinsically coupled Ca2+ and Zn2+ dyshomeostasis could be uncoupled in favor of antioxidant defenses by selectively increasing free [Zn2+]i and/or reducing [Ca2+]i using cotreatment with ZnSO4 or PDTC alone or ZnSO4+Amlod in combination.

Nutrient dyshomeostasis in congestive heart failure.

The clinical syndrome congestive heart failure (CHF) has its origins rooted in a salt-avid state mediated largely by effector hormones of the renin-angiotensin-aldosterone system. In recent years, this cardiorenal perspective of CHF has taken on a broader perspective. One which focuses on a progressive systemic illness, whose major features include the presence of oxidative stress in diverse tissues and elevated circulating levels of proinflammatory cytokines coupled with a wasting of soft tissues and bone. Experimental studies, which simulate chronic renin-angiotensin-aldosterone system activation, and translational studies in patients with salt avidity having decompensated biventricular failure with hepatic and splanchnic congestion have forged a broader understanding of this illness and the important contribution of a dyshomeostasis of Ca2+, Mg2+, Zn2+, Se2+, and vitamins D, B12, and B1. Herein, we review biomarkers indicative of the nutrient imbalance found in CHF and raise the question of a need for a polynutrient supplement in the overall management of CHF.