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1.
AIDS Res Hum Retroviruses ; 39(10): 511-517, 2023 10.
Article in English | MEDLINE | ID: mdl-37071218

ABSTRACT

Recent studies suggest that the introduction of antiretroviral agents such as integrase strand transfer inhibitors (INSTI) may lead to weight gain in people living with HIV (PLHIV). In this retrospective observational study, we report the weight changes observed in virologically suppressed HIV patients after 12 months of switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) due to a national change in public policy in Mexico. Patients on prior regimens based on TDF/FTC or ABC/3TC plus non-nucleoside retrotranscriptase inhibitor, INSTI, or protease inhibitor were included. In the 399 patients analyzed, a significant weight increase was found, as well as an increase in body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol (LDL-C), glucose, creatinine, and CD4+ cells after 12 months of switching treatment (all p ≤ .001). Mean weight gain was 1.63 kg [confidence interval (95% CI): 1.14-2.11], whereas the average percentage of weight gained was 2.5% (95% CI: 1.83-3.17). After considering the confounding effect of baseline weight status, the change in weight and BMI did not present significant differences between any of the prior treatment schemes. In conclusion, PLHIV switching to BIC/F/TAF therapy experienced weight gain after the first year of switching treatment. Although this weight gain could be due to the switch in treatment regimen, it cannot be excluded that it was caused by other factors since no comparable control group could be used for comparison.


Subject(s)
Anti-HIV Agents , HIV Infections , Humans , Adenine , Anti-HIV Agents/adverse effects , Cholesterol , Drug Combinations , Emtricitabine/adverse effects , Heterocyclic Compounds, 3-Ring/adverse effects , HIV Infections/drug therapy , Weight Gain
2.
Int J Med Educ ; 13: 35-46, 2022 Feb 26.
Article in English | MEDLINE | ID: mdl-35226614

ABSTRACT

OBJECTIVES: To investigate students' experience with medical education alongside their mental and physical health since the onset of the COVID-19 pandemic across nine countries. METHODS: A cross-sectional online survey was distributed by local collaborators to 2,280 medical students across 148 medical schools in Brazil, Chile, Colombia, Germany, Italy, Japan, Mexico, Spain, and Venezuela using non-probability convenience sampling from June 22 to July 24, 2020. Students answered questions regarding teaching, internet use, COVID-19, physical and mental well-being. A multivariate logistic regression examined factors associated with depressed mood, insomnia, and headache. RESULTS: Academic teaching shifted to a virtual (67%, n=1,534) or hybrid environment (23%, n=531), whilst bedside teaching was suspended or cancelled (93%, n=2,120). Across all countries students were equally satisfied with the teaching modality, quantity, quality, and the evaluation system of in-person, hybrid, and online curricula. Negative changes in mental (40% (n=912) insomnia, 57% (n=1,300) emotional irritability, 47% (n=1,072) emotional instability, 41% (n=935) anhedonia, 40% (n=912) depressed mood) and physical (36% (n=821) headache, 57% (n=1,299) ocular tiredness, 49% (n=1,117) backache) health symptoms were frequently observed. Positive associations between the number of daily screen hours and depressed mood (adjusted odds ratio (AOR)=1.09, 95%CI: 1.05-1.12, p<.001), insomnia (AOR=1.08, 95%CI: 1.05-1.11, p<.001), and headache (AOR=1.11, 95%CI: 1.07-1.14, p<.001) were identified. CONCLUSIONS: Students' experience with digital and hybrid medical curricula was diverse during the pandemic. Education modality, quantity, and quality were positively evaluated. However, students' mental and physical health worsened. Besides bedside teaching, faculties ought to digitalize and strengthen social communities and extend support services for students.


Subject(s)
COVID-19 , Education, Medical , Students, Medical , Cross-Sectional Studies , Humans , Mental Health , Pandemics , SARS-CoV-2
3.
Health Educ Behav ; 48(4): 446-454, 2021 08.
Article in English | MEDLINE | ID: mdl-34047207

ABSTRACT

The global pandemic caused by coronavirus disease-2019 (COVID-19) disrupted both public and private life for many. Concerning medical students, practical teaching and classrooms were substituted with a virtual curriculum. However, how this new academic environment has affected students' health and lifestyles has yet to be studied. In this study, we surveyed 2,776 students from nine different countries about changes in their university curricula and potential alterations in their daily habits, physical health, and psychological status. We found negative changes across all countries studied, in multiple categories. We found that 99% of respondents indicated changes in their instruction delivery system, with 90% stating a transition to online education, and 93% stating a reduction or suspension of their practical activities. On average, students spent 8.7 hours a day in front of a screen, with significant differences among countries. Students reported worsened studying, sleeping, and eating habits with substantial differences in Latin American countries. Finally, the participants frequently expressed onset and increase in both mental and physical health symptoms: backache, asthenopia, irritability, and emotional instability. Altogether, these results suggest a potential risk in the health and academic performance of future doctors if these new academic modalities are maintained.


Subject(s)
COVID-19 , Students, Medical , Humans , Life Style , Pandemics , SARS-CoV-2
4.
Transplant Proc ; 53(3): 1005-1009, 2021 Apr.
Article in English | MEDLINE | ID: mdl-32178925

ABSTRACT

CONTEXT: Thymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established. OBJECTIVE: Demonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression DESIGN, SETTING, PARTICIPANTS: Prospective randomized study in kidney transplant patients (12/2016-05/2018). INCLUSION CRITERIA: Recipients > 18 years, first living donor transplant. EXCLUSION CRITERIA: Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm3, platelets < 75,000 cells/mm3 and malignancy. INTERVENTION: Group A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids. MAIN OUTCOME MEASURES: Biopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months. RESULTS: 100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns). CONCLUSION: Low-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant.


Subject(s)
Antilymphocyte Serum/therapeutic use , Basiliximab/administration & dosage , Graft Rejection/prevention & control , Immunosuppression Therapy/methods , Immunosuppressive Agents/therapeutic use , Adult , Female , Graft Rejection/immunology , Graft Survival/drug effects , Humans , Kidney Transplantation/adverse effects , Living Donors , Male , Middle Aged , Prospective Studies , Transplant Recipients
5.
Fish Physiol Biochem ; 47(1): 33-47, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33118089

ABSTRACT

Reproduction in vertebrates is a complex process regulated by many hormones, and by paracrine factors and their receptors. This study aimed to examine the expression of pjGonadotropin-releasing hormone (GnRH 1), the kisspeptin receptor 2 (kissr2), and estradiol receptors α and ß (ER α and ER ß) during different stages of the sexual cycle and their distribution within the anterior brain of females of Chirostoma humboldtianum. Among these molecules, the kissr2 showed the maximal variation in expression, while GnRH 1 showed minimal variation of expression, and ERß and ERα had intermediate variation of expression. The distribution of these molecules in the anterior brain was consistent with their levels of expression; kissr2 was widely distributed throughout the telencephalon and diencephalon, while ER and GnRH 1 showed more restricted distributions. No coexpression of kissr2 and ER in GnRH 1ergic neurons, suggesting that regulation of this GnRH variant is indirectly mediated by kisspeptin and estradiol.


Subject(s)
Brain/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Fish Proteins/metabolism , Fishes/metabolism , Gonadotropin-Releasing Hormone/metabolism , Kisspeptins/metabolism , Animals , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Female , Fish Proteins/genetics , Fishes/genetics , Gonadotropin-Releasing Hormone/genetics , Kisspeptins/genetics , Pituitary Gland/metabolism
6.
J Med Chem ; 62(20): 9045-9060, 2019 10 24.
Article in English | MEDLINE | ID: mdl-31609613

ABSTRACT

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.


Subject(s)
Imidazoles/chemistry , Janus Kinase Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridones/chemistry , Respiratory Tract Diseases/drug therapy , Administration, Inhalation , Animals , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/chemistry , Janus Kinase Inhibitors/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Rats , Structure-Activity Relationship
7.
J Pharmacol Exp Ther ; 370(2): 137-147, 2019 08.
Article in English | MEDLINE | ID: mdl-31085698

ABSTRACT

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.


Subject(s)
Allergens/immunology , Asthma/drug therapy , Asthma/immunology , Janus Kinase Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Nitriles/pharmacology , Phosphoproteins/metabolism , Piperidines/pharmacology , Pyrimidines/pharmacology , STAT Transcription Factors/metabolism , Administration, Inhalation , Animals , Asthma/metabolism , Asthma/pathology , Inflammation/drug therapy , Isoenzymes/antagonists & inhibitors , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/pharmacokinetics , Janus Kinase Inhibitors/therapeutic use , Male , Nitriles/administration & dosage , Nitriles/pharmacokinetics , Nitriles/therapeutic use , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Time Factors
8.
Viruses ; 11(1)2019 01 03.
Article in English | MEDLINE | ID: mdl-30609806

ABSTRACT

Ranaviruses are the second deadliest pathogens for amphibian populations throughout the world. Despite their wide distribution in America, these viruses have never been reported in Mexico, the country with the fifth highest amphibian diversity in the world. This paper is the first to address an outbreak of ranavirus in captive American bullfrogs (Lithobates catesbeianus) from Sinaloa, Mexico. The farm experienced high mortality in an undetermined number of juveniles and sub-adult bullfrogs. Affected animals displayed clinical signs and gross lesions such as lethargy, edema, skin ulcers, and hemorrhages consistent with ranavirus infection. The main microscopic lesions included mild renal tubular necrosis and moderate congestion in several organs. Immunohistochemical analyses revealed scant infected hepatocytes and renal tubular epithelial cells. Phylogenetic analysis of five partial ranavirus genes showed that the causative agent clustered within the Frog virus 3 clade. Risk assessment with the Pandora⁺ protocol demonstrated a high risk for the pathogen to affect amphibians from neighboring regions (overall Pandora risk score: 0.619). Given the risk of American bullfrogs escaping and spreading the disease to wild amphibians, efforts should focus on implementing effective containment strategies and surveillance programs for ranavirus at facilities undertaking intensive farming of amphibians.


Subject(s)
DNA Virus Infections/epidemiology , Disease Outbreaks/veterinary , Rana catesbeiana/virology , Ranavirus/pathogenicity , Animals , Animals, Wild/virology , Aquaculture , DNA Virus Infections/mortality , Edema/epidemiology , Edema/virology , Mexico/epidemiology , Phylogeny , Ranavirus/genetics , Ranavirus/isolation & purification , Risk Assessment , Skin/pathology , Skin/virology , Viral Proteins/genetics
9.
J Med Chem ; 61(21): 9551-9567, 2018 11 08.
Article in English | MEDLINE | ID: mdl-30351000

ABSTRACT

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.


Subject(s)
Asthma/drug therapy , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Class I Phosphatidylinositol 3-Kinases/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Conformation
10.
Emerg Microbes Infect ; 7(1): 56, 2018 Apr 04.
Article in English | MEDLINE | ID: mdl-29615625

ABSTRACT

Ranaviruses are pathogenic viruses for poikilothermic vertebrates worldwide. The identification of a common midwife toad virus (CMTV) associated with massive die-offs in water frogs (Pelophylax spp.) in the Netherlands has increased awareness for emerging viruses in amphibians in the country. Complete genome sequencing of 13 ranavirus isolates collected from ten different sites in the period 2011-2016 revealed three CMTV groups present in distinct geographical areas in the Netherlands. Phylogenetic analysis showed that emerging viruses from the northern part of the Netherlands belonged to CMTV-NL group I. Group II and III viruses were derived from the animals located in the center-east and south of the country, and shared a more recent common ancestor to CMTV-amphibian associated ranaviruses reported in China, Italy, Denmark, and Switzerland. Field monitoring revealed differences in water frog host abundance at sites where distinct ranavirus groups occur; with ranavirus-associated deaths, host counts decreasing progressively, and few juveniles found in the north where CMTV-NL group I occurs but not in the south with CMTV-NL group III. Investigation of tandem repeats of coding genes gave no conclusive information about phylo-geographical clustering, while genetic analysis of the genomes revealed truncations in 17 genes across CMTV-NL groups II and III compared to group I. Further studies are needed to elucidate the contribution of these genes as well as environmental variables to explain the observed differences in host abundance.


Subject(s)
DNA Virus Infections/veterinary , Ranavirus/genetics , Ranidae/virology , Animals , DNA Virus Infections/virology , Genotype , Netherlands , Phylogeny , Ranavirus/classification , Ranavirus/isolation & purification , Ranavirus/pathogenicity , Virulence
11.
Pharmacol Res ; 99: 116-24, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26051661

ABSTRACT

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.


Subject(s)
Asthma/prevention & control , Azabicyclo Compounds/administration & dosage , Indazoles/administration & dosage , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Asthma/pathology , Asthma/physiopathology , Azabicyclo Compounds/pharmacokinetics , B-Lymphocytes/drug effects , B-Lymphocytes/physiology , Cell Degranulation/drug effects , Cell Line , Disease Models, Animal , Humans , Indazoles/pharmacokinetics , Male , Mast Cells/physiology , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Inbred BN , Rats, Wistar , Syk Kinase
12.
Bioorg Med Chem Lett ; 22(17): 5419-23, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22877633

ABSTRACT

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.


Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Binding Sites , Cell Degranulation/drug effects , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Mast Cells/enzymology , Mast Cells/physiology , Molecular Docking Simulation , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Syk Kinase
13.
Bioorg Med Chem Lett ; 22(8): 2784-8, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22425453

ABSTRACT

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrazines/chemistry , Syk Kinase
14.
J Med Chem ; 54(22): 7899-910, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-21999461

ABSTRACT

The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Naphthyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Binding Sites , Cell Line , Crystallography, X-Ray , Humans , Inflammation/drug therapy , Inflammation/etiology , Lipopolysaccharides/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Monocytes/drug effects , Monocytes/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Protein Binding , Protein Conformation , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis
15.
Rev Panam Salud Publica ; 29(5): 365-70, 2011 May.
Article in Spanish | MEDLINE | ID: mdl-21709942

ABSTRACT

A review of the management of blood supply and its administration during disasters was conducted based on the experience of several events that occurred primarily from 2000-2010, particularly the earthquake that measured 8.8 on the Richter scale that struck central and southern Chile on 27 February 2010. The objective was to provide information that could be useful in improving response plans and strategies during potential future disasters. The descriptive information on response procedures was obtained from interviews, internal reports, and the computer database from the Maule regional blood production center. The results lead to the conclusion that to respond efficiently and effectively to the need for blood in the immediate wake of a disaster it is essential to have both a centralized management system that facilitates the supply and administration of blood and volunteers with competence in health that are willing to swiftly arrive during these events. A change in the profile of blood donors during such emergencies was also observed. In Chile, for example, during the two weeks after the earthquake, the ratio of male/female donors was reversed. There was 61.1% participation by women, whereas in the week before the event women accounted for only 37%.


Subject(s)
Blood Banks/supply & distribution , Blood Donors/supply & distribution , Disasters , Earthquakes , Adolescent , Adult , Blood Banks/organization & administration , Child , Chile , Female , Humans , Male
16.
Behav Brain Res ; 224(1): 112-20, 2011 Oct 10.
Article in English | MEDLINE | ID: mdl-21664381

ABSTRACT

Reaching tasks are popular tools for investigating the neural mechanisms of motor skill learning and recovery from brain damage in rodents, but there is considerable unexplained variability across studies using these tasks. We investigated whether breeder, batch effects, experimenter, time of year, weight and other factors contribute to differences in the acquisition and performance of a skilled reaching task, the single pellet retrieval task, in adult male Long-Evans hooded rats. First, we retrospectively analyzed task acquisition and performance in rats from different breeding colonies that were used in several studies spanning a 3 year period in our laboratory. Second, we compared reaching variables in age-matched rats from different breeders that were trained together as a batch by the same experimenters. All rats had received daily training on the reaching task until they reached a criterion of successful reaches per attempt. We found significant breeder-dependent differences in learning rate and final performance level. This was found even when age-matched rats from different breeders were trained together by the same experimenters. There was also significant batch-to-batch variability within rats from the same breeder trained by the same experimenter. Other factors, including weight, paw preference and the experimenter, were not as strong or consistent in their contributions to differences across studies. The breeder and batch effects found within the same rat strain may reflect genetic and environmental influences on the neural substrates of motor skill learning. This is an important consideration when comparing baseline performance across studies and for controlling variability within studies.


Subject(s)
Breeding , Motor Skills/physiology , Movement/physiology , Age Factors , Analysis of Variance , Animals , Behavior, Animal , Male , Practice, Psychological , Rats , Rats, Long-Evans , Seasons
18.
Rev. panam. salud pública ; 29(5): 365-370, May 2011. graf, tab
Article in Spanish | LILACS | ID: lil-591440

ABSTRACT

Se realizó una revisión de la gestión del abastecimiento y suministro de sangre durante desastres a partir de las experiencias de diversos eventos ocurridos principalmente en la primera década de este siglo, y en particular el terremoto grado 8,8 en la escala de Richter que afectó la zona centro sur de Chile el 27 de febrero de 2010. El objetivo fue proporcionar información que pueda ser útil para mejorar las estrategias y planes de respuesta durante potenciales desastres futuros. La información descriptiva sobre los procedimientos de respuesta se obtuvo mediante entre-vistas, reportes internos y la base de datos del sistema informático del Centro Productivo Regional de Sangre del Maule. Los resultados permiten concluir que para responder de manera eficiente y efectiva a las necesidades de sangre inmediatamente después de un desastre es de importancia clave tener un sistema centralizado de gestión que facilite el abastecimiento y el suministro de sangre y con-tar con personal voluntario competente en salud que esté dispuesto a acudir con celeridad durante estos eventos. Asimismo, se ha observado que durante dichas emergencias se produce un cambio en el perfil de quienes donan sangre. En Chile, por ejemplo, durante las dos semanas siguientes al terremoto la razón hombre/mujer en los donantes se invirtió, con 61,1 por ciento de participación por parte de las mujeres, quienes en la semana previa al evento representaban a solo 37 por ciento.


A review of the management of blood supply and its administration during disasters was conducted based on the experience of several events that occurred primarily from 2000-2010, particularly the earthquake that measured 8.8 on the Richter scale that struck central and southern Chile on 27 February 2010. The objective was to provide information that could be useful in improving response plans and strategies during potential future disasters. The descriptive information on response procedures was obtained from interviews, internal reports, and the computer database from the Maule regional blood production center. The results lead to the conclusion that to respond efficiently and effectively to the need for blood in the immediate wake of a disaster it is essential to have both a centralized management system that facilitates the supply and administration of blood and volunteers with competence in health that are willing to swiftly arrive during these events. A change in the profile of blood donors during such emergencies was also observed. In Chile, for example, during the two weeks after the earthquake, the ratio of male/female donors was reversed. There was 61.1 percent participation by women, whereas in the week before the event women accounted for only 37 percent.


Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Blood Banks/supply & distribution , Blood Donors/supply & distribution , Disasters , Earthquakes , Blood Banks/organization & administration , Chile
19.
J Biol Chem ; 286(11): 8924-32, 2011 Mar 18.
Article in English | MEDLINE | ID: mdl-21266573

ABSTRACT

Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing Aß accumulation. Similarly, intrahippocampal injections of an anti-Aß antibody reduced Aß levels and normalized mTOR activity, indicating that high Aß levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted Aß is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the Aß-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the Aß-induced mTOR hyperactivity. Taken together, our data show that Aß accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which Aß exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Hippocampus/metabolism , Phosphoproteins/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/therapy , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/pharmacology , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activation/genetics , Mice , Mice, Transgenic , Phosphoproteins/genetics , Phosphorylation/drug effects , Phosphorylation/genetics , TOR Serine-Threonine Kinases/genetics
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