ABSTRACT
BACKGROUND: Monoclonal protein (M-protein) concentrations are measured by serum protein electrophoresis (SPE). Two methods are used for demarcating the M-protein area in the electropherogram: perpendicular drop (PD) and tangent skimming (TS). The aim of this study was tocompare both methods and to establish which is the most accurate and precise. METHODS: We studied 24 sera containing M-protein (5-44 g/L). The systematic error (SE) was evaluated in a dilution series of 12 sera. Within-day, between-day, and interobserver variability were assessed. SPE was performed by capillary and agarose gel electrophoresis. M-protein concentrations were measured using both cutoff methods. RESULTS: The PD method shows a constant SE ranged 1.00-2.27 g/L, while constant SE for TS is ranged -0.30--0.57 g/L. None of the cutoff methods or electrophoretic methods showed a proportional SE, with the exception of the TS method in capillary electrophoresis for ß-migrating M-protein. The PD method was more precise than the TS method in all three estimates of imprecision. An increased CV for concentrations < 10 g/L in between-day imprecision was observed with the TS method. Interobserver imprecision was greater for M-protein concentrations < 17 g/L for both cutoff methods (14.85%, 26.42% respectively). CONCLUSIONS: Despite being less precise, the TS method provides a more accurate measurement of M-protein concentration.
Subject(s)
Antibodies, Monoclonal , Electrophoresis, Capillary , Blood Protein Electrophoresis , Humans , Immunologic TestsABSTRACT
BACKGROUND: Besides clinical signs and imaging, in recent years, biomarkers have proven to be a viable diagnostic resource for acute appendicitis (AA). OBJECTIVE: The objective of this study was to develop a clinical score including clinical signs and a combination of biomarkers to identify children with abdominal pain at low risk of AA. DESIGN/METHODS: We prospectively included children 2 to 14â¯years of age with abdominal pain suggestive of AA who presented to the emergency department between July 2016 and September 2017. A new score, the Pediatric Appendicitis Laboratory Score (PALabS) including clinical signs, leucocyte (WBC) and neutrophil (ANC) counts and plasma C-reactive protein (CRP) and calprotectin (CP) levels was developed and validated through secondary analyses of two distinct cohorts The validation sample included visits to a single pediatric emergency department from 2012 to 2013 and 2016 to 2017. RESULTS: The derivation sample included 278 children, 35.9% of whom had AA and the validation sample included 255 children, 49% of whom had AA. Using logistic regression, we created a 6-part score that consisted of nausea (3 points), history of focal right lower quadrant pain (4 points), ANC of ≥7500/µL (7 points), WBC of ≥10,000/µL (4 points), CRPâ¯≥â¯10.0â¯mg/L (2 points) and CPâ¯≥â¯0.50â¯≥â¯ng/mL (3 points). This score exhibited a high discriminatory power (area under the curve: 0.88; 95% confidence interval: 0.84 to 0.92) and outperformed the PAS and Kharbanda scores (area under the curve: 0.76; 95% confidence interval: 0.71 to 0.82 and 0.82; 95% confidence interval: 0.77 to 0.87, respectively). A PALabS ≤6 had a sensitivity of 99.2% (95% confidence interval [CI]: 95.6-99.9), negative predictive value of 97.6% (95% CI: 87.7-99.6), and negative likelihood ratio of 0.03 (95% CI: 0.00-0.18) in the validation set. CONCLUSION: In our validation cohort of patients with acute abdominal pain, the new score can accurately predict which children are at low risk of appendicitis and could be safely managed with close observation.
Subject(s)
Abdominal Pain/etiology , Appendicitis/diagnosis , Risk Assessment/methods , Appendicitis/blood , Biomarkers/blood , C-Reactive Protein/metabolism , Case-Control Studies , Child , Female , Humans , Leukocyte Count , Leukocyte L1 Antigen Complex/blood , Male , Predictive Value of Tests , Prospective StudiesABSTRACT
OBJECTIVE: The objective of the study is to evaluate the usefulness of the leukocyte (white blood count [WBC]) and neutrophil (absolute neutrophil count [ANC]) counts; the values of C-reactive protein (CRP), procalcitonin, and calprotectin (CP); and the APPY1 Test panel of biomarkers, to identify children with abdominal pain at low risk for appendicitis. METHOD: Children 2 to 14 years of age with abdominal pain suggesting acute appendicitis (AA) were prospectively included. Procalcitonin, calprotectin, C-reactive protein, white blood count, ANC, and the new plasma APPY1 Test were performed. The final diagnosis was determined by histopathology in cases of AA and telephone follow-up in children discharged without AA. RESULTS: Between February 2012 and June 2013, 185 children were enrolled with an average age of 9.32±2.7 years. Eighty-nine (48.1%) were finally diagnosed with AA. The APPY1 Test panel showed the highest discriminatory power, sensitivity of 97.8 (95% confidence interval [CI], 92.2-99.4), negative predictive value of 95.1 (95% CI, 83.9-98.7), negative likelihood ratio of 0.06 (95% CI, 0.01-0.22), and specificity of 40.6 (95% CI, 31.3-50.5). A negative APPY1 Test and ANC less than 7500 per milliliter provided a sensitivity of 100 (95% CI, 95.9-100), negative predictive value of 100 (95% CI, 89.8-100), and specificity of 35.4 (95% CI, 26.6-45.4). In the multivariate analysis, only the APPY1 Test and ANC greater than 7500 per milliliter were significant risk factors for AA (odds ratio, 13.76; 95% CI, 3.02-62.57, and odds ratio, 6.37; 95% CI, 2.89-14.28, respectively). CONCLUSIONS: The APPY1 Test panel with ANC could be useful in identifying children with abdominal pain suggestive of AA who are at low risk for this disease.
Subject(s)
Abdominal Pain/etiology , Appendicitis/diagnosis , Biomarkers/blood , Adolescent , Appendicitis/blood , Appendicitis/complications , C-Reactive Protein/metabolism , Calcitonin/blood , Calcitonin Gene-Related Peptide , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Leukocyte Count , Leukocyte L1 Antigen Complex/blood , Logistic Models , Male , Prospective Studies , Protein Precursors/blood , Sensitivity and SpecificityABSTRACT
O presente trabalho consiste no primeiro relato de criptorquidismo em uma jaguatirica, adulta, de vida livre. Para a captura foram empregadas armadilhas com desarme de guilhotina, usando como isca vísceras de bovino. O animal foi contido quimicamente por meio de dardos anestésicos e mantido sob anestesia, utilizando a associação de cloridrato de quetamina e cloridrato de xilazina. Durante o exame andrológico, observou-se que o testículo esquerdo localizava-se subcutâneo, próximo à região inguinal, caracterizando-se criptorquidismo unilateral. Esse testículo apresentava-se flácido, com volume de 2,57mL, enquanto o testículo contralateral apresentava consistência firme e volume de 11,50mL. A área ocupada pelas espículas penianas mostrou-se compatível com a de animais reprodutores. O criptorquidismo é uma condição hereditária ligada à baixa variabilidade genética, já relatada em felinos silvestres consanguíneos. Nesse sentido, devido ao crescente isolamento populacional em fragmentos florestais, este achado torna-se preocupante, uma vez que pode ser indicativo de endogamia em populações de jaguatiricas de vida livre.
This paper is the first report of unilateral cryptorchidism in an adult wildlife ocelot, captured in Parque Estadual do Rio Doce. Cage traps were used to capture the animal, using bovine offal as bait. The animal was anesthetized with anesthetic darts and kept under anesthesia through a combination of ketamine and xylazine. The andrologycal examination showed that the left testicle was located subcutaneously near the inguinal region. In this case of unilateral cryptorchidism, the testis was soft and had a volume of 2.57mL, while the contralateral testis had a firm consistency and volume of 11.50mL. The length of the region occupied by the penile spikes was similar to other breeding animals. Cryptorchidism is an inherited condition linked to low genetic variability previously reported in consanguineous wild cats. Due to the increasing isolation of wild population in forest fragments, this finding is concerning because it can be indicative of inbreeding in wild ocelot populations.
Subject(s)
Cryptorchidism/diagnosis , Cryptorchidism/veterinary , Felidae/abnormalities , Felidae/growth & development , Anesthesia , Anesthesia/veterinaryABSTRACT
AIM: To determine whether calcium dobesilate can act in chronic venous insufficiency by similar antioxidant, anti-inflammatory mechanisms as in diabetic retinopathy. METHODS: Calcium dobesilate was tested in vitro for its protective action against oxidative/inflammatory stress in human varicose veins. Varicose greater saphenous veins were obtained from 14 patients (11 men, 3 women) aged 53-65 years. Oxidative stress was induced exogenously in the vein segments, with the phenazine methosulphate (PMS)/NADH couple. Total antioxidant status (TAS) and malondialdehyde (MDA) contents were used as markers of oxidative stress. RESULTS: Calcium dobesilate significantly prevented oxidative disturbances in the micromolar range. PMS/NADH-dependent TAS decrease was fully prevented with IC(50) = 11.4 ± 2.3 µmol/L (n = 6 veins), whereas MDA increase was fully prevented with IC(50) = (102 ± -3) µmol/L (n = 6 veins). Calcium dobesilate acted quali- and quantitatively like rutin, the reference compound. Comparison with pharmacokinetic data suggests that calcium dobesilate can act at therapeutic concentrations. CONCLUSION: Calcium dobesilate protected human varicose veins against oxidative stress in vitro at levels that correspond to therapeutic concentrations. Further studies are required to investigate whether a similar action is found in varicose veins from patients orally treated with calcium dobesilate.
Subject(s)
Antioxidants/metabolism , Calcium Dobesilate/pharmacology , Hemostatics/pharmacology , Malondialdehyde/metabolism , Oxidative Stress/drug effects , Saphenous Vein/metabolism , Varicose Veins/metabolism , Aged , Dose-Response Relationship, Drug , Female , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/pathology , Inflammation/physiopathology , Male , Methylphenazonium Methosulfate/toxicity , Middle Aged , Organ Culture Techniques , Saphenous Vein/pathology , Saphenous Vein/physiopathology , Varicose Veins/drug therapy , Varicose Veins/pathology , Varicose Veins/physiopathologyABSTRACT
INTRODUCTION: Anxiety is a major and frequent symptom of schizophrenia, which is associated with an increased risk of relapse, impaired functioning, lower quality of life and increased incidence of suicide attempts. Despite its clinical relevance, anxiety in schizophrenia remains poorly understood. In the prodromic phase, anxiety indicates a progression towards psychotic decompensation. After a first episode, it is an indicator of relapse. LITERATURE FINDINGS: Two approaches have been used to investigate anxiety in schizophrenia: (i) categorical approach (comorbidity of schizophrenia and anxiety disorders) and (ii) dimensional approach (anxiety as a major symptom of the "dysphoric" dimension). Clinical categorical studies reported an increased frequency of comorbidity between schizophrenia and obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, agoraphobia, and specific phobia. The dimensional approach proposes that five different factors contribute to the structure of the Positive and Negative Syndrome Scale (PANSS), with anxiety as a major symptom of the "dysphoria" dimension. Concerning diagnosis, it is unclear whether psychotic and neurotic anxiety differs in nature or intensity. Nevertheless, both are frequently opposed. DISCUSSION: Psychotic anxiety is intense, profound and hermetic. In contrast to neurotic anxiety, it is associated with psychomotor disturbances, such as agitation and sideration. There is no specific tool to evaluate anxiety in schizophrenia. The dimensional approach usually runs an evaluation using items or factors extracted from the most widely-used scales, i.e. PANSS or Brief Psychiatric Rating Scale (BPRS) or from anxiety scales developed in non-schizophrenic populations, such as the Hamilton Anxiety Scale (HAMA). Recently, we developed a specific scale for hetero-evaluation (Échelle Anxiété Schizophrénie [EAS scale]). The EAS scale was recently validated and the study of its sensitivity is ongoing. THERAPEUTICAL ISSUES: Several studies have examined the effects of antipsychotics on the anxious/depressive cluster extracted from the PANSS, and some other studies have specifically evaluated the effect of antipsychotics on depressive symptoms using the Montgomery and Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS), but to our knowledge, no study has reported the effect of antipsychotics or other treatment on anxiety when using a schizophrenia-specific scale. There are no specific guideline treatments for anxiety in schizophrenia. Among phenothiazines, cyamemazine is frequently prescribed in France, because of its potent anxiolytic activity and good neurological tolerance. Some authors have suggested a specific treatment with benzodiazepines. However, benzodiazepines should be used with caution, due to undesirable actions such as dependence, rebound and potentiation of certain lateral effects.
Subject(s)
Anti-Anxiety Agents/administration & dosage , Antipsychotic Agents/administration & dosage , Anxiety Disorders/drug therapy , Schizophrenia/drug therapy , Schizophrenic Psychology , Anti-Anxiety Agents/adverse effects , Antipsychotic Agents/adverse effects , Anxiety Disorders/diagnosis , Anxiety Disorders/psychology , Benzodiazepines/adverse effects , Benzodiazepines/therapeutic use , Comorbidity , Depressive Disorder/diagnosis , Depressive Disorder/drug therapy , Diagnosis, Differential , Drug Therapy, Combination , Humans , Personality Inventory , Phenothiazines/adverse effects , Phenothiazines/therapeutic use , Psychiatric Status Rating Scales , Schizophrenia/diagnosisABSTRACT
OBJECTIVES: To prospectively investigate the prevalence of definite and potential sources of cardiogenic embolism and embolism from ascending aorta and aortic arch in patients with a cryptogenic stroke or transient ischaemic attack (TIA). MATERIAL/METHODS: The study group consisted of 218 consecutive patients (146 males, mean age 59.4 +/- 11.5, range 38-83 years) without significant stenoses of carotic and vertebral arteries. All patients underwent biplane/multiplane transesophageal echocardiography (TEE). 77.5% of patients suffered a stroke and 22.5% had a TIA. Sinus rhythm was in 74.8% of the patients, atrial fibrillation in 22.0% and pacemaker rhythm in 3.2%. RESULTS: 1. Definite source of embolism was identified in 21.6% of patients. The most frequent finding was a thrombus of the left atrial (LA) appendage - 12.4%. Less frequently found were mobile thrombus of aortic arch - 3.7%, thrombus of LA body - 2.3%, left ventricular thrombus - 2.3%, thrombus of valvular prosthesis - 1.4% and heart tumor - 0.5%. 2. The total prevalence of potential sources of embolism was 61.5%. Only potential source (without definite source) was demonstrated in 52.3% of patients. Very frequently were found patent foramen ovale - 58.3% and atherosclerosis of ascending aorta or aortic arch - 53.7%. Further sources were LA spontaneous echocontrast - 21.1%, reduced function of LA appendage - 18.3%, atrial septal aneurysm - 7.8%, atrial septal defect - 1.4%, cardiac foreign body - 0.5%. 3. TEE did not reveal any source of embolism in 26.1% of patients. CONCLUSIONS: 1. 21.6% of the patients suffering from stroke/TIA without hemodynamically significant stenoses of extracranial cerebral arteries had a definite cardiogenic or aortic source of embolism, 2. additional 52.3% of patients had only potential source of embolism (without definite source), 3. we consider TEE necessary in patients with stroke/TIA without a known etiology, despite complete neurological examination and transthoracic echocardography.
Subject(s)
Aorta/diagnostic imaging , Echocardiography, Transesophageal , Heart Diseases/diagnostic imaging , Intracranial Embolism/etiology , Ischemic Attack, Transient/etiology , Thrombosis/diagnostic imaging , Adult , Aged , Aged, 80 and over , Female , Heart Atria , Heart Diseases/complications , Humans , Male , Middle Aged , Stroke/etiology , Thrombosis/complicationsABSTRACT
Renal NaCl reabsorption is increased in Dahl "salt-sensitive" (DS) rats, due to an increased activity of the Na-K-Cl cotransporter NKCC2. On the other hand, nitric oxide (NO) is an inhibitor of NKCC2 and a deficient nitric oxide synthase (NOS) seems to play an important role in salt-sensitivity of DS rats. Here, we investigated the hypothesis that NKCC2 hyperactivity in DS rats is due to a deficient NOS, via the interactions cyclic GMP (cGMP)/cyclic AMP (cAMP) at the level of the thick ascending Henle's loop (TAL). DS rats DS (males, 250-300 g) and their normotensive controls DR ("salt-resistant") are sacrificed, the kidneys removed and NKCC2 activity is measured in medullary TAL (mTAL) as previously described. Medullary contents of NO are measured with a NitroFlux analyser by heat-reduction of nitrates and nitrites to NO. AMPc levels in mTAL are measured by an EIA immunotest. Neither L-NAME (3 mM), nor L-arginine were able to modify NKCC2 activity in mTAL from DS (pre-hypertensive) or DR rats. Levels of NO in the medullary interstitium and AMPc in mTAL were not significantly different between DS and DR rats. Conversely, in DS rats charged with 2% salt (in the food) during 7 weeks, L-arginine significantly inhibited NKCC2 in DS (35.6 +/- 6.8 vs 25.3 +/- 4.9 nmoles/mg protein/min; p<0.05 non-paired Student's t-test), but not in DR rats. In conclusion, NKCC2 in our mTAL preparation of prehypertensive DS and DR rats is insensitive to L-NAME and L-arginine. This suggests the absence of a functional NOS. NKCC2 hyperactivity of prehypertensive DS is therefore not due to a deficient NOS. This was confirmed by the normal levels of interstitial NO and mTAL cAMP in prehypertensive DS rats. Finally, a salt-load seems to induce NOS expression in mTAL of DS rats. This last observation deserves further investigation.
Subject(s)
Hypertension/physiopathology , Nitric Oxide Synthase/pharmacology , Nitric Oxide/pharmacology , Sodium Chloride/metabolism , Sodium Chloride/pharmacokinetics , Sodium-Potassium-Chloride Symporters/genetics , Sodium-Potassium-Chloride Symporters/pharmacology , Animals , Disease Models, Animal , Male , Rats , Rats, Inbred Dahl , Solute Carrier Family 12, Member 1ABSTRACT
In vitro studies in rat mastocytes and human monocytes suggested that reproterol (a selective beta(2)-adrenoceptor agonist with a theophylline moiety) exerts anti-inflammatory actions through inhibition of cyclic AMP (cAMP) PDE activity. Thus, reproterol was tested for its ability to inhibit cAMP PDE in cultured mouse mastocytoma P-815 cells. cAMP PDE activity was measured in intact cells by spectrofluorometry using the fluorescent substrate 2'-O-anthraniloyl cAMP. Reproterol was more potent than theophylline to inhibit cAMP PDE (pIC(50)=4.28+/-0.25 vs. 3.16+/-0.05). This contrasted with disrupted cells, where the PDE inhibitory potency of reproterol was low (pIC(50)=2.85+/-0.03) and similar to that of theophylline (pIC(50)=2.66+/-0.19). No cAMP PDE inhibition was found with other beta(2)-agonists tested (fenoterol, salbutamol, salmeterol and formoterol). Finally, the selective PDE inhibitors calmidazolium (100 nM), milrinone (5 microM) and rolipram (50 microM) inhibited cAMP PDE activity by approximately 20, 30 and 25% respectively. In conclusion, reproterol potently and non-specifically inhibited intracellular cAMP phosphodiesterases in intact mastocytoma cells. This can explain the previously reported beta(2)-adrenoceptor-independent anti-inflammatory actions of reproterol in vitro. Further studies are required to define the anti-inflammatory potential of reproterol in asthma.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Adrenergic beta-Agonists/pharmacology , Bronchodilator Agents/pharmacology , Cyclic AMP/antagonists & inhibitors , Metaproterenol/analogs & derivatives , Metaproterenol/pharmacology , Theophylline/analogs & derivatives , Theophylline/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Adrenergic beta-Agonists/administration & dosage , Animals , Bronchodilator Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Combinations , Metaproterenol/administration & dosage , Mice , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/pharmacology , Theophylline/administration & dosage , Tumor Cells, CulturedABSTRACT
Nonallergic non-infectious perennial rhinitis (NANIPER) is a heterogeneous disorder comprising several pathophysiological entities. The etiology of some of these disorders (e.g. drug-induced rhinitis, nonallergic rhinitis with eosinophilia syndrome [NARES], occupational rhinitis, hormonal rhinitis, emotion-induced rhinitis, physical/chemical irritant-induced rhinitis) is well established. In contrast, the aetiology of idiopathic forms of rhinitis (also known as vasomotor rhinitis) is largely unknown. Mechanistic studies have suggested that non-IgE-mediated inflammatory and/or neurogenic processes may be involved. There is evidence that localized inflammation is the underlying cause of symptoms in drug-induced rhinitis and NARES, since eosinophilia is an important pathophysiological component in these conditions. In contrast, neurogenic reflex mechanisms initiated by environmental factors appear to be involved in idiopathic rhinitis. It has been suggested that there may be an imbalance of the sympathetic and parasympathetic nervous systems, with parasympathetic hyper-activity and sympathetic hypo-activity resulting in nasal congestion and rhinorrhoea. Indirect evidence suggests that C-fibres may also play an important role in the pathophysiology of idiopathic rhinitis.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Rhinitis, Vasomotor/etiology , Eosinophilia/physiopathology , Female , Humans , Male , Nasal Lavage Fluid/chemistry , Nasal Mucosa/immunology , Prognosis , Rhinitis, Vasomotor/physiopathology , Risk Assessment , Severity of Illness IndexABSTRACT
The low incidence of extrapyramidal effects with atypical neuroleptics has been ascribed to their 5-HT(2A)- and 5-HT(2C)-serotonin receptor antagonistic properties. On the other hand, the acute increase in striatal dopamine release by submaximal dopamine D(2) autoreceptor blockade can be respectively reduced and increased by 5-HT(2A)- and 5-HT(2C)-antagonists. Cyamemazine is a neuroleptic D(2)- and 5-HT(2A)-receptor antagonist, with small antagonistic activity at 5-HT(2C) receptors and low incidence of extrapyramidal side effects. Therefore, submaximal cyamemazine was tested in rats for its acute action on the extracellular concentrations of dopamine and dopamine metabolites (DOPAC: 3,4,dihydroxyphenylacetic acid and HVA: 4-hydroxy-3-methoxy-phenyl-acetic acid) in the corpus striatum. The serotonin metabolite 5-HIAA (5-hydroxy-indole-acetic acid) was measured in parallel. Rats prepared for microdialysis (striatum) were intraperitoneally given cyamemazine 1 mg/kg, 5 mg/kg or vehicle ( n=4 in each group). Dopamine, DOPAC, HVA and 5-HIAA concentrations in perfusates under basal conditions and after stimulation by high K(+) were measured by HPLC coupled to electrochemical detection. Cyamemazine 1 mg/kg significantly reduced extracellular concentrations of basal dopamine (-77%), DOPAC (-54%), HVA (-54%) and 5-HIAA (-65%). No such effects were seen with the dose of cyamemazine 5 mg/kg or for K(+)-evoked dopamine release. In conclusion, submaximal cyamemazine can acutely reduce basal dopamine release and metabolism in the rat striatum. Such unusual action can be explained by the original pharmacological profile of cyamemazine (potent D(2)- and 5-HT(2A)-antagonist, with small antagonistic activity at 5-HT(2C) receptors). Further experiments are required to explain the low incidence of extrapyramidal side actions with cyamemazine.
Subject(s)
Corpus Striatum/drug effects , Dopamine Antagonists/pharmacology , Dopamine/metabolism , Phenothiazines/pharmacology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Corpus Striatum/metabolism , Dopamine Antagonists/administration & dosage , Dose-Response Relationship, Drug , Homovanillic Acid/metabolism , Hydroxyindoleacetic Acid/metabolism , Injections, Intraperitoneal , Male , Microdialysis , Phenothiazines/administration & dosage , Rats , Rats, Wistar , Time FactorsABSTRACT
El artículo recoge dos experiencias prácticas de educación para el ocio y tiempo libre llevadas a cabo en la Fundación Síndrome de Down de Cantabria a lo largo de una década: el taller de teatro y las convivencias de verano. Se exponen los objetivos planteados para estas actividades y algunos de los aspectos característicos de ambas: su carácter motivador, su perspectiva social, su enfoque educativo y especialmente su vinculación directa con la realidad. Ofrecen tantas posibilidades, que pueden ser presentadas como ejemplo ideal de actividades formativas para el tiempo libre de niños y jóvenes con síndrome de Down
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Subject(s)
Humans , Male , Female , Child , Adolescent , Education of Intellectually Disabled/trends , Down Syndrome , Recreation , Holidays , Interpersonal Relations , Leisure ActivitiesABSTRACT
It is generally assumed that bumetanide possesses some selectivity for the renal Na-K-Cl cotransporter NKCC2, although the results are scarce in the literature and comparisons were done with extra-renal NKCC1 at its basal, almost silent state. Here we investigated NKCC2/NKCC1 selectivity of loop diuretic drugs (bumetanide, piretanide and furosemide) as a function of the NKCC1 activated state (NKCC1 was activated by hypertonic media). NKCC2 activity was measured in isolated rat medullary thick ascending limb (mTAL) and NKCC1 in rat thymocytes and erythrocytes. When NKCC2 was compared with NKCC1at its activated state, all three diuretic drugs inhibited NKCC2 and NKCC1 with the same potency (bumetanide pIC50=6.48, 6.48 and 6.47; piretanide pIC50=5.97, 5.99 and 6.29; and furosemide pIC50=5.15, 5.04 and 5.21 for mTAL NKCC2, erythrocyte NKCC1 and thymocyte NKCC1, respectively). Basal NKCC1 exhibited a lower diuretic sensitivity, although with marked differences depending on the diuretic drug and the cell type in consideration and with the notable exception of furosemide in erythrocytes. Molecular modelling showed that bumetanide and piretanide possess four potentially active groups, of which three are shared with furosemide at similar intergroup distances. Of these three common groups, one should not bind to basal NKCC1 in thymocytes. The fourth (phenoxy) group (absent in furosemide) confers higher lipophilicity and should not bind to basal NKCC1 in erythrocytes. In conclusion, loop diuretics had no NKCC2/NKCC1 selectivity, when NKCC1 is measured at its activated state. Basal NKCC1 has a reduced diuretic sensitivity, of very different magnitude depending on the diuretic drug and cell type in consideration.
Subject(s)
Diuretics/pharmacology , Ion Transport/drug effects , Loop of Henle/drug effects , Sodium-Potassium-Chloride Symporters/metabolism , Animals , Bumetanide/chemistry , Bumetanide/pharmacology , Diuretics/chemistry , Erythrocytes/drug effects , Erythrocytes/metabolism , Furosemide/chemistry , Furosemide/pharmacology , Loop of Henle/metabolism , Male , Rats , Rats, Wistar , Solute Carrier Family 12, Member 1 , Solute Carrier Family 12, Member 2 , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thymus Gland/cytology , Thymus Gland/drug effects , Thymus Gland/metabolismABSTRACT
Calcium dobesilate possesses antioxidant properties and protects against capillary permeability by reactive oxygen species in the rat peritoneal cavity, but whether a similar action can take place in the diabetic rat retina is unknown. We investigated the oral treatment of diabetic rats with calcium dobesilate on the prevention of free radical-mediated retinal injury induced by ischemia/reperfusion (90 min ischemia followed by 3 min and/or 24 h of reperfusion). Streptozotocin-induced diabetic rats were orally treated with 50 and 100 mg/kg of calcium dobesilate for 10 days (n=12 in each group). In the first series of studies, calcium dobesilate was found to significantly reduce the maldistribution of ion content in diabetic ischemic/reperfused rat retina. Thus, in diabetic rats treated with 100 mg/kg/day calcium dobesilate, ischemia/reperfusion provoked: (i) 27.5% increase in retinal Na(+) content compared to 51.8% in the vehicle-treated group (P<0.05), and (ii) 59.6% increase in retinal Ca(2+) content compared to 107.1% in vehicle-treated animals (P<0.05). In the second series of studies, calcium dobesilate was found to significantly protect diabetic rat retina against inhibition of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase activities by ischemia/reperfusion (54% and 41% reduction, respectively, with 100 mg/kg of calcium dobesilate) and also against changes in retinal ATP, reduced glutathione (GSH), and oxidized glutathione (GSSG) contents. In the third series of experiments, rats treated with 100 mg/kg of calcium dobesilate reduced the hydroxyl radical signal intensity to 41% (measured by electron paramagnetic resonance), induced by ischemia/reperfusion in diabetic rat retina. Finally, 100 mg/kg calcium dobesilate significantly reduced retinal edema (measured by the thickness of the inner plexiform layer) in diabetic rats. In conclusion, oral treatment with calcium dobesilate significantly protected diabetic rat retina against oxidative stress induced by ischemia/reperfusion. Whether the antioxidant properties of calcium dobesilate explain, at least in part, its beneficial therapeutic effects in diabetic retinopathy deserves further investigation.
Subject(s)
Antioxidants/pharmacology , Calcium Dobesilate/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetic Retinopathy/prevention & control , Reperfusion Injury/complications , Adenosine Triphosphate/metabolism , Animals , Antioxidants/therapeutic use , Ca(2+) Mg(2+)-ATPase/drug effects , Ca(2+) Mg(2+)-ATPase/metabolism , Calcium/metabolism , Calcium Dobesilate/therapeutic use , Cations/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Retinopathy/etiology , Diabetic Retinopathy/metabolism , Free Radicals/metabolism , Glutathione/drug effects , Glutathione/metabolism , Glutathione Disulfide/drug effects , Glutathione Disulfide/metabolism , Magnesium/metabolism , Male , Potassium/metabolism , Rats , Rats, Sprague-Dawley , Retina/drug effects , Retina/metabolism , Retina/pathology , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/drug effects , Sodium-Potassium-Exchanging ATPase/metabolismABSTRACT
The H(1) antagonist azelastine is used in nasal sprays for the treatment of allergic rhinitis, but its therapeutic efficacy in vasomotor rhinitis is unknown. We performed a multicenter randomized double-blind placebo-controlled study of the efficacy and tolerance of azelastine nasal spray in 89 adult patients with vasomotor rhinitis (confirmed by negative Phadiatop). Following a washout period, patients were treated for 15 days with one puff three times daily per nostril of azelastine (n = 44) or placebo (n = 45) nasal spray. Efficacy was evaluated by the reduction in symptomatology and by rhinoscopy. Intent-to-treat analysis revealed better results in the azelastine group for all assessed symptoms; the significance level was reached for nasal obstruction on day 15 (p = 0.042). Using per protocol analysis (in 85 patients complying with the protocol), the significance level was reached for nasal obstruction on day 15 (p = 0.017) and for the percentage of success in rhinorrhea (p = 0.023). In the azelastine group, rhinoscopy examination showed a significantly higher reduction in the inflammatory level and edema of the nasal mucosa (p = 0.03 and 0.02 for VAS on day 15 respectively, per protocol analysis). General efficacy assessment by the physician and the patient was in favor of azelastine (with significance levels <0.01). No drowsiness or serious adverse event was reported, and the frequency of mouth dryness and headaches was similar in the two treatment groups. The present study demonstrates the efficacy of azelastine nasal spray in the treatment of vasomotor rhinitis. The best achieved results were a decrease in nasal obstruction and mucosal edema. Further studies are required to investigate if this therapeutic benefit results from H(1) antagonism or from another, not well-characterized pharmacological action of azelastine.
Subject(s)
Histamine H1 Antagonists/therapeutic use , Phthalazines/therapeutic use , Rhinitis, Vasomotor/drug therapy , Administration, Intranasal , Adolescent , Adult , Aged , Aged, 80 and over , Female , Histamine H1 Antagonists/administration & dosage , Histamine H1 Antagonists/adverse effects , Humans , Male , Middle Aged , Nasal Obstruction/drug therapy , Phthalazines/administration & dosage , Phthalazines/adverse effects , Treatment OutcomeABSTRACT
Myosin is an ATPase, able to form filaments with actin, thus initiating smooth muscle contraction (conversion of chemical energy into mechanical energy). Myosin activity is regulated by cytosolic calcium, via a calcium-calmodulin-MLCK-dependent phosphorylation. Extrusion of cytosolic calcium via calcium pumps (in the plasma membrane and sarcoplasmic reticulum) and via a sodium-calcium exchange allow smooth muscle cells to maintain their resting state. Constrictor agonists (hormones, neurotransmitters or drugs) act at membrane receptors inducing: (i) a fast and transient calcium mobilization from the sarcoplasmic reticulum, via phospholipase C (PLC) stimulation and inositol triphosphate (IP3) production or via a "calcium-induced calcium release" mechanism and opening of calcium channels in the sarcoplasmic reticulum and (ii) a slow and maintained mobilization of extracellular calcium, via the opening of voltage-dependent calcium channels in plasma membranes. Smooth muscle relaxation is ensured by a phosphatase which hydrolyzes phosphorylated myosin and decreases the calcium sensitivity of the contractile apparatus. Calcium signal is regulated at that level by: (i) protein kinase C, tyrosine kinase and arachidonic acid which inhibit phosphatase activity and (ii) cyclic AMP (cAMP) and cyclic GMP (cGMP) which enhance phosphatase activity. A second regulatory site is situated at the level of the non-contractile calcium compartment, which buffers signal transduction and where cGMP and/or cAMP enhance calcium extrusion mechanisms.
Subject(s)
Muscle Contraction/physiology , Muscle, Smooth/cytology , Muscle, Smooth/physiology , Calcium Signaling , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Calcium-Transporting ATPases/metabolism , Humans , Muscle Proteins/metabolism , Muscle Proteins/physiology , Muscle Relaxation/physiology , Muscle, Smooth/enzymologyABSTRACT
When incubated in 150 mM KCl, rat thymocytes exhibited a very important magnesium efflux (11.4 +/- 0.7 mmoles/liter cells/20 min, n = 29), about 90 times higher than the physiological magnesium efflux catalyzed by the Na-Mg exchanger (0.126 +/- 0.093 mmoles/liter cells/20 min). Cells remained viable (trypan blue test) and membrane integrity was shown by the absence of an increase in sodium permeability. K(+)-induced magnesium efflux exhibited the following properties: (i) it required the presence of external chloride; (ii) it was fully blocked by DIOA, a selective KCl-cotransporter inhibitor (IC(50) = 35 microm); and (iii) it was associated to a progressive increase in cell volume via the DIOA-sensitive K-Cl cotransporter. Such cell swelling seems to play a causal role, because (i) hypertonic media (+400 mM sucrose) abolished K(+)-induced magnesium efflux and (ii) hypotonic Ringer media (205 mOsm) increased both cell volume and magnesium efflux (from a basal value of 0.35 +/- 0.03 mmoles/liter cells/20 min up to 1.44 +/- 0.24 mmoles/liter cells/20 min), even in the presence of DIOA. In conclusion, high potassium induced a dramatic release of intracellular magnesium from rat thymocytes. Such a phenomenon was, at least in part, caused by cell swelling via the DIOA-sensitive K-Cl cotransporter. The nature of the magnesium transport mechanism and its role in the transduction signal of K-Cl cotransporter activation by cell swelling deserve further investigation.
Subject(s)
Magnesium/metabolism , Potassium/pharmacology , Symporters , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Animals , Antiporters/metabolism , Carboxylic Acids/pharmacology , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Cell Size/drug effects , Chlorides/metabolism , In Vitro Techniques , Indenes/pharmacology , Ion Transport/drug effects , Male , Osmolar Concentration , Potassium/metabolism , Rats , Rats, Wistar , Signal Transduction , Sodium/metabolism , K Cl- CotransportersABSTRACT
RATIONALE: Cyamemazine is a neuroleptic compound which possesses anxiolytic properties in humans. On the other hand, 5-HT3- and 5-HT2C-receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types. OBJECTIVE: The present study was undertaken to establish whether cyamemazine antagonizes 5-HT3- and/or 5-HT2C-mediated responses, and whether it compares with reference compounds. METHODS: Cyamemazine was tested for its ability to antagonize: (i) 5-HT3-dependent contraction of the isolated guinea-pig ileum and bradycardic responses in the rat and (ii) 5-HT2C-dependent phospholipase C (PLC) stimulation in rat brain membranes. RESULTS: In isolated guinea-pig ileum, cyamemazine potently and competitively antagonized 5-HT-dependent contractions (pA2 = 7.52 +/- 0.08; n = 5). In this test, cyamemazine was 5-7 times more potent (pIC50 = 6.75 +/- 0.13) than tropisetron (pIC50 = 6.02 +/- 0.04). In rats, cyamemazine i.v. antagonized 5-HT-dependent bradycardic responses with ID50% = 3.2 +/- 1.5 mg/kg (n = 4). Finally, in rat brain membranes cyamemazine antagonized 5-HT2C-dependent PLC stimulation with Ki = 424 nM (mianserin exhibits a Ki = 113 nM). CONCLUSIONS: Cyamemazine behaves as an antagonist at both 5-HT3- and 5-HT2C-receptors, which compares well with reference compounds. These 5-HT3- and 5-HT2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antipsychotic Agents/pharmacology , Phenothiazines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Animals , Caudate Nucleus/enzymology , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Male , Membranes/metabolism , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Radioligand Assay , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin, 5-HT3 , Type C Phospholipases/metabolismABSTRACT
UNLABELLED: Although the renal receptor at which cicletanine acts is unknown, cicletanine was assumed to act like thiazide diuretics. Here we tested cicletanine and its natriuretic metabolite, cicletanine-sulfate, for inhibitory activity against the thiazide-sensitive NaCl cotransporter expressed in Xenopus oocytes. The renal thiazide-sensitive NaCl cotransporter was expressed in Xenopus laevis oocytes injected with rat cRNA TSCr (TSCr: thiazide-sensitive cotransporter from rat kidney) and both, racemic (+/-) cicletanine and its sulfoconjugated metabolite were tested for inhibitory activity against oocyte 22Na+ uptake catalyzed by this cotransporter. Polythiazide was used as reference thiazide. Polythiazide fully inhibited NaCl cotransporter function with IC50 approximately 1.2 x 10(-7) M. Conversely, neither cicletanine, nor cicletanine sulfate were able to inhibit such cotransporter, i.e.: a minimum concentration of 10(-4) M of cicletanine was necessary to induce a slight cotransporter inhibition (29.5 +/- 18.2%). Cicletanine sulfate was inactive, even at 10(-4) M. IN CONCLUSION: (i) the natriuretic metabolite of cicletanine (cicletanine sulfate) is unable to inhibit thiazide-sensitive NaCl cotransporter and (ii) inhibition of such cotransporter by cicletanine required concentrations equal or higher than 10(-4) M--concentrations much more higher than urinary therapeutic ones in humans (approximately 10(-6) M). These results clearly demonstrate that cicletanine does not act like thiazide diuretics.
Subject(s)
Benzothiadiazines , Carrier Proteins/drug effects , Diuretics/pharmacology , Oocytes/drug effects , Pyridines/pharmacology , Receptors, Drug/drug effects , Sodium Chloride Symporter Inhibitors/pharmacology , Symporters , Animals , Female , Sodium Chloride Symporters , Sodium Radioisotopes , Xenopus laevisABSTRACT
In the 80s, erythrocyte Na-K-Cl cotransporter of essential hypertensive was reported: (i) decreased in fresh erythrocytes and (ii) increased, following repeated cell washings and incubations. This suggested to us that the manipulation of erythrocytes (from essential hypertensives) was able to dissociate a cotransport inhibitory factor, thus unmasking up-regulation of membrane cotransport units. This working hypothesis was recently confirmed in Dahl salt-sensitive rats (DS). The primary defect of DS rats seems to be hyperactivity of cotransporter Na-K-Cl BSC1 at the thick ascending limb of Henle's loop (TAL). Moreover, oral salt-loading induces an abnormally high increase in the urinary and plasmatic CIF levels of DS rats. The increase in urinary CIF excretion seems to be a compensatory mechanism, able to reduce BSC1 hyperactivity and NaCl reabsorption at the TAL. The increase in plasmatic CIF should inhibit erythrocyte BSC2, thus inducing "up-regulation" of the membrane density of cotransport proteins. Further studies are required to test this model in human with "salt-sensitive" hypertension.