Bone Marrow Adipocytes—Role in Physiology and Various Nutritional Conditions in Human and Animal Models

In recent years, adipose tissue has attracted a lot of attention. It is not only an energy reservoir but also plays important immune, paracrine and endocrine roles. BMAT (bone marrow adipose tissue) is a heterogeneous tissue, found mostly in the medullary canal of the long bones (tibia, femur and humerus), in the vertebrae and iliac crest. Adipogenesis in bone marrow cavities is a consequence of ageing or may accompany pathologies like diabetes mellitus type 1 (T1DM), T2DM, anorexia nervosa, oestrogen and growth hormone deficiencies or impaired haematopoiesis and osteoporosis. This paper focuses on studies concerning BMAT and its physiology in dietary interventions, like obesity in humans and high fat diet in rodent studies; and opposite: anorexia nervosa and calorie restriction in animal models.     

The Association between Nutritional Status and In-Hospital Mortality among Patients with Heart Failure—A Result of the Retrospective Nutritional Status Heart Study 2 (NSHS2)

Background: A nutritional status is related to the prognosis and length of hospitalisation of patients with heart failure (HF). This study aims to assess the effect of nutritional status on in-hospital mortality in patients with heart failure. Methods: We conducted a retrospective study and analysis of medical records of 1056 patients admitted to the cardiology department of the University Clinical Hospital in Wroclaw (Poland). Results: A total of 1056 individuals were included in the analysis. A total of 5.5% of patients died during an in-hospital stay. It was found that in the sample group, 25% of patients who died had a BMI (body mass index) within the normal range, 6% were underweight, 47% were overweight, and 22% were obese. Our results show that non-survivors have a significantly higher nutrition risk screening (NRS) ≥3 (21% vs. 3%; p < 0.001); NYHA (New York Heart Association) grade 4 (70% vs. 24%; p < 0.001). The risk of death was lower in obese patients (HR = 0.51; p = 0.028) and those with LDL (low-density lipoprotein) levels from 116 to <190 mg/dL (HR = 0.10; p = 0.009, compared to those with LDL <55 mg/dL). The risk of death was higher in those with NRS (nutritional risk score) score ≥3 (HR = 2.31; p = 0.014), HFmrEF fraction (HR = 4.69; p < 0.001), and LDL levels > 190 mg/dL (HR = 3.20; p = 0.038). Conclusion: The malnutrition status correlates with an increased risk of death during hospitalisation. Higher TC (total cholesterol) level were related to a lower risk of death, which may indicate the “lipid paradox”. Higher BMI results were related to a lower risk of death, which may indicate the “obesity paradox”.     

Analgesic efficacy of sufentanil in dressings after surgical treatment of burn wounds

BackgroundThe aim of this study was to assess the analgesic efficacy of sufentanil in dressings after surgical treatment of burn wounds.Patients and methodsTwenty adult patients, who underwent surgical treatment of third–degree burn wounds under general anesthesia, were included. Two of the patients underwent surgery twice. During surgery, patients received 50–100 μg fentanyl every 20–30 min and, after surgery, patients received 100 mg ketoprofen twice daily. Additionally, ten patients (group 1) received 50 μg sufentanil added to the burn wound dressings soaked in octenidine and phenoxyethanol while 10 patients (group 2) received 25 μg sufentanil added to the same dressings. The rescue analgesic, which was administered when pain intensified, was 5 mg subcutaneous morphine. Plasma sufentanil concentrations were assayed at 1, 2, 3, and 6 h after surgery completion and when pain was reported, along with pain intensity evaluation.ResultsSufentanil was not detected in the serum of any patients. Rescue morphine was given during the postoperative period (24 h) in one patient in group 1 (who underwent surgery twice) and three patients in group 2. The mean sufentanil concentration in dressings was higher in group 1 (0.13 ± 0.03) than group 2 (0.06 ± 0.03 μg/mL; p < 0.001). The group 1 patient who received rescue morphine had a sufentanil concentration of 0.10 μg/mL, which was the lowest concentration in group 1. Group 2 patients who received rescue morphine had sufentanil concentrations of at least two–fold lower (0.03–0.05 μg/mL). No adverse effects were observed.ConclusionsSufentanil in dressings after burn wound surgery provides effective and safe analgesia and the sufentanil concentration in dressings should be ≥0.10 μg/mL in a solution of octenidine and phenoxyethanol.     

The impact of location and patency of the arteriovenous fistula on quality of life of kidney transplant recipients

BackgroundArteriovenous fistulae (AVFs) may remain patent after kidney transplantation (KTx), contributing to maladaptive cardiac remodeling. The flow in AVFs is associated with the diameter of its vessels and thus with the AVF location. The main objective of this study is to assess the influence of AVF location and its patency on the self-reported quality of life (QOL) of kidney transplant recipients (KTRs) with past history of hemodialysis.MethodsTo gain clinical data, during a scheduled visit, 353 KTRs were asked to fill out an anonymous questionnaire. From this group, 284 respondents were found eligible for analysis. The outcome was defined as prevalence of symptoms and health status, measured with the Left Ventricular Dysfunction-36 (LVD-36) Questionnaire in symptomatic patients.ResultsThe hemodialysis patients (n = 243) were divided into two groups according to AVF location, i.e., DAVF – distally located AVF – (n = 174) and PAVF – proximally located AVF – (n = 69). The proportion of patients with heart failure (HF) was higher in PAVF group (24% vs. 12%, p = 0.0482). In the multivariable regression, PAVF, serum creatinine levels, and the presence of HF or coronary artery disease (CAD) remained independent predictors of lower functional capacity. Among patients with heart disease, the presence of active AVF was independently associated with worse functional outcome (higher LVD-36 scores).ConclusionsThe influence of persistent PAVF in KTRs seems to be unfavorable, especially when coexisting with CAD or HF. Abbreviations: AVF arteriovenous fistula; BMI body mass index; CAD coronary artery disease; D-AVF distally-located arteriovenous fistula; EC exercise capacity; HD hemodialysis; HF heart failure; KTx kidney transplantation; KTR kidney transplant recipient; LVD-36 Left Ventricle Disfunction – 36; LVEF left ventricle ejection fraction; LVH left ventricle hypertrophy; NYHA New York Heart Association; P-AVF proximally located arteriovenous fistula; PD peritoneal dialysis; PRO patient-reported outcomes; QOL quality of life.     

Social Perception of Non-Binary Individuals

People can express their identity in different ways, one of which is through language. Non-binary individuals often speak in a gender-neutral way and use specific language forms. Language use not only reveals their identity but also can shape how others perceive them. The present study’s purpose was to analyze how non-binary people are perceived through the language they use. The research was conducted in Polish, a language that is especially challenging for non-binary individuals because it has many gender markers. To avoid using gendered forms, they often use a specific form of passive voice. In an experiment, participants (N?=?130, 102 women, 28 men) read a gendered (feminine or masculine) text and a gender-neutral text with passive voice. Most gave a masculine name to the person in the neutral text, but addressed them in a gender-neutral way when asked to react to them in presented scenarios. The gender-neutral text was evaluated as being less comprehensible than the gendered texts, and the non-binary person was rated less competent and colder than a man or a woman and was less socially accepted. Furthermore, the negative evaluation of non-binary people seemed to be attributable to unfamiliarity with gender-neutral language and its lower comprehensibility. More research is needed to understand these perceptions better and to be able to prevent their potential negative consequences.

     

Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice.

PURPOSE: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity. Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and (51)Cr release assays. RESULTS: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4(+) and CD8(+) T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8(+) and CD4(+) cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12. CONCLUSIONS: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.     

Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice.

PURPOSE: The aim of the present study was to potentiate the antitumor effectiveness of photodynamic therapy (PDT). A cDNA microarray analysis was used to evaluate the gene expression pattern after Photofrin-mediated PDT to find more effective combination treatment with PDT and inhibitor(s) of the identified gene product(s) overexpressed in tumor cells. EXPERIMENTAL DESIGN: Atlas Mouse Stress Array was used to compare the expression profile of control and PDT-treated C-26 cells. The microarray results have been confirmed using Western blotting. Cytostatic/cytotoxic in vitro assay as well as in vivo tumor models were used to investigate the antitumor effectiveness of PDT in combination with cyclooxygenase (COX) 2 inhibitors. RESULTS: PDT induced the expression of 5 of 140 stress-related genes. One of these genes encodes for COX-2, an enzyme important in the tumor progression. Inhibition of COX-2 in vitro with NS-398, rofecoxib, or nimesulide, or before PDT with nimesulide did not influence the therapeutic efficacy of the treatment. Administration of a selective COX-2 inhibitor after PDT produced potentiated antitumor effects leading to complete responses in the majority of treated animals. CONCLUSIONS: COX-2 inhibitors do not sensitize tumor cells to PDT-mediated killing. However, these drugs can be used to potentiate the antitumor effectiveness of this treatment regimen when administered after tumor illumination.     

Inhibition of cell cycle and induction of apoptosis by 2‐oxoheksyl isothiocyanate and alyssin in cell lines carrying various inherited BRCA1 mutations

An important aspect of the chemopreventive activity of isothiocyanates (ITC) is their ability to induce cell growth inhibition and apoptosis. In this study, the effect of two sulforaphane analogues, 2‐oxoheksyl isothiocyanate and alyssin, on lymphoblastoid cells, derived from people carrying four different germ‐line mutations in BRCA1 gene, was tested and compared to the effect on wild type cells. The mutations studied were: C61G; 3819del5; 4153delA, and 5382INSC. Changes in cell viability and density after 2‐oxoheksyl isothiocyanate and alyssin treatment were evaluated, as well as cell cycle progression, mitochondrial membrane potential changes, and phosphatidylserine externalization. Both isothiocyanates were shown to reduce cell viability and density in all cell lines tested, as well as the change in cell cycle phase's distribution. The response of cells to two ITC tested was various, as well as mutation type‐modulated. We found that change of cellular maintenance by chemopreventive agents can be modulated by single allele BRCA1 mutation. Drug Dev. Res. 65:84–92, 2005. © 2005 Wiley‐Liss, Inc.     

MET receptor is a potential therapeutic target in high grade cervical cancer

Cervical cancer is one of the leading causes of death among women suffering from tumors. Current treatment options are insufficient. Here, we investigated the MET receptor as a potential molecular target in advanced cervical cancer. Downregulation of MET receptor expression via RNA interference in different cervical carcinoma cell lines dramatically decreased tumor growth and forced tumor differentiation in vivo. MET receptor silencing also led to a dramatic decrease in cell size and a decrease in proliferation rate under normal and stress conditions. MET receptor downregulation also resulted in decreased cyclin D1 and c-myc levels but did not increase apoptosis. Subsequent experiments showed that downregulation of the MET receptor decreased the expression of a key regulator of the epithelial-to-mesenchymal transition, SLUG. and increased the expression of E-cadherin, a hallmark of the epithelial phenotype. Moreover, MET downregulation impairs expression and signaling of CXCR4 receptor, responsible for invasive phenotype.Taken together, our results strongly suggest that the MET receptor influences the oncogenic properties of cervical carcinoma cells in vitro and in vivo. These findings highlight a unique role of the MET receptor in cervical carcinoma cells and indicate the MET receptor as a potential therapeutic target for advanced cervical carcinoma.