Topical application of the adenosine A2A receptor agonist CGS‐21680 prevents phorbol‐induced epidermal hyperplasia and inflammation in mice

The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti‐inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A_2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS‐21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS‐21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS‐21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB₄ and CXCL‐1, and the inflammatory cytokine TNF‐α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS‐21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist‐treated mice. Our results showed that CGS 21680 efficiently prevents phorbol‐induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.     

The new K+ channel opener Aprikalim (RP 52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes.

The objective of the present study was to determine the effect of a novel K+ channel opener, Aprikalim (RP 52891; [trans-(-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothio-pyran carbothiamide-1-oxide]), on myocardial infarct size in barbital-anesthetized dogs subjected to 90 min of left circumflex coronary artery occlusion followed by 5 hr of reperfusion. To determine if RP 52891 is mediating its effects by opening adenosine triphosphate regulated potassium channels (KATP), glibenclamide, a KATP channel antagonist was used. Dogs were pretreated with vehicle, a nonhypotensive dose of RP 52891 (10 micrograms/kg + 0.1 microgram/kg/min i.v.), glibenclamide (1 mg/kg; i.v. bolus) or RP 52891 (10 micrograms/kg and 0.1 microgram/kg/min i.v.) after pretreatment with glibenclamide (1 mg/kg i.v. bolus). At the end of reperfusion, myocardial infarct size was determined by triphenyltetrazolium staining. There were no significant differences in systemic hemodynamics, myocardial oxygen demand, collateral blood flow or ischemic bed size among groups with the exception of an increase in coronary blood flow to the ischemic area at 3 and 5 hr of reperfusion in both RP-treated groups. However, myocardial infarct size, expressed as a percentage of the area at risk, was significantly (P less than .05) reduced (38%) by RP 52891 and significantly increased (38%) by glibenclamide (vehicle, 39 +/- 4%; RP 52891, 24 +/- 2%; and glibenclamide, 54 +/- 5%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of adrenocortical hormones on the ontogenesis of ventricular action potential of rat myocardium

The ontogenesis of the rat epiventricular action potential was studied using hearts isolated from fetuses aged 13.5 to 21.5 days and from newly born animals. The resting membrane potential (RP), the overshoot (OS) and the maximal rate of depolarization of the action potential ($\text{V}\text{?}{}_{\max }$) were slightly but significantly increased during the studied period of gestation through to the second day following birth. From the 16th day of gestation, the duration of action potential (APD) began to decrease gradually to attain a characteristic triangular shape at birth. Under these in vitro conditions the intrinsic cardiac frequency did not vary during the period investigated. The duration of the cardiac action potential recorded at the end of the gestation was greater for fetuses which had been deprived of hypophyseal hormonal influence by decapitation on day 15.5 or 16.5 than for control fetuses of the same litter. Maternal adrenalectomy performed on day 13.5 of gestation did not affect cardiac electrogenesis in normal fetuses but led to the absence of the normal shortening of the action potential in decapitated fetuses. This effect was prevented by cortisol as well as d-aldosterone administered to the fetus on day 19.5 of gestation.In conclusion, corticoids of fetal and/or maternal origin appear to play an important role in the modifications of the repolarization phase of the epicardial action potential during the final days of gestation.     

Perfil clínico y evolución de la amiloidosis cardiaca en un centro español de referencia

Introduction and objectivesCardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center.MethodsWe included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival.ResultsWe included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65 ± 11 years) and 116 had ATTR (72% men; mean age 79 ± 11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P < .01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8 ± 4.3 vs 0.6 ± 0.7 years, P < .001), but mortality was greater in AL patients (48% vs 32%, P = .028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P = .01), female sex (HR, 2.35; 95%CI,1.24-4.46; P = .01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P = .02).ConclusionsCA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.     

Silicone posterior chamber phakic intraocular lens dislocated into the vitreous cavity

PURPOSE: To report two highly myopic patients with silicone posterior chamber phakic intraocular lenses (Phakic Refractive Lens; CIBA Vision, Duluth, Ga) that luxated into the vitreous cavity without history of ocular trauma. METHODS: Two patients with posterior chamber phakic intraocular lenses (PIOLs) that luxated into the vitreous cavity of the right eye were examined. Each eye underwent pars plana vitrectomy and removal of the posterior chamber PIOL under retrobulbar anesthesia. RESULTS: Both patients were treated successfully. In the first patient, the posterior chamber PIOL luxated into the anterior vitreous cavity whereas in the second patient, the posterior chamber PIOL lay on the posterior pole. No ocular complications developed postoperatively. CONCLUSION: Luxation into the vitreous cavity is a rare, but potentially severe complication of posterior chamber PIOL refractive surgery in highly myopic eyes. Successful management includes pars plana vitrectomy and removal of the posterior chamber PIOL.     

The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance. April 11-12, 2005, Bethesda, MD, USA

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered approximately 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the 'thorough QT/QTc study' recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes--one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.     

Ethnoveterinary knowledge in Navarra (Iberian Peninsula)

Aim of the study

To collect, analyze and evaluate the ethnoveterinary knowledge about medicinal plants in a northern Iberian region (Navarra, 10,421 km², 620,377 inhabitants).

Methodology

Field work was conducted between 2003 and 2007, using semi-structured questionnaire and participant observation as well as transects walks in wild herbal plant collection areas. We performed semi-structured interviews with 667 informants (mean age 72; 55.47% women, 44.53% men) in 265 locations, identified the plant reported and analyzed the results, comparing them with those from other territories.

Results

Out of 287 species reported to be used in the health field (human and veterinary medicine), 36 are linked to veterinary medicine. 69.4% of these species are new or rarely reported in veterinarian uses. The most frequently used plants were Malva sylvestris, Juglans regia and Verbena officinalis. All different plant parts were used; aerial part was exploited more frequently than other plant parts. Most remedies listed used a single ingredient, typically soaked in water. The route of administration was primarily oral followed by topical applications. These remedies are mostly for cows, calves, sheep, pigs and horses, but cover almost all domestic animal species. The main ailments treated are digestive troubles, wounds and dermatological problems, and respiratory affections.

Conclusions

The folk knowledge about medicinal plant use is still alive in the studied region, and a number of scarcely reported plant uses has been detected, some of them with promising phytotherapeutical applications.     

Systemic epigallocatechin gallate protects against retinal degeneration and hepatic oxidative stress in the P23H-1 rat

Retinitis pigmentosa(RP) is a group of inherited retinal disorders that lead to photoreceptor loss.RP has been reported to be related to oxidative stress,autophagy,and inflammation.(-)-Epigallocatechin gallate(EGCG),the most abundant catechin-based flavonoid in green tea leaves,has significant antioxidant,anti-carcinogenic,antimicrobial,and neuroprotective properties.EGCG,given its low molecular weight and hydrophilic properties,can cross the blood-retinal barrier and is able to reach different ocular tissues such as the lens,cornea,and retina.EGCG has been shown to provide retinal protection against ischemia;sodium nitroprusside-,N-methyl-D-aspartate-,lipopolysaccharide-,light-,sodium iodate-,or H2 O2-induced damage and diabetic retinopathy.This suggests that systemic EGCG administration has the potential to protect against retinal degenerative or neurodegenerative diseases such as RP.The aim of this work was to investigate whether EGCG can protect against RP progression in the animal P23 H line 1,the model of RP.Albino P23 H rats were crossed with pigmented Long Evans rats to produce offspring exhibiting the clinical features of RP.Pigmented P23 H rats were treated via intraperitoneal injection with saline or EGCG at a dose of 25 mg/kg every week from P100 to P160 and then compared to wild-type Long Evans rats.Rats treated with EGCG showed better visual and retinal electrical function with increased contrast sensitivity and b-wave values compared with those observed in P23 H rats treated with vehicle.EGCG reduced lipid peroxidation and increased total antioxidant capacity and catalase and superoxide dismutase activities.No differences were observed in visual acuity,nitrate levels,nitrite levels or glutathione S-transferase activity.In conclusion,EGCG not only reduced the loss of visual function in P23 H rats but also improved the levels of antioxidant enzymes and reduced oxidative damage.This study was approved by the Institutional Animal Care and Use Committee(CEICA) from the University of Zaragoza under project license PI12/14 on July 11,2014.