Evolving Strategies for Use of Phytochemicals in Prevention and Long-Term Management of Cardiovascular Diseases (CVD).

This report describes major pathomechanisms of disease in which the dysregulation of host inflammatory processes is a major factor, with cardiovascular disease (CVD) as a primary model, and reviews strategies for countermeasures based on synergistic interaction between various agents, including drugs and generally regarded as safe (GRAS) natural medical material (NMM), such as Ginkgo biloba, spice phytochemicals, and fruit seed flavonoids. The 15 well-defined CVD classes are explored with particular emphasis on the extent to which oxidative stressors and associated ischemia-reperfusion tissue injury contribute to major symptoms. The four major categories of pharmaceutical agents used for the prevention of and therapy for CVD: statins, beta blockers (ß-blockers), blood thinners (anticoagulants), and aspirin, are presented along with their adverse effects. Analyses of major cellular and molecular features of drug- and NMM-mediated cardioprotective processes are provided in the context of their development for human clinical application. Future directions of the evolving research described here will be particularly focused on the characterization and manipulation of calcium- and calcineurin-mediated cascades of signaling from cell surface receptors on cardiovascular and immune cells to the nucleus, with the emergence of both protective and pathological epigenetic features that may be modulated by synergistically-acting combinations of drugs and phytochemicals in which phytochemicals interact with cells to promote signaling that reduces the effective dosage and thus (often) toxicity of drugs.

Water quality limitations for tadpoles of the Wood Frog in the northern Great Plains, Canada.

Some wetlands in the northern Great Plains support hundreds to thousands of late-stage tadpoles providing important sources of recruitment to the Wood Frog (Lithobates sylvaticus) population while many other wetlands produce none. Relationships between water quality and late-stage tadpole abundance were determined to identify the water quality parameters associated with tadpole abundance. Water samples were collected, and late-stage tadpole abundances were assessed once each year in late June for 12 years in 26 wetlands. Catch or abundance was the number of tadpoles captured in 30 min with a dip-net. The catch of tadpoles was variable both among wetlands and over the long-term for individual wetlands, and ranged from 0 to several hundred individuals. Wood Frog tadpoles were especially sensitive to sodium and chloride concentrations. At Cl concentrations less than 5 mg/L, occupancy for late-stage tadpoles was 84%, and declined by about 8% for each 5 mg/L increase in Cl to 40.1 mg/L Cl, the maximum concentration associated with the detection of tadpoles. Optimal water quality for late-stage Wood Frog tadpoles included low concentrations of Na [Formula: see text] = 8.1 mg/L), and Cl [Formula: see text] = 4.2 mg/L) relative to total dissolved solids and other ions, and high concentrations of phosphorus. In a landscape where ion concentrations in wetlands can range over 3 orders of magnitude, water quality analyses suggest that abundant Wood Frog tadpole populations occur in wetlands dominated by snow-melt runoff with its characteristic low ion concentrations. The present study highlights the importance to amphibian conservation of the water quality environment of tadpole habitat.

Heme Degradation in Pathophysiology of and Countermeasures to Inflammation-Associated Disease.

The class of tetrapyrrol "coordination complexes" called hemes are prosthetic group components of metalloproteins including hemoglobin, which provide functionality to these physiologically essential macromolecules by reversibly binding diatomic gasses, notably O2, which complexes to ferrous (reduced/Fe(II)) iron within the heme porphyrin ring of hemoglobin in a pH- and PCO2-dependent manner-thus allowing their transport and delivery to anatomic sites of their function. Here, pathologies associated with aberrant heme degradation are explored in the context of their underlying mechanisms and emerging medical countermeasures developed using heme oxygenase (HO), its major degradative enzyme and bioactive metabolites produced by HO activity. Tissue deposits of heme accumulate as a result of the removal of senescent or damaged erythrocytes from circulation by splenic macrophages, which destroy the cells and internal proteins, including hemoglobin, leaving free heme to accumulate, posing a significant toxicogenic challenge. In humans, HO uses NADPH as a reducing agent, along with molecular oxygen, to degrade heme into carbon monoxide (CO), free ferrous iron (FeII), which is sequestered by ferritin protein, and biliverdin, subsequently metabolized to bilirubin, a potent inhibitor of oxidative stress-mediated tissue damage. CO acts as a cellular messenger and augments vasodilation. Nevertheless, disease- or trauma-associated oxidative stressors sufficiently intense to overwhelm HO may trigger or exacerbate a wide range of diseases, including cardiovascular and neurologic syndromes. Here, strategies are described for counteracting the effects of aberrant heme degradation, with a particular focus on "bioflavonoids" as HO inducers, shown to cause amelioration of severe inflammatory diseases.

Concentrations of Herbicides in Wetlands on Organic and Minimum-Tillage Farms.

Wetlands are abundant throughout the agricultural landscape of central Saskatchewan, Canada, and the biota present in these wetlands may be vulnerable to the toxic effects of pesticides used on nearby crops. We hypothesized that herbicide concentrations would be higher in wetlands on minimum-tillage farms than on organic (no herbicide use) farms, and that the principal transport mechanisms of runoff versus atmospheric deposition could be identified based on the concentrations in these two wetland types. To test these hypotheses, 29 herbicides were monitored for 5 yr in 16 wetlands on minimum-tillage farms and in seven wetlands on organic farms. Twenty herbicides were detected in wetlands on minimum-tillage farms versus 12 in wetlands on organic farms. Clopyralid, MCPA, 2,4-D, bromoxynil, dichlorprop, and dicamba were detected at a >50% frequency in wetlands on both minimum-tillage and organic farms. Concentrations of clopyralid were significantly higher in wetlands on minimum-tillage farms than in those on organic farms, whereas no significant difference was observed for any of the other five herbicides. Glyphosate, including its degradation product AMPA, was detected in >50% frequency only in wetlands on minimum-tillage farms where the mean concentration (1278 ng L) was higher than the concentration of other herbicides. Mass applied, vapor pressure, and water solubility were important determinants of herbicide concentrations and detections in wetlands. Herbicide concentrations in all but two samples were less than their respective Canadian guideline for protection of aquatic life, suggesting that, overall, individual herbicide concentrations in the wetlands were not toxic to biota.

Relationships for mercury and selenium in muscle and ova of gravid freshwater fish.

At high concentrations, mercury (Hg) is toxic to vertebrates, causing neurological, behavioral, and teratological dysfunction. Selenium (Se) not only is an essential element but also has a high affinity for Hg, binding to organic methyl mercury at a molar ratio of Se/Hg of 1:1. Ratios of <1 increase risk of Hg toxicity. For gravid fish, low concentrations of Se in ova could increase potential for Hg toxicity, compromising embryonic development and fitness of fry. Mercury and selenium concentrations and ratios were investigated in the muscle and ovaries of six species from five families of fish to assess potential for risk to ecological fitness. Molar ratios of Se/Hg in muscle were typically >18 for lower trophic level species but ≤2 for piscivores. For all species combined, the concentrations of Hg in ova were significantly related to concentrations of Hg in muscle. Concentrations of Se in ova versus muscle showed a similar significant relationship that was independent of muscle Hg concentration. Mean ova molar Se/Hg ratios were high, ranging from 69 to 955 for the 6 species. However, a declining relationship between the ova Se/Hg molar ratio and the muscle concentration of Hg for all species combined suggests that development of ova and fry might be compromised for those piscivores with the highest muscle Hg concentrations because of Hg-related Se deficiency.

Persistence of the Sulfonylurea Herbicides Sulfosulfuron, Rimsulfuron, and Nicosulfuron in Farm Dugouts (Ponds).

Sulfonylurea herbicides are applied at relatively low rates (3-40 g ha) to control weeds in a variety of crops grown in the prairie pothole region of south-central Canada. Because of their high phytotoxicity and the likelihood of their transport in surface runoff, there is concern about impacts of sulfonylurea herbicides to wetland ecosystems embedded in agricultural landscapes. In a previous study, dissipation half-lives (DT values) were determined for three sulfonylurea herbicides (thifensulfuron-methyl, ethametsulfuron-methyl, and metsulfuron-methyl), each possessing a hydrolyzable methyl ester linkage. In the current study, persistence of three sulfonylurea herbicides without a methyl ester linkage was determined in prairie farm dugouts (ponds). The dugouts were fortified with environmentally relevant concentrations (3.3-6.5 µg L) of either sulfosulfuron, rimsulfuron, or nicosulfuron. The order of persistence of these herbicides in dugout water from May and June to November and December was nicosulfuron > sulfosulfuron > rimsulfuron, with DT values of 75, 44, and 10 d, respectively. The lack of a methyl ester linkage in these herbicides did not significantly affect their overall persistence relative to those with the ester linkage. In all three dugouts, the decrease in herbicide mass in the water column from water loss via hydrological discharge to groundwater was minimal. The relatively long persistence of these herbicides in the water column of the dugouts reflects the stability of the sulfonylurea linkage to hydrolysis in weakly alkaline waters and indicates not only that microbial and photolytic degradation were low but also that there was little partitioning into sediments.

Recent Global Trends and Hotspots in Occipitocervical Fusion: A Bibliometric Analysis and Visualization Study.

Occipitocervical arthrodesis has a variety of indications to treat craniocervical and atlantoaxial pathologies for which a selective cervical fusion would not provide sufficient stability. Over time, the indications for occipitocervical fusions (OCF) have evolved, as new technologies and surgical techniques were developed. In this bibliometric analysis, we aim to explore the progression of OCF literature over time, analyzing the trends in publications and citations, publishing countries and authors, keywords and topics. The Web of Science database was used for data retrieval on July 3rd, 2024, with the search "occipitocervical fusion" OR "occipito-cervical fusion" OR "occipitocervical arthrodesis" OR "occipital cervical fusion" OR "occipital cervical arthrodesis" OR ("OCF" AND "spine surgery"). Excel was used to create the citation analysis and publication trend figures, along with the publishing countries and author analysis. The bibliometric software VosViewer was used to generate the keyword co-occurrence network visualizations. Overall, 762 articles were extracted. The number of pertinent publications and citations increased until 2020 before beginning to decrease. We found that Ehlers Danlos syndrome (EDS) has become a more prevalent topic, as the association between EDS and craniocervical instability has received further scrutiny. "Dysphagia" continues to be a commonly cited topic, while, conversely, rheumatoid arthritis has decreased in publication frequency, possibly related to advances in medical management and surgical techniques. Overall, the United States of America, China, and Japan are the top publishing countries. This analysis of OCF literature provides a helpful overview of emerging trends and clinician concerns, especially as seen through the perspective of time.

The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1.

We have recently described the immunosuppressive properties of AR-C117977 and AR-C122982, representatives of a group of compounds identified as inhibitors of lactate transporters (monocarboxylate transporters; MCTs). These compounds demonstrate the potential therapeutic usefulness of inhibiting MCT-1, but their physical and metabolic properties made them unsuitable for further development. We have therefore tried to find analogues with similar immunosuppressive efficacy and a more suitable profile for oral administration. Five analogues of AR-C117977 were synthesised and screened for binding to the transporter, for inhibition of proliferation of both human and rat lymphocytes, for in vivo activity in a model of graft-versus-host (GvH) response in the rat, and in high- and low-responder cardiac transplant models in the rat. There was a good correlation between levels of binding of the five analogues to MCT and their inhibition of lymphocyte proliferation in human and rat cells. Furthermore, activity in both the GvH response and the cardiac transplant models correlated well with the determined concentrations of test compound in plasma. These findings on new analogues of MCT-1 inhibitors have taken us further towards defining the pharmacokinetic properties that may help to identify future drug candidates among inhibitors of MCT-1.

Anterior Skull Base Reconstruction.

Anterior skull base reconstruction requires careful preoperative planning to use the most effective technique for the expected defect. Adherence to the principles of skull base reconstruction is imperative to minimize complications and improve patient outcomes.

Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice.

Previous investigations have demonstrated that treatment of animals with rapamycin increases levels of autophagy, which is a process by which cells degrade intracellular detritus, thus suppressing the emergence of senescent cells, whose pro-inflammatory properties, are primary drivers of age-associated physical decline. A hypothesis is tested here that rapamycin treatment of mice approaching the end of their normal lifespan exhibits increased survival, enhanced expression of autophagic proteins; and klotho protein-a biomarker of aging that affects whole organism senescence, and systemic suppression of inflammatory mediator production. Test groups of 24-month-old C57BL mice were injected intraperitoneally with either 1.5 mg/kg/week rapamycin or vehicle. All mice administered rapamycin survived the 12-week course, whereas 43% of the controls died. Relative to controls, rapamycin-treated mice experienced minor but significant weight loss; moreover, nonsignificant trends toward decreased levels of leptin, IL-6, IL-1ß, TNF-α, IL-1α, and IGF-1, along with slight elevations in VEGF, MCP-1 were observed in the blood serum of rapamycin-treated mice. Rapamycin-treated mice exhibited significantly enhanced autophagy and elevated expression of klotho protein, particularly in the kidney. Rapamycin treatment also increased cardiomyocyte Ca2+ -sensitivity and enhanced the rate constant of force re-development, which may also contribute to the enhanced survival rate in elderly mice.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H1 antagonists. Part II: optimising in vivo clearance.

The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H1 antagonists. Part I.

The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.

Total autogenous mandibular reconstruction using virtual surgical planning.

Free fibula transfer has become the workhorse in mandibular reconstruction. Total mandibular reconstruction is an uncommon procedure with added complexity. Numerous techniques have been described for such reconstruction, many requiring a temporomandibular joint prosthesis. We present a novel method where simultaneous bilateral free fibula transfer utilizing preoperative virtual surgical planning was used to produce a total autogenous reconstruction. The virtual surgical planning allows to effectively quantify the bone stock required preoperatively and facilitates intraoperative modeling of the fibula. Therefore, a more anatomically correct reconstruction is obtained resulting in improved functional and aesthetic outcomes.

Outcomes and Utility of Intracranial Free Tissue Transfer.

OBJECTIVE: Complications associated with intracranial vault compromise can be neurologically and systemically devastating. Primary and secondary repair of these deficits require an air and watertight barrier between the intracranial and extracranial environments. This study evaluated the outcomes and utility of using intracranial free tissue transfer as both primary and salvage surgical repair of reconstruction. METHODS: A retrospective review was performed of all subjects who underwent intracranial free tissue transfer as primary or salvage repair. RESULTS: A total of 13 intracranial free tissue transfers were performed on 11 subjects: osteocutaneous radial forearm free flaps (n = 6), partial myofascial rectus abdominis flaps (n = 5), temporoparietal fascia flap (n = 1), and serratus anterior myofascial flap (n = 1). Primary reconstruction was performed on 4 subjects with the remaining being salvage repair. Indications for surgery included neoplasm (n = 6 of 11), ballistic trauma (n = 3 of 11), motor vehicle accident (n = 1 of 11), and infection (n = 1 of 11). Three subjects required additional surgical repair for CSF leak and pneumocephalus, with 2 subjects requiring an additional free tissue transfer at a different site. CONCLUSION: In our experience, free tissue transfer is an effective primary and salvage surgical technique in the reconstruction of complex intracranial problems.

The discovery of AZD9164, a novel muscarinic M3 antagonist.

The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.

The discovery of new spirocyclic muscarinic M3 antagonists.

The optimisation of a new series of high potency muscarinic M3 antagonists, derived from high throughput screening library hit is described.

Mercury and other metals in muscle and ovaries of goldeye (Hiodon alosoides).

Concentrations of 24 trace metals were assessed in gravid ovaries and in muscle of female juvenile and adult female goldeye (Hiodon alosoides), a fish with both low annual growth (16 g/year as adults) and a long life span (maximum longevity of 30 years). It was hypothesized that adult fish with these life-history characteristics would maintain stable concentrations of metals in their tissues with higher levels of essential elements compared with those that are potentially toxic. As hypothesized, the concentration of most metals in muscle of adult female goldeye was similar at all ages, suggesting that uptake and excretion of metals was equal. Mercury was a notable exception. Total Hg concentrations in muscle of adults increased throughout life from a mean of 206 ng/g wet weight at age 8 to 809 ng/g at age 28, or by 26.2 ng/g/year. Concentrations of Hg were low in ovaries (mean 21.1 ng/g wet wt) compared to the mean for muscle, only 7% of the concentration in muscle. This was the lowest percent of muscle concentration of all 24 metals. Concentrations of Al, Ba, La, V, and Mn were significantly greater in muscle of juveniles and in ovaries than in muscle of adults. Concentrations of 13 metals were higher in ovaries relative to muscle, seven were similar, and four were depleted. Silver was enriched by over 50-fold in ovaries. Overall, the present study suggests that low concentrations of some metals in muscle of adult female goldeye, relative to concentrations in female juveniles and ovaries, may be maintained in part by transfer of metals to the external environment in eggs at spawning.

Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties.

We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

Discovery of potent and selective adamantane-based small-molecule P2X(7) receptor antagonists/interleukin-1beta inhibitors.

A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.