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SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinical and clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.
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Medicamentos Biossimilares , Neoplasias do Colo , Neoplasias Retais , Humanos , Bevacizumab/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Aprovação de DrogasRESUMO
BACKGROUND: Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates. AIM: To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent. PATIENTS AND METHODS: We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab. RESULTS: Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR. CONCLUSIONS: Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.
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Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Feminino , Humanos , Infusões Intravenosas/efeitos adversos , Ipilimumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nivolumabe , Estudos RetrospectivosRESUMO
AIMS: To conduct a review in order to assess the safety of intranasal human insulin in clinical studies as well as the temporal stability of nasal insulin sprays. MATERIAL AND METHODS: An electronic search was performed using MEDLINE. We selected original research on intranasal human insulin without further additives in humans. The studies included could be of any design as long as they used human intranasal insulin as their study product. All outcomes and adverse side effects were extracted. RESULTS: A total of 38 studies in 1092 individuals receiving acute human intranasal insulin treatment and 18 studies in 832 individuals receiving human intranasal insulin treatment lasting between 21 days and 9.7 years were identified. No cases of symptomatic hypoglycaemia or severe adverse events (AEs) were reported. Transient local side effects in the nasal area were frequently experienced after intranasal insulin and placebo spray, while other AEs were less commonly reported. There were no reports of participants being excluded as a result of AEs. No instances of temporal stability of nasal insulin were reported in the literature. Tests on insulin that had been repacked into spray flasks showed that it had a chemical stability of up to 57 days. CONCLUSIONS: Our retrospective review of published studies on intranasal insulin did not reveal any safety concerns; however, there were insufficient data to ensure the long-term safety of this method of chronic insulin administration. Improved insulin preparations that cause less nasal irritation would be desirable for future treatment.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Regular Humana/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Administração Intranasal , Aerossóis , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina Regular Humana/efeitos adversos , Insulina Regular Humana/química , Insulina Regular Humana/uso terapêutico , Estabilidade Proteica , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêuticoRESUMO
Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.
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Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Colite/etiologia , Feminino , Humanos , Imunoterapia/efeitos adversos , Ipilimumab , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Mammalian adult neurogenesis has remained enigmatic. Two lines of research have emerged. One focuses on a potential repair mechanism in the human brain. The other aims at elucidating its functional role in the hippocampal formation, chiefly in cognitive processes; however, thus far it has been unsuccessful. Here, we try to recognize the sources of errors and conceptual confusion in comparative studies and neurobehavioral approaches with a focus on mice. Evolutionarily, mammalian adult neurogenesis appears as protracted juvenile neurogenesis originating from precursor cells in the secondary proliferation zones, from where newly formed cells migrate to target regions in the forebrain. This late developmental process is downregulated differentially in various brain structures depending on species and age. Adult neurogenesis declines substantially during early adulthood and persists at low levels into senescence. Short-lasting episodes in proliferation or reduction of adult neurogenesis may reflect a multitude of factors, and have been studied chiefly in mice and rats. Comparative studies face both species-specific variations in staining and technical abilities of laboratories, lacking quantification of important reference measures (e.g. granule cell number) and evaluation of maturational markers whose persistence might be functionally more relevant than proliferation rates. Likewise, the confusion about the functional role of variations in adult hippocampal neurogenesis has many causes. Prominent is an inferential statistical approach, usually with low statistical power. Interpretation is complicated by multiple theories about hippocampal function, often unrealistically extrapolating from humans to rodents. We believe that the field of mammalian adult neurogenesis needs more critical thinking, more sophisticated hypotheses, better statistical, technical and behavioral approaches, and a broader conceptual perspective incorporating comparative aspects rather than neglecting them.
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Invasive aspergillosis (IA) is a life-threatening complication in hematological cancer patients. Voriconazole (VCZ) is the established first-line treatment of IA. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, therapeutic drug monitoring (TDM) of VCZ may help to improve treatment results in IA patients, but evidence-based data on the clinical use of TDM in patients treated with VCZ for IA are scarce. Evidence-based guidance is needed to support decisions on the use of TDM in routine VCZ therapy of IA. Our present analysis assessed published studies for evidence-based criteria for TDM of VCZ to improve efficacy and safety of IA therapy in cancer patients. Literature searches of MEDLINE and Cochrane database were performed. We identified 27 clinical studies reporting on the use of plasma level monitoring and/or TDM for VCZ. For each study, strength of recommendation and quality of evidence were categorized according to predefined criteria. A number of studies were published on plasma level monitoring (PLM) and TDM in VCZ therapy of IA. Across studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity, while reaching minimum levels of >1-2 mg/L appeared to improve efficacy. Timing, frequency, and intervention thresholds and dosage increments of VCZ for adjustment of plasma levels remain to be established. Currently, there is still no conclusive evidence for recommendations in routine clinical practice. More data from prospective randomized studies with TDM are desirable to provide a solid evidence basis for these approaches.
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Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Voriconazol/uso terapêutico , Aspergilose/complicações , Aspergilose/epidemiologia , Prática Clínica Baseada em Evidências , Humanos , Neoplasias/complicações , Neoplasias/epidemiologiaRESUMO
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.
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Anticonvulsivantes/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Proteína 25 Associada a Sinaptossoma/metabolismo , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Carbamazepina/uso terapêutico , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Etossuximida/uso terapêutico , Hipercinese/tratamento farmacológico , Hipercinese/patologia , Hipercinese/fisiopatologia , Ácido Caínico , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nimodipina/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Proteína 25 Associada a Sinaptossoma/genética , Ácido Valproico/uso terapêuticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antivirais/efeitos adversos , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/complicações , Humanos , Imidazóis/uso terapêutico , Melanoma/complicações , Melanoma/secundário , Oximas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/complicações , Sofosbuvir , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêuticoRESUMO
Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mice.
Assuntos
Transtornos Cognitivos/genética , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Plasticidade Neuronal/genética , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Fatores de Troca de Nucleotídeo Guanina RhoRESUMO
The gravity vector theory postulates that birds determine their position to set a home course by comparing the memorized gravity vector at the home loft with the local gravity vector at the release site, and that they should adjust their flight course to the gravity anomalies encountered. As gravity anomalies are often intermingled with geomagnetic anomalies, we released experienced pigeons from the center of a strong circular gravity anomaly (25 km diameter) not associated with magnetic anomalies and from a geophysical control site, equidistant from the home loft (91 km). After crossing the border zone of the anomaly--expected to be most critical for pigeon navigation--they dispersed significantly more than control birds, except for those having met a gravity anomaly en route. These data increase the credibility of the gravity vector hypothesis.
Assuntos
Columbidae/fisiologia , Sistemas de Informação Geográfica/instrumentação , Gravitação , Comportamento de Retorno ao Território Vital/fisiologia , Animais , Feminino , Voo Animal , Masculino , Orientação , UcrâniaRESUMO
OBJECTIVES: The aim of this study was to determine the stability of commercially available eribulin mesylate containing injection solution as well as diluted ready-to-administer solutions stored under refrigeration or at room temperature. METHODS: Stability was studied by a novel developed stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with ultraviolet detection (detection wavelength 200 nm). Triplicate test solutions of eribulin mesylate containing injection concentrate (0.5 mg/mL) and with 0.9% sodium chloride solution diluted ready-to-administer preparations (0.205 mg/mL eribulin mesylate in polypropylene (PP) syringes, 0.020 mg/mL eribulin mesylate in polypropylene/polyethylene (PE) bags) were stored protected from light either at room temperature (25) or under refrigeration (2-8). Samples were withdrawn on day 0 (initial), 1, 3, 5, 7, 14, 21 and 28 of storage and assayed. Physical stability was determined by measuring the pH value once a week and checking for visible precipitations or colour changes. RESULTS: The stability tests revealed that concentrations of eribulin mesylate remained unchanged over a period of 28 days irrespective of concentration, container material or storage temperature. Neither colour changes nor visible particles have been observed. The pH value varied slightly over time but remained in the stability favourable range of 5-9. CONCLUSION: Eribulin mesylate injection (0.5 mg/mL) is physico-chemically stable over a period of 28 days after first puncture of the vial. After dilution with 0.9% NaCl vehicle solution, ready-to-administer eribulin mesylate injection solutions (0.205 mg/mL in PP syringe) and infusion solutions (0.02 mg/mL in prefilled PP/PE bags) are physico-chemically stable for a period of at least four weeks either refrigerated or stored at room temperature. For microbiological reasons storage under refrigeration is recommended.
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Furanos/química , Cetonas/química , Cromatografia Líquida de Alta Pressão , Embalagem de Medicamentos , Estabilidade de Medicamentos , Furanos/administração & dosagem , Cetonas/administração & dosagem , Soluções Farmacêuticas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Cytotoxic extravasation is a rare but potentially serious and painful complication of intravenous drug administration in oncology. Literature is anecdotal, and systematic clinical trials are scarce. The German working group for Supportive Care in Cancer (ASORS) has prepared an expert opinion for the diagnosis, prophylaxis and management of cytotoxic extravasation based on an interdisciplinary expert panel. MATERIAL AND METHODS: A Pubmed search was conducted for diagnosis, risk factors, symptoms, prophylaxis, and treatment of extravasation by the respective responsible expert. A writing committee compiled the manuscript and proposed the level of recommendation. In a consensus meeting, 13 experts reviewed and discussed the current practice in diagnosis and management of cytotoxic extravasation. In a telephone voting among the experts, the level of recommendation by ASORS was determined. RESULTS: Every effort should be made to reduce the risk of extravasation. Staff training, patient education, usage of right materials and infusion techniques have been identified to be mandatory to minimalize the risk of extravasation. Extravasation must be diagnosed as soon as possible, and specific therapy including antidotes dependent on the extravasated drug should be initiated immediately. An extravasation emergency set should be available wherever intravenous cytotoxics are applied. Documentation and post-treatment follow-up are recommended. CONCLUSION: We have developed a literature- and expert-based consensus recommendation to avoid cytotoxic extravasation. It also provides practical management instructions which should help to avoid surgery and serious late effects.
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Antineoplásicos/administração & dosagem , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico , Extravasamento de Materiais Terapêuticos e Diagnósticos/prevenção & controle , Oncologia/normas , Neoplasias/tratamento farmacológico , Guias de Prática Clínica como Assunto , Administração Intravenosa/efeitos adversos , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Alemanha , Humanos , Fatores de RiscoRESUMO
Within the last decade, the incidence ofclostridium difficile infection (CDI) has increased in many regions all over the world including the highly virulent B1/NAP1/027 strain. Meanwhile, the value of predisposing risk factors and diagnostic measures as well as the spectrum of therapeutic options has been elucidated in more detail. Most commonly applied antiinfective agents include metronidazole, vancomycin and fidaxomicin, however, several questions remain unanswered in respect to their optimized use which is also true for some further drugs which have not yet been approved for this indication. Based on the complexity and potential severity of CID, antibiotic stewardships should be implemented more intensively in order to avoid a further spread of highly virulent and resistant strains in the near future.
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Anti-Infecciosos/uso terapêutico , Clostridioides difficile , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/epidemiologia , Enterocolite Pseudomembranosa/microbiologia , Humanos , Medição de RiscoRESUMO
Nanoparticle-albumin bound paclitaxel (nab-paclitaxel) represents an innovative taxane-containing formulation lacking any critical solvents with minimal risks for any hypersensitivity reactions as well as perspectives for dose escalation as a consequence. Preclinical data indicated an increase of drug accumulation in tumor tissues via nab-paclitaxel administration which appears to be related to direct interaction with albumin-binding proteins including stromal SPARC. Phase III study results revealed clinically relevant advantages regarding efficacy and tolerability associated with nab-paclitaxel compared to conventional docetaxel and paclitaxel in patients with metastatic breast cancer. Further experience may encourage its use in other tumor entities including NSCLC, ovarian and pancreatic carcinoma as well as melanoma. As a consequence, the development of algorithms is ongoing in order to be able to select patients in more detail who will particularly benefit from nab-paclitaxel treatment.
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Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Química Farmacêutica , Feminino , Humanos , Pessoa de Meia-Idade , Nanopartículas , Paclitaxel/efeitos adversosRESUMO
IntelliCage for mice is a rodent home-cage equipped with four corner structures harboring symmetrical double panels for operant conditioning at each of the two sides, either by reward (access to water) or by aversion (non-painful stimuli: air-puffs, LED lights). Corner visits, nose-pokes and actual licks at bottle-nipples are recorded individually using subcutaneously implanted transponders for RFID identification of up to 16 adult mice housed in the same home-cage. This allows for recording individual in-cage activity of mice and applying reward/punishment operant conditioning schemes in corners using workflows designed on a versatile graphic user interface. IntelliCage development had four roots: (i) dissatisfaction with standard approaches for analyzing mouse behavior, including standardization and reproducibility issues, (ii) response to handling and housing animal welfare issues, (iii) the increasing number of mouse models had produced a high work burden on classic manual behavioral phenotyping of single mice. and (iv), studies of transponder-chipped mice in outdoor settings revealed clear genetic behavioral differences in mouse models corresponding to those observed by classic testing in the laboratory. The latter observations were important for the development of home-cage testing in social groups, because they contradicted the traditional belief that animals must be tested under social isolation to prevent disturbance by other group members. The use of IntelliCages reduced indeed the amount of classic testing remarkably, while its flexibility was proved in a wide range of applications worldwide including transcontinental parallel testing. Essentially, two lines of testing emerged: sophisticated analysis of spontaneous behavior in the IntelliCage for screening of new genetic models, and hypothesis testing in many fields of behavioral neuroscience. Upcoming developments of the IntelliCage aim at improved stimulus presentation in the learning corners and videotracking of social interactions within the IntelliCage. Its main advantages are (i) that mice live in social context and are not stressfully handled for experiments, (ii) that studies are not restricted in time and can run in absence of humans, (iii) that it increases reproducibility of behavioral phenotyping worldwide, and (iv) that the industrial standardization of the cage permits retrospective data analysis with new statistical tools even after many years.
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Octopuses, which are among the most intelligent invertebrates,1,2,3,4 have no skeleton and eight flexible arms whose sensory and motor activities are at once autonomous and coordinated by a complex central nervous system.5,6,7,8 The octopus brain contains a very large number of neurons, organized into numerous distinct lobes, the functions of which have been proposed based largely on the results of lesioning experiments.9,10,11,12,13 In other species, linking brain activity to behavior is done by implanting electrodes and directly correlating electrical activity with observed animal behavior. However, because the octopus lacks any hard structure to which recording equipment can be anchored, and because it uses its eight flexible arms to remove any foreign object attached to the outside of its body, in vivo recording of electrical activity from untethered, behaving octopuses has thus far not been possible. Here, we describe a novel technique for inserting a portable data logger into the octopus and implanting electrodes into the vertical lobe system, such that brain activity can be recorded for up to 12 h from unanesthetized, untethered octopuses and can be synchronized with simultaneous video recordings of behavior. In the brain activity, we identified several distinct patterns that appeared consistently in all animals. While some resemble activity patterns in mammalian neural tissue, others, such as episodes of 2 Hz, large amplitude oscillations, have not been reported. By providing an experimental platform for recording brain activity in behaving octopuses, our study is a critical step toward understanding how the brain controls behavior in these remarkable animals.
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Fenômenos Fisiológicos do Sistema Nervoso , Octopodiformes , Animais , Octopodiformes/fisiologia , Encéfalo/fisiologia , Comportamento Animal , Neurônios , MamíferosRESUMO
BACKGROUND: Anticoagulants and antiplatelet drugs are risk factors for gross hematuria (GH). Moreover, co-medication and drug-drug interactions (DDIs) may influence GH and its clinical course. OBJECTIVE: To investigate the relationship between GH and administration of oral anticoagulants and antiplatelet drugs. DESIGN, SETTING, AND PARTICIPANTS: Hospitalized patients with GH in an academic tertiary reference center were included. The use of individual compounds and DDIs were recorded and correlated to relevant clinical outcome factors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association between GH, DDIs, and clinical outcome parameters was analyzed using χ2 and Kruskal-Wallis tests. DDIs were systematically evaluated using a previously published calculator. RESULTS AND LIMITATIONS: A total of 189 patients with GH were eligible for the study. Of these, 76.2% took anticoagulants or antiplatelet drugs. The mean hospitalization duration was 4.7 d. The mean bladder irrigation duration was 3.1 d and the mean volume of irrigation fluid used was 22.8 l. Overall, 30.7% of patients had a pre-existing genitourinary malignancy. DDIs were observed in 31.9% of cases. The irrigation duration (p = 0.01) and volume of irrigation fluid (p = 0.05) were significantly associated with the use of anticoagulants or antiplatelet drugs. Specific DDI patterns were not predictive of clinical outcome. CONCLUSIONS: Medication with anticoagulants or antiplatelet drugs has a significant impact on GH and its clinical course. DDIs are a relevant issue and may lead to adverse clinical events or greater drug toxicity. Critical evaluation of medication and interdisciplinary counseling for patients with GH and urinary tract disease are recommended. PATIENT SUMMARY: Drugs taken to reduce the risk of blood clotting can increase the risk of blood in the urine (called hematuria) and medical expenses for treatment. Drug-drug interactions are a relevant issue, especially in elderly patients and those with other medical conditions who are taking several drugs. Thoughtful discussion of individual risk profiles for hematuria and medication is therefore recommended.
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Aging is accompanied by poor learning and memory abilities and by decreased hippocampal neurogenesis, a process that is also modulated by oxidative stress (OS). P66(Shc) has recently emerged as a novel mammalian gerontogene able to affect healthspan during aging. Deletion of this gene in mice leads to reduced OS accompanied by decreased incidence of age-related pathologies and reduced signs of behavioral aging. We hypothesized that p66(Shc-/-) mutants might show increased neurogenesis in the hippocampus, a brain region involved in learning and memory processes. To this aim, granule cell number, proliferation, neuronal differentiation, and cell death were assessed in the hippocampus in senescent p66(Shc-/-) [knock out (KO)] and p66(Shc+/+) [wild type (WT)] male and female mice. Spatial learning abilities and spontaneous activity were also investigated in a multifunctional behavioral system-IntelliCages. The behavioral analysis revealed that females in general perform better in spatial learning tasks, with genotype effects being apparent in the activity pattern only. Likewise, all females showed increased neuronal differentiation, whereas increased proliferation was found only in those belonging to the p66(Shc-/-) genotype, indicating that they might be protected from precursor cell loss. The number of dying cells was not affected by genotype or sex; however, all KO mice showed less granule cells than WT. Overall, our data suggest that hippocampal function is protected in the female gender at older age, an effect amplified by reduced OS in the p66(Shc-/-) mutant.
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Envelhecimento/fisiologia , Hipocampo/fisiologia , Neurogênese/fisiologia , Caracteres Sexuais , Proteínas Adaptadoras da Sinalização Shc/genética , Animais , Morte Celular/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células , Feminino , Imuno-Histoquímica , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Neurônios/citologia , Neurônios/fisiologia , Estresse Oxidativo/fisiologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de SrcRESUMO
The IntelliMaze allows automated behavioral analysis of group housed laboratory mice while individually assigned protocols can be applied concomitantly for different operant conditioning components. Here we evaluate the effect of additional component availability (enrichment) on behavioral and cognitive performance of mice in the IntelliCage, by focusing on aspects that had previously been found to consistently differ between three strains, in four European laboratories. Enrichment decreased the activity level in the IntelliCages and enhanced spatial learning performance. However, it did not alter strain differences, except for activity during the initial experimental phase. Our results from non-enriched IntelliCages proved consistent between laboratories, but overall laboratory-consistency for data collected using different IntelliCage set-ups, did not hold for activity levels during the initial adaptation phase. Our results suggest that the multiple conditioning in spatially and cognitively enriched environments are feasible without affecting external validity for a specific task, provided animals have adapted to such an IntelliMaze.