The adipose tissue stores excess energy in the form of neutral lipids within adipocyte lipid droplets (LDs). The correct function of LDs requires the interaction with other organelles, such as the ...endoplasmic reticulum (ER) as well as with LD coat-associated proteins, including Rab18, a mediator of intracellular lipid trafficking and ER-LD interaction. Although perturbations of the inter-organelle contact sites have been linked to several diseases, such as cancer, no information regarding ER-LD contact sites in dysfunctional adipocytes from the obese adipose tissue has been published to date. Herein, the ER-LD connection and Rab18 distribution at ER-LD contact sites are examined in adipocytes challenged with fibrosis and inflammatory conditions, which represent known hallmarks of the adipose tissue in obesity. Our results show that adipocytes differentiated in fibrotic conditions caused ER fragmentation, the expansion of ER-LD contact sites, and modified Rab18 dynamics. Likewise, adipocytes exposed to inflammatory conditions favored ER-LD contact, Rab18 accumulation in the ER, and Rab18 redistribution to large LDs. Finally, our studies in human adipocytes supported the suggestion that Rab18 transitions to the LD coat from the ER. Taken together, our results suggest that obesity-related pathogenic processes alter the maintenance of ER-LD interactions and interfere with Rab18 trafficking through these contact sites.
To present the results of occupational radiation doses investigated through a national survey promoted by the National Society of Interventional Radiology in Spain.
The monthly dosimetric records of ...28 interventional radiologists from 10 hospitals were analyzed and filtered to remove inconsistent dosimeter readings. The evaluation of the results includes different workloads as well as different radiation protection habits.
Poor use of personal dosimetry by some interventional radiologists was brought to light. Most professionals do not use an over-apron dosimeter as recommended by the International Commission on Radiological Protection. Ceiling-suspended protective screens are used irregularly in many cases. All interventionalists perform digital subtraction angiographic imaging from a control room in more than 80% of procedures. The maximum monthly doses recorded were 3.8 mSv under the apron, 20.2 mSv over the apron, and 63.1 mSv to the hands.
For under-apron and hand readings, extrapolated median values were below 30% of annual dose limits, but in the case of over-apron readings, the extrapolated median dose was higher than the newly recommended limit for the eye lens of 20 mSv per year. This study mainly highlights the need to use radiation protection tools and personal dosimeters to protect staff and monitor eye lens doses.
Background Adenoma detection rate (ADR) has become the most important quality indicator for colonoscopy. Objective The aim of this study was to investigate which modifiable factors, directly related ...to the endoscopic procedure, influenced the ADR in screening colonoscopies. Design Observational, nested study. Setting Multicenter, randomized, controlled trials. Patients Asymptomatic people aged 50 to 69 years were eligible for a multicenter, randomized, controlled trial designed to compare colonoscopy and fecal immunochemical testing in colorectal cancer screening. A total of 4539 individuals undergoing a direct screening colonoscopy were included in this study. Intervention Colonoscopy. Main Outcome Measurements Bowel cleansing, sedation, withdrawal time in normal colonoscopies, and cecal intubation were analyzed as possible predictors of adenoma detection by using logistic regression analysis, adjusted for age and sex. Results In multivariate analysis, after adjustment for age and sex, factors independently related to the ADR were a mean withdrawal time longer than 8 minutes (odds ratio OR 1.51; 95% CI, 1.17-1.96) in normal colonoscopies and split preparation (OR 1.26; 95% CI, 1.01-1.57). For advanced adenomas, only withdrawal time maintained statistical significance in the multivariate analysis. For proximal adenomas, withdrawal time and cecal intubation maintained independent statistical significance, whereas only withdrawal time longer than 8 minutes and a <10-hour period between the end of preparation and colonoscopy showed independent associations for distal adenomas. Limitations Only endoscopic variables have been analyzed. Conclusion Withdrawal time was the only modifiable factor related to the ADR in colorectal cancer screening colonoscopies associated with an increased detection rate of overall, advanced, proximal, and distal adenomas.
Primary care is a major access point for the initial treatment of depression, but the management of these patients is far from optimal. The lack of time in primary care is one of the major ...difficulties for the delivery of evidence-based psychotherapy. During the last decade, research has focused on the development of brief psychotherapy and cost-effective internet-based interventions mostly based on cognitive behavioral therapy (CBT). Very little research has focused on alternative methods of treatment for depression using CBT. Thus, there is a need for research into other therapeutic approaches.
This study aimed to assess the effectiveness of 3 low-intensity, internet-based psychological interventions (healthy lifestyle psychoeducational program HLP, focused program on positive affect promotion PAPP, and brief intervention based on mindfulness MP) compared with a control condition (improved treatment as usual iTAU).
A multicenter, 4-arm, parallel randomized controlled trial was conducted between March 2015 and March 2016, with a follow-up of 12 months. In total, 221 adults with mild or moderate major depression were recruited in primary care settings from 3 Spanish regions. Patients were randomly distributed to iTAU (n=57), HLP (n=54), PAPP (n=56), and MP (n=54). All patients received iTAU from their general practitioners. The main outcome was the Spanish version of the Patient Health Questionnaire-9 (PHQ-9) from pretreatment (time 1) to posttreatment (time 2) and up to 6 (time 3) and 12 (time 4) months' follow-up. Secondary outcomes included the visual analog scale of the EuroQol, the Short-Form Health Survey (SF-12), the Positive and Negative Affect Schedule (PANAS), and the Pemberton Happiness Index (PHI). We conducted regression models to estimate outcome differences along study stages.
A moderate decrease was detected in PHQ-9 scores from HLP (β=-3.05; P=.01) and MP (β=-3.00; P=.01) compared with iTAU at posttreatment. There were significant differences between all intervention groups and iTAU in physical SF-12 scores at 6 months after treatment. Regarding well-being, MP and PAPP reported better PHI results than iTAU at 6 months post treatment. PAPP intervention significantly decreased PANAS negative affect scores compared with iTAU 12 months after treatment.
The low-intensity, internet-based psychological interventions (HLP and MP) for the treatment of depression in primary care are more effective than iTAU at posttreatment. Moreover, all low-intensity psychological interventions are also effective in improving medium- and long-term quality of life. PAPP is effective for improving health-related quality of life, negative affect, and well-being in patients with depression. Nevertheless, it is important to examine possible reasons that could be implicated for PAPP not being effective in reducing depressive symptomatology; in addition, more research is still needed to assess the cost-effectiveness analysis of these interventions.
ISRCTN Registry ISRCTN82388279; http://www.isrctn.com/ISRCTN82388279.
RR2-10.1186/s12888-015-0475-0.
Obesity is characterized by adipose tissue dysregulation and predisposes individuals to insulin resistance and type 2 diabetes. At the molecular level, adipocyte dysfunction has been linked to ...obesity-triggered oxidative stress and protein carbonylation, considering protein carbonylation as a link between oxidative stress and metabolic dysfunction. The identification of specific carbonylated proteins in adipose tissue could provide novel biomarkers of oxidative damage related to metabolic status (i.e prediabetes). Thus, we aimed at characterizing the subcutaneous and omental human adipose tissue carbonylome in obesity-associated insulin resistance.
2D-PAGE was used to identify carbonylated proteins, and clinical correlations studies and molecular biology approaches including intracellular trafficking, reactive oxygen species assay, and iron content were performed using in vitro models of insulin resistance.
The carbonylome of human adipose tissue included common (serotransferrin, vimentin, actin, and annexin A2) and depot-specific (carbonic anhydrase and α-crystallin B in the subcutaneous depot; and α-1-antitrypsin and tubulin in the omental depot) differences that point out the complexity of oxidative stress at the metabolic level, highlighting changes in carbonylated transferrin expression. Posterior studies using in vitro prediabetic model evidence alteration in transferrin receptor translocation, linked to the prediabetic environment. Finally, ligand-receptor molecular docking studies showed a reduced affinity for carbonylated transferrin binding to its receptor compared to wild-type transferrin, emphasizing the role of transferrin carbonylation in the link between oxidative stress and metabolic dysfunction.
The adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance.
There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to ...severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality.
This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO
/FiO
≤ 200 mmHg on PEEP ≥ 10 cmH
O and FiO
≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle.
This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2.
ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.
Depression is one of the most common disorders in psychiatric and primary care settings, and is associated with disability, loss in quality of life, and economic costs. Internet-based psychological ...interventions have been shown to be effective in depression treatment but present problems with a low degree of adherence. The main aim of this study is to analyze the adherence predictors in three low-intensity interventions programs applied by Information and Communication Technologies (ICTs) for depression. A multi-center, randomized, controlled clinical trial was conducted with 164 participants with depression, who were allocated to: Healthy Lifestyle Program, Positive Affect Promotion Program or Mindfulness Program. Sociodemographic characteristics, Patient Health Questionnaire-9, Visual Analog Scale, Short Form Health Survey, Positive and Negative Affect Schedule, Five Facets Mindfulness Questionnaire, Pemberton Happiness Index and Treatment Expectancy Questionnaire were used to study adherence. Results showed that positive affect resulted in a predictor variable for Healthy Lifestyle Program and Positive Affect Promotion Program. Perceived health was also a negative adherence predictor for the Positive Affect Promotion Program. Our findings demonstrate that there are differences in clinical variables between treatment completers and non-completers and we provide adherence predictors in two intervention groups. Although new additional predictors have been examined, further research is essential in order to improve tailored interventions and increase adherence treatment.
According to the adenosine hypothesis of schizophrenia, the classically associated hyperdopaminergic state may be secondary to a loss of function of the adenosinergic system. Such a hypoadenosinergic ...state might either be due to a reduction of the extracellular levels of adenosine or alterations in the density of adenosine A
receptors (A
Rs) or their degree of functional heteromerization with dopamine D
receptors (D
R). In the present study, we provide preclinical and clinical evidences for this latter mechanism. Two animal models for the study of schizophrenia endophenotypes, namely the phencyclidine (PCP) mouse model and the A
R knockout mice, were used to establish correlations between behavioural and molecular studies. In addition, a new AlphaLISA-based method was implemented to detect native A
R-D
R heteromers in mouse and human brain. First, we observed a reduction of prepulse inhibition in A
R knockout mice, similar to that observed in the PCP animal model of sensory gating impairment of schizophrenia, as well as a significant upregulation of striatal D
R without changes in A
R expression in PCP-treated animals. In addition, PCP-treated animals showed a significant reduction of striatal A
R-D
R heteromers, as demonstrated by the AlphaLISA-based method. A significant and pronounced reduction of A
R-D
R heteromers was next demonstrated in postmortem caudate nucleus from schizophrenic subjects, even though both D
R and A
R were upregulated. Finally, in PCP-treated animals, sub-chronic administration of haloperidol or clozapine counteracted the reduction of striatal A
R-D
R heteromers. The degree of A
R-D
R heteromer formation in schizophrenia might constitute a hallmark of the illness, which indeed should be further studied to establish possible correlations with chronic antipsychotic treatments.
This work shows the utility of the carbon dots, prepared from candle shoot, as promising candidates for nanothermometry devices based on temperature dependence of their emission lifetimes and of the ...changes of the full width at half maximum of the emission spectrum. The results indicate that both parameters show appreciable changes over the physiological temperature range (20–60°C).
Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main ...communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
PDF
