Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia

Media attention and the volatility effect

Stocks with low return volatility have high risk-adjusted returns, which might be driven by low media attention for such stocks. Using news coverage data we formally test whether the „attention-grabbing‟ hypothesis can explain the volatility effect for a sample of international stocks over the period 2001 to 2018. A low-volatility effect is still pre

Development of an instrument to analyze organizational characteristics in multidisciplinary care pathways:the case of colorectal cancer

Background: To analyze the organization of multidisciplinary care pathways such as colorectal cancer care, an instrument was developed based on a recently published framework that was earlier used in analyzing (monodisciplinary) specialist cataract care from a lean perspective. Methods: The instrument was constructed using semi-structured interviews and direct observation of the colorectal care process based on a Rapid Plant Assessment. Six lean aspects that were earlier established that highly impact process design, were investigated: operational focus, autonomous work cell, physical lay-out of resources, multi-skilled team, pull planning and non-value adding activities. To test reliability, clarity and face validity of the instrument, a pilot study was performed in eight Dutch hospitals.ResultsIn the pilot it proved feasible to apply the instrument and generate the intended information. The instrument consisted of 83 quantitative and 24 qualitative items. Examples of results show differences in operational focus, number of patient visits needed for diagnosis, numbers of staff involved with treatment, the implementation of protocols and utilization of one-stop-shops. Identification of waste and non-value adding activities may need further attention. Based on feedback from involved clinicians the face validity was acceptable and the results provided useful feedback- and benchmark data. The instrument proved to be reliable and valid for broader implementation in Dutch health care. The limited number of cases made statistical analysis not possible and further validation studies may shed better light on variation. Conclusions: This paper demonstrates the use of an instrument to analyze organizational characteristics in colorectal cancer care from a lean perspective. Wider use might help to identify best organizational practices for colorectal surgery. In larger series the instrument might be used for in-depth research into the relation between organization and patient outcomes.Although we found no reason to adapt the underlying framework, recommendations were made for further development to enable use in different tumor- and treatment modalities and in larger (international) samples that allow for more advanced statistical analysis. Waste from defective care or from wasted human potential will need further elaboration of the instrumen

Host resistance to rat cytomegalovirus (RCMV) and immune function in adult PVG rats fed herring from the contaminated Baltic Sea

The immunotoxic potential of many classes of environmental contaminants has been well established in laboratory studies, with much attention being focussed on aryl hydrocarbon (Ah)-receptor binding polychlorinated biphenyl (PCB), polychlorinated dibenzo-p-dioxin (PCDD), and polychlorinated dibenzofuran (PCDF) congeners. In a semi-field study, we previously showed that harbour seals (Phoca vitulina) fed herring from the contaminated Baltic Sea had lower natural killer cell activity, T-lymphocyte functionality and delayed-type hypersensitivity responses than seals fed herring from the relatively uncontaminated Atlantic Ocean. While ethical and practical constraints preclude in-depth studies in seals, specific reagents and a wider array of immune function tests allow such studies in laboratory rats. We therefore carried out a feeding study in rats aimed at extending our observations of contaminant-induced immunosuppression in harbour seals. The same two herring batches used in the seal study were freeze-dried, supplemented and fed. to female adult PVG rats for a period of 4 1/4 months. Daily contaminant intakes of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalents (TEQ) were estimated to be 0.3 ng/kg body weight and 1.6 ng/kg in the Atlantic and Baltic groups, respectively. At the end of the feeding experiment, no contaminant-related changes in spleen CD4+/CD8+cellularity, natural killer cell activity, or mitogen-induced proliferative responses of thymus or spleen cells could be detected. However, total thymocyte numbers and thymus CD4+/CD8+ratios were reduced in the Baltic group. A novel model was established to assess the specific T-cell response to rat cytomegalovirus (RCMV). When applied to the feeding study, no differences between the Atlantic and Baltic groups in the RCMV-induced proliferative T-lymphocyte responses could be detected, but virus titres in salivary glands of infected rats of the Baltic Sea group were higher. These elevated RCMV titres and changes in thymus cellularity suggest that the dietary exposure to low levels of contaminants may have been immunotoxic at a level which our immune function test could not otherwise detect. While the herring diet per se appeared to have an effect on several immune function parameters, lower plasma thyroid hormone levels in the Baltic Sea group of rats confirmed that exposure to the environmental mixture of contaminants led to adverse PHAH-related health effects

A framework for complexity in palliative care: A qualitative study with patients, family carers and professionals

Background:Palliative care patients are often described as complex but evidence on complexity is limited. We need to understand complexity, including at individual patient-level, to define specialist palliative care, characterise palliative care populations and meaningfully compare interventions/outcomes.Aim:To explore palliative care stakeholders’ views on what makes a patient more or less complex and insights on capturing complexity at patient-level.Design:In-depth qualitative interviews, analysed using Framework analysis.Participants/setting:Semi-structured interviews across six UK centres with patients, family, professionals, managers and senior leads, purposively sampled by experience, background, location and setting (hospital, hospice and community).Results:65 participants provided an understanding of complexity, which extended far beyond the commonly used physical, psychological, social and spiritual domains. Complexity included how patients interact with family/professionals, how services’ respond to needs and societal perspectives on care. ‘Pre-existing’, ‘cumulative’ and ‘invisible’ complexity are further important dimensions to delivering effective palliative and end-of-life care. The dynamic nature of illness and needs over time was also profoundly influential. Adapting Bronfenbrenner’s Ecological Systems Theory, we categorised findings into the microsystem (person, needs and characteristics), chronosystem (dynamic influences of time), mesosystem (interactions with family/health professionals), exosystem (palliative care services/systems) and macrosystem (societal influences). Stakeholders found it acceptable to capture complexity at the patient-level, with perceived benefits for improving palliative care resource allocation.Conclusion:Our conceptual framework encompasses additional elements beyond physical, psychological, social and spiritual domains and advances systematic understanding of complexity within the context of palliative care. This framework helps capture patient-level complexity and target resource provision in specialist palliative care

The influence of preoperative determinants on quality of life, functioning and pain after total knee and hip replacement:A pooled analysis of Dutch cohorts

Background: Previous research has identified preoperative determinants that predict health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA), but these differed between studies and had opposite directions. This may be due to lack of power and not adjusting for confounders. The present study aims to identify the preoperative determinants that influence health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA). Methods: We pooled individual patient from 20 cohorts with OA patients data (n = 1783 TKA and n = 2400 THA) in the Netherlands. We examined the influence of age, gender, BMI and preoperative values of HRQoL, functioning and pain on postoperative status and total improvement. Linear mixed models were used to estimate the effect of each preoperative variable on a particular outcome for each cohort separately. These effects were pooled across cohorts using a random effects model. Results: For each increase in preoperative point in HRQoL, the postoperative HRQoL increased by 0.51 points in TKA and 0.37 points in THA (SF-36 scale). Similarly, each point increase in preoperative functioning, resulted in a higher postoperative functioning of 0.31 (TKA) and 0.21 (THA) points (KOOS/HOOS-ADL scale). For pain this was 0.18 (TKA) and 0.15 (THA) points higher (KOOS/HOOS-pain scale) (higher means less pain). Even though patients with better preoperative values achieved better postoperative outcomes, their improvement was smaller. Women and patients with a higher BMI had more pain after a TKA and THA. Higher age and higher BMI was associated with lower postoperative HRQoL and functioning and more pain after a THA.Conclusions: Patients with a better preoperative health status have better outcomes, but less improvement. Even though the independent effects may seem small, combined results of preoperative variables may result in larger effects on postoperative outcomes.</p

(R)-[11C]Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus

<p>Abstract</p> <p>Background</p> <p>Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.</p> <p>Methods</p> <p><it>(R)</it>-[¹¹C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on <it>(R)</it>-[¹¹C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. <it>(R)</it>-[¹¹C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).</p> <p>Results</p> <p>All data analysis approaches indicated only modest differences in brain distribution of <it>(R)</it>-[¹¹C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.</p> <p>Conclusions</p> <p>P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.</p

The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis. Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24-48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26). At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24-48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels. IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8