Hippocampal Neurogenesis and Dendritic Plasticity Support Running-Improved Spatial Learning and Depression-Like Behaviour in Stressed Rats

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Prospective study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in a regional hospital in Hong Kong

Abstract Background Human fecal carriage of Enterobacteriaceae possessing mobilized colistin resistance genes (mcr-1 and mcr-2) remains obscure in Hong Kong. As part of routine surveillance on emerging antibiotic resistance, we conducted a prospective study on this topic in a regional hospital in Hong Kong. Methods From October 31 to November 25, 2016, all fecal specimens submitted for routine analysis were included in this surveillance study. These comprised 672 consecutive routine fecal specimens collected from 616 individuals. Fecal specimens were screened for colistin-resistant Enterobacteriaceae by culture-based method, and the presence of mcr-1 and mcr-2 genes in resistant isolates was identified by polymerase chain reaction and Sanger sequencing. Whole genome sequencing (WGS) of mcr-1-possessing Escherichia coli strains was facilitated using Illumina® MiSeq® followed by sequence analysis with appropriate bioinformatics tools. Results Fourteen mcr-1-positive E. coli strains were isolated from 14 separate individuals (2.08% of total fecal specimens), with 9 of them being asymptomatic, healthy clients coming for health assessment. No mcr-2-possessing Enterobacteriaceae was identified. Colistin minimum inhibitory concentrations of these mcr-1-positive isolates ranged from 2 to 4 μg/mL. All these isolates were susceptible to carbapenems with 2 being extended spectrum β-lactamase producers. WGS data revealed that these isolates belonged to at least 12 different sequence types (STs) and possessed diversified plasmid replicons, virulence and acquired antibiotic resistance genes. Further study on an E. coli ST201 strain (Pasteur scheme) revealed coexistence of 47,818-bp IncP-1 and 33,309-bp IncX4 types of mcr-1 plasmids, which was a combination of stability and high transmissibility. Conclusions To the best of our knowledge, this is the first study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in Hong Kong. Our data further revealed asymptomatic carriage of mcr-1-possessing Enterobacteriaceae by both patients and healthy individuals. This is alarming considering wide diversity and high transmissibility of mcr-1 plasmids, which potentially facilitate emergence of pan-drug-resistant bacteria in future infection. This also highlights the importance of surveillance on emerging antibiotic resistance, especially for patients under intensive care

Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients

Cardiovascular disease is the leading cause of death in ESRD patients and is strongly associated with malnutrition. The mechanism of malnutrition is not clear, but hypermetabolism is suggested to contribute to cardiac cachexia. This study examined resting energy expenditure (REE) in relation to the clinical outcomes of ESRD patients who receive continuous ambulatory peritoneal dialysis (CAPD) treatment. A prospective observational cohort study was performed in 251 CAPD patients. REE was measured at study baseline using indirect calorimetry together with other clinical, nutritional, and dialysis parameters. Patients were followed up for a mean ± SD duration of 28.7 ± 14.3 mo. REE was 39.1 ± 9.6 and 40.1 ± 9.0 kcal/kg fat-free edema-free body mass per day for men and women, respectively (P = 0.391). Using multiple regression analysis, fat-free edema-free body mass-adjusted REE was negatively associated with residual GFR (P < 0.001) and serum albumin (P = 0.046) and positively associated with diabetes (P = 0.002), cardiovascular disease (P = 0.009), and C-reactive protein (P = 0.009). At 2 yr, the overall survival was 63.3, 73.6, and 95.9% (P < 0.0001), and cardiovascular event-free survival was 72.3, 84.6, and 97.2% (P = 0.0003), respectively, for patients in the upper, middle, and lower tertiles of REE. Adjusting for age, gender, diabetes, and cardiovascular disease, patients in the upper and middle tertiles showed a 4.19-fold (95% confidence interval, 2.15 to 8.16; P < 0.001) and a 2.90-fold (95% confidence interval, 1.49, 5.63; P = 0.002) respective increase in the risk of all-cause mortality compared with those in the lower tertile. However, the significance of REE in predicting mortality was gradually reduced when additional adjustment was made for C-reactive protein, serum albumin, and residual GFR in a stepwise manner. In conclusion, a higher REE is associated with increased mortality and cardiovascular death in CAPD patients and is partly related to its close correlations with residual kidney function, cardiovascular disease, inflammation, and malnutrition in these patients.Link_to_subscribed_fulltex

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Abstract Macrophage‐myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro‐tumoral cancer‐associated fibroblasts (CAFs) in non‐small cell lung carcinoma (NSCLC) in a TGF‐β1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor‐associated macrophage at single‐cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT‐specific TGF‐β1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT‐derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage‐specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage‐specific genetic deletion and systemic pharmacological inhibition of TGF‐β1/Smad3/Runx1 signaling effectively prevent MMT‐driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC

The Use of Close Friends on Instagram, Help-Seeking Willingness, and Suicidality Among Hong Kong Youth: Exploratory Sequential Mixed Methods Study

BackgroundSocial networking sites (SNSs) have gained popularity in recent years for help seeking and self-distress expression among adolescents. Although online suicidal expression is believed to have major benefits, various concerns have also been raised, particularly around privacy issues. Understanding youths’ help-seeking behavior on SNSs is critical for effective suicide prevention; however, most research neglects the impacts of the private SNS context. ObjectiveThis study aims to examine youths’ private SNS use via the new Instagram feature, Close Friends, and its association with both online and offline help-seeking willingness as well as youths’ suicidality. MethodsThis study employed an exploratory sequential mixed methods approach with a combination of explorative qualitative interviews and a systematic quantitative survey, targeting youth aged 15-19 years in Hong Kong. The motivations for utilizing Close Friends and concerns regarding online expression were addressed in the focus group and individual interviews (n=40). A cross-sectional survey (n=1676) was conducted subsequently with eligible secondary school students to examine the prevalence of Close Friends usage, their online and offline help-seeking willingness, and suicide-related experiences. ResultsA total of 3 primary motives for using Close Friends were identified during interviews, including (1) interaction and help seeking, (2) release of negative emotions, and (3) ventilation and self-expression. Most participants also highlighted the privacy concerns associated with public online communication and the importance of contacting close friends for emotional support. Survey results showed that use of Close Friends was quite prevalent among adolescents (1163/1646, 70.66%), with around 46% (754/1646, 45.81%) of respondents being frequent users. Differences by gender and school academic banding were also revealed. Regarding help-seeking intentions, youths were generally positive about seeking help from peers and friends offline (1010/1266, 79.78%) yet negative about seeking assistance from online friends or professionals with whom they had not yet developed a real-world connection (173/1266, 13.67%). Most notably, frequencies of Close Friends usage were differentially associated with online and offline help-seeking willingness and youths’ suicidality. Compared with nonusers, those who had ever used the feature were more likely to seek offline support (adjusted odds ratios [AORs] 1.82-2.36), whereas heavy use of Close Friends was associated with increased odds of online help-seeking willingness (AOR 1.76, 95% CI 1.06-2.93) and a higher risk of suicidality (AOR 1.53, 95% CI 1.01-2.31). ConclusionsThe popularity of Close Friends reflects the increasing need for private online expression among youth. This study demonstrates the importance of Close Friends for self-expression and private conversation and inadequacy of peer support for suicidal adolescents. Further research is needed to identify the causal relationship between Close Friends usage and help-seeking willingness to guide the advancement of suicide prevention strategies. Researchers and social media platforms may cooperate to co-design a risk monitoring system tailored to the private SNS context, assisting professionals in identifying youth at risk of suicide

Characterization of early IgA nephropathy

Histological grading of 45 patients with clinical early immunoglobulin A (IgA) nephropathy was correlated with disease progression over a median follow-up of 123 months. Clinical early IgA nephropathy was defined as a serum creatinine level of 1.3 mg/dL or less, proteinuria of 0.4 g/d or less of protein, and the absence of hypertension at the time of renal biopsy. Disease progression was related to the occurrence of impaired renal function, increased proteinuria, and hypertension. We applied a previously described chronicity-based histological grading to the renal biopsy specimen and also assessed acute glomerular lesions. Disease progression was observed in 44.4% of these patients. Forty patients (89%) showed glomerular grade 1 (GG1) and 5 patients (11%) showed GG2, but this grading did not correlate with disease progression. However, when GG1 was subdivided into GG1a (mean sclerosis per glomerulus <10%) and GG1b (mean sclerosis per glomerulus 10% to <25%), GG1a correlated with nonprogressive disease. Tubulointerstitial grade also correlated with disease progression but was associated with a low sensitivity for predicting nonprogressive disease. Hyaline arteriolosclerosis and acute glomerular lesions did not correlate with disease progression. The chronicity-based histological grading is not only applicable to clinical early IgA nephropathy, but also more importantly, it characterizes GG1a in a subset of patients with a very low risk for disease progression, which can be regarded as genuine early IgA nephropathy. (C) 2000 by the National Kidney Foundation, Inc.Link_to_subscribed_fulltex

Energy intake and expenditure profile in chronic peritoneal dialysis patients complicated with circulatory congestion

Background: Circulatory congestion is an adverse predictor of mortality in peritoneal dialysis (PD) patients. Objective: This study evaluated the nutritional status, energy intake, and expenditure profile of PD patients with and without previous circulatory congestion. Design: We conducted a cross-sectional study in 244 PD patients, of whom 92 had previous circulatory congestion. We estimated dietary energy intake by using a locally validated 7-d food-frequency questionnaire and by assessing resting energy expenditure (REE) and total energy expenditure (TEE) with indirect calorimetry and a locally validated physical activity questionnaire, respectively. Results: In comparison with those without circulatory congestion, patients with previous circulatory congestion were more malnourished by subjective global assessment (59% compared with 36%; P < 0.001), had lower handgrip strength, had lower midarm muscle circumference, had lower dietary protein (0.98 ± 0.45 compared with 1.19 ± 0.44 g · kg-1 · d-1; P < 0.001), and had lower energy intake (92.5 ± 37.0 compared with 110.9 ± 35.7 kJ · kg-1 · d-1; P < 0.001) but had higher C-reactive protein (P = 0.025) and higher REE (P < 0.001). However, no difference in TEE was noted between the 2 groups, which indicated lower activity energy expenditure among patients with previous circulatory congestion. The resulting energy balance was significantly more negative for patients with previous circulatory congestion than for those without previous circulatory congestion (P = 0.050). Furthermore, the prevalence of malnutrition increased with increasing episodes of circulatory congestion (P = 0.017). Conclusions: Patients with previous circulatory congestion had significantly more inflammation, more muscle wasting, and higher REE but lower activity energy expenditure and energy and protein intakes in keeping with an anorexia-cachexia syndrome. The mechanisms of increased REE and reduced energy intake among patients with previous circulatory congestion warrant further investigation. © 2009 American Society for Nutrition.Link_to_subscribed_fulltex

LncRNA-Dependent Mechanisms of Transforming Growth Factor-β: From Tissue Fibrosis to Cancer Progression

Transforming growth factor-β (TGF-β) is a crucial pathogenic mediator of inflammatory diseases. In tissue fibrosis, TGF-β regulates the pathogenic activity of infiltrated immunocytes and promotes extracellular matrix production via de novo myofibroblast generation and kidney cell activation. In cancer, TGF-β promotes cancer invasion and metastasis by enhancing the stemness and epithelial mesenchymal transition of cancer cells. However, TGF-β is highly pleiotropic in both tissue fibrosis and cancers, and thus, direct targeting of TGF-β may also block its protective anti-inflammatory and tumor-suppressive effects, resulting in undesirable outcomes. Increasing evidence suggests the involvement of long non-coding RNAs (lncRNAs) in TGF-β-driven tissue fibrosis and cancer progression with a high cell-type and disease specificity, serving as an ideal target for therapeutic development. In this review, the mechanism and translational potential of TGF-β-associated lncRNAs in tissue fibrosis and cancer will be discussed