Патогенетическое значение эндотелиальной дисфункции при первичной глаукоме

В эксперименте на модели глаукомы установлено, что дизрегуляция эндотелиальных факторов сосудистого тонуса (ЭТ-1, NO) вызывала формирование дисфункции эндотелия, которая усиливалась гиперхолестеринемией и дислипопротеидемией, а также патологическим уровнем перекисного окисления липидов. Эндотелиальная дисфункция способствовала дизрегуляции гемо- и гидродинамики глаз и развитию ишемично-реперфузионного повреждения нервных тканей глаза, что позволяет считать этот фактор патогенетическим в развитии глаукомы.The experiment with glaucoma model showed that dysregulation of endothelial factors of vascular tone (ET-1 and NO) determined the development of endothelial dysfunction. This process was intensified by hypercholesteremia, dyslipoproteidemia and high level of lipid peroxidation. Endothelial dysfunction induced changes in the eye hemo- and hydrodynamics as a development of ischemia-reperfusion injury of the eye nerve tissues. It let us consider this process to be pathogenetic one in glaucoma pathology

Better Safe than Sorry - Socio-Spatial Group Structure Emerges from Individual Variation in Fleeing, Avoidance or Velocity in an Agent-Based Model

In group-living animals, such as primates, the average spatial group structure often reflects the dominance hierarchy, with central dominants and peripheral subordinates. This central-peripheral group structure can arise by self-organization as a result of subordinates fleeing from dominants after losing a fight. However, in real primates, subordinates often avoid interactions with potentially aggressive group members, thereby preventing aggression and subsequent fleeing. Using agent-based modeling, we investigated which spatial and encounter structures emerge when subordinates also avoid known potential aggressors at a distance as compared with the model which only included fleeing after losing a fight (fleeing model). A central-peripheral group structure emerged in most conditions. When avoidance was employed at small or intermediate distances, centrality of dominants emerged similar to the fleeing model, but in a more pronounced way. This result was also found when fleeing after a fight was made independent of dominance rank, i.e. occurred randomly. Employing avoidance at larger distances yielded more spread out groups. This provides a possible explanation of larger group spread in more aggressive species. With avoidance at very large distances, spatially and socially distinct subgroups emerged. We also investigated how encounters were distributed amongst group members. In the fleeing model all individuals encountered all group members equally often, whereas in the avoidance model encounters occurred mostly among similar-ranking individuals. Finally, we also identified a very general and simple mechanism causing a central-peripheral group structure: when individuals merely differed in velocity, faster individuals automatically ended up at the periphery. In summary, a central-peripheral group pattern can easily emerge from individual variation in different movement properties in general, such as fleeing, avoidance or velocity. Moreover, avoidance behavior also affects the encounter structure and can lead to subgroup formation

Factors Influencing Preferences and Responses Towards Drug Safety Communications:A Conjoint Experiment Among Hospital-Based Healthcare Professionals in the Netherlands

Introduction Healthcare professionals (HCPs) are informed about new drug safety issues through Direct Healthcare Professional Communications (DHPCs). The influence of DHPC content on the impact of the communication is unclear. Objectives The aim of this study was to assess the effect of content elements 'frequency of the safety issue', 'seriousness of the safety issue', 'need to take action', 'life span of drug involved' and 'type of evidence supporting the safety issue' on hospital-based HCPs' preferences and responses towards DHPCs. Methods A survey study including a conjoint experiment was performed among hospital-based HCPs in the Netherlands. Hypothetical DHPCs varying on the five content elements were constructed. Each respondent received eight out of 16 hypothetical DHPCs and was asked about (1) importance to be informed (fixed-point scale), (2) preferred communication timing (multiple options) and (3) their stated actions (multiple options). Associations were tested using generalized linear mixed models. Results In total, 178 HCPs participated. DHPCs concerning more frequent or serious safety issues, or requiring action, were associated with a higher perceived importance to be informed and a preference for immediate communication. Periodic communication was preferred for DPHCs concerning less frequent or serious safety issues. The most commonly stated action was to discuss the DHPC with colleagues. Monitoring was common when this was recommended. High frequency and seriousness were associated with more prescribing-related actions. Conclusion Frequency and seriousness of the safety issue and the recommended action are likely to influence the impact of DHPCs. The timing of communication could be tailored depending on the content, where less urgent safety issues might be communicated periodically

Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Handling of New Drug Safety Information in the Dutch Hospital Setting:A Mixed Methods Approach

INTRODUCTION: The implementation of new drug safety information and Direct Healthcare Professional Communications (DHPCs) in hospitals is important for patient safety. OBJECTIVES: The aim of this study was to gain insight into which procedures and practices are in place to handle new drug safety information and particularly DHPCs in the Dutch hospital setting. METHODS: We first conducted focus groups including medical specialists and hospital pharmacists, focusing on handling of drug safety information at the individual and organisational level. A survey was then developed and distributed among hospital pharmacists in all Dutch hospitals to quantify the existence of specific procedures and committees to handle drug safety information and DHPCs. RESULTS: Eleven specialists and 14 pharmacists from six hospitals participated in focus groups. Drug safety information was usually considered before drugs were included in formularies or treatment protocols. Furthermore, drug safety information was consulted in response to patients experiencing adverse events. DHPCs were mostly dealt with by individual professionals. DHPCs could lead to actions but this was very uncommon. Completed surveys were received from 40 (53%) of the hospitals. In 32 (80%), the hospital pharmacy had procedures to deal with new drug safety information, whereas in 11 (28%) a hospital-wide procedure was in place. Drug safety was considered in committees concerning drug formulary decisions (69%) and antibiotic policies (63%). DHPCs were assessed by a hospital pharmacist in 50% of the hospitals. CONCLUSIONS: Drug safety information was used for evaluation of new treatments and in response to adverse events. Assessment of whether a DHPC requires action was primarily an individual task

Analyzing the Estrogen Receptor Status of Liver Metastases with [F-18]-FES-PET in Patients with Breast Cancer

Background: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]-FES) can visualize estrogen receptor (ER) expression, but it is challenging to determine the ER status of liver metastases, due to high physiological [18F]-FES uptake. We evaluated whether [18F]-FES-PET can be used to determine the ER status of liver metastases, using corresponding liver biopsies as the gold standard. Methods: Patients with metastatic breast cancer (n = 23) were included if they had undergone a [18F]-FES-PET, liver metastasis biopsy, CT-scan, and [18F]-FDG-PET. [18F]-FES-PET scans were assessed by visual and quantitative analysis, tracer uptake was correlated with ER expression measured by immunohistochemical staining and the effects of region-of-interest size and background correction were determined. Results: Visual analysis allowed ER assessment of liver metastases with 100% specificity and 18% sensitivity. Quantitative analysis improved the sensitivity. Reduction of the region-of-interest size did not further improve the results, but background correction improved ER assessment, resulting in 83% specificity and 77% sensitivity. Using separate thresholds for ER+ and ER− metastases, positive and negative predictive values of 100% and 75%, respectively, could be obtained, although 30% of metastases remained inconclusive. Conclusion: In the majority of liver metastases, ER status can be determined with [18F]-FES-PET if background correction and separate thresholds are applied

Reconsider radiation exposure from imaging during immune checkpoint inhibitor trials to reduce risk of secondary cancers in long-term survivors?

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with advanced cancers, and results in increasing numbers of long-term survivors. For registration studies, progression-free survival and disease-free survival often serve as primary endpoints. This requires repeated computed tomography (CT) scans for tumour imaging which might lead to major radiation exposure. To determine this, all immune checkpoint inhibitors trials that led to FDA approval were retrieved up to July 29, 2019. From the available protocols, imaging modalities and schedules used in each trial were identified. The anticipated cumulative number of scans made after 1, 3, 5, and 10 years study participation were calculated. The percentage of lifetime attributable cancer risk was calculated using the Biological Effects of Ionizing Radiation VII report. Fifty-one trials were identified, from which 39 protocols were retrieved. Four were adjuvant trials. All protocols required repeated chest-abdomen imaging and specified CT scans as preferred imaging modality. Median calculated cumulative numbers of chest-abdomen CT scans after 1, 3, 5, and 10 years study participation were 7, 16, 24 and 46, respectively. For ages 20-70 years at study entry, the average lifetime attributable cancer risk after 1 year of study participation ranged from 1.11 to 0.40% for men and from 1.87 to 0.46% for women. At 10 years study participation, this risk increased to a range of 5.91 to 1.96% for men and 9.64 to 2.32% for women. Given high imaging radiation exposure for long-term survivors in current ICI trials an adaptive imaging interval and imaging termination rules should be considered for long-term survivors

The ability to inhibit impulses is related to social behavior in long‐tailed macaques

Performance in cognitive tasks has been linked to differences in species' social organization, yet to understand its function its relationship to within-species variation in behavior should also be explored. One important cognitive capacity, the ability to inhibit impulses, is typically better in egalitarian than despotic primate species and in primate species with strong fission-fusion dynamics. A different line of research indicates that a high ability to inhibit impulses is related to less aggressive behavior and more socio-positive behavior. However, within species the relationship between performance on cognitive inhibition tasks and variation in social behavior remains to be explored. Here we investigate how performance in a typical inhibition task in cognitive research is related to aggressive and socio-positive behavior in despotic long-tailed macaques. Twenty individuals living in two naturalistic mixed-sex groups were tested with the Plexiglass Hole Task. Aggressive behavior and three types of socio-positive behavior (neutral/friendly approaches, socio-positive signaling, and grooming others) among group members were measured. Individuals differed in their ability to inhibit impulses. Individuals that were not good at inhibiting impulses showed higher rates of aggressive behavior, but also more socio-positive signals, whereas inhibition was not related to neutral/friendly approaches and grooming. These results confirm the positive link between impulsiveness and aggression. In addition, the results indicate that some social-positive behavior may be enhanced when inhibition is limited. In this species, benefits potentially derived from aggression and socio-positive signals match a low ability to inhibit impulses, suggesting that a low ability to inhibit impulses may actually be advantageous. To understand differences between species in cognitive skills, understanding the benefits of variation in a cognitive capacity within a species is crucial

Objective allergy markers and risk of cancer mortality and hospitalization in a large population-based cohort

PURPOSE: There are indications that a history of allergy may offer some protection against cancer. We studied the relation of three objectively determined allergy markers with cancer mortality and hospitalization risk. METHODS: Associations between three allergy markers (number of peripheral blood eosinophil counts, skin test positivity, and serum total IgE) with mortality and hospitalization from any type and four common types of cancer (lung, colorectal, prostate, and breast cancer) were assessed in the Vlagtwedde-Vlaardingen cohort (1965-1990), with follow-up of mortality until 31 December 2008. Hospitalization data were available since 1 January 1995. RESULTS: There were no significant associations between objective allergy markers and cancer mortality or hospitalization. We found several associations in specific subgroups. A higher number of eosinophils was associated with a decreased risk of colorectal cancer mortality in ever smokers HR (95 % CI) = 0.61 (0.45-0.83) and in males 0.59 (0.42-0.83); however, no overall association was observed 0.84 (0.64-1.09). Skin test positivity was associated with a decreased risk of any cancer mortality only among females 0.59 (0.38-0.91) and showed no overall association 0.83 (0.67-1.04). Serum total IgE levels were associated with an increased risk of lung cancer mortality among females 4.64 (1.04-20.70), but with a decreased risk of cancer hospitalization in ever smokers 0.77 (0.61-0.97) and males 0.72 (0.55-0.93); however, no overall associations were observed [mortality 0.99 (0.79-1.25), and hospitalization 0.86 (0.71-1.04)]. CONCLUSIONS: We found no associations between objective allergy markers and cancer in the total population. However, skin test positivity and a high number of eosinophils were associated with a reduced risk to die of cancer in specific subgroups. Hence, it seems important to study specific subgroups defined by gender and smoking habits in order to identify allergy markers of predictive value for cancer mortality