Evaluation of BASE eConsult Manitoba: patient perspectives on the use of electronic consultation to improve access to specialty advice in Manitoba.

BACKGROUND: The burden of waiting to access specialist expertise may contribute to poorer health outcomes and causes distress for patients and providers. One solution to improve access to specialist care is to use innovative tools such as remote asynchronous electronic consultation (eConsult). Modeled after the Champlain BASE™ (Building Access to Specialist Advice) eConsult service, BASE™ eConsult Manitoba was launched in 2017 to help address long waits for patients to access specialist advice. OBJECTIVE: We aimed to evaluate patients' experiences after obtaining a BASE™ eConsult Manitoba service in their primary care setting. METHODS: Patients whose Primary Care Providers (PCPs) used BASE™ eConsult as part of their care were asked to participate and complete a telephone-based or online 29-question survey between January 2021 and October 2021. The survey questions were created in consultation with patient partners and based on questions asked in studies done in other jurisdictions. RESULTS: Of the 36 patients who chose to participate, 29 completed the entire survey (80%). Two-thirds (n = 22) agreed that eConsult has been helpful in their situation, and over 80% (n = 24) of participants agreed that eConsult was an acceptable way to access specialist care. During the visit when their PCP sent the eConsult, 7 patients were expecting to be referred to a specialist for a face-to-face consultation. Over half of all respondents (n = 15) reported that before the eConsult occurred, their PCP asked them what questions they wanted to be answered by the specialist. Almost all of these respondents' questions were fully answered by the eConsult. All of the respondents were satisfied with the experience of receiving an eConsult. CONCLUSION: Using eConsult is an acceptable way to improve access to specialist advice from patients' perspectives. Consideration should be given to expanding the use of eConsult services to improve access to specialist expertise for PCPs and their patients.

Chitosan-coated Zn-metal-organic framework nanocomposites for effective targeted delivery of LNA-antisense miR-224 to colon tumor: in vitro studies.

Nowadays, nano-compartments are considered as an effective drug delivery system (DDS) for cancer therapy. Targeted delivery of therapeutic agents is an advantageous approach by which cancer cells can be targeted without harming normal cells, and eliminates the negative effects of conventional therapies such as chemotherapy. In this research, a novel zinc-based nanoscale metal-organic framework (Zn-NMOF) coated with folic acid (FA) functionalized chitosan (CS) has been constructed and applied as efficient delivery of LNA (locked nucleic acid)-antisense miR-224 to colon cancer cell lines. LNA-antisense miR-224 as a therapeutic sequence was able to considerably block highly expressed miR-224 and downregulated cancer cell growth. The prepared nano-complex was characterized by analytical devices such as FT-IR, UV-Vis spectrophotometry, DLS, TEM, and XRD. The size range of NMOF-CS-FA-LNA-antisense miR-224 (MCFL224) nano-complex was obtained nearly at 200 nm. The entrapment efficiency of LNA-antisense miR-224 was calculated 72 ± 5% and a significant release profile of LNA-antisense miR-224 was observed at first 6 h (about 50%). Then, in vitro assays were implemented on HCT116 (folic acid receptor-positive colon cancer cell line) and CRL1831 (normal colon cell line) to evaluate the therapeutic efficiency of the MCFL224 nano-complex. In these investigations, decreased cell viability (14.22 ± 0.3% after 72 h treatment), increased apoptotic and autophagy-related genes expression level (BECLIN1: 34-folds, BAX: 36-folds, mTORC1: 10-folds, and Caspase-9: 9-folds more than control), higher cell cycle arrest in sub-G1 phase (19.53% of cells in sub-G1 phase), and more apoptosis analyses (late apoptosis: 67.7%) were evaluated in colon cancer cells treated with MCFL224 nano-complex. Results remarkably indicate the inhibited growth of colon cancer cells and induced cell apoptosis which suggests MCFL224 as a promising nanocomposite for colon cancer therapy.

Differential expression of HNF1A and HNF1A-AS1 in colon cancer cells.

The human hepatocyte nuclear factor 1 homeobox A (HNF1A) gene loci express the protein-coding HNF1A transcript and a long non-coding RNA in the anti-sense (HNF1A-AS1) direction. HNF1A-AS1 is expressed in numerous types of cancers and poor clinical outcomes such as higher mortality rates, greater metastatic capacity, and poor prognosis of the disease are the results of this expression. In this study, we determined the epigenetic features of the HNF1A gene loci, and expression and cellular localization of HNF1A-AS1 RNA, HNF1A RNA, and HNF1A protein in colorectal cancer (HT-29, HTC116, RKO, and SW480) and normal colon epithelial (CCD841) cells. The HT-29 HNF1A gene had active histone marks (H3K4me3, H3K27ac) and DNase 1 accessible sites at the promoter regions of the HNF1A and HNF1A-AS1 genes. These epigenetic marks were not observed in the other colorectal cancer cells or in the normal colon epithelial cells. Consistent with the active gene epigenetic signature of the HNF1A gene in HT-29 cells, HNF1A protein, and HNF1A/HNF1A-AS1 transcripts were detected in HT-29 cells but poorly, if at all observed, in the other cell types. In HT-29 cells, HNF1A-AS1 localized to the nucleus and was found to bind to the enhancer of zeste homolog 2 (EZH2, a member of PRC2 complex) and potentially form RNA-DNA triplexes with DNase 1 accessible sites in the HT-29 genome. These activities of HNF1A-AS1 may contribute to the oncogenic properties of this long non-coding RNA.

Comparison of serum levels of IL-6, IL-8, TGF-ß and TNF-α in coronary artery diseases, stable angina and participants with normal coronary artery.

Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-ß and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-ß, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines.

Toll-like receptor 2 and type 2 diabetes.

Innate immunity plays a crucial role in the pathogenesis of type 2 diabetes and related complications. Since the toll-like receptors (TLRs) are central to innate immunity, it appears that they are important participants in the development and pathogenesis of the disease. Previous investigations demonstrated that TLR2 homodimers and TLR2 heterodimers with TLR1 or TLR6 activate innate immunity upon recognition of damage-associated molecular patterns (DAMPs). Several DAMPs are released during type 2 diabetes, so it may be hypothesized that TLR2 is significantly involved in its progression. Here, we review recent data on the important roles and status of TLR2 in type 2 diabetes and related complications.

Role of C-fibers during acute and chronic stress on formalin-induced paw edema in rats.

Stimulation of peripheral nociceptors leads to releasing of some mediators such as substance P (SP) and Calcitonin gene-related peptide (CGRP) and contributes to the edema formation by vasodilatation induction. On the other hand glucocorticoids have anti-inflammatory action, and they are elevated in the plasma during stress. This communication reports C-fibers inflammatory role and the effects of chronic and acute stress and/or dexamethasone (as stress mimicry) on paw edema induced by formalin at presence/deficit C-fibers rats. Acute stress and dexamethasone and chronic dexamethasone have shown an anti-inflammatory effect in C-normal groups, but chronic stress had no effect on inflammation. C-fibers reduction (C-lesion) had anti-inflammatory effects. In deficit C-fibers rats, acute and chronic stress had not stronger anti-inflammatory effect, but acute dexamethasone reduced the anti-inflammatory effect of C-fibers reduction while in the same condition, chronic dexamethasone induced stronger anti-inflammatory effect. The results show C-fiber nerve produce and release the peripheral inflammatory mediators, "C-fibers reduction" decreased the paw inflammation. Counter adaptation in C-lesion animals may reduce the modulatory effects of dexamethasone on the remaining C-fibers. Acute dexamethasone diminished the "C-fibers reduction" anti-inflammatory effect, but at chronic treatment, the modulatory effects of dexamethasone aggregated and it augmented the C-fibers reduction antiinflammatory effect.

Single course of high dose dexamethasone is more effective than conventional prednisolone therapy in the treatment of primary newly diagnosed immune thrombocytopenia.

INTRODUCTION: Immune thrombocytopenia (ITP) is an immune disorder commonly presents as isolated thrombocytopenia. Generally corticosteroids are the main treatment of ITP. This study was designed to evaluate effectiveness of high dose dexamethasone comparing conventional corticosteroid therapy in the treatment of ITP. MATERIALS AND METHODS: In a randomized prospective study, sixty adult patients with newly diagnosed primary symptomatic ITP (Platelet count < 20,000) were evaluated. Patients divided into two groups. In group A, thirty patients (mean age of 24.9 years) received Dexamethasone 40 mg/IV/daily for four days (10 mg/q6h); and then Prednisolone 1 mg/kg/day/PO with rapid tapering of prednisolone (10 mg/week). From the other hand, in group B, thirty patients (mean age of 27.2 years) were treated with Prednisolone 1 mg/kg/day/PO for four weeks, then the drug tapered weekly. RESULTS: All the patients in group A showed favorable response within the first seven days, 27 cases presented complete response (CR) and three cases revealed response (R). In group B, 11 cases had CR, 13 cases showed R and six cases had No response (NR). After three months, rates of CR were 80% and 23.3% in group A and B; respectively. Responses were 16.7% and 33.3%, NRs were 6.6% and 43.3% in group A and B; respectively (P < 0.0001). After 6 months, CR was 73.3% vs.16.7%, and R was 16.7% vs.36.7% and NR was 10% vs. 46.7% in group A and B; respectively (P < 0.0001). After 12 months, there was no change in response rate in group A, but in group B 53% were non responsive, 40% showed R (chronic ITP) and complete response was observed only in 6.7% (P < 0.0001). Three cases in group A and 12 cases in group B had needed splenectomy (P < 0.00002). CONCLUSION: We showed that high dose dexamethasone is more effective than conventional steroid therapy in newly diagnosed ITP as initial treatment with less relapses and toxicities.

Toll-Like Receptor 4 as an Immune Receptor Against Mycobacterium tuberculosis: A Systematic Review.

OBJECTIVE: To review the main Mycobacterium tuberculosis (Mtb) pathogen-associated molecular patterns (PAMPs) and the roles played by toll-like receptor (TLR)4 in determination of Mtb infection outcome. METHODS: Several scientific databases, including Scopus, PubMed, and Google Scholar, were used for searching appropriate research articles from the literature for information on our topic. RESULTS: TLR4 plays positive roles in induction of immune responses against Mtb and participates in eradication of the infection. Some limited investigations approved the roles of TLR4 in induction of apoptosis in macrophages during tuberculosis (TB) and attenuation of immune responses in some situations. CONCLUSIONS: TB outcome appears to be dependent on TLR4/Mtb interaction and several factors, including bacterial load and immune or nonimmune cells, as hosts. Also, other TLR/Mtb interactions can affect TLR4 responses.

Changes in serum level of trace elements in pulmonary tuberculosis patients during anti-tuberculosis treatment.

INTRODUCTIONS: Tuberculosis is spreading throughout the globe, while it is a crucial cause of death in developing countries. In this study, trace elements concentrations and their alterations were determined in TB patients during anti-tuberculosis treatment period. MATERIALS AND METHODS: We have collected blood samples from a total of 180 TB patients with pulmonary Tuberculosis, and 180 healthy controls in Sistan, Iran. The serum iron, copper, lead, calcium, arsenic and selenium concentrations were detected at the beginning of anti-TB chemotherapy, at the end of 2nd, 4th and 6th month after treatment initiation. Data were then analyzed using SPSS version 20. RESULTS AND DISCUSSIONS: Although Ca, Pb, and As levels did not change during the treatment period, serum concentrations of Fe, Zn, Cu, and Se were diminished in TB patients significantly during treatment in comparison with controls (P < 0.001).We also found that there was a significant difference in the Cu/Se and Cu/Zn ratios in tuberculosis patients in comparison with healthy individuals (P < 0.001). CONCLUSIONS: Trace elements serum concentrations are affected by TB infection and anti-TB therapy. Their serum levels were strongly perturbed during infection as well as anti-TB treatment.

C677T and A1298C polymorphisms of methylene tetrahydrofolate reductase in non-Hodgkin lymphoma: southeast Iran.

PURPOSE: Polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene have been reported as risk factors for non-Hodgkin lymphoma (NHL) in some populations. Our goal was to evaluate the potential role of A1298C and C677T polymorphisms of MTHFR in risk of NHL in southeast Iran. METHODS: In the present case-control study, 127 patients with newly diagnosed NHL along with 150 ethnicity- and age-matched controls were examined. The A1298C and C677T polymorphisms were genotyped using the Tetra Amplification Refractory Mutation System polymerase chain reaction method. RESULTS: There were no significant differences in genotype frequencies between cases and controls regarding either A1298C polymorphism. For this polymorphism, 53.8% of the controls and 54.3% of the patients with NHL showed homozygous wild-type (AA) genotype. Variant 1298C allele was recognized with overall frequency of 34.6% in both groups. Frequencies of CC, CT, and TT genotypes of C677T polymorphism were observed in 73.1%, 25.8%, and 1.3% of the controls, and 64.5%, 33.1%, and 2.4% of the patients with NHL (p>0.05). In combination, CT + TT conferred a significantly higher risk of NHL (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.9-2.4, p = 0.03). Overall, variant 677T allele presented with higher frequency in the patients with NHL than the controls (26.7% versus 21.3%, respectively; OR 1.3, 95% CI 0.8-2.1, p>0.05). Although statistically insignificant, the highest risk of NHL was identified in patients with C677T; A1298C: CT; CC haplotype (OR 4.7, 95% CI 0.4-46.4, p = 0.1). CONCLUSIONS: Combination of CT and TT genotypes of C677T polymorphism conferred a significantly higher risk for NHL. It is recommended to investigate further the potential role of this polymorphism in NHL development.

Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response.

Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.

Myocardial Cell Signaling During the Transition to Heart Failure: Cellular Signaling and Therapeutic Approaches.

Cardiovascular disease leading to heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Improved pharmacological and interventional coronary procedures have led to improved outcomes following acute myocardial infarction. This success has translated into an unforeseen increased incidence in HF. This review summarizes the signaling pathways implicated in the transition to HF following cardiac injury. In addition, we provide an update on cell death signaling and discuss recent advances in cardiac fibrosis as an independent event leading to HF. Finally, we discuss cell-based therapies and their possible use to avert the deteriorating nature of HF. © 2019 American Physiological Society. Compr Physiol 9:75-125, 2019.

Inflammasomes and type 2 diabetes: An updated systematic review.

Type 2 diabetes (T2D) is a metabolic disorder that is accompanied by chronic inflammation. The main mechanisms and molecular signaling of the induction of inflammation in T2D are still unknown. It seems that intracellular sensors that participate in recognition of endogenous damage associated molecular patterns (DAMPs) play key roles in the induction/stimulation of chronic inflammation in T2D. The Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing (NLRP) family and accompanying Inflammasomes are important intracellular receptors of inflammatory pathogens and stress signals that elevate caspase-1-mediated release of IL-1ß and IL-18. Studies suggest that disruption of NLRP1 and NLRP3 has a major role for these inflammasomes in internal immunity and inflammation as well as metabolic disorders. Thus, it seems that these mediators may participate in the induction/stimulation of chronic inflammation in patients. This systematic review provides an up-to-date evaluation of our current understanding of the roles of inflammasomes in the pathogenesis of T2D and its complications.

Toll like receptor 4 and hepatocellular carcinoma; A systematic review.

INTRODUCTION: Toll like receptor 4 (TLR4) is an extracellular pathogen recognition receptor (PRR) which recognizes a wide range of pathogens and damage associated molecular patterns (PAMPs and DAMPs). It can activate intracellular signaling and consequently transcription factors which participate in transcription from either immune related or malignancy genes. Thus, it has been hypothesized that TLR4 may be a cause of hepatocellular carcinoma (HCC). This article has reviewed the roles of TLR4 in the pathogenesis of HCC. METHOD: "TLR4", "hepatocellular carcinoma", "liver tumor" and "liver cancer" were used as key words for searching in Scopus, Google Scholar and MEDLINE scientific databases. RESULTS: Most of the investigations documented the roles of TLR4 in induction of HCC via several mechanisms including increased number of T regulatory lymphocytes and liver resident follicular helper like cells, increased production of pro-inflammatory and malignancy related molecules including cytokines, NANOG, Caspase-1, Ephrin-A1, NO and BCL6. TLR4 participates in the proliferation of the cells and also production of the molecules in both chronic infectious and non-infectious inflammatory diseases. DISCUSSION: TLR4 is an innate immunity receptor which plays a pathogenic role during chronic inflammation and can induce HCC in human.

Spontaneous rupture of continent cutaneous urinary diversion after 25 years.

Spontaneous rupture of a continent cutaneous urinary diversion is uncommon and diagnosis of this situation requires a high degree of suspicion. In this paper we present a 66-year-old man with continent cutaneous pouch after radical cystoprostatectomy that presented with spontaneous perforation 25 years after surgery. Spontaneous pouch perforation in our case after 25 years emphasizes the need for long follow-up in patients with continent diversion.

Role of essential trace elements in tuberculosis infection: A review article.

Malnutrition is one of the risk factors in tuberculosis (TB) infection. Mineral levels perturbation is seen in patients with TB. Moreover there are some strategies to starve pathogens of essential metals. Here we decided to conclude association between some essential elements and TB. Copper, calcium and iron are essential for hosts' immune system although calcium and iron are necessary for Mycobacterium tuberculosis vitality. Changing these elements alongside with anti-TB therapy is suggested for better treatment outcomes.

A Cross-Sectional Study of Glycemic Status and Zinc Level in Patients with Beta-Thalassemia Major.

Background: Endocrinopathies and diabetes mellitus are prevalent in patients with beta-thalassemia major Recently some studies demonstrate a link between low levels of serum zinc level and higher prevalence of diabetes. The aim of this study was to evaluate the glucose tolerance in patients suffered from beta-thalassemia major and determine the association of Homeostasis Model Assessment (HOMA) parameters with zinc status among these patients. Materials andMethods: In this cross sectional study, clinical data of patients who were suffered from thalassemia major, aged≥10 years were collected. Serum ferritin concentration, fasting blood sugar, fasting blood insulin and serum zinc level were assessed after overnight fasting. Moreover, oral glucose tolerance test was performed. Homeostasis Model Assessment (HOMA-2) was used for calculating beta-cell function, insulin resistance and sensitivity for normoglycemic and pre-diabetic subjects. Results: of the 163 patients diagnosed with beta-thalassemia major, 10%, 53% and 37% were diabetic, pre-diabetic and normal, respectively. Mean serum zinc concentration was equal to 18.90±10.93µg/dl, and it was not significantly different across diabetic, pre-diabetic and normal groups. Pre-diabetic patients had significantly lower beta-cell function compared to normal subjects (P=0.0001). An inverse relation was documented between beta-cell function on one hand and total units of blood transfusion and ferritin level on the other hand (r=-0.29, P=0.004 and r=-0.27, P=0.03, respectively). The analysis adjusted for multiple possible confounders showed that there is no significant association between HOMA parameters and serum zinc level. Conclusion: Impaired glucose metabolism and low serum zinc level were quite common among our study participants. The findings of the study also signifies the substantial role of follow-up in early detection and appropriate treatment.

Essential and toxic metals in serum of individuals with active pulmonary tuberculosis in an endemic region.

Trace elements play an important role in tuberculosis infection because their deficiencies can be associated with impaired immunity. Blood samples were collected from a total of 320 active pulmonary tuberculosis patients and healthy individuals. The serum concentrations of Zinc, Iron, Copper, Calcium, lead, Arsenic and Selenium were analyzed by atomic absorption spectrometry. The levels of trace elements were measured after 2, 4 and 6 months of anti-TB treatment initiation in TB infected groups. Compared to the control group, the concentrations of Zinc, Selenium, and Iron were significantly lower (P < 0.001) in tuberculosis patients; however, that of Arsenic, Lead, and copper was significantly higher (P < 0.001) in the serum of patients. Cu/Zn and Cu/Se ratios were also significantly higher (P < 0.001) in TB patients compared to the control group. In addition, serum concentration calcium was similar in both TB patients and healthy controls. Our results indicated that trace elements concentrations in tuberculosis patients are related to each element role in immune system. Wherever the element is essential for the pathogenesis of bacteria, its concentration will remain low; and contrariwise, when the element is toxic for the bacteria, its level will be regulated up to provide a perfect condition for bacterial growth.

Correction: Atorvastatin, Losartan and Captopril Lead to Upregulation of TGF-ß, and Downregulation of IL-6 in Coronary Artery Disease and Hypertension.

[This corrects the article DOI: 10.1371/journal.pone.0168312.].

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets.

Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.