Opioid growth factor modulates angiogenesis

AbstractObjective: Induced angiogenesis has recently been attempted as a therapeutic modality in patients with occlusive arterial atherosclerotic disease. We investigated the possible role of endogenous opioids in the modulation of angiogenesis. Methods: Chick chorioallantoic membrane was used as an in vivo model to study angiogenesis. Fertilized chick eggs were incubated for 3 days, explanted, and incubated for an additional 2 days. Three-millimeter methylcellulose disks were placed on the surface of the chorioallantoic membrane; each disk contained opioid growth factor ([Met5]-enkephalin; 5 μg), the short-acting opioid receptor antagonist naloxone (5 μg), opioid growth factor and naloxone together (5 μg of each), the long-acting opioid antagonist naltrexone (5 μg), or distilled water (control). A second series of experiments was performed with distilled water, the angiogenic inhibitor retinoic acid (1 μg), and vascular endothelial growth factor (1 μg) to further evaluate our model. The developing vasculature was imaged 2 days later with a digital camera and exported to a computer for image analysis. Total number of blood vessels, total vessel length, and mean vessel length were measured within a 100-mm2 region surrounding each applied disk. Immunocytochemical analysis was performed with antibodies directed against opioid growth factor and its receptor (OGFr). Results: Opioid growth factor had a significant inhibitory effect on angiogenesis, both the number of blood vessels and the total vessel length being decreased (by 35% and 20%, respectively) in comparison with control levels (P <.005). The simultaneous addition of naloxone and opioid growth factor had no effect on blood vessel growth, nor did naloxone alone. Chorioallantoic membranes exposed to naltrexone displayed increases of 51% and 24% in blood vessel number and length, respectively, in comparison with control specimens (P <.005). These results indicate that the opioid growth factor effects are receptor mediated and tonically active. Immunocytochemistry demonstrated the presence of both opioid growth factor and OGFr within the endothelial cells and mesenchymal cells of the developing chorioallantoic membrane vessel wall. Retinoic acid significantly reduced the number and the total length of blood vessels, whereas vascular endothelial growth factor increased both the number and the length of blood vessels in comparison with the controls (P <.0001). The magnitude of opioid growth factor's effects were comparable to those seen with retinoic acid, whereas inhibition of opioid growth factor with naltrexone induced an increase in total vessel length comparable to that for vascular endothelial growth factor. Conclusions: These results demonstrate for the first time that endogenous opioids modulate in vivo angiogenesis. Opioid growth factor is a tonically active peptide that has a receptor-mediated action in regulating angiogenesis in developing endothelial and mesenchymal vascular cells. (J Vasc Surg 2000;32:364-73.

Vitamin D deficiency in chronic conditions. When and how much do we supplement?

Introducere. Deficitul de vitamina D este o problema globală, majoritatea pacienților sunt asimptomatici. Doza de vitamina D poate varia, în funcție de vârsta, greutate și condiția medicală, dar și în funcție de alte stări patologice. Scopul lucrării. Lucrarea de față are ca obiectiv principal prezentarea afecțiunilor cu deficit de vitamina D, când și cum suplimentăm, în funcție de stările patologice. Material și metode. Am corelat datele din literatură subliniind importanța fiecărui tip de terapie în patologia asociată. Rezultate. Rezultatele cercetării au arătat că suplimentarea cu vitamina D contribuie la scăderea riscului de fractură, scăderea riscului de cădere și reducerea mortalității globale. Diferite forme de vitamina D sunt administare pentru prevenirea şi tratamentul stărilor carențiale (hipovitaminozei) D; rahitism (la copii), osteomalacie (la adulți) în osteoporoză, hipocalcemie, hipoparatiroidie, tuberculoză cutanată. La pacienții cu boală cronică reală sau cu osteodistrofie renală se folosește calcitriolul, pentru că acești pacienți nu pot hidroxila calcifediolul. În forme ușoare și medii de psoriazis se folosește calcipotriolul (derivat de calcitriol). Pe de altă parte, alfacalcidolul (1-ahidroxicolecalciferol), precursor sintetic al calcitriolului (metabolit activ al vitaminei D3), nu necesită hidroxilare în rinichi, ceea ce îl face medicamentul de ales în prezența insuficienței renale. Calcitriolul (1α,25 dihidroxicolecalciferol) este un metabolit activ al vitaminei D, format în principal în rinichi prin hidroxilarea moleculei de calcidiol (dependent de enzima 1α-hidroxilaza), utilizat în hiperparatiroidism secundar recurent sever sau progresiv și rahitism hipofosfatemic ereditar. Concluzii. Nivelurile între 50–125 nmol/L (20–50 ng/mL) sunt considerate sigure și suficiente pentru sănătatea scheletului la populația generală. O concentrație mai mare de 75 nmol/L (30ng/mL) este recomandată de Societatea Endocrină din SUA pentru beneficii optime pentru sănătate, în special la subiecții vârstnici cu risc crescut de fracturi, pacienți cu patologii la nivelul sistemului osos, renal și digestiv.Introduction. Vitamin D deficiency is a global problem, most patients are asymptomatic. The dose of vitamin D can vary, depending on age, weight and medical condition, but also according to other pathological conditions. Aim of the study. The main objective of this paper is to present the conditions with vitamin D deficiency, when and how to supplement, depending on the pathological states. Material and methods. We correlated the data from the literature emphasizing the importance of each type of therapy in the associated pathology. Results. Research results have shown that vitamin D supplementation contributes to lowering the risk of fracture, lowering the risk of falling, and reducing overall mortality. Different forms of vitamin D are administered for the prevention and treatment of deficiency states (hypovitaminosis) D; rickets (in children), osteomalacia (in adults) in osteoporosis, hypocalcemia, hypoparathyroidism, cutaneous tuberculosis. In patients with real chronic disease or renal osteodystrophy, calcitriol is used, because these patients cannot hydroxylate calcifediol. In mild and medium forms of psoriasis, calcipotriol (derived from calcitriol) is used. On the other hand, alphacalcidol (1-ahydroxycholecalciferol), a synthetic precursor of calcitriol (active metabolite of vitamin D3), does not require hydroxylation in the kidneys, making it the drug of choice in the presence of kidney failure. Calcitriol (1α,25-dihydroxycholecalciferol) is an active metabolite of vitamin D, formed mainly in the kidneys by hydroxylation of the calcidiol molecule (dependent on the enzyme 1α-hydroxylase), used in severe or progressive recurrent secondary hyperparathyroidism and hereditary hypophosphatemic rickets. Conclusions: Levels between 50–125 nmol/L (20–50 ng/mL) are considered safe and sufficient for skeletal health in the general population. A concentration greater than 75 nmol/L (30ng/mL) is recommended by the US Endocrine Society for optimal health benefits, especially in elderly subjects at increased risk of fractures, patients with pathologies in the bone, renal and digestive systems

Evaluation of allodynia and hyperalgesia in rodents with aloxan-induced diabetic neuropathy

Introducere. Diabetul afectează aproximativ 600 de milioane de oameni la nivel global, iar neuropatia diabetică este una dintre cele mai debilitante complicații ale acestuia. Deși opțiunile terapeutice actuale pentru ameliorarea durerii neuropatice sunt limitate în eficacitate și prezintă efecte secundare importante, identificarea unor noi strategii terapeutice este esențială. Utilizarea unor modele animale standardizate de neuropatie diabetică este esențială pentru testarea eficacității noilor substanțe. Scopul lucrării. Evaluarea sensibilității dureroase la rozătoare (șoareci și șobolani) la care a fost indusă neuropatia diabetică prin administrarea de aloxan. Material şi metode. Pentru a induce diabetul aloxanic, șoarecii albi (sușa NMRI) au primit 3 doze unice, la intervale de 2 zile, de aloxan (150 mg/kg), iar șobolanii albi Wistar o doză unică de 130 mg/kg. Sensibilitatea termică a fost evaluată la șoareci, iar sensibilitatea termică și mecanică la șobolani inițial, la 7 și 14. La finalul experimentului, am determinat nivelul citokinelor proinflamatorii (TNF-α și IL-6) în țesuturile cerebrale. Rezultate. Inducerea neuropatiei diabetice cu aloxan a generat o creștere a sensibilității la durere în cazul ambelor specii. De asemenea, nivelurile citokinelor proinflamatorii (TNF-α) au fost crescute în creier la rozătoarele diabetice, comparativ cu lotul nondiabetic. Concluzii. Modelele de neuropatie diabetică induse cu aloxan la șoareci și șobolani s-au dovedit a fi viabile pentru testarea unor potențiale tratamente destinate neuropatiei diabetice. Aceste modele pot facilita dezvoltarea unor terapii noi, eficiente și mai sigure.Introduction. Diabetes affects approximately 600 million people worldwide, and diabetic neuropathy is one of its most debilitating complications. Current therapeutic options for managing neuropathic pain are limited in efficacy and carry significant side effects, making the identification of new therapeutic strategies essential. Standardized animal models of diabetic neuropathy are crucial for testing the efficacy of new compounds. Aim of the study. To evaluate pain sensitivity in rodents (mice and rats) with diabetic neuropathy induced by aloxan administration. Material and methods. For aloxan-induced diabetes, NMRI white mice received 3 single doses of aloxan (150 mg/kg) at 2-day intervals, while Wistar white rats received a single dose of 130 mg/kg. Thermal sensitivity was assessed in mice, while both thermal and mechanical sensitivity were assessed in rats at baseline, day 7, and day 14. At the end of the experiment, levels of pro-inflammatory cytokines (TNF-α and IL-6) were measured in brain homogenates. Results. Aloxan-induced diabetic neuropathy resulted in increased pain sensitivity in both species. Additionally, pro-inflammatory cytokine levels (TNF-α and IL-6) were elevated in the brain of diabetic rodents when compared to the non-diabetic group. Conclusions: Aloxan-induced diabetic neuropathy models in mice and rats have proven viable for testing potential treatments targeting diabetic neuropathy. These models could facilitate the development of new, more effective, and safer therapies

Particularities in the treatment of beningne hypertensive nephroangiosclerosis

Introducere. Nefroangioscleroza hipertensivă benignă este o nefropatie vasculară bilaterală, cu progresie lentă spre insuficiență renală. În România sunt aproximativ 2 milioane de pacienți diagnosticați cu această afecțiune (studiul SEPHAR). Material și metodă. Caz clinic: pacientul R.T. 68 ani, sex masculin, provenind din mediul rural. Motivele prezentării la medic: cefalee fronto-occipital, greață, alterarea stării generale.HTA grad III, diagnosticată de aproximativ 10 ani. Cardiopatie hipertensivă și ischemică. Angor stabil de efort. Steatoză hepatică etanolică, Hernie ombilical operată (în urmă cu 5 ani). Examen clinic pe aparate și sisteme, explorări paraclinice, diagnostic diferențial, stratificare risc CV, tratament, măsuri igieno-dietetice. Rezultate. În tratamentul nefroangiosclerozei hipertensive benigne se recomandă menținerea unei presiuni arteriale normale sau reduse la niveluri acceptabile pentru a preveni deteriorarea rinichilor și apariția complicațiilor renale, se recomandă utilizarea inhibitorilor enzimei de conversie a angiotensinei (IECA) sau blocanților receptorilor de angiotensină II (BRA) pentru a scădea presiunea arterială și a proteja rinichii împotriva leziunilor. Asocierea cu diuretice (tiazide) și blocanți ai canalelor de calciu (BCC) poate fi benefică în controlul presiunii arteriale la pacienții cu nefropatie hipertensivă ca și ai inhibitorilor cotransportorului sodiu-glucoză de tip 2 (SGLT2), pentru efectul lor renoprotector. De asemenea monitorizarea regulată a funcției renale este esențială pentru a evalua eficacitatea tratamentului și pentru a detecta precoce eventualele modificări. Concluzii. Activitatea de consiliere atență a pacientului cu patologie renală de către farmacist are un rol important precum și colaborarea cu medicul nefrolog și cardiolog. Tratamentul se modifică în funcție de forma şi de severitatea patologiei în cauză.Introduction. Benign hypertensive nephrangiosclerosis is a bilateral vascular nephropathy with slow progression to renal failure. In Romania there are about 2 million patients diagnosed with this condition (SEPHAR study). Material and method.Clinical case: patient R.T. 68 years old, male, coming from rural areas. Reasons for presenting to the doctor: fronto-occipital headache, nausea, alteration of the general condition. HTA grade III, diagnosed about 10 years ago. Hypertensive and ischemic heart disease. Stable angina of exertion. Ethanolic hepatic steatosis, Umbilical hernia operated (5 years ago). Clinical examination on devices and systems, paraclinical explorations, differential diagnosis, CV risk stratification, treatment, hygienic-dietary measures. Results. In the treatment of benign hypertensive nephrangiosclerosis, it is recommended to maintain normal or reduced blood pressure at acceptable levels to prevent kidney damage and kidney complications, the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is recommended to lower blood pressure and protect the kidneys against injury. The combination with diuretics (thiazides) and calcium channel blockers (BCCs) may be beneficial in blood pressure control in patients with hypertensive nephropathy as well as sodium-glucose cotransporter type 2 (SGLT2) inhibitors, for their renoprotective effect. Regular monitoring of kidney function is also essential to assess the effectiveness of treatment and to detect any changes early. Conclusions.The activity of counseling the patient with renal pathology by the pharmacist has an important role, as well as the collaboration with the nephrologist and cardiologist. The treatment is modified depending on the form and severity of the pathology in question

Muscle Fiber Viability, a Novel Method for the Fast Detection of Ischemic Muscle Injury in Rats

Acute lower extremity ischemia is a limb- and life-threatening clinical problem. Rapid detection of the degree of injury is crucial, however at present there are no exact diagnostic tests available to achieve this purpose. Our goal was to examine a novel technique - which has the potential to accurately assess the degree of ischemic muscle injury within a short period of time - in a clinically relevant rodent model. Male Wistar rats were exposed to 4, 6, 8 and 9 hours of bilateral lower limb ischemia induced by the occlusion of the infrarenal aorta. Additional animals underwent 8 and 9 hours of ischemia followed by 2 hours of reperfusion to examine the effects of revascularization. Muscle samples were collected from the left anterior tibial muscle for viability assessment. The degree of muscle damage (muscle fiber viability) was assessed by morphometric evaluation of NADH-tetrazolium reductase reaction on frozen sections. Right hind limbs were perfusion-fixed with paraformaldehyde and glutaraldehyde for light and electron microscopic examinations. Muscle fiber viability decreased progressively over the time of ischemia, with significant differences found between the consecutive times. High correlation was detected between the length of ischemia and the values of muscle fiber viability. After reperfusion, viability showed significant reduction in the 8-hour-ischemia and 2-hour-reperfusion group compared to the 8-hour-ischemia-only group, and decreased further after 9 hours of ischemia and 2 hours of reperfusion. Light- and electron microscopic findings correlated strongly with the values of muscle fiber viability: lesser viability values represented higher degree of ultrastructural injury while similar viability results corresponded to similar morphological injury. Muscle fiber viability was capable of accurately determining the degree of muscle injury in our rat model. Our method might therefore be useful in clinical settings in the diagnostics of acute ischemic muscle injury

The cannabinoids – important therapeutic approach in the field of oncology

Oncological diseases are the most common cause of death worldwide, it is estimated that 25% of the population will face the diagnosis of cancer during life. Phytochemicals such as cannabinoids (CBs) have been used in various branches of medicine for their properties, and the discovery of the anti-tumor, anti-emetic and anti-inflammatory effects of some of these substances has encouraged their use in oncology. Phytocannabinoids, cannabidiol (CBD) and Δ-9-tetra-hydrocannabinol (THC), have numerous anti-emetic, analgesic, orexigenic, anti-inflammatory / immunosuppressive pharmacodynamic effects. In recent years, studies have been aimed at evaluating their efficacy as antineoplastic agents. Much in vivo and in vitro research has demonstrated the efficacy of CBs on certain tumor cell lines, highlighting their potential role in the complementary treatment of cancer. This paper suggests that exploring the molecular mechanisms induced by CBs in cancer cells may contribute to the development of effective treatments in oncological diseases

Radionuclide imaging of bone marrow disorders

Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as 99mTc-nanocolloid, 99mTc-sulphur colloid, 111In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using 18F-FDG and 18F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed

Performance study of a 3 x 1 x 1 m(3) dual phase liquid Argon Time Projection Chamber exposed to cosmic rays

This work would not have been possible without the support of the Swiss National Science Foundation, Switzerland; CEA and CNRS/IN2P3, France; KEK and the JSPS program, Japan; Ministerio de Ciencia e Innovacion in Spain under grants FPA2016-77347-C2, SEV-2016-0588 and MdM-2015-0509, Comunidad de Madrid, the CERCA program of the Generalitat de Catalunya and the fellowship (LCF/BQ/DI18/11660043) from "La Caixa" Foundation (ID 100010434); the Programme PNCDI III, CERN-RO, under Contract 2/2020, Romania; the U.S. Department of Energy under Grant No. DE-SC0011686. This project has received funding from the European Union's Horizon 2020 Research and Innovation program under Grant Agreement no. 654168. The authors are also grateful to the French government operated by the National Research Agency (ANR) for the LABEX Enigmass, LABEX Lyon Institute of Origins (ANR-10-LABX-0066) of the Universite de Lyon for its financial support within the program "Investissements d'Avenir" (ANR-11-IDEX-0007).We report the results of the analyses of the cosmic ray data collected with a 4 tonne (3x1x1 m(3)) active mass (volume) Liquid Argon Time-Projection Chamber (TPC) operated in a dual-phase mode. We present a detailed study of the TPC's response, its main detector parameters and performance. The results are important for the understanding and further developments of the dual-phase technology, thanks to the verification of key aspects, such as the extraction of electrons from liquid to gas and their amplification through the entire one square metre readout plain, gain stability, purity and charge sharing between readout views.Swiss National Science Foundation (SNSF)French Atomic Energy CommissionCentre National de la Recherche Scientifique (CNRS)High Energy Accelerator Research Organization (KEK)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceSpanish Government FPA2016-77347-C2 SEV-2016-0588MdM-2015-0509Comunidad de MadridCERCA program of the Generalitat de CatalunyaLa Caixa Foundation LCF/BQ/DI18/11660043 100010434Programme PNCDI III, RomaniaCERN-RO, Romania 2/2020United States Department of Energy (DOE) SC0011686European Commission 654168Universite de Lyon ANR-10-LABX-0066 ANR-11-IDEX-000