To investigate potential harm and benefits of antiepileptic drugs (AED) given prophylactically to prevent de novo brain tumour-related epilepsy after craniotomy.
Randomised controlled trials (RCT) ...and retrospective studies published before 27 November 2018 were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied. Eligible patients were diagnosed with a brain tumour, were seizure naïve and underwent craniotomy. The random effects model was used for quantitative synthesis. The analysis was adjusted for the confounding effect of including patients with a history of seizure prior to study inclusion.
A total of 454 patients received prophylactic AED whereas 333 were allocated to placebo or no treatment. Two RCTs and four retrospective studies were identified. The OR was 1.09 (95% CI 0.7 to 1.8, p=0.7, I
=5.6%, χ
p=0.5), indicating study consistency and no significant differences. An additional two RCTs and one retrospective study combined craniotomy and diagnostic biopsy, and were subgroup analysed-which supported no difference in odds for epilepsy.
A prophylactic effect of AED could not be demonstrated (nor rejected statistically). Levetiracetam was associated with less adverse effects than phenytoin. The potential harm of AED was not balanced by the potential prophylactic benefit. This study suggests that prophylactic AED should not be administered to prevent brain tumour-related epilepsy after craniotomy.
The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein ...(mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca2+ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.
P-glycoprotein (P-gp), a membrane transport protein overexpressed in certain drug-resistant cancer cells, has been the target of numerous drug discovery projects aimed at overcoming drug resistance ...in cancer. Most characterized P-gp inhibitors bind at the large hydrophobic drug binding domain (DBD), but none have yet attained regulatory approval. In this study, we explored the potential of designing inhibitors that target the nucleotide binding domains (NBDs), by computationally screening a large library of 2.6 billion synthesizable molecules, using a combination of machine learning-guided molecular docking and molecular dynamics (MD). 14 of the computationally best-scoring molecules were subsequently tested for their ability to inhibit P-gp mediated calcein-AM efflux. In total, five diverse compounds exhibited inhibitory effects in the calcein-AM assay without displaying toxicity. The activity of these compounds was confirmed by their ability to decrease the verapamil-stimulated ATPase activity of P-gp in a subsequent assay. The discovery of these five novel P-gp inhibitors demonstrates the potential of in-silico screening in drug discovery and provides a new stepping point towards future potent P-gp inhibitors.
Review of Mixed-Methods Research in Nursing Younas, Ahtisham; Pedersen, Maria; Tayaben, Jude Laoagan
Nursing research (New York),
2019-November/December, Letnik:
68, Številka:
6
Journal Article
Recenzirano
Inadequate justification for using mixed-methods and inadequate data integration compromises the rigor of mixed-methods studies, and data integration remains a challenge for nurse researchers.
The ...aim of the study was to determine the 5-year prevalence of mixed-methods research in nursing journals and to determine the extent of integration of qualitative and quantitative findings.
Ten journals were hand-searched, and additional search was conducted within three databases. Prevalence was calculated by counting the number of published mixed-methods studies divided by the number of published studies over 5 years. Three reviewers independently performed methodological assessment using a checklist based on guidelines by expert methodologists.
Prevalence of mixed-methods studies was 1.89%. Concerning methodological assessment, of 175 studies, 29% did not provide an explicit label of the study design and four studies incorrectly labeled the design. In total, 31% of the studies did not justify using mixed methods, 95% did not identify the research paradigm, and 78% did not state the weight given to individual phases. The extent of data integration was 73%, but 83% of studies integrated data using narrative summaries with integration occurring at the interpretation (69.8%). Few studies used joint displays (10.9%), transformation (3.1%), and triangulation (1.6%) for data integration.
Mixed-methods research is still in its infancy in nursing, and researchers encounter challenges during its conduct, analysis, and reporting. There is a need to determine researchers' attitudes and challenges toward using mixed methods and educate them about advanced mixed methods. Emphasis should be placed on use of advanced data integration methods so that the rigor and quality of mixed research can be enhanced in nursing research.
Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas.
We performed an individual patient data ...meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates.
We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%.
To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS.
The human colon adenocarcinoma (Caco-2) cell line is a well-established in vitro model for studying transport phenomena for prediction of intestinal nutrient and drug absorption. However, substances ...depending on transporters such predictions are complicated due to variable transporter expression and limited knowledge about transporter function during multiple cell passaging and cell thawings. In the case of sodium glucose transporter 1 (SGLT1), a key transporter of oral absorption of d-glucose, one reason for compromised prediction could be inadequate expression of SGLT1 in Caco-2 cells and thereby limited sensitivity in the determination of SGLT1-mediated permeability (P
). Here, the objective is to characterize and compare SGLT1-mediated uptake in Caco-2 cells obtained from different cell banks. SGLT1-mediated uptake of the standard SGLT1 substrate, methyl-α-d-glucopyranoside, in Caco-2 cells was shown to be highly dependent on cell bank origin. The most robust and reliable SGLT1 functionality was identified in Caco-2 cells from Deutsche Sammlung für Mikroorganismen und Zellkulturen (DSMZ), whereas cells from the American Type Culture Collection and European Collection of Authenticated Cell Cultures have lower SGLT1 transport activity. Transepithelial P
across Caco-2 cells from DSMZ showed that P
likely accounts for approximately 97% of absorptive methyl-α-d-glucopyranoside P
. In conclusion, Caco-2 cells from DSMZ provide a robust in vitro model for studying SGLT1-mediated uptake and transport-over multiple cell passages and independent cell stock thawings.
During age-related macular degeneration (AMD), chronic inflammatory processes, possibly fueled by high glucose levels, cause a breakdown of the retinal pigment epithelium (RPE), leading to vision ...loss. Phloretin, a natural dihydroxychalcone found in apples, targets several anti-inflammatory signaling pathways and effectively inhibits transporter-mediated glucose uptake. It could potentially prevent inflammation and cell death of RPE cells through either direct regulation of inflammatory signaling pathways or through amelioration of high glucose levels. To test this hypothesis, ARPE-19 cells were incubated with or without phloretin for 1 h before exposure to lipopolysaccharide (LPS). Cell viability and the release of pro-inflammatory cytokines interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor (VEGF) were measured. Glucose uptake was studied using isotope uptake studies. The nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were determined alongside the phosphorylation levels of mitogen-activated protein kinases. Phloretin pretreatment reduced the LPS-induced release of IL-6 and IL-8 as well as VEGF. Phloretin increased intracellular levels of reactive oxygen species and nuclear translocation of Nrf2. It also inhibited glucose uptake into ARPE-19 cells and the phosphorylation of Jun-activated kinase (JNK). Subsequent studies revealed that Nrf2, but not the inhibition of glucose uptake or JNK phosphorylation, was the main pathway of phloretin’s anti-inflammatory activities. Phloretin was robustly anti-inflammatory in RPE cells and reduced IL-8 secretion via activation of Nrf2 but the evaluation of its potential in the treatment or prevention of AMD requires further studies.
OBJECTIVE This cross-sectional clinical study compared the pathophysiology of type 2 diabetes in Japanese and Caucasians and investigated the role of demographic, genetic, and lifestyle-related risk ...factors for insulin resistance and β-cell response. RESEARCH DESIGN AND METHODS A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity. RESULTS Insulin sensitivity was higher in Japanese compared with Caucasians, as indicated by the homeostatic model assessment of insulin resistance and Matsuda indices, whereas β-cell response was higher in Caucasians, as measured by homeostatic model assessment of β-cell function, the insulinogenic indices, and insulin secretion ratios. Disposition indices were similar for Japanese and Caucasians at all glucose tolerance states, indicating similar β-cell response relative to the degree of insulin resistance. The main determinants for differences in metabolic indices were measures of body composition, such as BMI and distribution of adipose tissue. Differences in β-cell response between Japanese and Caucasians were not statistically significant following adjustment by differences in BMI. CONCLUSIONS Our study showed similar disposition indices in Japanese and Caucasians and that the major part of the differences in insulin sensitivity and β-cell response between Japanese and Caucasians can be explained by differences in body composition.
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