Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K (1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Acute necrotizing myopathy and podophyllin toxicity: report of a fatal case

A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbances resolved within three weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a still unreported feature of podophyllin toxicity.Paciente de 21 anos, sexo masculino, ingeriu 20 mL de podofilina a 25% como tentativa de suicídio. O quadro clínico caracterizou-se por crises convulsivas, coma, neuropatia periférica, insuficiência renal e miopatia necrotizante aguda. O estado de coma e os distúrbios sistêmicos resolveram-se em 3 semanas. A miopatia resolveu-se em 7 semanas, demonstrando uma alta capacidade de recuperação muscular. A neuropatia periférica sensitivo-motora persistiu até o óbito do paciente, por septicemia, 9 semanas após a ingestão da podofilina. Esta descrição confirma os achados de literatura com alterações transitórias do sistema nervoso central e persistentes do nervo periférico relacionadas à podofilina, e descreve uma miopatia necrotizante associada com anormalidades mitocondriais, mas de caráter reversível, característica até então não reportada de toxicidade pela podofilina

Impaired Embryonic Development in Mice Overexpressing the RNA-Binding Protein TIAR

TIA-1-related (TIAR) protein is a shuttling RNA-binding protein involved in several steps of RNA metabolism. While in the nucleus TIAR participates to alternative splicing events, in the cytoplasm TIAR acts as a translational repressor on specific transcripts such as those containing AU-Rich Elements (AREs). Due to its ability to assemble abortive pre-initiation complexes coalescing into cytoplasmic granules called stress granules, TIAR is also involved in the general translational arrest observed in cells exposed to environmental stress. However, the in vivo role of this protein has not been studied so far mainly due to severe embryonic lethality upon tiar invalidation.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

O discurso médico e a Educação Física nas escolas (Brasil, século XIX)

Para os médicos, a reforma da sociedade não residia apenas nas ruas, nas avenidas, nas construções, enfim, em uma urbanização com base em preceitos da saúde. Era impreterível incutir uma reforma dos corpos, que ocorria primeiro no núcleo familiar através da educação higiênica na infância. É neste campo específico da Higiene que os exercícios físicos tornaram-se foco de interesse dos médicos. O objetivo deste estudo é descrever o contexto de escolarização da Educação Física mediante o discurso médico do século XIX. Para isto, realizou-se uma pesquisa histórica e documental que teve como fontes: as teses para a obtenção do título de doutor da Faculdade de Medicina do Rio de Janeiro e Bahia. Conclui-se que a mentalidade higienista colaborou para a lenta difusão dos exercícios físicos no contexto educacional do século XIX. Contudo a relevância da ginástica era secundária no projeto higienista

Tropical field stations yield high conservation return on investment

Conservation funding is currently limited; cost-effective conservation solutions are essential. We suggest that the thousands of field stations worldwide can play key roles at the frontline of biodiversity conservation and have high intrinsic value. We assessed field stations’ conservation return on investment and explored the impact of COVID-19. We surveyed leaders of field stations across tropical regions that host primate research; 157 field stations in 56 countries responded. Respondents reported improved habitat quality and reduced hunting rates at over 80% of field stations and lower operational costs per km2 than protected areas, yet half of those surveyed have less funding now than in 2019. Spatial analyses support field station presence as reducing deforestation. These “earth observatories” provide a high return on investment; we advocate for increased support of field station programs and for governments to support their vital conservation efforts by investing accordingly

Encoding of Spatio-Temporal Input Characteristics by a CA1 Pyramidal Neuron Model

The in vivo activity of CA1 pyramidal neurons alternates between regular spiking and bursting, but how these changes affect information processing remains unclear. Using a detailed CA1 pyramidal neuron model, we investigate how timing and spatial arrangement variations in synaptic inputs to the distal and proximal dendritic layers influence the information content of model responses. We find that the temporal delay between activation of the two layers acts as a switch between excitability modes: short delays induce bursting while long delays decrease firing. For long delays, the average firing frequency of the model response discriminates spatially clustered from diffused inputs to the distal dendritic tree. For short delays, the onset latency and inter-spike-interval succession of model responses can accurately classify input signals as temporally close or distant and spatially clustered or diffused across different stimulation protocols. These findings suggest that a CA1 pyramidal neuron may be capable of encoding and transmitting presynaptic spatiotemporal information about the activity of the entorhinal cortex-hippocampal network to higher brain regions via the selective use of either a temporal or a rate code

Can a person-centred-care intervention improve health-related quality of life in patients with head and neck cancer? A randomized, controlled study

BACKGROUND: The incidence of head and neck cancer is increasing slightly. Head and neck cancer but also it’s necessary and often successful treatment may affect general domains of health-related quality of life and provoke a variety of adverse symptoms and side effects, both during and after treatment. The objective of this study was to compare a person-centred care intervention in terms of health-related quality of life, disease-specific symptoms or problems, with traditional care as a control group for patients with head and neck cancer. METHODS: In this randomized controlled trial, person–centred-care intervention and traditional care (control) groups comprised 54 and 42 patients, respectively. Outcome measures used were: the EORTC QLQ-C30 and the EORTC QLQ-C35. Both groups answered the questionnaires at baseline and after 4, 10, 18 and 52 weeks from start of treatment. The questionnaires’ scores were compared between groups by using independent samples test and non-parametric test for continuous variables. For categorical data, Fisher’s exact test was used. Longitudinal data were analysed using generalized linear models for normally distributed repeated measures data. RESULTS: At baseline, the intervention and control groups were comparable in terms of medical and sociodemographic variables, clinical characteristics, health-related quality of life and disease-specific symptoms or problems. At all the follow-up points, even during the worst period for the patients, the person-centred-care group consistently reported better scores than the control group. The differences were numerically but not always statistically significant. When testing longitudinal data, statistically significant results were found for head and neck cancer-specific problems, swallowing (p = 0.014), social eating (p = 0.048) and feeling ill (p = 0.021). CONCLUSIONS: The results from this study suggest that adopting the person-centred-care concept practiced here could be a way to improve function and wellbeing in patients with head and neck cancer. TRIAL REGISTRATION: The study was retrospectively registered in 2016-12-05 in Clinical Trials gov. “Can a Person-centred-care Intervention Improve Health-related Quality of Life in Patients With Head and Neck Cancer” registration number: NCT02982746

Static compression regulates OPG expression in periodontal ligament cells via the CAMK II pathway

ABSTRACT Objective This study aimed to investigate the potential role of CAMK II pathway in the compression-regulated OPG expression in periodontal ligament cells (PDLCs). Material and Methods The PDL tissue model was developed by 3-D culturing human PDLCs in a thin sheet of poly lactic-co-glycolic acid (PLGA) scaffolds, which was subjected to static compression of 25 g/cm2 for 3, 6 and 12 h, with or without treatment of KN-93. After that, the expression of OPG, RANKL and NFATC2 was investigated through real-time PCR and western blot analysis. Results After static compression, the NFATC2 and RANKL expression was significantly up-regulated, while partially suppressed by KN-93 for 6 and 12 h respectively. The OPG expression was significantly down-regulated by compression in 3 h, started to elevate in 6 h, and significantly up-regulated in 12 h. The up-regulation after 12 h was significantly suppressed by KN-93. Conclusions Long-term static compression increases OPG expression in PDLCs, at least partially, via the CAMK II pathway